Risk Factors

African Americans with transient ischemic attack (TIA) or stroke are more likely than Caucasian Americans to have intracranial stenosis, whereas the latter are more likely to have extracranial carotid atherosclerotic stenosis.² Asian Americans have a higher proportion of MCA stenosis compared with Caucasian and African Americans.⁶ Hypertension is present in up to 75% of individuals with intracranial atherosclerosis.⁸ Diabetes, coronary artery disease, cigarette smoking, hypercholesterolemia, and peripheral arterial occlusive disease are also strongly associated. Individuals without carotid bifurcation disease are more likely to demonstrate progression of intracranial stenosis than those with carotid bifurcation disease.⁹ Metabolic syndrome is present in approximately 50% of individuals who have symptomatic intracranial atherosclerotic disease and is associated with a substantially higher risk of major vascular events.¹⁰

Natural History

In a study of patients with intracranial stenosis undergoing repeat angiography at an average interval of 26.7 months, 40% of lesions had stabilized, 20% had regressed, and 40% had progressed.⁹ Stenosis progression, as detected by transcranial Doppler imaging, was an independent predictor of stroke recurrence.¹¹ Extracranial–intracranial (EC-IC) bypass surgery appears to promote progression of the lesion and occlusion of the MCA in patients with nonoccluded MCA stenosis.¹²

Asymptomatic intracranial stenosis is believed by some to be benign. In a series of 50 patients with asymptomatic MCA stenosis followed for a mean of 351 days, no patient had an ischemic stroke in the corresponding territory.⁸

The most definitive study of symptomatic intracranial stenosis thus far is the prospective Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial, which found an 11% to 12% first-year risk of ischemic stroke in territory attributable to the patient’s symptoms.⁴ The majority of strokes (73%) in WASID patients were in the territory of the stenotic artery.¹³ The risk of stroke in the territory of the stenotic artery was greatest in patients with severe (70%) stenosis (p = 0.0025) and among patients enrolled early (17 days) (p = 0.028). At 1 year, the stroke risk for patients with 50% to 69% stenosis was 6%, compared with 19% for those with 70% to 99% stenosis. The recent results of the WASID trial suggest that perhaps an indication for endovascular therapy can be extended to those patients who present with stroke (regardless of previous medical therapy) and have stenosis of a major intracranial artery exceeding 70%.¹³

The subset of patients in the EC-IC Bypass Study with MCA stenosis randomized to medical therapy had an annual ipsilateral ischemic stroke rate of 7.8% per year.^6,14 In the prospective, nonrandomized Groupe d’Etude des Sténoses Intra-Crâniennes Athéromateuses Symptomatiques study, 102 patients with more than 50% symptomatic intracranial stenosis had “optimal” medical therapy, with a follow-up of 23.4 months.¹⁵ Risks in the territory of the affected artery were 12.6% for TIA and 7.0% for stroke.

Primary Angioplasty

Initially, coronary angioplasty balloons were used off-label to perform intracranial percutaneous transluminal angioplasty (PTA) (Fig. 87-1). In 1999, Connors and Wojak¹⁶ published the report of their learning curve with a series of 70 patients who underwent angioplasty for intracranial atherosclerotic disease. Their technique progressed from directly sizing the balloon to the artery caliber with rapid balloon inflation to undersizing the balloon with slow inflation. The occurrence of acute vessel occlusion and dissection dropped from 75% to 14% with this technique. Currently, we utilize a technique of slow inflation (1 atmosphere, or atm, per minute) when performing angioplasty. In addition, we tend to undersize the balloon relative to the parent vessel.

FIGURE 87-1 A 74-year-old who had two TIAs characterized by aphasia and right hemiparesis and left M1 stenosis by CT angiography (A) and digital subtraction angiography (B) (the arrow in each image depicts the stenosis). Episodes were refractory to aspirin–clopidogrel dual therapy. B and C, pre- and postangioplasty angiographic runs, respectively. C, Gateway balloon (arrow). D, AP (left) and lateral (right) postprocedural runs. Notice the improved caliber of the M1 and normal filling of the MCA candelabra.

Mori et al.^17,18 reported on angioplasty without stenting in 42 patients with more than 70% intracranial stenosis. The risk of recurrent stenosis was strongly associated with lesion length and complexity. Lesion types were categorized as follows: type A as 5 mm or less in length, concentric or moderately eccentric lesions that were less than totally occlusive; type B as tubular, 5 to 10 mm in length, extremely eccentric or totally occluded lesions that were less than 3 months old; and type C as diffuse, more than 10 mm in length, extremely angulated (approximately 90 degrees) lesions with excessive tortuosity of the proximal segment or totally occluded lesions that were 3 months old. At the 1-year follow-up evaluation, restenosis rates associated with these lesion types were 0%, 33%, and 100%, respectively; the risk of major stroke or death was 8%, 26%, and 87%, respectively.

In 2006, Marks et al.¹⁹ reported on 20 patients with 50% intracranial stenosis who were treated with angioplasty without stenting. A total of 116 patients were available for a mean follow-up duration of 42.3 months. The degree of stenosis was reduced by angioplasty from a mean of 82.2% to a mean of 36.0%. The combined 30-day periprocedural stroke and death rate was 5.8%. The annual postprocedure stroke rate in the territory of the treatment was 3.2%, and the annual overall stroke rate was 4.4%.

Balloon-Mounted Coronary Stents

Angioplasty without stenting was associated with a significant risk of restenosis, which led to interest in angioplasty with stenting. Balloon-mounted coronary stents, however, are limited by the high inflation pressures needed for deployment in fragile intracranial vessels and the risk of shearing the stent from the balloon while navigating to the target lesion. These stents were associated with relatively high rates of technical failure due to the tortuosity of the intracranial circulation and the relative stiffness of coronary platforms; for successful procedures, the rates of periprocedural morbidity and mortality were acceptable.^20–22 Jiang et al.²² reported a technical success rate (defined as equal to 20% residual stenosis) of 97.6%, with a 10% major complication rate in 40 patients with 42 symptomatic M1 stenotic lesions treated with angioplasty and balloon-mounted coronary stents.

Balloon-Mounted Intracranial Stents

The Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA) trial was a multicenter, prospective, nonrandomized feasibility study involving the balloon-mounted Neurolink intracranial stent system (a product of the Guidant Corporation, which is now part of Boston Scientific, Natick, MA).²³ A total of 43 patients with symptomatic intracranial stenosis and 18 patients with extracranial VA stenosis were enrolled. Successful stent placement was achieved in 95% of cases. The 30-day periprocedural stroke rate was 6.6%. No deaths occurred. Two strokes occurred during the procedure. At the 6-month angiographic follow-up, more than 50% restenosis occurred in 32.4% of intracranial vessels and 42.9% of extracranial VAs; 39% of the recurrent stenoses were symptomatic. Strokes in the distribution of the target lesion occurring after 30 days but within 12 months were seen in 7.3% of patients. On the basis of the results of this study, the U.S. Food and Drug Administration (FDA) granted a humanitarian device exemption (HDE) to treat patients with significant intracranial and extracranial atherosclerotic disease via balloon angioplasty and stent placement. Boston Scientific is not currently marketing the Neurolink device in favor of its Wingspan system (discussed later).

The Pharos Vitesse intracranial stent (Micrus Endovascular, San Jose, CA) is a relatively new balloon-expandable stent developed for the treatment of intracranial stenosis. The first clinical experience of 21 patients with symptomatic intracranial stenoses (more than 70%) who were treated with the Pharos stent reported one stroke due to restenosis and one death during a median follow-up period of 7.3 months.²⁴ This pilot study was limited by the small sample size and severe morbidity of the included patients. The Pharos stent received Conformité Européen mark of approval in June 2008. The Vitesse Intracranial Stent Study for Ischemic Therapy clinical trial is currently under way to evaluate the efficacy of this stent. In our experience, this balloon-mounted stent navigates the intracranial circulation with relative ease.

Staged Submaximal Angioplasty with Delayed Stenting

Because blood flow is directly proportional to the fourth power of the vessel radius (according to Poiseuille’s law), small increases in luminal diameter increase blood flow significantly, thereby alleviating hemodynamic insufficiency and changing the milieu such that an embolism is less likely to form. A technique of submaximal angioplasty followed by delayed repeat angioplasty and, if necessary, stenting was developed for intracranial symptomatic atherosclerotic disease.²⁵ In this staged treatment approach, the patient returned for angiography approximately 4 to 6 weeks after angioplasty. If there was evidence of binary stenosis in the lesion (50% luminal-diameter stenosis), stenting was performed. The rationale for this approach is that during the weeks of delay, neointimal proliferation and scar formation after angioplasty result in a thickened fibrous lesion,^26,27 which may incur a lower risk for “snow-plowing” (stent struts pushing plaque into branch vessels), plaque embolization, and vessel dissection during a subsequent stenting procedure. With this strategy, the composite rate of mortality and permanent neurologic morbidity for the procedure dropped to below 5%, and 20% to 30% of patients did not require further intervention at follow-up.²⁸

Self-expanding Stents

The Wingspan stent system with a Gateway PTA balloon catheter (Boston Scientific) was designed for the treatment of intracranial atherosclerotic stenosis. Prestent dilation of the lesion is done with the angioplasty balloon; the stent, a self-expanding nitinol device, is then deployed (Fig. 87-2). The device received FDA approval as a new HDE device in August 2005. The approval was based on a 45-patient Wingspan HDE safety study that was conducted at 12 sites in Europe and Asia.²⁹ Patients who had a stroke caused by an intracranial lesion (stenosis of 50% or more) and for whom medical treatment was ineffective were enrolled in the study. Among the 45 patients, 44 patients subsequently underwent stent placement; in 1 patient, the lesion could not be traversed by the microwire. The procedural success rate was 98%, and a 4.4% incidence (n = 2) of death or ipsilateral stroke was observed 30 days after the procedure. The mean severity of angiographic stenosis decreased after the procedure from 75% to 32%. Among the 43 patients who completed the 6-month follow-up, the incidence of death or ipsilateral stroke was 7.0% (n = 3). Further lesion reduction was observed in 24 of 40 patients (mean severity 28%) who underwent follow-up angiography at 6 months. Angiograms in 3 patients (6.8%) showed more than 50% restenosis; all patients were asymptomatic. In contrast to SSYLVIA, which reported a rate of restenosis of more than 50% in 32.4% of patients at 6 months, the mean degree of stenosis at 6 months in the Wingspan study was not significantly different from the degree of stenosis immediately after the procedure.

FIGURE 87-2 A 36-year-old with cardiomyopathy and atrial fibrillation (on warfarin therapy) presented with an NIH Stroke Scale score of 16. A, An angiogram (left) shows stasis of the contrast material in the ICA due to carotid terminus occlusion and (right) a Penumbra aspiration device in distal M1 after traversing the lesion into the M1 sequentially with a Nautica microcatheter (ev3)/Terumo gold-tipped microwire (Tokyo, Japan), and a Balance Middle Weight (Abbott Vascular) exchange wire, and a Penumbra aspiration device (right). B, Combination endovascular therapy with the Merci retrieval device (Concentric Medical, Mountain View, CA), Penumbra device, and intra-arterial reteplase were successful (left = AP intracranial, middle = lateral intracranial, right = extracranial carotid) with reconstitution of the ICA, anterior cerebral artery, and MCA distributions. The patient experienced only mild, residual right-upper extremity numbness. Nine months later, the patient reported coincident worsening of his right-upper extremity numbness and new-onset insidious weakness.C, CT perfusion (color) images show increased left frontal time to peak (upper right), slightly decreased cerebral blood flow (lower left), and preserved cerebral blood volume (upper middle) in the same distribution.D, An angiogram shows supraclinoid ICA and M1 stenosis (left = intracranial, right = extracranial) of possible iatrogenic origin. E and F, Angiograms before (left = AP, right = lateral) and after (left = AP, right = lateral), respectively, placement of a self-expanding intracranial stent.

In the U.S. Wingspan registry,^30–32 treatment with the stent system was attempted in 158 patients with 168 intracranial atheromatous lesions (updated statistics, Fiorella DJ, personal communication, November 2009). Of these, 161 lesions (96.0%) were successfully treated during the first treatment session. Of the 168 lesions in which treatment was attempted, there were 9 (5.4%) major periprocedural neurologic complications, 4 of which ultimately led to the death of the patient within 30 days of the procedure. The total periprocedural event rate was 12.5% (21 of 168 cases). Most postprocedure events (18 of 21) were related to definable (and potentially controllable) issues: early antiplatelet interruption (n = 6) and in-stent restenosis (ISR) (n = 13). There were 10 patients with strokes and 12 patients with TIAs that occurred 30 days after the procedure. Imaging follow-up was available for 129 treated lesions (75 anterior circulation and 54 posterior circulation). Post-Wingspan ISR was more common in patients younger than 55 years (2.6 odds ratio). This increased risk can be accounted for by a high prevalence of anterior circulation lesions in this population, specifically those affecting the supraclinoid segment. When patients of all ages were considered, much higher rates of both ISR (66.6% vs. 24.4%) and symptomatic ISR (40% vs. 3.9%) were associated with supraclinoid segment lesions, in comparison with all other locations. Of 129 patients with imaging follow-up of treated lesions, 36 patients (27.9%) experienced ISR. Of these 36, 29 patients (80.6%) underwent target lesion revascularization (TLR) with angioplasty alone (n = 26) or angioplasty with restenting (n = 3). Restenting was performed for in-stent dissections that occurred after the initial PTA. Among the retreated lesions, 23 were located within the anterior circulation (79.3%) versus 6 in the posterior circulation. ISR lesions selected for retreatment were often either symptomatic (n = 4), angiographically more severe (longer segment involved or greater percentage of stenosis) than the presenting stenosis (n = 8), or both (n = 9). In some cases (n = 8), however, retreatment was performed in the absence of any of these factors. When symptomatic (n = 13), approximately two thirds of patients presented with TIA (n = 9) and one third presented with ipsilateral stroke (n = 4). Of the 29 patients undergoing primary TLR, 9 required 1 intervention for recurrent ISR, for a total of 42 TLR interventions. Only 1 major complication, a postprocedural reperfusion hemorrhage, was encountered during TLR (complication rates: 2.4% per procedure, 3.5% per patient). Angiographic follow-up was available for 22 of 29 patients after primary TLR. Of the 22 patients, 11 patients (50%) demonstrated recurrent ISR at follow-up angiography. Subsequently, 9 of these patients have undergone multiple retreatments (6 patients had two retreatments each, 2 had three retreatments each, and 1 had four retreatments) for recurrent ISR.

In the Wingspan National Institutes of Health (NIH) registry,³³ 129 patients with symptomatic 70% to 99% intracranial stenosis were enrolled from 16 medical centers. The rate of technical success rate (stent placement across the target lesion with less than 50% residual stenosis) was 97%. The rate of any stroke, intracerebral hemorrhage, or death within 30 days or ipsilateral stroke beyond 30 days was 14% at 6 months. The rate of 50% restenosis on follow-up angiography was 25% among 52 patients with follow-up. The NIH registry investigators published a post hoc analysis report of 158 of 160 patients who had successful placement for intracranial atherosclerotic lesion with 50% to 99% stenosis.³⁴ The primary endpoint(any stroke or death within 30 days or stroke in the territory of the stented artery beyond 30 days) at 6 months occurred in 13.9%. In multivariable analysis, the primary endpoint was associated with posterior circulation stenosis (vs. anterior circulation), with a hazard ratio (HR) of 3.4 (p = 0.018); stenting at low enrollment sites with fewer than 10 patients each (vs. high enrollment sites) and an HR of 2.8 (p = 0.038); 10 days from the qualifying event to stenting (vs. 10 days), with an HR of 2.7 (p = 0.058); and stroke as a qualifying event (vs. TIA or another cerebral ischemic event, e.g., vertebrobasilar insufficiency), with an HR of 3.2 (p = 0.064).

Drug-Eluting Stents

In a recent systematic review of 31 studies including 1177 procedures for symptomatic high-grade intracranial atheromatous disease, ISR occurred more frequently after the use of a self-expandable stent (16 of 92 cases, or 17.4%; mean follow-up period 5.4 months) than after use of a balloon-mounted stent (61 of 443 cases, or 13.8%; mean follow-up period 8.7 months; p < 0.001).³⁵ Thus, ISR is a major potential downfall of the predicate technologies that might be overcome with the implementation of drug-eluting stents (DESs) (Figs. 87-3 and 87-4). First-generation balloon-mounted coronary DESs coated with sirolimus or paclitaxel have reduced the coronary ISR rate to 10% from the 30% observed with bare-metal stents.³⁶ There have been a few reports of the use of the first-generation DESs in patients with intracranial arterial stenosis,^37–41 and the safety of implanting these devices has been studied in the intracranial vasculature of canine models.^42,43 The Xience V everolimus-eluting stent (EES) (Abbott Vascular, Abbott Park, IL) is a new second-generation DES that was approved by the FDA for coronary stenting in July 2008. This stent has a thin cobalt-chromium strut stent platform that allows greater deliverability in tortuous vasculature⁴⁴ and is coated with an antirestenotic drug, everolimus, that has proven ability to suppress ISR to a degree equivalent to that with sirolimus and more than that for paclitaxel-eluting stents.^45,46 The DESs may reduce the overall ISR rate if they can be used selectively in patients with lesions who have been identified to have a higher incidence of ISR. We have reported our initial experience with EES in patients with intracranial arterial stenosis.⁴⁷ These devices are used off-label in the intracranial vasculature.

FIGURE 87-3 A 69-year-old with an old left MCA infarct due to ICA occlusion treated with carotid artery stenting (A, angiogram) with good recovery. B, A follow-up angiogram shows new severe left petrous ICA stenosis (arrow

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