Intracranial Atherosclerosis

Stroke is the most common life-threatening neurologic disease and the third leading cause of death in the United States. Approximately 750,000 people suffer a stroke annually, costing an estimated $45-50 billion in treatment and lost productivity. Intracranial atherosclerosis accounts for about 8 to 9% of all ischemic strokes in population-based or hospital-based studies. It is estimated that approximately 40,000 strokes annually are due to intracranial atherosclerosis in the United States. In general, intracranial atherosclerosis occurs in the setting of widespread atherosclerosis. Besides race and ethnicity, risk factors associated with intracranial atherosclerosis include insulin-dependent diabetes mellitus, hypercholesterolemia, cigarette smoking and hypertension.

Current imaging does not establish the future course of a given lesion, and the precise nature of the underlying lesion.

Intracranial stenoses are usually detected in patients presenting with acute ischemic events. Most published data on the natural history of intracranial atherosclerosis are from patients examined either by conventional angiography or transcranial Doppler sonography (TCD). Intracranial stenoses may undergo progression, regression, or remain stable during the follow-up period. Intracranial stenoses are dynamic lesions and a significant portion of intracranial stenoses diagnosed in the setting of acute ischemic events will regress with medical treatment only. However, current imaging does not establish the future course of a given lesion, and the precise nature of the underlying lesion, that is, local thrombosis or stenotic atherosclerosis, is difficult to distinguish with current imaging techniques.

Most of our knowledge about the pathology of intracranial atherosclerosis and associated stenoses is based on autopsy studies. In most cases, the narrowing is due to atherosclerotic plaque and pathologic evidence exists that plaque morphology in intracranial vessels resembles those of other vascular territories. Plaque morphology appears to be important in the setting of acute coronary syndromes and by extension this might apply also to acute cerebrovascular syndromes. Angioscopy of coronary and carotid arteries reveals two types of plaques, white and yellow plaques. White plaques are also named as stable plaques, while yellow plaques are named as unstable.

Ischemic strokes in intracranial atherosclerosis can be caused by either perfusion failure, local thrombosis at the site of the stenosis with arterio-arterial thromboembolism, or occlusion at the origin of small penetrators arteries. Depending on both stenosis grade and adequacy of collateral circulation, stenosis of cerebral arteries may lead to reduction of blood flow distal to it. In cerebral angiography, hemodynamic effects are usually demonstrated by delayed flow or border-zone shift. The hemodynamic effects of cerebrovascular stenoses have been categorized into three stages:

  • Stage 0: Normal cerebral hemodynamics;
  • Stage 1: Reflex vasodilatation in response to inadequate collaterals and falling perfusion pressure with increased cerebral blood volume (CBV) and prolongation of mean transit time (MTT) but preservation of cerebral blood flow (CBF) and normal oxygen extraction coefficient (OEF);
  • Stage 2: Misery perfusion with falling CBF and increased OEF.

Hemodynamic compromise as defined by neuroimaging seems to be an independent risk factor for ipsilateral stroke. The presence of a high-grade stenosis or even occlusion does not necessarily imply that there is actual perfusion failure. Patients with hemodynamic compromise due to intracranial atherosclerosis may represent a subgroup of patients for whom endovascular revascularization may have the greatest chance of being proven effective.

Findings of several autopsy studies suggest that thrombosis complicates intracranial atherosclerosis associated with a pre-existing stenosis. In some cases, intramural hemorrhage due to fibrinoid degeneration of the capillaries in the plaque could be responsible for cerebral arterial thrombosis.

Stenotic atheromatous plaque can include the origin of small arteries. The main point is that stenotic atheromatous plaques in large intracranial arteries might cause symptomatic stenosis or occlusion of small penetrating arteries. Careful correlation of the ischemic clinical syndrome with neuroimaging is necessary in these cases because angioplasty of the stenotic plaque may result in complete obstruction and subsequent ischemic stroke in the territory of the penetrators, resulting in an adverse outcome of the procedure.

Prognosis of Patients with Intracranial Atherosclerosis
The prognosis after stroke associated with intracranial stenoses seems to be dependent on location and extent of intracranial atherosclerosis. Most of our knowledge about prognosis in intracranial atherosclerosis is based on retrospective series.

Table 1: Annual Death and Stroke Rates According to the Distribution of Stenosis

  Per Annum
Disease Distribution Death Rate Any Stroke Ipsilateral Stroke
Carotid 9.5% - 17.2 % 3.9% - 11.7% 3.1% - 8.1%
MCA 3.3% - 7.7% 2.8% - 4.2% 4.7%
Vertebrobasilar 6.1% - 9.7% 2.4% - 13.1% 0% - 8.7%

At the present time, angioplasty and stenting is usually performed for patients with symptomatic intracranial stenoses. It is important to evaluate all patients prior to any angioplasty to correlate the patient’s symptoms and clinical findings with the presumed symptomatic vessel and to exclude other potential diagnoses with alternative treatment options, e.g. cerebral vasculitis. Part of this evaluation should include type and duration of medical therapy and adjusting of medical treatment as necessary.

The usual vascular work-up of stroke patients includes transcranial Doppler or Duplex sonography, CT-angiography, or MRI with MRA. Intracranial stenoses in the arteries accessible to angioplasty and stenting can be easily identified with any of those studies. In individual cases, verification of the findings of the non-invasive studies with conventional cerebral angiography might be necessary. Impaired cerebrovascular reserve as an indicator for perfusion failure distal to the stenosis is diagnosed by several methods, each of them having its own advantages and disadvantages. Currently, the diagnosis of Stage 2 of hemodynamic compromise (increased oxygen extraction fraction) is only possible with positron emission tomography (PET) using 015-labeled radiotracer. To what extent the information of these studies might be helpful for the indication and timing to perform an angioplasty remains to be established in future studies.

The medical treatment of intracranial atherosclerosis is similar to the treatment of atherosclerosis in other vascular territories and includes the control of vascular risk factors and the prescription of antithrombotics (platelet-active drugs or warfarin), statins and ACE inhibitors. Patients are usually referred for elective intracranial angioplasty if they have failed ‘maximal medical’ therapy. However, the term ‘maximal medical’ therapy is not clearly defined. In most instances, failure to maximal medical therapy is defined as of transient ischemic attacks or recurrent ischemic stroke while on therapeutic doses of aspirin (≥ 81 mg /day), ticlopidine (500 mg/day), clopidogrel (75 mg/day), warfarin (International Normalized Ration [INR] ≥ 2.0), or intravenous heparin (prolongation of partial thromboplastin time > 1.2 times baseline value).

During the last decade, dramatic improvements in microcatheter technology have allowed for innovative endovascular neurovascular procedures and popularization of existing technology. The successful use of balloon angioplasty for the treatment of intracranial atherosclerosis has been reported by an increasing number of medical centers, predominantly academic centers and high volume medical centers with significant neurovascular expertise. Results to date are encouraging, yet the procedure is technically demanding at many levels and carries substantial risk. In general, most practitioners reserve endovascular revascularization for patients who are refractory to maximal medical therapy.

Not all patients with cerebrovascular stenoses are equivalent: careful neurological and imaging assessments are mandatory for planning a successful individualized treatment strategy. Moreover, treatment requires a multi-disciplinary approach as weakness in any link of the chain can have devastating consequences. An important theme of this monograph is the customized approach needed to address each patient. No single operator works in a vacuum. Technically successful revascularization of cerebrovascular stenosis is only one step to achievement of acceptable treatment outcomes.

Mori et al. developed an arteriographic classification system to predict the outcome of cerebral revascularization with primary angioplasty alone. Lesions were categorized at high-resolution digital subtraction arteriography by length and geometry:

  • Type A: short (<5mm in length); concentric or moderately eccentric; non-occlusive concentric or moderately eccentric; non-occlusive moderately eccentric; non-occlusive eccentric; non-occlusive
  • Type B: tubular (5-10mm in length); extremely eccentric; moderately angulated (curved)
  • Type C: diffuse (>10mm in length); extremely angulated (>90 degrees); very tortuous proximal segment

In general, the more complex the target lesion, the less satisfactory are immediate and long-term outcomes become using the currently available devices. For instance, the treatment success for Mori Type A lesions was 92%, while treatment success for Type C lesions was only 33% with 100% one-year restenosis. As we will discuss, the use of currently available stent technology resolves certain limitations inherent to angioplasty alone.

Immediate complications of balloon angioplasty without stenting include plaque/vessel recoil, vessel dissection, acute closure, perforation and rupture. Stent-assisted angioplasty in the peripheral, extracranial cerebral and coronary circulation has been shown to have a superior safety profile and efficacy compared with balloon angioplasty alone. Stents limit vessel wall recoil and the extent of iatrogenic dissection by compressing the intimal flap.

The feasibility of stent-assisted angioplasty of the intracranial circulation was until recently limited by the inability of available devices to negotiate the tortuosity of intracranial vessels. Newer coronary stents are lighter and more flexible than their predecessors providing the required performance for intracranial navigation. Moreover, thin struts that are widely spaced may have a theoretical advantage in preserving side branches such as perforating arteries. The successful use of coronary stents including the GRII (Cook, Bloomington, IN), Multilink Duet (Guidant, Santa Clara, CA), and GFX I & II (Medtronic/AVE, Santa Rosa, CA) for treatment of intracranial stenoses has been reported. Most applications have related to the vertebrobasilar system with limited reports of their use in the middle cerebral artery and intracranial internal carotid. Investigations utilizing the INX stent (Medtronic/AVE, Santa Rosa, CA), the first stent designed primarily for neurovascular use are ongoing. However, most work has focused on its application in stent-supported coil embolization for wide-necked aneurysms rather than intracranial stenoses.
Subacute-to-late restenosis is related to intimal hyperplasia (cellular proliferation) and vascular remodeling. MRI with MRA is useful for non-invasive surveillance but not all stenoses are detected with these modalities and measurements of stenosis severity can be inaccurate. The role of CT angiography to accurately depict restenosis is uncertain but likely limited by beam-hardening artifact. Some equipment vendors have begun to advertise imaging systems that overcome artifacts related to metallic prosthetics. In the interim, certain authors advocate rigorous angiographic follow-up beginning at 3 months given the 33% and 100% incidence of restenosis for Mori Type B and Type C lesions, respectively, at 1 year. It is recommended that conventional angiographic follow-up be obtained initially at 3 months at which stage additional endovascular treatment can be undertaken if required. Depending on patient age, medical condition, and other angiographic risk factors, the value of aggressive arteriographic surveillance must be weighed against the risk of complications.

The poor prognosis of patients with symptomatic intracranial atherosclerotic stenoses despite best medical management has defined a new role for endovascular revascularization of the intracranial circulation. However, the procedure is associated with a morbidity and mortality rate up to 10-20% in minimally symptomatic patients, possibly much higher in neurologically unstable patients. Under-sizing of the angioplasty balloon is recommended to minimize complications. Stent-assisted angioplasty is now feasible with recent stent technology allowing improved restoration of vessel diameter while reducing the incidence of some local complications. Restenosis after stenting appears less problematic at early follow-up compared with angioplasty alone but the adaptation of coronary technology and long-term patency of intracranial stenting has yet to be determined. A multi-disciplinary approach to patients with symptomatic intracranial atherosclerosis is imperative to achieve appropriate outcomes across the spectrum of disease.