Pathophysiology

Arterial atherosclerotic plaques originate in regions of high permeability that are indistinguishable from surrounding tissue except on a microscopic level. Permeability is governed by the endothelial layer and appears to be the dysfunctional result of a combination of initial stressors that can include elevated or modified low-density lipoprotein (LDL) levels, flow-related mechanical stress, elevated serum cholesterol, elevated homocysteine levels, and potentially infection in some cases. The consequence of this excess permeability is that a higher than normal level of plasma components enters into the subendothelial layers and begins to aggregate.

The substance found to correlate highest with the generation of macroscopic plaques is unquestionably LDL, which initiates the fatty streak upon deposition in the subendothelial layers via focal activation and recruitment of monocytes. This inflammatory process is greatly exacerbated by the oxidation of LDL via lipoxygenases, nitric oxide, myeloperoxidase, and other mechanisms to the point of no longer being recognized by LDL receptors. Highly oxidized LDL thus becomes trapped in the subendothelial layers, promoting focal accumulations that stimulate local cells to secrete monocyte chemoattractants. Stimulation of scavenger receptors on local monocytes by oxidized LDL can also directly promote monocyte invasion into the subendothelial layer and subsequent differentiation into macrophages.

Macrophage uptake of LDL ultimately results in accumulation of LDL and cholesterol metabolites within these cells and the “foamy” histological appearance. The scavenger receptor pathway responsible for uptake is not down-regulated by this accumulation, which eventually results in unsustainable overload and cell death. The debris from early foamy cell death serves to promote more monocyte invasion fatty streak formation. An immunofibrotic plaque begins to form as foamy cells accumulate in subendothelial layers. Smooth muscle cells proliferate in the region of the growing fatty streak and begin to deposit collagen as a means of stabilizing the lesion, ultimately forming a fibrotic cap. The artery dilates to compensate for the thickening layer of smooth muscle and collagen, but years of plaque growth will ultimately surmount the maximum compensatory capacity of the vessel and a reduction in lumen volume occurs. This stenosis and the growing instability of the plaque due to size and inflammatory damage to its integrity both contribute to potential cerebrovascular injury via the risk of ischemia and thromboembolic events.

Clinical Features

Given the chronic nature of cerebrovascular atherosclerosis, the cerebrovascular system can show a remarkable level of resilience prior to symptomatic presentation and often remains undiagnosed for many years. The remainder of the discussion will be focused on carotid disease given its responsiveness to neurosurgical intervention. Vertebrobasilar and intracranial atherosclerosis share a similar clinical presentation with carotid artery stenosis but specific neurological findings are localized to the vascular territories involved (Table 12.1).

TABLE 12.1 Clinical Syndromes with Cerebrovascular Occlusion

Asymptomatic patients with carotid disease frequently are discovered because of the presence of a carotid bruit over the site of stenosis. Other signs in both asymptomatic and symptomatic patients include ocular bruits, pulsatile arteries arising from the external carotid artery. Nonetheless, the absence of signs does not exclude the presence of severe stenosis and subsequent complications, nor does the presence of these signs rule out other causes.

Symptomatic carotid disease is defined by the presence of neurological symptoms that are sudden in onset and referable to the appropriate carotid artery via its zone of dominant blood supply. Such disease often manifests in the form of a transient ischemic attack (TIA) or ischemic stroke. In most cases, carotid disease TIAs are less than 15 minutes in duration and present with either sensory, motor, or combined deficits of the contralateral side. Mechanistically, ischemic symptoms may result from embolism of platelet aggregates that form over the surface of the lesion leading to occlusion of a distal vessel or from hypoperfusion secondary to critical stenosis and hemodynamic alterations. In the former case, deficits may be quite specific (i.e., monocular blindness) and in the latter case, they are usually generalized to major vascular territories.

Diagnosis

The radiological evaluation of cerebrovascular atherosclerotic disease, specifically disease of the carotid arteries, consists of identifying the level and location of stenosis/occlusion, defining the etiology of these lesions, surgical planning, and patient follow-up. The four major modalities (most invasive to the least invasive techniques) are digital subtraction cerebral angiography (CA), computed tomographic angiography (CTA), magnetic resonance angiography (MRA), and duplex ultrasound (DUS).^2–4

Cerebral angiography is the gold standard for imaging the carotid arteries (Fig. 12.2). Cerebral angiography has superior accuracy compared to noninvasive techniques, which may overestimate or underestimate the degree of stenosis, an important characteristic for accurately determining the extent of disease and for surgical planning. Moreover, more than one noninvasive modality is usually required to perform an accurate and comprehensive assessment of atherosclerotic disease. The advent of digital subtraction angiography (DSA) has reduced the size of catheter needed, the amount of contrast required, and the duration of this procedure. Although there is lower spatial resolution, DSA allows for dynamic visualization of blood flow at the site of stenosis as well as collateralization and flow around the vascular lesion; this information provides an indication of the clinical impact of the stenosis. Patients should be screened for history of adverse reaction to contrast agent and renal disease, as contrast nephropathy and allergy are potential complications of cerebral angiography.

FIGURE 12.2 Diagnostic imaging of carotid artery stenosis. A, Color duplex sonography of the neck showing narrowing of the carotid artery and associated increase in flow velocity. B, Digital subtraction angiography of carotid artery demonstrating stenosis at the level of the carotid bifurcation and internal carotid artery.

CTA combines CT technique with venous injection of contrast dye to visualize the supra-aortic vessels (both intracranially and extracranially). Unlike CA and DSA, CTA provides an anatomical description of the surrounding structures in addition to the vasculature, which is extremely useful in identifying nonatherosclerotic causes of stenosis. This technique is less invasive than DSA but requires contrast bolus comparable to angiography, and so contrast allergy and nephropathy are possible complications. Furthermore, as the quality and accuracy of the obtained image depends on both the timing of the injection and the scan itself, CTA often suffers from overestimation or underestimation of the degree of disease.

MRA uses intravenous injection of gadolinium and may be useful in evaluating extracranial carotid arteries. Alternative techniques are used without contrast enhancement, such as time-of-flight (TOF) measurement, which is often used for assessing intracranial lesions. MRA produces a reproducible three-dimensional image of the carotid bifurcation with good sensitivity for detecting high-grade carotid artery stenosis and is especially informative in the setting of symptomatic disease.

Carotid DUS is a relatively easy technique that can be performed at the bedside. It detects a focal increase in blood flow velocity, suggesting vessel stenosis. The peak systolic velocity is the most frequently used measurement to gauge the severity of the stenosis but the end-diastolic velocity, spectral configuration, and the carotid index or peak internal carotid artery velocity/common carotid artery velocity ratio provide additional information and allow accurate estimation of the lesion. Trancranial US is used to detect intracranial circulation as well and is very useful to assess intracranial atherosclerotic status. Although relatively inexpensive, portable, and easy to use at the bedside, this technique is still very physician and technician dependent.

Measurement of Carotid Artery Stenosis

Current indications for surgical intervention of carotid atherosclerotic disease require objective and reproducible methods to evaluate the degree of stenosis. Two major methods of measuring carotid stenosis were developed for use in the major clinical trials evaluating the efficacy of carotid endarterectomy: the North American Symptomatic Carotid Endarterectomy Trial (NASCET)⁵ method and the European Carotid Surgery Trial (ESCT)⁶ method. The primary difference in these methods lies in how the observer estimates the diameter of the reference vessel. The NASCET utilizes the normal carotid wall just distal to the stenotic lesion as the reference vessel, and ESCT defines the reference as the estimated diameter of the carotid bulb. Figure 12.3 diagrams each method of measurement and the mathematical relationship between these two methods. Note that the ECST and NASCET approximations are comparable with severe disease, but that their values diverge when the stenosis is not as pronounced. In contemporary practice, most patients are determined to have high-grade (>60-70%) stenosis on the basis of noninvasive color flow Doppler, CTA, or MRA. When two of these three modalities agree on the degree of stenosis and no other modality questions the result, the correlation with catheter angiography is excellent. Given the risk of catheter angiography, this is generally reserved for patients in whom the studies are not concordant.

FIGURE 12.3 Methods of assessing carotid stenosis severity. A, Residual lumen diameter at most stenotic portion of vessel. B, Estimated diamater of carotid wall at the level of the lesion. C, Diameter of normal carotid artery just distal to stenosis.