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).

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.

Management

Alternatives to Carotid Endarterectomy

Moyamoya Disease

Moyamoya disease is a relatively rare cause of cerebrovascular occlusive disease, with a typical reported incidence of less than 1 per 100,000 per year.¹⁸ More common in females, moyamoya disease has a bimodal age distribution, with peak incidence in the first and fourth decades of life. Moyamoya disease manifests as chronic, progressive occlusion of the internal carotid artery at and distal to the carotid siphon that may also involve the proximal segments of the middle and anterior cerebral arteries. Over time, patients with moyamoya disease 3 develop networks of fragile, collateral vessels that resemble a “puff of smoke” on angiogram, hence its name.

The pathophysiology of moyamoya disease remains somewhat elusive. Cerebrospinal fluid (CSF) levels of cytokines, growth factors, and adhesion molecules are elevated in patients with moyamoya disease. Additionally, hepatocyte growth factor, which has increased expression in the media and thickened intima in moyamoya patients, has been implicated in the migration and proliferation of smooth muscle cells within the intima. Linkage studies also suggest that genetics may play a role in the development of moyamoya disease.

The clinical presentation depends on the age of the patient. Most pediatric patients present with ischemic symptoms (TIA or stroke), and adult patients can present with either ischemic or hemorrhagic symptoms. TIA or stroke in these patients usually involves the ICA distribution (usually centered around the frontal lobe) and results in focal neurological deficits. Pediatric patients, in particular, may present with intellectual impairments, and moyamoya disease can rarely masquerade as psychiatric illness. Crying spells in pediatric patients can precipitate ischemic events, as hyperventilation, with resulting hypocapnia and vasoconstriction, can lead to reduced blood flow to vulnerable and chronically poorly perfused tissues. Hemorrhage can result from ruptured fragile collateral vessels, commonly occurring in the basal ganglia, thalamus, or around the ventricles leading to intraventricular hemorrhage. Other causes of hemorrhage in these patients include rupture of intracranial aneurysm leading to subarachnoid hemorrhage. Atypical symptoms of moyamoya disease include migraine-like headaches, seizures, and involuntary movements.

Diagnosis

Cerebral angiography is the gold standard for diagnosing moyamoya disease. Hallmark features include narrowing of the C1 and C2 segments of the internal carotid artery and proximal involvement of the middle cerebral artery (MCA) and anterior cerebral artery (ACA) bilaterally. The pathognomonic, delicate collateral vessels typically are visualized near deep brain structures supplied by the thalamoperforating, lenticulostriate, and anterior choroidal vessels. The ethmoidal arteries may also be recruited to supply the ACA (ethmoidal moyamoya) and anastomoses between dural and pial vessels (vault moyamoya). As collateral vessels disappear following revascularization, cerebral angiography may be used to assess success of bypass during follow-up. MRA is a noninvasive alternative, and angiography need not be performed if MRA/MRI shows the following bilaterally: (1) stenosis/occlusion of the terminal ICA and proximal ACA and MCA; (2) abnormal vascular network within the basal ganglia.¹⁹

Management

No interventions in the setting of acute ischemic stroke secondary to moyamoya disease have proved effective. Treatment is largely supportive and aimed at decreasing cerebral edema and increasing cerebral perfusion. Intravenous/intra-arterial thrombolysis is not typically performed in this patient population given the fragility of collateral vessels and the increased risk for intracerebral hemorrhage. Patients with intracerebral hemorrhage may benefit from surgical decompression and ventricular drainage.

Prevention of further ischemic or hemorrhagic events in moyamoya disease involves revascularization procedures.²⁰ Direct revascularization involves creating anastomoses between a branch of the external carotid artery and a branch of the internal carotid artery (typically the superficial temporal artery and M3 or M4 segment of the middle cerebral artery, respectively). This results in an immediate restoration of flow to previously poorly perfused areas of the brain. See later discussion for in-depth description of the operative technique for EC-IC bypass.

Indirect revascularization involves placement of vascularized tissue on the surface of ischemic brain, stimulation of angiogenesis, and formation of collateral networks between donor and recipient tissue. Vascularized donor tissue may consist of temporal muscle (encephalomyosynangiosis), galea (encephalogaleosynangiosis), superficial temporal artery (encephaloduroarteriosynangiosis), or combinations of these techniques (e.g., encephaloduroarteriomyosynangiosis). Although indirect bypass is not as technically challenging as direct revascularization and is a suitable alternative in moyamoya disease, angiogenesis may take months and patients remain at increased risk of ischemic stroke. A combination of direct and indirect revascularization techniques may be used to provide an immediate improvement of perfusion in addition to the progressive formation of collateral networks.

Dissection

Cerebral arterial dissection results from a tear in the arterial wall and extravasation of blood between the intima and media layers, with subsequent luminal narrowing or occlusion. The etiology of arterial dissection is multifactorial but can be grossly categorized as traumatic or spontaneous, although spontaneous dissections may be due to minor trauma to an already predisposed vessel. Conditions commonly associated with cerebral arterial dissections include fibromuscular dysplasia, Marfan syndrome, polycystic kidney disease, and vasculitides. The annual incidence of dissection is approximately 3.6 per 100,000, and vertebrobasilar dissections occur more frequently than carotid dissections.²¹

The clinical manifestations of cranial arterial dissection vary, but patients often present with either ischemic stroke (more common with carotid) or subarachnoid hemorrhage (more common with vertebrobasilar); however, patients may only have mild complaints, including headache, neck pain, incomplete Horner syndrome, transient deficits, or neck swelling. Ischemic symptoms represent occlusion of the cerebral arteries and can occur secondary to embolization of thrombus formed at the site of dissection, from intraluminal thrombosis, or from expansion of the false lumen with occlusion of the true lumen. As with atherosclerotic cerebrovascular disease, the clinical symptoms reflect the vascular territory involved.

Diagnosis

Cerebral angiography is the gold standard for diagnosis of cerebral arterial dissection.²¹ Notable angiographic findings include a smooth, but irregular narrowing of the vessel, presence of a double lumen, or intimal flap, and arterial occlusion. The diagnosis may sometimes be confused with atherosclerosis or vasospasm in the setting of subarachnoid hemorrhage (SAH); the former can be distinguished by unusual location and relatively young age of the patient in dissection, and the latter occurs several days following the SAH. Angiography also has the advantage of allowing for immediate, endovascular intervention in select patients. However, there is a small, but real risk of ischemic stroke (<0.5%) as well as contrast nephropathy in patients with renal disease.²¹ CTA has high sensitivity for both extracranial carotid and vertebral dissections. Additionally, this quick diagnostic allows for rapid diagnosis of dissection in patients, which is ideal for patients presenting acutely. However, as with angiography, patients are at risk of contrast-induced nephropathy and are exposed to significant levels of radiation. MRI/MRA is gaining favor and has particularly high sensitivity for detecting extracranial carotid dissection. Moreover, MRI allows for visualization of ischemic brain lesions. However, MRI/MRA has less utility in detecting vertebrobasilar dissections and may be associated with significant motion artifact in the restless patient. Finally, Doppler ultrasound can be used at the bedside to rapidly to diagnose extracranial carotid dissection the good sensitivity, but is not useful at identifying other dissecting vessels.

Management

Management of cerebral arterial dissection remains controversial given the absence of large, randomized clinical trials.²¹ However, patients without evidence of hemorrhage and with extracranial disease (especially those with evidence of thromboembolic phenomena) may be treated with anticoagulation (intravenous heparin during the first week or so followed by several months of oral anticoagulation). Patients who do not respond to anticoagulation may benefit from endovascular or surgical intervention. Angioplasty, stenting, and intra-arterial thrombolysis are potential endovascular treatments. EC-IC bypass using high-flow conduit (either saphenous vein or radial artery grafts) with subsequent ligation of the ICA may be used in rare cases. Dissections that present with subarachnoid hemorrhage (usually intracranial cases involving the vertebral artery) usually require surgery. Options include sacrifice of the vertebral artery with or without vascular bypass, surgical clipping of dissection aneurysm, and endovascular coiling.

Surgical Management of Cerebrovascular Occlusive Disease

Carotid Endarterectomy

Choice of Anesthesia

Patients may undergo either local or general anesthesia per surgeon and patient preference, as previous studies have demonstrated that rates of poor short-term outcome following surgery are similar.²² Choice of anesthesia determines intraoperative monitoring. Patients undergoing local anesthesia may be followed clinically throughout the procedure by frequently assessing neurological function. For patients receiving general anesthesia, EEG monitoring may be used to monitor for warning signs of intraoperative ischemia.

Operative Technique

Patients are placed in the supine position, with the neck extended and rotated gently contralateral from the side of the lesion of interest to maximize exposure of the internal carotid artery (the degree of neck rotation needed for optimal exposure may be ascertained by preoperative imaging) (Fig. 12.4). Care must be taken not to cause trauma to the lesion and subsequent thromboembolism to distal cerebral vessels when the operative region is prepped and draped.

FIGURE 12.4 Dissection of internal carotid artery. A, Anteroposterior view of magnetic resonance angiography demonstrating site of dissection. B, T1-weighted magnetic resonance imaging scan identifying false lumen of the dissected internal carotid artery imposing on the true lumen.

The skin incision typically follows the anterior portion of the sternocleidomastoid; a transverse incision along the skinfold at the level of the carotid bulb may be more cosmetically pleasing but requires preoperative determination of the bulb location. Dissection of subcutaneous tissue and fascia, separation of the platysma muscle, and dissection of the neck to reveal the carotid sheath are performed. Meticulous hemostasis is maintained throughout. Medial retraction must be performed with care so as not to injure recurrent laryngeal nerves.

Once the carotid sheath is identified (Fig. 12.5), the jugular vein, which lies parallel and anteriorlateral to the carotid artery, is gently dissected from the carotid artery along its medial aspect. Division of the common facial vein enhances exposure of the carotid artery at the level of the bulb and the proximal common carotid, respectively. Following incision through the carotid sheath, the common, external, and internal segments of the carotid artery are identified and controlled using umbilical tape. Any hemodynamic instability noted during this time, principally bradycardia, can be treated with application of lidocaine to the carotid bulb. The patient is then heparinized and the internal, common, and external segments of the carotid artery are sequentially clamped. Cerebral shunting may be performed at this time, depending on surgeon preference; however, intraoperative neurological monitoring must be performed throughout the surgery and a shunt should be prepared and ready for insertion in the event that brain ischemia is suspected.

FIGURE 12.5 Intraoperative view of carotid endarterectomy. Prearterotomy view of carotid artery immediately prior to systemic heparinization and clamping the internal, common, and external carotid arteries in sequential fashion.

Longitudinal arterotomy of the common carotid near the bifurcation is made and extended proximally and distally through the internal segment. The atherosclerotic plaque (Fig. 12.6) must be carefully dissected away from the arterial wall; a smooth transition between normal and endarterectomized vessel should be made to avoid the creation of a false lumen of the artery.

FIGURE 12.6 Postendarterectomy atherosclerotic plaque measuring approximately 1.8 inches in length.

Although primary closure of the arterotomy is preferred, a prosthetic or venous patch graft (usually harvested from the saphenous vein) may be indicated in patients with repeat endarterectomy or with unusually small carotid arteries. In the latter case, a patch graft may be avoided by visualizing the artery under the microscope during closure. Unclamping for flushing before complete closure is routine. Carotid segments are unclamped following closure of the arterotomy beginning with the external carotid artery, and then the common carotid artery and internal carotid artery, in that order. Prior to final wound closure, meticulous hemostasis is performed and sufficient time is allowed to pass to guarantee its success. A Jackson-Pratt drain may be placed to avoid formation of neck hematomas, and the platysma, fascial layer, and skin are sutured.

Postoperative Care

Patients should be monitored in an intensive care unit with an arterial line in place. Blood pressure lability is common within the first 24 hours postoperatively and pressures should be kept within 110 mm Hg to 150 mm Hg, ideally with short-acting agents to avoid prolonged rebound hypotension or hypertension. Antiplatelet agents should be held for 24 to 48 hours after surgery but may be restarted as soon as 24 hours after surgery. Frequent postoperative evaluations should focus on the identification of new neurological deficits, which may be due to iatrogenic nerve injury or postoperative stroke, evidence of hematoma development at surgical site, and cardiac abnormalities.

Postoperative Complications

Although CEA is an effective and durable treatment for carotid atherosclerosis, complications following CEA are common. The mortality rate of carotid endarterectomy varies between 0.5% and 2.5% depending on the experience and volume at individual institutions. Cardiac complications constitute the most common cause of death after CEA; patients should have the appropriate preoperative cardiac workup to assess risk and minimize postoperative cardiac complications.

Stroke is the second most common cause of death following CEA, occurring in approximately 5% of patients, and patients should have frequent neurological checks postoperatively to promptly identify those who are exhibiting signs of brain ischemia or infarction. Occlusion of the ICA is responsible for most cases of major stroke postoperatively, and thromboembolism originating at the endarterectomy site causes most minor strokes. The management of postoperative stroke varies depending on the surgeon and the institution. Bedside ultrasound may be used to assess for flow in the operated ICA, but many surgeons may prefer to reoperate and examine the surgical site visually. Although large randomized clinical trials are lacking, possible interventions include intravenous or intra-arterial alteplase administration or carotid stenting.

Nerve injury is not an uncommon complication of carotid surgery. The hypoglossal nerve is the most commonly affected and results in tongue deviation to the ipsilateral side. This injury usually results secondary to prolonged compression during retraction. Injury to this nerve can be minimized by early identification during neck dissection and gentle retraction. Common complaints include difficulty in speaking and swallowing, although bilateral injury from a contralateral endarterectomy can result in airway obstruction. Hence, in patients needing bilateral endarterectomy, hypoglossal nerve injury during the primary endarterectomy must resolve before proceeding to surgery on the contralateral side. Other commonly affected nerves include the recurrent laryngeal nerve, which may result in unilateral vocal cord paralysis, and the vagus nerve, which lies posteriorly within the carotid sheath.

Neck hematomas are not uncommon, especially in patients taking Plavix, but those requiring reintubation and evacuation are decidedly rare. In the advent of any sign of airway compromise, early elective intubation is usually best.

Hyperperfusion, which occurs in approximately 9% to 14% of patients postoperatively, is defined as more than 100% increase in cerebral blood flow over preoperative baseline. Cerebral hyperperfusion syndrome is a less common but serious complication of CEA characterized by ipsilateral headache, seizure, and focal neurological deficits in the absence of evidence of ischemia; symptoms usually occur secondary to ipsilateral hemorrhage or edema.²³ It occurs in approximately 0.75% to 3.0% of patients; it can occur at any time from hours to a month after surgery, but most commonly begins several days after surgery. Although the exact pathophysiology is unknown, a combination of ischemia-reperfusion injury, impaired cerebral autoregulation, and hypertension is thought to play a role. Hence, it is critical to maintain the systolic blood pressure less than 150 mm Hg following surgery to decrease the risk of developing this syndrome. Trans-cranial Doppler may be used to screen for patients at risk of developing hyperperfusion syndrome; urgent CT is warranted in suspected cases to rule out intracerebral hemorrhage.