Laboratory Evaluation
Laboratory and radiologic investigations allow anatomic localization of the cerebrovascular event and assist in the determination of its pathogenesis. Techniques that are available to aid the physician in the diagnosis and management of potential cerebrovascular disease include computed tomography (CT), magnetic resonance imaging (MRI), cerebral arteriography, noninvasive neurovascular studies, and other ancillary studies. The proper use of these techniques requires an understanding of the underlying disease process, the principles of the test involved, and the advantages and limitations of each procedure. Specific attention should be focused on how each investigation influences the management of a patient.
COMPUTED TOMOGRAPHY
Soon after its introduction in 1973, CT became the preferred method for imaging tissue damage from stroke, and its use was extended to the body and the spine. In CT of the head, multiple rotating beams of x-rays pass through the patient’s head, and diametrically opposed detectors measure the extent of absorption values for multiple, small blocks of tissue (voxels). Computerized reconstruction of these areas on a two-dimensional, gray-scaled display (pixels) provides the characteristic CT scan appearance. Modern CT scanners have spatial resolutions from 1 to 2 mm (for routine scanning, slices are usually 5-10 mm thick). White and gray matter usually are differentiated easily (Fig. 7-1), and the major arteries may be visualized after the infusion of contrast material.
CT Findings in Patients with Ischemic Lesions
The ability of CT to reveal an ischemic lesion depends on the resolution of the scanner, the size and the location of the lesion, and the time after onset of symptoms (Table 7-1). After a person has had transient neurologic symptoms because of focal cerebral ischemia, the CT scan may be normal or it may show an area of decreased density compatible with a small infarction (or, rarely, an area of increased density compatible with a small hematoma) in the distribution of the symptoms. The main role of CT in patients with transient symptoms is to rule out an unexpected pathologic lesion, such as intracranial hemorrhage, vascular tumor, or arteriovenous malformation (AVM), which may change the investigative approach and management.
On admission, the CT is negative in approximately one third of patients in whom ischemic stroke has been diagnosed clinically. However, a negative result does not exclude the diagnosis of ischemic stroke. A CT scan may not detect relatively small infarctions in the vertebrobasilar system, infarcts near the skull base (because of bone-related artifact), infarcts that are less than 5 mm in diameter,
or infarcts with little edema. Furthermore, within the first 24 hours after cerebral infarction, the CT scan may be negative in approximately 50% of cases. For patients in whom the presence of the ischemic stroke is not defined clearly by an area of decreased attenuation, one must scrutinize the scan carefully for the following suggestive findings: (1) flattening of the sulci (sulcal effacement), (2) loss of gray-white delineation (in the middle cerebral artery [MCA] distribution, this may manifest as loss of the insular ribbon), (3) loss of the outline of the lentiform nucleus, and (4) subtle area of subcortical hypointensity. A hyperdense MCA may suggest a clot within the artery. The location of the lesion is important for making the diagnosis of cerebral infarction and may suggest an underlying pathophysiologic mechanism that produced it. For example, infarcted tissue within a vascular territory of one or more major arteries may suggest large vessel disease or a cardiac source for emboli. In contrast, a tiny lesion in the basal ganglia area may suggest small vessel disease (e.g., a lacunar infarct) or a lesion in a border zone between different vascular territories (watershed infarction) may suggest proximal occlusive disease with hemodynamic infarction.
or infarcts with little edema. Furthermore, within the first 24 hours after cerebral infarction, the CT scan may be negative in approximately 50% of cases. For patients in whom the presence of the ischemic stroke is not defined clearly by an area of decreased attenuation, one must scrutinize the scan carefully for the following suggestive findings: (1) flattening of the sulci (sulcal effacement), (2) loss of gray-white delineation (in the middle cerebral artery [MCA] distribution, this may manifest as loss of the insular ribbon), (3) loss of the outline of the lentiform nucleus, and (4) subtle area of subcortical hypointensity. A hyperdense MCA may suggest a clot within the artery. The location of the lesion is important for making the diagnosis of cerebral infarction and may suggest an underlying pathophysiologic mechanism that produced it. For example, infarcted tissue within a vascular territory of one or more major arteries may suggest large vessel disease or a cardiac source for emboli. In contrast, a tiny lesion in the basal ganglia area may suggest small vessel disease (e.g., a lacunar infarct) or a lesion in a border zone between different vascular territories (watershed infarction) may suggest proximal occlusive disease with hemodynamic infarction.
 FIGURE 7-1. Normal computed tomography (CT) head scans. |
Characteristic CT findings in patients with ischemic stroke include an area of decreased density, which often appears 12 to 48 hours after the stroke. The hypodensity initially is mild and poorly defined, but on the third or fourth day after the stroke, the density decreases (in this period, edema is maximal and manifests as decreased density involving both gray and white matter in the area affected by ischemia), the margins of the lesion become more clearly defined, and
the lesion is better visualized (Fig. 7-2). Later, the edema and mass effect gradually subside, and the hypodensity becomes less evident. This change sometimes leads to radiologic disappearance of the infarcted area, which may become indistinguishable from the normal surrounding brain. The fogging effect occurs usually
during the second or third week after the stroke and corresponds to the period of invasion by macrophages and proliferation of capillaries.
the lesion is better visualized (Fig. 7-2). Later, the edema and mass effect gradually subside, and the hypodensity becomes less evident. This change sometimes leads to radiologic disappearance of the infarcted area, which may become indistinguishable from the normal surrounding brain. The fogging effect occurs usually
during the second or third week after the stroke and corresponds to the period of invasion by macrophages and proliferation of capillaries.
TABLE 7-1 Common CT Findings in Patients with Cerebral Infarction and Intracranial Hemorrhage, by Time from Event to Evaluation | ||||||||||||||||||||||||||||||||||||
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 FIGURE 7-2. Computed tomography head scan without contrast, 72 hours after onset of symptoms: area of decreased density in the distribution of right posterior cerebral artery, consistent with cerebral infarction. |
The Alberta Stroke Program Early CT Score (ASPECTS) is sometimes used to define the severity of MCA infarction on a CT scan. The score is calculated by subtracting 1 point from 10 for change suggestive of early ischemia for each of the 10 MCA regions: caudate, putamen, internal capsule, insular ribbon, M1: anterior MCA cortex (frontal operculum), M2: MCA cortex lateral to the insular ribbon (anterior temporal lobe), M3: posterior MCA cortex (posterior temporal lobe), M4: anterior MCA cortex superior to M1, M5: lateral MCA cortex superior to M2, M6: posterior MCA cortex superior to M3. M1 to M3 are assessed at the basal ganglia level, and M4 to M6 are assessed just above the basal ganglia. A normal CT scan would be scored 10, and an infarction of the entire MCA distribution would have a score of 0.
Thus, the peak period for detection of brain infarction by standard CT techniques is between the third and tenth days after stroke. However, small infarcts, particularly lacunes and brainstem infarcts, may not be visible on CT scan even after an appropriate delay. After the third week, phagocytosis of affected tissue ensues, the infarcted area gradually becomes replaced by cystic spaces filled with fluid, and the CT scan again shows a smaller and better defined area of hypodensity with sharply demarcated margins of the infarct. In this phase, the density of the affected area is closely matched to the density of cerebrospinal fluid (CSF).
The combination of a hyperdense zone and adjacent hypodense white matter is characteristic of a hemorrhagic infarction, which more commonly occurs
in embolic arterial occlusions and usually involves the cerebral cortex with sparing of the subcortical white matter. The hyperdense hemorrhagic portion usually appears smaller than a hypodense component representing the infarct, and this hemorrhage is usually absorbed within 3 weeks. CT findings in patients with hypertensive encephalopathy usually include signs of generalized cerebral edema and mass effect, including compression of lateral ventricles, basal cisterns, and cortical sulcal spaces.
in embolic arterial occlusions and usually involves the cerebral cortex with sparing of the subcortical white matter. The hyperdense hemorrhagic portion usually appears smaller than a hypodense component representing the infarct, and this hemorrhage is usually absorbed within 3 weeks. CT findings in patients with hypertensive encephalopathy usually include signs of generalized cerebral edema and mass effect, including compression of lateral ventricles, basal cisterns, and cortical sulcal spaces.
Under normal circumstances, contrast agents do not enter the brain, but if the blood-brain barrier is disrupted by a stroke, tumor, abscess, or other process, then contrast material leaks into that area and produces better visualization (enhancement). Therefore, the use of a contrast agent (usually iodinated, water-soluble contrast medium administered intravenously) allows visualization of a small percentage of otherwise isodense and undetectable infarcts, particularly in the second to fourth weeks after stroke, when the fogging effect is present. After 1 month, the area of infarction typically will not enhance with administration of the contrast medium. Other indications for contrast administration are suspected AVM, intracranial tumor, and intracerebral abscess. Contrast agents (particularly in high doses) may also have neurotoxic effects and cause clinical deterioration. MRI has lessened the need for CT scans with contrast agents, but the technique may still be of use in patients who cannot undergo MRI.
CT perfusion (CTP) is used to assess the blood flow to the brain and is commonly used in emergency settings in combination with CT angiography (CTA; summarized below). CTP may clarify brain tissue that is potentially still salvageable (ischemic penumbra) as opposed to tissue that is irreparably damaged (infarct core). Three CTP parameters used to clarify these areas include mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV). An area of infarcted tissue will have significantly reduced CBF and CBV and prolonged MTT. The ischemic penumbra will also have a prolonged MTT but only moderately reduced CBF and near normal or increased CBV. Automated processes are commonly used to define the infarct core and ischemic penumbra providing rapidly available information in the emergency setting.
In patients with venous infarction caused by venous sinus or cortical venous thrombosis, CT of the head usually reveals extensive areas of edema with patchy contrast enhancement and multiple small hemorrhages. In the case of sagittal sinus thrombosis, changes tend to occur in a bilateral parasagittal pattern. Areas of lobar hemorrhage of otherwise unclear cause or of infarctions that cross arterial territories with or without a hemorrhagic component increase the likelihood of an underlying venous etiology.
CT Findings in Patients with Hemorrhagic Lesions
Immediately after a person has had a hemorrhagic stroke, CT detects freshly extravasated blood (areas of increased density) in virtually all cases of intracerebral hemorrhage and in 80% to 90% of patients with subarachnoid hemorrhage (small amounts of subarachnoid blood may not be detected). Characteristic CT findings in patients with acute intracerebral hematoma (the first few days after ictus) include a well-defined, homogeneous, hyperdense mass lesion of a rounded, oval, or more irregular shape. The initial hyperdensity of the hematoma then begins to decline. The average lesion decreases in density by 1.4 Hounsfield units per day as a result of hemoglobin breakdown, progressing through an isodense (subacute) phase to a hypodense (chronic) phase. Therefore, the differentiation between infarction and intracerebral hematoma is readily made by CT at any time
within the first 7 to 10 days after stroke (or as long as 3-4 weeks with large hematomas, in which disappearance of the hyperdensity is slower). In the chronic phase, a hematoma is often reduced to a slit-like cavity (with attenuation values similar to those of CSF) or may even disappear. Subarachnoid hemorrhage is even more transient, and CSF examination should be considered within 1 day to as long as 6 weeks after the ictus when the clinical history suggests this diagnosis and the CT scan is negative. In patients with intraventricular hemorrhage, CT demonstrates a hyperdense cast outlining the ventricular system.
within the first 7 to 10 days after stroke (or as long as 3-4 weeks with large hematomas, in which disappearance of the hyperdensity is slower). In the chronic phase, a hematoma is often reduced to a slit-like cavity (with attenuation values similar to those of CSF) or may even disappear. Subarachnoid hemorrhage is even more transient, and CSF examination should be considered within 1 day to as long as 6 weeks after the ictus when the clinical history suggests this diagnosis and the CT scan is negative. In patients with intraventricular hemorrhage, CT demonstrates a hyperdense cast outlining the ventricular system.
Administration of an intravenous (IV) contrast agent is usually unnecessary in the early stages of intracerebral hemorrhage, and no significant changes are shown on the CT in the first 7 to 10 days. However, a contrast CT (or MRI study) is required when the plain CT scan shows white matter abnormalities around the acute hematoma or abnormal densities adjacent to or surrounding the hematoma, because these findings may indicate possible underlying AVM, aneurysm, tumor, or abscess. Often, contrast CT or MRI is either delayed or repeated a few weeks after the acute hemorrhage to provide a better chance for visualizing possible underlying lesions.
Epidural hematomas appear on CT as biconvex to lenticular, hyperdense, homogeneous extracerebral zones adjacent to the inner table of the skull with sharp margins. In cases of subacute epidural hematoma, CT usually shows a biconvex mixed-density lesion (the detached dura can often be seen on plain CT or on contrast CT as a thin, hyperdense stripe between the hematoma and the brain). In patients with acute subdural hematoma, the CT scan shows hyperdense, homogeneous, crescent-shaped lesions located between the calvarium and the underlying cortex, often accompanied by marked ipsilateral edema and mass effect. Chronic subdural hematoma usually appears as a hypodense, crescent-shaped, extracerebral lesion that is characteristically surrounded by a well-defined capsule.
Computed Tomography Angiography
Noninvasive real-time modalities such as CTA (including four-dimensional and three-dimensional CTA) using spiral CT scanners are increasingly replacing conventional cerebral arteriography in the evaluation of craniocervical arterial lesions such as carotid artery stenosis and intracranial aneurysms. Compared with magnetic resonance angiography (MRA), which is discussed in the next section, CTA may be less costly, may require less physician supervision, provides faster patient throughput, and is better tolerated by claustrophobic patients. CTA does utilize some ionizing radiation and requires contrast doses associated with slightly higher complication rates. However, the risk of contrast nephropathy is very low, and the overall risk of renal compromise from CTA may not be higher than in patients with acute stroke who do not receive contrast. CTA is increasingly performed in the emergency setting following acute ischemic stroke to evaluate the large arteries and contribute to early management decisions.
The major venous sinuses are well visualized on CT venography (CTV), providing a rapid, readily available initial assessment option. CTV has high sensitivity for thrombosis of a major venous sinus, similar to magnetic resonance venography (MRV).
MAGNETIC RESONANCE IMAGING
For MRI, the patient is placed within a uniform, powerful magnetic field. The procedure is based on the resultant interaction within body tissues between pulsed magnetic waves and nuclei of interest. Hydrogen nuclei (such as those in water)
absorb energy and are deflected from their alignment. As the nuclei return from a stage of excitation to their rest state, a signal is induced in a receiver, which converts it into a diagnostic image. During the process of energy release en route to tissue relaxation, two tissue-specific relaxation constants (T1, longitudinal or spin-lattice relaxation time, and T2, transverse or spin-spin relaxation time) can be used to reconstruct T1-weighted images, in which CSF has decreased signal intensity relative to the brain and fat has increased signal (ventricles appear dark, and gray matter is darker than white matter), and T2-weighted images, in which CSF has increased signal intensity relative to the brain (ventricles appear white, and gray matter is lighter than white matter) (Fig. 7-3).
absorb energy and are deflected from their alignment. As the nuclei return from a stage of excitation to their rest state, a signal is induced in a receiver, which converts it into a diagnostic image. During the process of energy release en route to tissue relaxation, two tissue-specific relaxation constants (T1, longitudinal or spin-lattice relaxation time, and T2, transverse or spin-spin relaxation time) can be used to reconstruct T1-weighted images, in which CSF has decreased signal intensity relative to the brain and fat has increased signal (ventricles appear dark, and gray matter is darker than white matter), and T2-weighted images, in which CSF has increased signal intensity relative to the brain (ventricles appear white, and gray matter is lighter than white matter) (Fig. 7-3).
Disease processes such as edema, ischemia, hemorrhage, tumor, abscess, and demyelination typically cause an increase in free water concentration and hence an increase in the observed T1 and T2 relaxation times. An MRI scan can be obtained to accentuate either the T1 or the T2 characteristics of the tissue. The T1 and T2 signal characteristics of cerebral infarction and cerebral hemorrhage are outlined in Table 7-2, and a cerebral infarction is shown in Figure 7-4.
MRI produces images that generally are more detailed than those of CT and that provide more information about tissue characteristics. In many cases of stroke, this technique is not superior to CT, but MRI does have some advantages over CT: (1) any plane can be selected (coronal, sagittal, and oblique), (2) there is no ionizing radiation, (3) it is more sensitive to tissue changes (small infarcts may be detected earlier, within the first few hours, and more precisely), (4) cavernous
malformations or small AVMs may be more easily visible, (5) there are no bone-related artifacts to obscure small infarctions in the vertebrobasilar system and infarcts near the skull base, (6) iodinated contrast agents are not required (paramagnetic contrast agents such as gadolinium allow differentiation of new strokes from old ones on the basis of their enhancement), (7) cerebral infarction may be differentiated from cerebral hemorrhage even after several weeks have passed, and (8) T2-weighted gradient echo and susceptibility-weighted MRI sequences are very sensitive to the presence of hemorrhage, including previous small intracerebral hemorrhages.
malformations or small AVMs may be more easily visible, (5) there are no bone-related artifacts to obscure small infarctions in the vertebrobasilar system and infarcts near the skull base, (6) iodinated contrast agents are not required (paramagnetic contrast agents such as gadolinium allow differentiation of new strokes from old ones on the basis of their enhancement), (7) cerebral infarction may be differentiated from cerebral hemorrhage even after several weeks have passed, and (8) T2-weighted gradient echo and susceptibility-weighted MRI sequences are very sensitive to the presence of hemorrhage, including previous small intracerebral hemorrhages.
 FIGURE 7-3. Normal magnetic resonance imaging (MRI) head scans. |
TABLE 7-2 Major MRI Signal Characteristics of Cerebral Infarction and Cerebral Hemorrhage | ||||||||||||||||||||||||||||||||||
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 FIGURE 7-4. Magnetic resonance imaging head scan 72 hours after onset of symptoms: area of increased T2 signal in anterior temporal region consistent with cerebral infarction. |
The major disadvantages of MRI compared with CT are that (1) slice thickness is limited (3 mm wide), (2) bone imaging is limited to the display of marrow, (3) scanning time is relatively long, (4) claustrophobia occurs in approximately 10% of patients, (5) some patients do not fit into the machine, and (6) MRI cannot be done if a patient has a pacemaker and is pacemaker dependent, or other ferromagnetic materials such as shrapnel or certain surgical clips are in the body. A gadolinium-related complication, nephrogenic systemic fibrosis, can occasionally occur in patients with moderate or severe kidney failure who receive gadolinium. The disorder can lead to thickening and darkening of the skin; fibrosis of the heart, kidneys, and lungs; and shortening of the tendons and muscles.
Since the initial investigations into the use of MRI techniques to demonstrate vascular structures in the mid-1980s, MRA has become available on a widespread basis. MRA is a subtype of MRI that can noninvasively visualize extracranial and intracranial arterial and venous circulations. Major advantages over standard x-ray arteriography include imaging without administration of potentially toxic contrast media and without the risks associated with arterial puncture and catheterization. The technique is especially useful for the noninvasive identification of intracranial aneurysms (a three-dimensional image that can be rotated through 360 degrees may be obtained, a feature that is helpful for differentiating arterial loops from aneurysms). MRA also enables identification
of increased intracranial vascularity that may occur with AVMs. However, MRA does not clearly distinguish high-grade cervical vessel stenosis from occlusion; may tend to overestimate the degree of carotid arterial stenosis; cannot clearly detect intimal irregularities; does not provide sequential information on the filling of the cerebral circulation; and generally has limited use in the evaluation of distal intracranial vessels. Overall, for evaluating extracranial carotid arteries, the ability of MRA to detect carotid arterial stenosis is similar to that of color duplex ultrasonography. The sensitivity and the specificity of MRA for the detection of hemodynamically significant stenoses in the vertebrobasilar system are also excellent. Carotid artery atherosclerotic plaques may also be assessed with MRI for findings that may potentially predict a higher risk of future stroke beyond the degree of stenosis, including the presence of lipid-rich necrotic core, intraplaque hemorrhage, and thinning and rupture of fibrous cap.
of increased intracranial vascularity that may occur with AVMs. However, MRA does not clearly distinguish high-grade cervical vessel stenosis from occlusion; may tend to overestimate the degree of carotid arterial stenosis; cannot clearly detect intimal irregularities; does not provide sequential information on the filling of the cerebral circulation; and generally has limited use in the evaluation of distal intracranial vessels. Overall, for evaluating extracranial carotid arteries, the ability of MRA to detect carotid arterial stenosis is similar to that of color duplex ultrasonography. The sensitivity and the specificity of MRA for the detection of hemodynamically significant stenoses in the vertebrobasilar system are also excellent. Carotid artery atherosclerotic plaques may also be assessed with MRI for findings that may potentially predict a higher risk of future stroke beyond the degree of stenosis, including the presence of lipid-rich necrotic core, intraplaque hemorrhage, and thinning and rupture of fibrous cap.
The intracranial arterial wall may be directly visualized with high-resolution intracranial vessel wall imaging. This technique may be useful in combination with standard MRA in differentiating between atherosclerosis, vasculitis, reversible cerebral vasoconstriction syndrome, dissection, and other causes of intracranial arterial stenosis. Findings in the setting of atherosclerosis include arterial wall thickening with eccentric (nonuniform) involvement and plaque enhancement, whereas findings in vasculitis include a more uniform circumferential arterial wall thickening and enhancement. In reversible cerebral vasoconstriction syndrome, although arterial wall thickening may be present akin to the findings in vasculitis, there is typically no or minimal arterial wall enhancement. An intimal flap or luminal enhancement is seen on vessel wall imaging in nearly half of those with dissection, with intramural hematoma noted in most patients.
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