Dr. McKernan received her MD-PhD degree from the University of Texas Medical Branch, Galveston, in 1999. She is currently a Co-Chief Resident at Wake Forest University, Winston-Salem, NC, and plans to pursue a Fellowship in Magnetic Resonance or Body Imaging.

Stroke is a leading cause of permanent disability and death in the United States. Noncontrast computed tomography (CT) is the mainstay for imaging of acute stroke in the emergency setting, while more definitive characterization of stroke, often in the subacute stage, is achieved in a more limited fashion with magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography. However, the combination of noncontrast head CT, CT angiography, and the developing technique of first-pass CT perfusion imaging provides a rapid, well-tolerated and widely available means of characterizing acute stroke and selecting appropriate candidates for thrombolytic therapy.

Stroke is the leading cause of permanent disability and third leading cause of death in the United States. ¹ In the emergency setting, noncontrast computed tomography (CT) is the mainstay for imaging of acute stroke. The primary role of CT is to exclude both hemorrhagic infarct (an absolute contraindication to thrombolytic therapy) and tumor mimicking the symptoms of stroke. Noncontrast CT can often demonstrate areas of acute cerebral ischemia or infarction, manifested by regions of hypoattenuation, but these can be difficult to detect within the first few hours, ^2,3 making more precise localization and characterization of stroke difficult (Figure 1A).

Yet, the first few hours are precisely when such information is most critical, as current guidelines suggest initiating intravenous thrombolytic therapy within 3 hours of stroke onset, and intra-arterial thrombolytic agents within 6 hours; intra-arterial thrombolysis is most effective in patients with proximal large-vessel occlusions, making timely localization of the site of vessel occlusion a priority (Figure 1B). ^4-6 Diffusion-weighted magnetic resonance imaging (MRI) is a sensitive marker for acute cerebral ischemia and is used in acute and subacute stroke imaging, but this use is primarily restricted to academic centers. ⁷ The 24-hour-a-day availability of MRI remains very limited, particularly in community and general hospitals, where the majority of stroke patients initially seek medical care. ⁸ Furthermore, MRI is less sensitive than CT for acute hemorrhage, an absolute contraindication for the administration of thrombolytics. The ideal technology for imaging acute stroke would combine ready availability with the ability to provide timely anatomic and functional characterization of cerebral ischemia, allowing more accurate selection of candidates for intervention.

A three-tiered approach: CT imaging of acute stroke

A three-tiered approach to CT imaging of acute stroke incorporates noncontrast CT (NCCT) of the head, CT angiography (CTA) and CT perfusion imaging (CTP). CT angiography and CT perfusion imaging can be added to the standard noncontrast head CT protocol with little increase in scanning time (<10 to 15 minutes total scanner time), particularly with faster multi-detector CT scanners. ^8-10 The majority of stroke patients tolerate iodinated contrast material well, ¹¹ and experimental animal models have demonstrated the safety of iodinated contrast material in the setting of acute stroke. ¹² Furthermore, both CTA and CTP can be performed using single- and multichannel CT scanners widely available in the emergency setting, and commercially available processing software.

Imaging techniques

Table 1 summarizes techniques used in noncontrast CT, CTA, and CTP protocols. A more detailed description is included below.

Noncontrast head CT

Standard NCCT of the head can be performed using existing protocols. Briefly, with the patient in a headholder, 2.5- to 5-mm contiguous axial slices from the skull base to the vertex are obtained at approximately 120 kVp and 170 mA. After evaluating the scan at standard window width and level settings (eg, 90 HU, 40 HU), window width and level settings can also be narrowed (8 HU, 32 HU) to improve detection of regions of relative hypo-attenuation, which may correspond to acute infarct (Figure 2A). ²

CT angiography

After noncontrast CT, CTA of the vertebrobasilar system and circle of Willis is performed. The lateral scout image can be used to select a coverage area extending from the skull base to the suprasellar region.

Contrast-- 50 mL (370 to 400 mg I/mL) of nonionic iodinated contrast material is injected via power injector at 2.5 to 4 mL/sec via an 18- or 20-gauge antecubital intravenous line. ^8,13-14

Scan-- After a 20- to 25-second delay, the scan is initiated in the caudal-cranial direction. The remainder of the scanning protocol will be dictated by the limitations of the scanner--ie, single channel versus multidetector. Please refer to Table 1 for more precise specifications.

Postprocessing ­­ Postprocessing typically involves the creation of overlapping limited-volume maximum intensity projection (OLIVE MIP) reformats of the source data, which can often be performed by the technologist in a semiautomated fashion. ⁸ Such reformatted images significantly improve the sensitivity for arterial occlusion, particularly in the case of distal-branch occlusion. ⁹ They can be reviewed at an offline workstation with three-dimensional (3D) display capability, or can be sent to an integrated picture archiving and communications system (PACS) station for review alongside the NCCT. The source images can be reconstructed in 3-mm slices for qualitative estimates of whole brain perfusion (Figure 2B). ¹⁰

Dynamic CT perfusion

Dynamic CT perfusion images are generated by tracking over time the passage of a bolus of contrast material ("first pass") through the cerebral vasculature. Typically, the selected location contains all three vascular territories (anterior cerebral, middle cerebral, and posterior cerebral arteries), usually near the level of the basal ganglia. Alternately, an abnormality detected on NCCT can be used for localization.

Contrast ­­ 40 mL (370 mg I/mL) is administered at 4 to 5 mL/sec via an 18- or 20-gauge IV. ^8,15,16

Scan ­­ After a 5-second scan delay, the scan is initiated in cine mode (typically 1 image/sec) at 80 kVp, 200 mA. A low-voltage protocol has the effect of increasing relative enhancement (due to dependence on iodine) and decreasing patient radiation exposure. On a standard helical CT scanner, one 10-mm slice can be evaluated; multidetector scanners allow greater coverage and the ability to obtain multiple slices. ¹⁰ To reduce lens irradiation, most institutions select a level or scan angle that avoids direct irradiation of the eye.

Postprocessing ­­ The collected data are either processed directly on the scanner or transferred to an offline workstation. The majority of commercially available software packages use a complicated mathematical model known as deconvolution analysis to map multiple parameters, including cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). The deconvolution model has the advantage of allowing for lower (3 to 6 mL/sec), and more clinically acceptable, injection rates than does an alternative, the maximum slope model (injection rates, 10 to 20 mL/sec). ¹⁷ Typically, the operator is required to manually select arterial and venous regions of interest (ROIs) as input functions for the analysis (Figure 3A). The unaffected anterior cerebral artery, middle cerebral artery (MCA), and superior sagittal sinus are often used as reference vessels for the ROIs. ¹⁰ The first pass of contrast material is tracked from the arterial to venous side of the circulation (Figure 3B).

The analysis yields several measurements. Cerebral blood flow is the volume flow rate of the blood through the cerebral vasculature per unit time (normal: 50 to 60 mL/100 g/min). Cerebral blood volume (CBV) is the amount of blood in a given amount of tissue at any given time (normal: 4 mL/100 g of tissue). Finally, mean transit time (MTT) is the average time it takes for blood to travel from the arterial to the venous side of the brain circulation; it is also a factor of CBV and CBF (normal: 5 seconds) [above characterizations of CBF, CBV and MTT adapted from Ortiz and Mueller, 2002]. ¹⁷ These parameters are mapped on a color-coded composite image (Figures 3C and D), enabling qualitative and quantitative evaluation of decreased perfusion.

A reduction in CBF of greater than 34% relative to the unaffected hemisphere ¹⁸ or an absolute CBF value of <13 mL/100g/min ¹⁹ have been shown to be markers for severe acute cerebral ischemia, likely to progress to infarct in the absence of thrombolytic intervention. Nonviable or infarcted tissue, which is unlikely to respond to intervention and is, indeed, at high risk for reperfusion injury, may be categorized by CBV; a CBV below 1.5 to 2.5 mL/100 g appears to be related to irreversible infarct. ^10,18 The difference between the regions of severe ischemia and irreversible infarct represents the ischemic penumbra, or the tissue that may be salvageable with therapeutic intervention. Prolongation of mean transit time (MTT) also occurs with cerebral ischemia, with a threshold value of >6 seconds. ¹⁰ While MTT is one of the most qualitatively sensitive markers of cerebral ischemia, its quantitative use is limited primarily to the calculation of CBF (CBF = CBV/MTT). ^8,18

The source images from the CTA can also be reconstructed in 3-mm slices to yield perfused blood volume estimates. ^10,14 These images highlight hypoperfused tissue as regions of decreased enhancement; the presence of a hypodense lesion on the CTA source images correlates strongly with irreversible infarct, even in conjunction with a normal NCCT. ²⁰ Unenhanced images can be subtracted from the CTA source images to yield "perfused blood volume maps." ¹⁰ This protocol obviates a second contrast bolus and shortens the total scan time, both of which may be important considerations in this patient population. However, it cannot provide the qualitative measurements of CBV and MTT that are provided by first-pass CT perfusion.

Validation of CTA and CTP

Experimental models and clinical studies

Experimental animal models of CT perfusion have provided some direct validation of the ability of CT perfusion to accurately predict the final extent of cerebral infarct. Hamberg et al used a primate stroke model to demonstrate that CBV or CBF functional maps obtained as soon as 30 minutes after balloon occlusion of the MCA correlated strongly with final infarct size. ²¹

The combination of CTA and CTP was shown in one study to improve the accuracy of diagnosing cerebral ischemia when compared with a combination of noncontrast CT and clinical examination, particularly in localizing the stroke (40% improvement) and the site of vascular occlusion (38% improvement). ⁹ CT perfusion accurately predicts the final infarct size, ²⁰ has been used in the acute setting to estimate the extent of the penumbra, ¹⁵ and correlates strongly with clinical outcome. ^15,20 The accuracy of CT perfusion for detecting acute infarct has also been validated against a number of other imaging modalities, including diffusion MRI ^14,15,18 and xenon CT. ²²

Limitations of CTA and CTP

The most important shortcoming of CT perfusion is the limited anatomic coverage necessitated by the demands of dynamic data acquisition. A scan limited to 1 or 2 slices may miss an area of perfusion abnormality, particularly when a normal noncontrast CT precludes a more specific slice selection. ¹⁰ As multidetector CT technology continues to develop, this limitation is likely to become a less important consideration, as significantly increased scan speeds on 16- and 32-channel scanners will allow the acquisition of data from a larger volume of brain without a loss of temporal resolution. Roberts et al ²³ have suggested a modification of the CTP technique (using a
4-channel multidetector CT), to incorporate a "toggling-table" approach. Briefly, the use of alternating table positions enables acquisition of 2 different sets of CT perfusion images, each consisting of 2 1-cm slices. Total coverage is increased to 4 cm, double that of a conventional technique. Another option is to repeat the CT perfusion protocol at 2 anatomic locations, the additional location typically being superior to the first. ²⁴ However, this has the disadvantage of increasing contrast dose and radiation exposure, as well as requiring substantially more postprocessing. Finally, the CTA source images can be used to generate a whole-brain perfusion map, as previously described. ^10,14 However, these generate only CBV data by extrapolation of density change in a reference vessel, and are not as sensitive for quantitative measurement of perfusion. ²³

CTA, CTP, and thrombolytic therapy

One of the areas of greatest promise for CTA and CTP is in the selection of appropriate candidates for thrombolytic therapy. The benefit is twofold: CT angiography enables more accurate localization of arterial occlusion, while perfusion data enables risk stratification and prediction of treatment outcome.

CT angiography demonstrates good agreement with catheter angiography for large-vessel occlusion. ^13,25,26 Accurate localization and confirmation of vessel occlusion has important implications for therapy; in the Prourokinase in Acute Cerebral Thromboembolism (PROACT) trial, 62% of patients triaged to catheter angiography because of strong clinical suggestion of proximal MCA occlusion did not demonstrate such an occlusion on angiography, and were excluded from treatment. ²⁷ Clearly, a minimally invasive, rapid screening technique such as CTA has the potential to prevent patients from undergoing unnecessary invasive procedures.

The potential benefits of thrombolytic therapy--chiefly, the prevention of incapacitating disability--must always be weighed against the risk of intracranial hemorrhage arising from the reperfusion of irreversibly infarcted tissue. ^6,13 The practice of initiating thrombolytic therapy within 6 hours of symptom onset is intended to exclude patients in whom the ischemic penumbra has, in the face of ongoing hypoperfusion, progressed to infarction. With perfusion CT, however, CBF can be calculated directly and used to select appropriate candidates for thrombolytic therapy. It has been suggested that the ideal target for intervention is tissue with a CBF of 8 to 25 mL/100g/min. ¹⁶ Direct measurement of CBF may exclude some patients who seek medical attention within 6 hours, as well as include some whose symptoms are of longer standing, providing a more rational basis for risk stratification. Some initial reports suggest that CTA and CTP may also be useful immediately after intervention, as a tool for assessing recanalization of the involved vessel. ²⁸

Imaging of acute stroke: CT versus MR

Definitive imaging of acute ischemic stroke has focused largely on diffusion-weighted magnetic resonance imaging (DW-MRI), which relies on the phenomenon of restricted diffusion of water in areas of cerebral infarction, likely resulting from cytotoxic edema. ⁷ Diffusion-weighted MRI accurately reflects the extent of cerebral infarction within the first few hours of clinical stroke (Figure 4). ¹⁶ Furthermore, whole-brain MR perfusion imaging can be used to generate cerebral blood flow (CBF) maps. The mismatch between perfusion and diffusion defects has been used to characterize the ischemic penumbra. ⁷

However, a number of recent studies have demonstrated that a combination of noncontrast CT, CTA, and CTP enable comparable characterization of acute stroke as that achieved by MRI. Accurate identification of the ischemic penumbra ¹⁸ and assessment of lesion volume ¹⁴ did not differ between the two modalities. Furthermore, CT perfusion has the potential to more accurately quantify cerebral blood flow, because unlike MRI, it is characterized by a linear relationship between attenuation change and contrast dye concentration, and CT demonstrates better spatial resolution. ²⁹ The main advantage of MR perfusion imaging is its ability to evaluate the entire brain, instead of being constrained to a more limited anatomic area.

However, there are additional considerations beyond these technical factors. The majority of patients with acute stroke receive treatment at a local or small regional hospital, not at a large academic center. Handschu et al ³⁰ reported that of 103 patients admitted to a general hospital for acute stroke, only one-third underwent brain imaging and only one underwent MRI. MRI continues to have limited availability, particularly in the emergency setting, and the majority of stroke patients are initially admitted to hospitals without MR scanners. ¹⁴ CT is much more widely accessible, and is already being used in the majority of patients imaged for acute stroke to exclude intracranial hemorrhage; thus, a framework is already in place for the widespread utilization of CTA and CTP. Its potential to more rationally select candidates for thrombolytic therapy suggests it may also play a role in broadening the use of interventional therapy for acute ischemia.

PET and SPECT

Positron emission tomography (PET) performed with ¹⁵ O- or ¹⁸ F-labeled ligands is considered the gold standard for absolute brain perfusion, and was used to generate normal and ischemic threshold values for cerebral blood flow. ^31,32 However, the short half-life of these agents essentially necessitates an on-site cyclotron and markedly limits the availability of PET for perfusion imaging. Single-photon emission computed tomography (SPECT) is much more widely available and can be performed in a somewhat timely fashion in centers with adequate nuclear medicine departments. Multiple studies have demonstrated the ability of SPECT to measure relative cerebral blood flow and to predict clinical outcome in patients with acute stroke. ^33-35 However, SPECT is unable to identify intracranial hemorrhage or definitively localize the site of a large-vessel occlusion, and its spatial resolution is much poorer than that of CT and MR. Thus, while SPECT might be able to provide perfusion data, noncontrast CT and CTA would still be required for full characterization of acute stroke. Given this, it is much more time- and cost-efficient to perform an exam that combines NCCT, CTA, and CTP, rather than separate nuclear medicine and CT studies.

Conclusion

There are only a few hours during which thrombolytic therapy may be used in the treatment of acute cerebral ischemia. The combination of noncontrast head CT, CT angiography, and dynamic CT perfusion provides a rapid, well-tolerated, and widely available means of characterizing acute stroke and selecting appropriate candidates for intervention. No other single imaging modality, whether MRI, PET, or SPECT, matches the widespread availability and diagnostic capacity of CT. CT truly comes closest to providing "one-stop shopping" in the imaging of acute stroke.

Acknowledgments

The author thanks Michael Lev, MD, for providing many of the images used in this paper and Jonathan Burdette, MD, for assistance with the manuscript.