Ischemic stroke is the third leading cause of death in the Western world. Many stroke survivors remain profoundly disabled.¹ Prospective, randomized studies have demonstrated that thrombolysis reduces the risk of permanent disability in selected patients if it is administered within three to six hours after symptomatic onset.^2-4 This treatment, however, is successful only if large areas of brain tissue are not already irreversibly damaged. Application of a thrombolytic agent such as alteplase could lead to intracranial hemorrhage in the area of infarction, worsening rather than improving patient prognosis.⁵

If a major cerebral artery is occluded, collateral flow via leptomeningeal arteries is often adequate to maintain reduced perfusion. While not sufficient for neuronal cell function, this can ensure the survival of neurons for a limited time. This area of reduced perfusion is called the "ischemic penumbra" or "tissue at risk."^6,7 Early reperfusion often leads to complete recovery of this tissue. Consequently, diagnostic imaging should identify the size of infarction, the extent of tissue at risk, and the status of major arteries supplying the brain.⁸

Although a combination of diffusion-weighted MRI, MR perfusion, and MR angiography (MRA) can provide this information,⁹ many institutions have no access to MRI for emergency situations. The findings of most large prospective studies have been based on unenhanced CT. This modality detects hemorrhage reliably, although early identification of infarction is often impossible within the first two hours. Experienced investigators can see early signs of infarction, such as subtle swelling and hypodensities, after this time.^10,11 Detecting these signs can be difficult, however, and dependent on investigator experience.¹² A more reliable method of describing the extent of infarction is therefore desirable.

Introduction of spiral CT has led to the development of CT angiography (CTA) and CT perfusion (CTP), two methods now widely accepted in clinical practice. CTA demonstrates relevant stenosis and occlusion of major intracerebral and extracranial carotid arteries reliably.^13-16 Multislice CT (MSCT) makes it possible to investigate the carotid and intracranial arteries in one session. CTP studies discriminate between brain tissue that is already irreversibly damaged and tissue at risk.^17-19 The method is restricted to the acquisition of a small section of 1 or 2 cm, which is sufficient for the evaluation of a large territorial stroke.

The MSCT stroke protocol consists of three steps. We have opted for a fast combination of unenhanced CT, CTP, and CTA on a four-slice scanner (Somatom Volume Zoom, Siemens Medical Solutions). An 18-gauge catheter is placed within the patient's right cubital vein after the patient has been positioned inside the scanner. Meanwhile, 150 mL of nonionic contrast (Ultravist 300, Schering) is prepared in a power injector. Unenhanced CT is performed first to exclude hemorrhage and detect early signs of infarction. The gantry is tilted parallel to the orbitomeatal line, with a slice thickness of 4 mm for the posterior fossa and 8 mm for the supratentorial region.

CTP is performed within the area that clinical investigation has identified as most likely to be affected. The scan section is usually placed in the basal ganglia area if symptoms indicate occlusion of a middle cerebral artery (MCA). A 40-mL dose of contrast is then injected at 8 mL/sec. We use a 20-gauge needle and flow rate of 5 mL/sec whenever placement of an 18-gauge needle is impossible. This will lead to underestimation of absolute cerebral blood flow (CBF) values, but it allows recognition of nonperfused brain tissue and evaluation of values of CBF relative to the opposite hemisphere.

The MSCT scanner allows acquisition of two 1-cm-thick sections every second for 40 seconds. Acquisition parameters are set to 80 kVp and 187 mAs. CTA is then begun immediately, covering the area from the fifth cervical vertebral body to the vertex with acquisition parameters of 120 kVp and 200 mAs (slice collimation 4 x 1 mm, table feed 5.5 cm per rotation). A bolus tracking function is used for timing once a region of interest has been identified in the common carotid artery. An additional 100 mL of contrast is then injected at 4 mL/sec.

Reconstruction is carried out using overlapping 1.25-mm-thick slices with an increment of 0.7 mm. A 120-mm field-of-view is sufficient to cover all relevant arteries and also assures excellent in-plane resolution. We evaluate the CTP data using the scanner's postprocessing software during acquisition and reconstruction of CTA. Generation of color maps for time to peak (TTP), CBF, and cerebral blood volume (CBV) is followed by more detailed analysis if pathologic findings are present on the maps. Multiplanar reconstructions (MPR) and maximum intensity projections (MIP) from CTA data are used for evaluation and 3D visualization of the circle of Willis and carotid arteries.

Average time for data acquisition is approximately eight minutes. Patients can then leave the scanner. Reconstruction of the CTA and 3D visualization of the arteries requires another four minutes, so the entire investigation (including postprocessing) can be finalized in approximately 12 minutes. Complete information about early signs of stroke, brain perfusion, and the status of the major cerebral arteries is then available for initial analysis.

ROUTINE PRACTICE

This protocol has been used routinely since spring 2000 at the University of Erlangen-Nuremberg and has formed part of the evaluation for all patients with signs of acute ischemic stroke. More than 100 patients have been studied to date with no adverse effects related to contrast injection. All studies were of diagnostic quality, even those of uncooperative patients.

CTP and CTA are well known as adjuncts to unenhanced CT for investigating patients with ischemic stroke. Several studies have shown that CTP can differentiate between infarction and tissue at risk.²⁰ Assessment of the most important values of brain perfusion requires evaluation of each of the three color maps (TTP, CBF, and CBV). The TTP map shows the time needed for contrast enhancement to reach its maximum in a defined region and has high sensitivity for depiction of hemodynamic disturbances. CBF and CBV maps are more specific for the prediction of tissue outcome.

Several typical observations emerge when the CTP and CTA findings are combined. Prolongation of TTP without pathologic findings in CBF and CBV is often associated with high-grade stenosis of a major artery or even internal carotid artery (ICA) occlusion with cross-flow from the unaffected side. Prolongation of TTP with moderate decrease of CBF (>60%) but nearly normal values of CBV (>80%) is frequently consistent with occlusion of one branch of the MCA with the remaining branches not affected. Larger infarction is unlikely to occur under these circumstances. If both CBF and CBV decrease markedly (CBF 30% to 60%, CBV 60% to 80%), the occlusion of a major intracerebral artery is likely.

The level of CBF and CBV reduction is related to the amount of collateral flow via leptomeningeal arteries. If collateral flow is sufficient, brain tissue can recover even without reperfusion or survive for an undefined time. But the brain tissue will be irreversibly damaged if CBF and CBV decrease toward or reach their lower threshold (CBF <30%, CBV <40%).

The thresholds described above are valid for our particular CTP approach^17,19,21 but may vary for other approaches.22 Because many factors influence outcome, the thresholds should not be used as absolute, singular classification values, but as guidelines aiding the interpretation of CTP results.

Clinical case histories can illustrate the value of stroke protocols. In one case, a 55-year-old man was admitted to our hospital two hours after onset of right-sided hemiplegia and complete aphasia. Unenhanced CT (Figure 1) showed a hyperdense MCA sign known to indicate thrombosis.²³ Available information regarding clinical symptoms helped us recognize a slight swelling within the insular region. CTP revealed an area of severely reduced perfusion within the left frontotemporal and insular cortex (Figure 2). Further analysis of the affected area, compared with the same region on the opposite side, indicated relative values of 22% for CBF and 37% for CBV. These values are clearly below the thresholds for tissue survival, according to our protocol.¹⁹

A second area of disturbed perfusion was found in the posterior temporal MCA territory. Evaluation of this region showed slightly reduced CBF (87%) as compared with the right side. A normal CBV value indicated sufficient collateral flow for brain tissue survival. CTA showed an occluded distal MCA with thrombotic material within the proximal part of the artery. The temporal branch demonstrated patency (Figure 3A). Occlusion of the left ICA was also found (Figure 3C).

Unenhanced CT alone would have suggested that this patient should undergo systemic or intra-arterial thrombolysis. CTA showed the left ICA to be occluded, however, making intra-arterial thrombolysis unsuitable. The CTP maps indicated irreversible damage to the frontotemporal area but suggested that the temporoparietal area would survive even without reperfusion of the MCA. Follow-up CT examination 12 hours after onset of stroke confirmed this (Figure 4).

While the possible therapeutic options open to this patient might raise controversy, the case illustrates how CTP maps can help differentiate irreversibly damaged brain tissue and estimate the amount of tissue at risk. CTA provides additional important information about occlusion or stenosis of major vessels. As mentioned previously, complete occlusion of the right ICA made intra-arterial thrombolysis impossible in this patient. It can also be assumed that thrombosis of this artery caused his stroke.

Multislice CT enables the combination of unenhanced CT, CTP, and CTA to be performed within a reasonable time. Important information about hemorrhage, brain perfusion, and arteries supplying the brain is available in less than 15 minutes. Prospective studies must show how this information contributes to therapeutic decisions, such as patient selection for thrombolysis.

DR. TOMANDL is a staff neuroradiologist, PROF. DR. HUK is head of neuroradiology, DR. STEMPER is a neurology resident, and DR. FATEH-MOGHADAM is a staff internist in internal medicine, all at the University of Erlangen-Nuremberg, Germany. MR. KLOTZ is a senior scientist at Siemens Medical Solutions, Germany.

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