Applied Radiology

Dr. Ueda is the Director of the Division of Neuroendovascular Therapy in the Department of Neurosurgery, Ehime University School of Medicine, Ehime, Japan. Dr. Yuh is Professor and Chairman of and Dr. Sonnad is an Assistant Professor in the Department of Radiological Sciences, Oklahoma University Health Science Center, Oklahoma City, OK.

With the recent advances in and increasing availability of new imaging techniques and therapies, stroke victims now have a realistic opportunity for recovery. The role of stroke imaging has, therefore, broadened from its traditional role of diagnosing acute stroke to that of directing the emergency treatment plan for optimal outcome following stroke. In order to optimize this outcome, at least five important sequential stages of evaluation must be considered in the treatment plan for the emergency management of acute ischemic stroke. These are: 1) confirmation and delineation of ischemia; 2) prediction of prognosis for untreated ischemia; 3) evaluation of viability and possible reversibility of injury to ischemic tissue; 4) prediction of treatment outcome; and 5) selection of treatment (risk versus benefit). Although imaging has already had an important role in the first two of these stages, its current role has expanded to include the remaining three stages of the treatment plan.

Despite some exciting reports of the use of these new imaging techniques in the management of stroke, some controversy still remains. This is, in part, due to several reports that were based upon results from a relatively small and untreated patient population in which recanalization did not occur. ^1-3 In addition, there is still a lack of communication between the basic and clinical scientists with regard to: 1) the logistics and practicality of using these techniques in the emergency clinical setting; 2) the expanding role of stroke imaging; and 3) the dynamic nature of the underlying pathophysiology. This article attempts to clarify some of these issues.

Perfusion imaging in the management of acute stroke

Perfusion imaging is an effective technique for assessing the status of blood flow to ischemic tissue that will ultimately affect the viability of the tissue (live versus dead) and reversibility of the ischemia (penumbra) (stage 3). It can also assess what the ischemic outcome will be, with (stage 4) and without (stage 2) treatment (recanalization). This information is essential prior to selecting the appropriate treatment plan to optimize the treatment outcome (stage 5). Perfusion imaging techniques based upon single-photon emission computed tomography (SPECT), computed tomography (CT), and magnetic resonance (MR) are available readily and can be performed promptly, both of which are critical elements for the success of emergency treatment of acute stroke. SPECT is already established as an excellent modality for the confirmation or delineation of acute ischemic stroke (stage 1) and prediction of prognosis in untreated patients (stage 2). ^1,2,4-11 In patients with spontaneous reperfusion ^2,12 or successful recanalization, it can show evidence of improved perfusion status of the ischemic tissue. Furthermore, perfusion imaging has great potential for assessing tissue viability and possible reversibility of ischemia prior to treatment ¹³ (stages 3, 4, and 5), as well as for assessing the status of tissue reperfusion after recanalization. ^11,13 Both correlate with clinical outcome.

Stage 1: Confirmation and delineation

Perfusion imaging using ^99m Tc-HMPAO SPECT can detect hypoperfusion of ischemic tissue soon after onset of an occlusion due to changes in cerebral blood flow (CBF). ^1,3-8,14-16 Perfusion imaging can demonstrate abnormalities prior to their being seen on CT and MR images using diffusion-weighted imaging (DWI), fluid-attenuated inversion recovery (FLAIR), or T2-weighted sequences. ^17-19 Because perfusion imaging, using this technique, reflects the parenchymal uptake of tracer kinetics, an area of ischemic tissue supplied by a major blood vessel is appreciated much more readily than those supplied by smaller terminal branches, such as those in the deep white matter, watershed territories, and brainstem. In contrast, small-vessel ischemia is seen more readily on DWI than on perfusion imaging, despite the onset of abnormalities occurring several hours later on the former.

Stage 2: Prediction of prognosis in untreated patients

On studies using ^99m Tc-HMPAO SPECT imaging, findings correlated with the severity of neurological deficit, infarction size, or clinical outcome in untreated patients who had no evidence of recanalization. ^1,2,8-11,16 Early severe hypoperfusion was seen by SPECT within 6 hours of onset of symptoms and was highly predictive (92%) of poor neurological outcome. ^8,9 SPECT, performed within 72 hours of stroke onset, was shown to be superior to neurological deficit scores in predicting short-term outcome of ischemic stroke and was also better than SPECT studies performed later during the first week. ⁷ A strong correlation between the infarct size predicted by SPECT and that measured by CT scans has also been reported. ¹⁰

Stage 3: Evaluate viability and reversibility of ischemic tissue

Prediction of tissue viability and reversibility can be adequately assessed only when studies are performed on a patient population that has proven early and successful recanalization. When early, successful reperfusion occurs, the nonviable (dead tissue) and reversible ischemic tissues can be recognized on posttreatment MR/CT by the presence of hemorrhage (dead tissue) and absence of infarction (recovery), respectively, when compared with the pretreatment perfusion image and posttreatment CT/MR. Based upon a series of 42 lesions in 30 patients who underwent successful intra-arterial (IA) recanalization within 12 hours of onset of symptoms, Ueda et al, ¹³ using SPECT imaging, reported that the CBF thresholds for ischemic viability and reversibility are approximately 35% and 55% compared with the ipsilateral cerebellar hemisphere (figure 1). The treatment outcome is independent of the duration of the ischemia but correlates significantly with the CBF threshold of viability and reversibility. In another study that evaluated MR perfusion images in untreated patients, the same authors found the CBF threshold for ischemic viability was approximately 39%, a similar result to the 35% found in their early report using SPECT in treated patients. ²⁰

Stage 4: Prediction of treatment outcome

Pretreatment perfusion imaging can predict the treatment outcome (reversible ischemia, infarction, and/or development of hemorrhage) in patients who have early and successful recanalization. The treatment outcome following IA recanalization correlates with the residual CBF estimated by the pretreatment perfusion image. ¹³ The duration of ischemia, location of the occlusion, sex of the patient, and dosage of urokinase given does not significantly influence the treatment outcome. In a study using intravenous (IV) thrombolysis, Grotta and Alexandrov ¹¹ reported that CBF estimated by SPECT perfusion imaging performed before and after IV recombinant tissue plasminogen activator (rt-PA) infusion correlated with both outcome and response to therapy.

Stage 5: Selection of treatment (risk versus benefit)

The therapeutic window for treatment of stroke is traditionally defined as 3 hours for IV rt-PA infusion or 6 hours for the IA thrombolysis. ²¹ However, we believe that the therapeutic window in which ischemic tissue is potentially salvageable is not a fixed time period but instead is likely dependent on the degree of collateral flow and metabolic status of the tissue and can be estimated by perfusion imaging. ^13,22,23 It is not the period of time since the event occurred, but the residual CBF demonstrated on the perfusion imaging that influences the treatment outcome. Unfortunately, recent clinical trials of thrombolytic therapy for acute ischemic stroke have not emphasized or even considered using a rapid assessment of the status of the collateral circulation and associated tissue viability and reversibility before giving treatment. There are few but convincing data that suggest that pretreatment perfusion imaging can assess each patient's therapeutic window and therefore have the potential to improve his or her eligibility for treatment and predict outcome. ^21,23

SPECT and thrombolytic therapy

SPECT imaging has advantages over other perfusion modalities in the evaluation of acute stroke in that it is both readily available and can be performed quickly in emergency cases. The fixation of HMPAO within 2 minutes of IV injection with minimal washout from the brain occurring permits scanning for up to 4 hours after injection. Moreover, SPECT scanning with triple-head cameras can be completed within 15 to 20 minutes. Several studies have reported the usefulness of SPECT in the diagnosis of acute ischemic stroke patients, demonstrating that the perfusion abnormality seen on SPECT images correlates with the extent of injury, its severity, and the short-term outcome in acute stroke patients.

Ueda et al ¹⁶ demonstrated that this modality can identify those patients who have a significant high risk of hemorrhagic transformation after successful IA thrombolysis. To do this they used a semiquantitative analysis of residual CBF in ischemic tissue that is quite simple, as well as rapidly obtained, does not need a special computer, and is available to any institution. The axial section that shows the ischemic region the most clearly is selected, then three regions are selected: (a) the ischemic region, (b) the corresponding region on the contralateral side, and (c) the whole cerebellar hemisphere on the ischemic side. The mean count is determined in each region of interest. The residual CBF is assessed by calculating two parameters: 1) ischemic regional activity/cerebellar activity (R/CE) ratio = a/c, and 2) asymmetry index = 1 + (b-a)/(a+b). Hemorrhagic transformation after successful IA thrombolysis occurred in all patients with R/CE ratios <0.35 and asymmetry index >1.5. ¹⁶

Recently, we investigated the ischemic outcome (reversible ischemia, infarction, and hemorrhage) and neurologic outcome of acute stroke treated with IA thrombolysis and the predictive value of SPECT. ¹³ Thirty patients who had complete recanalization by IA thrombolysis after pretreatment SPECT were analyzed retrospectively. Outcomes of patients with acute cerebral ischemia who had early and complete recanalization using IA thrombolytic therapy are significantly different and are influenced markedly by pretreatment CBF assessed by SPECT. Furthermore, CBF thresholds evaluated by SPECT provide important information that can be potentially useful in the management of acute stroke patients with IA thrombolysis (figure 1). Relevant factors include: 1) ischemic tissue with a flow index >0.55 may still be salvageable even if treatment is initiated 6 hours after onset of symptoms; 2) ischemic tissue with a flow index >0.35 may still be salvageable with early treatment (<5 hours); and 3) ischemic tissue with a flow index <0.35 may be at risk for hemorrhage even if treatment is started within the critical time window.

Representative cases

Case 1

A 33-year-old woman presented with sudden onset of complete right hemiparesis and total aphasia. CT showed no focal, low-density areas. SPECT shows left frontotemporoparietal perfusion deficit; the R/CE ratio was 0.51 (figure 2). Carotid angiography demonstrated complete occlusion of the proximal M1 segment of the left middle cerebral artery. Intra-arterial thrombolysis was performed 4 hours after the onset and complete recanalization was obtained with injection of 480,000 units urokinase. The neurological signs showed marked improvement, and a posttreatment CT scan showed no apparent infarction.

Case 2

A 48-year-old man presented with sudden onset of complete right hemiparesis and total aphasia. Computed tomography showed no low-density areas. SPECT revealed left frontotemporoparietal perfusion deficit and the R/CE ratio was 0.24 (figure 3) Carotid angiography demonstrated complete occlusion of the proximal M1 segment of the left middle cerebral artery. Although complete recanalization was obtained by IA thrombolysis, the neurological signs showed no improvement, and a CT scan after treatment demonstrated hemorrhagic transformation in the left basal ganglia.

Conclusion

Currently, there is no golden standard to identify the extent of ischemic tissue that is neither viable nor salvageable. However, perfusion imaging using modalities such as SPECT and MRI may have the potential for providing useful information that determines tissue viability and/or reversibility. SPECT may be potentially useful to improve patient selection for thrombolytic therapy, but a prospective study is needed to prove the efficacy of pretreatment SPECT in acute ischemic patients who undergo acute therapeutic interventions. AR