Single-Photon Emission Computed Tomography–Derived Relative Hypoperfusion Volume After Ischemic Stroke
To the Editor:
I read with interest the recent article by Barber and colleagues.1 In this report, repeated studies with 99Tc-hexamethylpropyleneamine oxime (99Tc-HMPAO) single-photon emission computed tomography (SPECT) were applied to 41 patients at acute, subacute, and/or chronic phases of their ischemic stroke. Barber and colleagues concluded that the benefit of spontaneous “reperfusion” after ischemic stroke was established and that SPECT-derived hypoperfusion volume carried a prognostic value. In addition, the authors proposed the use of 99Tc-HMPAO SPECT in screening and grouping patients in therapeutic trials on acute ischemic stroke. I would raise the following comments.
First, time is a critical factor in therapeutic trials on acute ischemic stroke, and symptomatic hemorrhagic transformation is the major complication of acute thrombolytic therapy.2 3 Before clinicians would consider SPECT in screening and grouping patients in therapeutic trials on acute ischemic stroke, we need to know the extra time required for performing SPECT and obtaining the relative hypoperfusion volume. In addition, SPECT studies may not identify patients at risk of symptomatic hemorrhagic transformation, because SPECT provides no information on the integrity of the blood-brain barrier and SPECT cannot delineate the infarcted core at the acute stage.
Second, SPECT-derived relative hypoperfusion volume at the acute, subacute, or chronic phase of ischemic stroke was found to be significantly correlated with clinical outcome measures and final infarct size.1 The significant association between the latter parameters and “early reperfusion” or “nutritional reperfusion” is not unexpected, because “early reperfusion” was defined as the difference in the SPECT-derived relative hypoperfusion volumes between the acute and subacute studies and because “nutritional reperfusion” was the difference between the acute and chronic SPECT studies. While I agree with the authors that SPECT-derived relative hypoperfusion volume at different times after stroke onset carries a prognostic value, the benefit of spontaneous “reperfusion” after ischemic stroke has not been established by the results of the study. Multivariate analysis may be useful in identifying independent predictors of the clinical and radiological outcome measures.
Third, I am concerned about the use of physiological terms such as “reperfusion,” “nutritional,” and “nonnutritional” in the article.1 Although SPECT can assess perfusion and predict prognosis for recovery,1 4 SPECT provides only a relative index of cerebral perfusion. The formula used in the paper for deriving the relative hypoperfusion volume introduces 2 factors other than the actual perfusion in the region of the infarct: the overall perfusion of the brain and the perfusion of the so-regarded normal brain tissue over the mirror-image region of the infarct.1 Table 1 of the article illustrates an inconsistent relationship between the SPECT-derived relative hypoperfusion volume detected at the chronic phase and the CT-derived final infarct size: the SPECT-derived volume can be quite similar to or may be much smaller or larger than the CT-derived volume.
Fourth, the timing of some of the acute SPECT studies was rather close to the 24-hour limit, whereas some of the subacute SPECT studies were done shortly after this time limit.1 Given the dramatic but variable changes in the SPECT-derived relative hypoperfusion volume over time, the acute studies should be performed within a short time after stroke onset, and the interval between the acute and subacute studies should be fairly constant.
Finally, 4 patterns of change in the SPECT-derived relative hypoperfusion volume were found by the authors.1 Early “reperfusion” followed by late “expansion” can be explained by the presence of mainly “nonnutritional reperfusion.” I wonder whether the authors can postulate any explanation for the very delayed “reperfusion” 24 hours after stroke onset that persisted into the chronic stable phase. Concerning the delayed “expansion” of the hypoperfusion volume between the subacute and chronic SPECT studies in the 4 patients, the explanations proposed by the authors failed to explain the clinical course, since the patients either remained stable or improved during this interval.
- Copyright © 1999 by American Heart Association
Barber PA, Davis SM, Infeld B, Baird AR, Donnan GA, Jolley D, Lichtenstein M. Spontaneous reperfusion after ischemic stroke is associated with improved outcome. Stroke.. 1998;29:2522–2528.
Adams HP Jr, Brott TG, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Kwiatkowski T, Lyden PD, Marler JR, Torner J, Feinberg W, Mayberg M, Thies W. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. Stroke.. 1996;27:1711–1718.
Alexandrov AV, Black SE, Ehrlich LE, Bladin CF, Smurawska LT, Pirisi A, Caldwell CB. Simple visual analysis of brain perfusion on HMPAO SPECT predicts early outcome in acute stroke. Stroke.. 1996;27:1537–1542.
Thank you for the opportunity to address the points raised by Dr Cheung. We acknowledge that SPECT provides a relative index of cerebral perfusion and in ischemic stroke is unable to delineate the infarct core. In addition, second studies are required from which reperfusion can only be retrospectively inferred. We do not suggest that SPECT should replace other imaging modalities. CT remains the investigation of choice in the triage of stroke patients. The aim of our studyR1 was not to find the best imaging technique but to clarify the individual effects of “nutritional” and “nonnutritional” reperfusion on stroke outcome.
Thus, our major interest was in the change in the measured hypoperfusion volumes between studies. The volumetric analysis algorithm we used has been validated,R2 and as the same protocol was used for all studies in each patient, we believe that changes in hypoperfusion volumes reflect true changes in perfusion. As such, we feel justified in using physiological terms such as “reperfusion” to describe a contraction of the hypoperfusion volume between acute and subacute studies as well as further division into “nutritional” (if maintained) or “nonnutritional” (if not maintained) at outcome.
We found clear correlations between hypoperfusion volume measures and stroke outcome, and although multivariate analysis was not performed, we would like to point out an earlier study by Baird et al.R3 They found that the percentage “perfusion change” between SPECT studies at a mean of 8 and 33 hours after stroke onset provided independent prognostic information by multiple linear regression analysis.
Although the results of recent thrombolytic drug trials have focused interest on the first 3 to 6 hours after the onset of stroke, there is evidence from PET and combined MR perfusion- and diffusion-weighted imaging that potentially viable tissue may persist well beyond this time.R4 R5 As a result, we chose a 24-hour cutoff point for the acute studies. Despite this, 34 of 41 patients (83%) had acute SPECT studies performed within 12 hours of stroke onset. The prolonged persistence of potentially viable cerebral tissue may also explain the delayed reperfusion that was maintained at outcome in some patients.
In 3 of the 4 patients with early and late expansion of the hypoperfusion volumes, the late hypoperfusion volume expansion was <20%. We were therefore not surprised by the finding that these patients remained clinically stable. In the remaining patient, the late expansion of the hypoperfusion volume was 47%. Because there was no late deterioration, we can only surmise that the expansion of the hypoperfusion deficit may have been into noneloquent cerebral tissue.
We would disagree with the contention that there is an inconsistent relationship between the outcome hypoperfusion volumes and eventual infarct size. In most patients these 2 volumes are roughly similar, with a mean difference of 3 cm3 and a median of 11.1 cm3. One possible explanation for the larger outcome hypoperfusion volume seen in some individuals is peri-infarct diaschisis.
Our study has shown that SPECT can be performed in the acute setting. Despite a 24-hour acute study window, we were able to image almost one third of patients with CT and SPECT within 6 hours. Analysis of the acquired images is straightforward and rapid. SPECT may be a useful tool in the screening of acute stroke patients before thrombolytic therapy. If a small hypoperfusion deficit is seen, we would hypothesize that there is less potential to benefit from such therapy, whereas severe hypoperfusion deficits may predict a greater risk of hemorrhagic transformation.R6 SPECT may also allow the grouping of patients in therapeutic drug trials. Like others,R7 we suggest that the time is right for the investigation of these hypotheses with randomized multicenter trials.
Barber PA, Davis SM, Infeld B, Baird AE, Donnan GA, Jolley D, Lichtenstein M. Spontaneous reperfusion after ischemic stroke is associated with improved outcome. Stroke.. 1998;29:2522–2528.
Infeld B, Binns D, Lichtenstein M, Hopper JL, Davis SM. Volumetric analysis of cerebral hypoperfusion on SPECT: validation and reliability. J Nucl Med.. 1997;38:1447–1453.
Baird AE, Austin MC, McKay WJ, Donnan GA. Changes in cerebral tissue perfusion during the first 48 hours of ischaemic stroke: relation to clinical outcome. J Neurol Neurosurg Psychiatry.. 1996;61:26–29.
Marchal G, Beaudouin V, Rioux P, de la Sayette V, Le Doze F, Viader F, Derlon JM, Baron JC. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel based data analysis. Stroke.. 1996;27:599–606.
Barber PA, Darby DG, Desmond PM, Yang Q, Gerraty RP, Jolley D, Donnan GA, Tress BM, Davis SM. Prediction of stroke outcome with echoplanar perfusion- and diffusion-weighted magnetic resonance imaging. Neurology.. 1998;51:418–426.
Ueda T, Hatakeyama T, Kumon Y, Sakaki S, Uraoka T. Evaluation of risk of hemorrhagic transformation in local intra-arterial thrombolysis in acute ischemic stroke by initial SPECT. Stroke.. 1994;25:298–303.
Alexandrov AV, Grotta JC, Davis SM, Lassen NA. Brain SPECT and thrombolysis in acute ischemic stroke: time for a clinical trial. J Nucl Med.. 1996;37:1259–1262.