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(Stroke. 1996;27:1537-1542.)
© 1996 American Heart Association, Inc.
Articles |
the Stroke Research Unit (A.V.A., S.E.B., C.F.B., L.T.S., A.P.), the Division of Nuclear Medicine (L.E.E.), and the Department of Medical Imaging (C.B.C.), Sunnybrook Health Science Centre, University of Toronto, Ontario, Canada.
Correspondence to Dr A.V. Alexandrov, Stroke Research Unit, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5.
| Abstract |
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Methods Consecutive patients with hemispheric stroke were studied prospectively with serial neurological examinations using the Canadian Neurological Scale (CNS), CT, and 99mTchexamethylpropyleneamine oxime (HMPAO) SPECT. Visual SPECT patterns of brain perfusion (normal, high, mixed, low, and absent) were correlated with the severity of stroke, lesion volume, and short-term outcome.
Results SPECT studies were performed in a total of 458 consecutive acute stroke patients within 2 weeks after the onset (mean time, 5 days; range, 1 to 12 days). SPECT perfusion patterns correlated with stroke severity (CNS score) during the first 2 weeks (P<.001). Focal absence of brain perfusion on SPECT was associated with the largest volume of brain damage: 104±84 mL (P<.0001). SPECT perfusion patterns predicted the short-term outcome: 97% of patients with normal and increased HMPAO uptake made good recovery, 52% of those with decreased perfusion had moderate stroke, and 62% of patients with absent patterns fared badly. In a multiple logistic regression model, admission CNS scores had the strongest predictive value (P=.0001). SPECT had its own prognostic value independent of clinical judgment (P=.03). SPECT statistically improved predictive power of the CNS score (+1% receiver operating characteristic curve area, [
2]2=20, P<.001) because of distinction between focal decrease or absence of brain perfusion in patients studied within the first 72 hours of stroke.
Conclusions Visual brain perfusion patterns correlate with the extent, severity, and short-term outcome of hemispheric stroke. HMPAO SPECT may improve the prognostic value of clinical examination if performed during the first 72 hours of stroke.
Key Words: prognosis stroke assessment tomography, emission computed
| Introduction |
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Several studies have reported SPECT as being potentially useful in the diagnostic workup of acute stroke patients admitted within the first 6 hours.7 8 9 A variety of methods quantifying SPECT perfusion abnormalities were suggested,10 11 12 13 but these methods are relatively time consuming and may prove impractical for rapid evaluation of acute stroke patients. No quantitative method is applied to diagnose ischemic hypodensities or hemorrhagic hyperdensities on routine CT scan, and visual analysis of CT images remains standard for this purpose. Simple visual analysis of brain perfusion images would improve clinical use of SPECT. In our pilot studies, we used a standard imaging acquisition protocol and showed feasibility and good intraobserver and interobserver reproducibility of qualitative visual criteria (
0.8) for brain perfusion abnormalities with SPECT.7 14 15 Our aim was to determine whether a simple visual classification of SPECT could provide useful supplementary information to the clinical and CT examinations in diagnosis and prognostication of acute stroke. We assessed the relation of SPECT patterns to the severity of stroke and volume of brain damage, and we assessed their prognostic value.
| Subjects and Methods |
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SPECT Scanning
Patients received intravenous injections of 740 MBq (20 mCi) 99mTc-HMPAO (Ceretec, Amersham Ltd) and were scanned approximately 30 minutes after the injection. A single-head gamma camera (General Electric 400 AT) was used to generate images with attenuation correction. Sixty-four frames were acquired, each for 25 seconds in step-and-shoot mode. A low-energy, high-resolution hole collimator was used. The reconstructed full-width half-maximum resolution of the system was approximately 1.5 cm, and the average volume of lacunar lesions that did not produce any abnormality on SPECT scans was 2.5±1.2 cm3.7 14 15 Images were tilt- and flow-corrected for nonlinear uptake of HMPAO to improve contrast in high-flow regions and to ensure optimal intraobserver and interobserver agreement.14 15 Images were reoriented to correct for head tilt in all three directions and motion.
Diagnostic Criteria
SPECT images of brain perfusion were visually analyzed to determine whether HMPAO was distributed symmetrically in both hemispheres or any focal absence or decreased and increased uptake of the tracer was present. Brain location of the lesion and the type of clinically relevant stroke were known to the observer from clinical and CT data. All SPECT images were classified into five patterns of brain perfusion (Fig 1
) as previously described7 17 : (1) Normal perfusion pattern is present when HMPAO is distributed symmetrically in both affected and nonaffected hemispheres. (2) High perfusion pattern is seen when the entire infarction zone represents an area of focal increased uptake of the tracer. The increased deposition of HMPAO may overestimate actual cerebral blood flow18 ; therefore, the term "high perfusion pattern" was used not to diagnose "luxury perfusion syndrome"19 but as a marker of a distinct increased uptake of HMPAO visualized in the involved region. (3) Mixed perfusion pattern is present when areas of increased and decreased uptake of the tracer are seen within the involved region. These focal zones of increased and decreased tracer deposition must be asymmetrical compared with HMPAO distribution in the nonaffected hemisphere. (4) Low perfusion pattern is seen when there is only a focal area of decreased HMPAO deposition. Importantly, there is a unilateral focus of decreased but not absent uptake of the tracer. (5) Absent perfusion pattern is present when no focal uptake of the tracer is noted in the involved region. The focal absence of HMPAO distribution may be produced by an acutely occluded intracranial artery with lack of collateral supply to the ischemic area,20 or by ICH, and differs from the global absence of cerebral perfusion in brain death.3 Areas of absent perfusion were evaluated by comparison with CT scan to exclude enlarged subarachnoid spaces and chronic infarction.
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Prognostic Criteria
In accordance with previous reports,7 16 17 the following prognostic model was used: acutely normal and high perfusion patterns predict minor stroke (CNS scores 11.5 to 9.1), mixed and low patterns predict moderate stroke (CNS scores 9.0 to 5.1), and absent perfusion pattern is a predictor of severe stroke and death (CNS scores 5.0 to 0). Similarly, admission CNS scores of 11.5 to 9.1, 9.0 to 5.1, and 5.0 to 0 were used to predict the early stroke outcome at 2 weeks after onset (mild, moderate, and severe stroke, respectively).7 17 Although stroke patients may continue to improve after the first 2 weeks after onset, this is the time by which most discharge and management decisions have to be made. Thus, clinical and SPECT prognostic criteria were compared separately and in a combined model to predict early stroke outcome at 2 weeks.
Statistical Analysis
The association between SPECT perfusion patterns, stroke severity, and death within the first 2 weeks after stroke was evaluated using
2 analysis. Tukey's studentized range test was used to assess the difference in mean volume of CT lesions corresponding to each perfusion pattern. Spearman's correlation coefficient was used to correlate SPECT patterns and the severity of neurological deficit after stroke. Prognostic value of SPECT criteria was assessed using polychotomous multiple logistic regression analysis. Statistical models included clinical examination (CNS scores) and SPECT patterns as combined and independent predictors of short-term recovery in all patients and in those studied acutely within the first 72 hours.
| Results |
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Brain Perfusion Patterns
A total of 458 SPECT studies performed at a mean of 5 days (range, 1 to 12 days) after onset were eligible for analysis: 36% of SPECT studies were performed within the first 72 hours, 48% during days 3 through 7, and 16% within 8 to 12 days after stroke. Perfusion patterns were normal in 7.2%, high in 2.4%, mixed in 15.5%, low in 53.9%, and absent in 20.9% of patients (Table
). No patients were treated with thrombolytic agents.
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Severity of Stroke
CNS scores on admission and on days 3 and 7 significantly correlated with simultaneous SPECT findings with use of the proposed SPECT criteria (R2=.28, P<.0001, Spearman's correlation). This correlation was significant and demonstrated that there was a relationship between HMPAO-SPECT perfusion pattern and the degree of neurological deficit within the first 14 days after stroke. Thus, normal and high perfusion patterns were associated with minor deficits, whereas focal absence of brain perfusion pointed to a severe stroke and poor neurological improvement during this period. SPECT patterns also correlated with the severity of stroke at 2 weeks after the onset as measured by CNS scores (R2=.24, P<.001). These CNS scores were used to estimate early outcome of stroke. Normal and high perfusion patterns were associated with mild neurological deficit: 97% of these patients had a minor stroke (CNS scores at day 14 >9.0). Low and mixed perfusion patterns correlated with moderate impairment: 52% of these patients had CNS scores
9.0 to >5.0 at day 14. Of the patients with absent perfusion, 62% had poor outcome at day 14 (CNS scores
5.0; Table). The 99 patients with fatal stroke during hospital admission were divided into 25 early deaths (within the first 2 weeks after stroke) and 74 delayed deaths (after 2 weeks after stroke). Absent perfusion pattern was found in 11 scans of patients who died early (44%) and in 19 scans of patients who died later (26%, P=.05, 5x2
2). The remaining patients with fatal stroke had low and mixed perfusion patterns, except for 1 patient who had normal perfusion and died of pneumonia 24 days after stroke onset.
Volume of Brain Damage
SPECT perfusion patterns were compared with CT volume of brain damage (n=363). Mean±SD volume was calculated for each perfusion pattern: normal, 16±52 (range, 0 to 102) mL, n=21; high, 8±14 (range, 0 to 35) mL, n=8; mixed, 26±24 (range, 10 to 82) mL, n=56; low, 16±94 (range, 8 to 95) mL, n=184; and absent, 104±84 (range, 28 to 620) mL, n=94 (Fig 2
). There was no significant difference between the mean volumes corresponding to normal, high, mixed, and low perfusion patterns. Absent perfusion pattern was associated with the largest volume of brain damage after stroke (P<.0001, Tukey's test).
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Prognosis
A combined model of clinical examination and SPECT classification predicted recovery at 2 weeks after onset (P=.0001, polychotomous multiple logistic regression). Clinical examination on admission had the strongest predictive value (P=.0001). After allowance for CNS scores to predict the outcome, SPECT provided additional value (P=.03) in refinement of the short-term prognosis. Clinical and SPECT findings were also compared in 152 patients who were studied within the first 72 hours of stroke. CNS scores on admission in these patients were strong predictors of the short-term outcome (P<.0001, multiple logistic regression). When SPECT prognostic criteria were also considered, the predictive power of the prognostic model increased ([
2]2=20, P=.0001), with modest improvement of accuracy of clinical prognosis by 1% (cCNS=0.75, cCNS+SPECT=0.76, where c indicates the area under the ROC curve). A further analysis of maximum-likelihood estimates showed that the statistical increase in predictive power of the model was due to distinction between the low and absent perfusion patterns within the first 72 hours of stroke (P=.04).
| Discussion |
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The sensitivity of SPECT and its prognostic value increase when SPECT is performed closer to the onset of stroke in this and other studies.19 21 Since spontaneous recanalization is common during the first hours of stroke,17 19 time dependency of brain perfusion changes attenuates the prognostic value of subacute SPECT studies. This study supports the view that SPECT has better prognostic power the earlier it is used. In our study, SPECT was a better predictor of 2-week outcome if performed during the first 72 hours of stroke. Other studies have suggested that it is most useful if performed during the first 6 hours.3 17 19 During the first 6 hours, stroke is a medical emergency, and effective treatment strategies are becoming available.3 6 CT scanning has dubious prognostic value during the first 24 hours of ischemic stroke,5 6 whereas SPECT accurately predicts the outcome and lesion volume.6 9 10 14 17 19
SPECT patterns of perfusion were associated with stroke severity and the extent of brain damage in this study. Strokes due to occlusion of a major cerebral artery and ICH produced focal absence of perfusion, as reported previously7 9 10 12 and verified angiographically by Giubilei et al.20 Lacunar infarction and minor strokes account for at least a quarter of false-negative SPECT scans,22 23 thus indicating patency of the circle of Willis and good prognosis. Differentiation of stroke pathogenesis and lesion volume with SPECT may have important applications for therapeutic decisions if the CT results are negative. We hypothesize that the following algorithm can be tested in future clinical trials. A normal brain perfusion on SPECT during the first 6 hours of stroke implies minor or lacunar stroke with minor tissue damage, suggesting no need for thrombolysis. Acutely decreased perfusion patterns indicate moderate severity of ischemia and would identify the target patient population for safe and effective thrombolysis. Patients with acutely absent perfusion pattern may also be candidates for thrombolysis, but this pattern shows the most severe ischemia with a potential for symptomatic hemorrhagic transformation and predicts large-volume lesions and an increased risk of death if occlusion persists for too long. Thus, SPECT may be used to identify patients who do not need thrombolysis because they will recover spontaneously or the risk of complications is too high, securing interventions for patients with moderate extent and severity of ischemia.
SPECT findings correlate with the severity of neurological deficit in this and other studies.24 25 26 27 28 Other correlations were less successful26 29 30 because the criteria used and the populations of patients studied need to be standardized. The clinical value of SPECT increases if consecutive patients are studied, particularly when patients with minor stroke and transient/reversible deficits are involved.7 17 31 The correlation of SPECT perfusion patterns and short-term outcome of stroke in this study can be explained by an association with the volume of brain damage. Thus, an absent pattern produced by lesions of the greatest volume of tissue damage predicts the poorest outcome and early death, whereas patients with subacutely normal and decreased patterns had smaller brain lesions. Hence, early reperfusion manifesting within the first 48 hours as improved or normal flow pattern on SPECT correlated with smaller infarct size on CT, decreased mortality, and better outcome in another study.32 In our study, a normal perfusion pattern also was associated with better outcome and smaller volume of brain damage than the absent perfusion pattern. However, a large standard deviation of 52 mL was produced by one lesion of 102 mL, whereas the rest were less than 50 mL. That deviation reflects the only patient in this group who had severe neurological deficit and died subacutely from pneumonia. The presence of normal flow in these lesions can be explained by the average 5-day delay of SPECT scanning, at which time normal perfusion often represents "irrigating the ruins." However, patients with similar volumes of brain damage but different perfusion patterns were likely to have poorer outcomes. The normal and high perfusion patterns are prognostically favorable signs, while others indicate lesser recoverability for stroke patients. Thus, although affected by the time of scanning, SPECT still provides prognostically valuable information. Therefore, SPECT may be able to identify those patients unlikely to respond to reperfusion in addition to help avoid treatment of individuals at high risk of reperfusion injury. When 15 patients were studied at 3 hours after the ictus, a threshold of the severity of SPECT perfusion defect was found above which all patients suffered massive cerebral edema or hemorrhagic conversion of infarction.33 Distinction between focal decrease and absence of perfusion was the most critical prognostic finding in the present study. These results indicate that as a diagnostic tool SPECT is more sensitive to ischemia than CT, particularly when used earlier in the course of stroke.
Clinical examination on admission had the strongest predictive value in this and in another study.12 Although SPECT has its own prognostic value, brain perfusion patterns were weak predictors of recovery compared with clinical examination if SPECT was performed at any time within the first 2 weeks. Davis et al8 evaluated 38 patients with middle cerebral artery strokes within 72 hours of onset. In that study, SPECT hypoperfusion did not improve the prognostic value of clinical examination. We also compared prognostic value of neurological examination and SPECT during the first 72 hours of stroke and in consecutive patients, including those with minor deficits and normal SPECT scans. SPECT statistically improved the prognostic value of the combined examination, yet the improvement of diagnostic accuracy was only 1% for the ROC-curve area, findings similar to those of Laloux et al.12
The question also remains as to the kinetics of the HMPAO tracer, which may produce "filling-in phenomenon" or "hyperfixation," thus spuriously overestimating the actual cerebral blood flow.18 Our latest analysis showed that increased uptake of HMPAO correlates with a stroke pathogenic mechanism. It is most common in patients with cardioembolic stroke: 29% compared with 15% in patients with other types of ischemic stroke.34 This phenomenon has a physiological explanation in the trapping mechanism of HMPAO, which is a simple chemical interaction with intracellular glutathione.35 Glutathione levels increase with reperfusion, thus producing the excessive HMPAO trapping seen on subacute SPECT scans.34 Furthermore, glutathione is a protector against free radicals, and in this series we found normal and high HMPAO uptake to be prognostically more favorable signs.
We conclude that SPECT findings are time dependent and have the highest prognostic value during the first 48 hours after stroke,17 19 21 32 33 with no advantage over clinical examination beyond 72 hours. Visual patterns of brain perfusion aid clinical examination after negative admission CT because HMPAO SPECT indicates the extent and severity of cerebral ischemia and prognosis of stroke. Early SPECT scanning improves clinical prognostication because of the differentiation between the focal absence and relatively restored perfusion or collateral flow in the involved area of the brain. We suggest that the clinical value of SPECT should be tested in future clinical trials of therapies for acute stroke.36
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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| Footnotes |
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Received January 3, 1996; revision received April 24, 1996; accepted April 24, 1996.
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J V Bowler, J P H Wade, B E Jones, K S Nijran, and T J Steiner Natural history of the spontaneous reperfusion of human cerebral infarcts as assessed by 99mTc HMPAO SPECT J. Neurol. Neurosurg. Psychiatry, January 1, 1998; 64(1): 90 - 97. [Abstract] [Full Text] |
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A. V. Alexandrov, J. C. Masdeu, M. D. Devous Sr, S. E. Black, and J. C. Grotta Brain Single-Photon Emission CT With HMPAO and Safety of Thrombolytic Therapy in Acute Ischemic Stroke : Proceedings of the Meeting of the SPECT Safe Thrombolysis Study Collaborators and the Members of the Brain Imaging Council of the Society of Nuclear Medicine Stroke, September 1, 1997; 28(9): 1830 - 1834. [Abstract] [Full Text] |
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A. V. Alexandrov, S. E. Black, L. E. Ehrlich, C. B. Caldwell, and J. W. Norris Predictors of Hemorrhagic Transformation Occurring Spontaneously and on Anticoagulants in Patients With Acute Ischemic Stroke Stroke, June 1, 1997; 28(6): 1198 - 1202. [Abstract] [Full Text] |
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