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(Stroke. 1996;27:1537-1542.)
© 1996 American Heart Association, Inc.

Articles

Simple Visual Analysis of Brain Perfusion on HMPAO SPECT Predicts Early Outcome in Acute Stroke

Andrei V. Alexandrov, MD; Sandra E. Black, MD, FRCP(C); Lisa E. Ehrlich, MD; Christopher F. Bladin, MBBS, FRACP; Liliana T. Smurawska, MD; Angelo Pirisi, MD Curtis B. Caldwell, PhD

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Single-photon emission computed tomography (SPECT) is used in patients with acute stroke but as yet is of controversial value. We investigated an association of brain perfusion changes in stroke patients with stroke severity, volume of brain damage, and recovery.

Methods Consecutive patients with hemispheric stroke were studied prospectively with serial neurological examinations using the Canadian Neurological Scale (CNS), CT, and ^99mTc–hexamethylpropyleneamine 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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
SPECT is a potential diagnostic tool in stroke,^{1 2} and noninvasive perfusion studies are clearly needed in future thrombolytic stroke trials.³ There is growing interest in SPECT applications for predicting recovery, differentiating stroke pathogenesis, and monitoring therapies.^{2 3} The results of such testing help in the formulation of a working diagnostic hypothesis, leading to decisions regarding further invasive testing, treatment, or prognostication.⁴ A valuable test in clinical medicine provides information that otherwise cannot be obtained by clinical examination or other available investigations. CT scans usually reveal anatomic changes far later than during the present concept of the therapeutic window (ie, up to 6 hours after stroke).² Admission CT scanning can differentiate ICH from ischemic stroke but has little prognostic value because its false-negative rate is up to 50% in cerebral infarcts during the first 24 hours.^{5 6} SPECT testing therefore may have clinical value in addition to clinical and CT examinations in acute stroke because it may detect ischemic lesions earlier than CT and distinguish the stroke type and severity of cerebral ischemia.² However, SPECT has not yet been used in randomized clinical trials, partly because no clinically valid and widely adopted diagnostic criteria have been developed.

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients and Study Design
Consecutive patients with hemispheric stroke admitted to the hospital were studied prospectively according to a standard stroke protocol, which included admission CT scanning and scoring of neurological deficit using the CNS¹⁶ on admission and days 3, 7, and 14 after the onset of symptoms. Patients also underwent carotid duplex scanning and cardiac workup including electrocardiogram and, in cases of suspected cardioembolism or strokes of undetermined etiology, echocardiography and Holter monitoring. Brain SPECT scanning was performed with ^99mTc-HMPAO, and SPECT images were interpreted by an experienced nuclear medicine physician and a neurologist (L.E.E., S.E.B.) independently from three other neurologists (A.V.A., C.F.B., A.P.) who scored the neurological deficit. The diagnosis of ICH or ischemic stroke was based on the initial CT scan. CT scans were repeated after the third day after stroke when clinically indicated, and the volumes of the CT lesions were obtained by planimetric measurements using Sigma Scan software (Jandel Scientific) as described previously.^{7 17}

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 described^{7 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.

View larger version (539K): [in this window] [in a new window]   Figure 1. Visual patterns of brain perfusion on HMPAO-SPECT scans. With normal perfusion, HMPAO is distributed symmetrically in both affected and nonaffected hemispheres. If the entire infarction zone represents an area of focal hyperactivity of the tracer (new event, arrow), a high perfusion pattern is reported. A focal absence of perfusion may also be present in the same hemisphere in the area of an old infarction (arrow) and should be excluded from the analysis by a comparison with CT scans. Mixed perfusion pattern is present when asymmetrical areas of increased and decreased uptake of the tracer are seen within the involved region. Low perfusion pattern represents a focal area of HMPAO hypoactivity. Absent perfusion pattern is present when no focal uptake of the tracer is noted in the involved region. 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).

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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
General Data
Five hundred consecutive patients with acute hemispheric stroke were studied (267 men and 233 women; mean age, 75±11 years). Patients with transient ischemic attacks were not included in the study. Forty-two patients were excluded because they did not have an admission CT scan, refused SPECT scan, or could not tolerate both tests. Of the remaining 458 patients, 46 (10%) had ICH and 412 patients had hemispheric ischemic stroke.

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.

View this table: [in this window] [in a new window]   Table 1. Brain Perfusion and Recovery From Stroke

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).

View larger version (16K): [in this window] [in a new window]   Figure 2. Absent perfusion pattern is associated with the largest volume of brain damage after stroke (P<.0001, Tukey's studentized range test).

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% (c_CNS=0.75, c_CNS+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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Visual patterns of brain perfusion seen on HMPAO-SPECT scans in acute stroke correlate with the severity of stroke, volume of brain damage, and short-term outcome. Quantified SPECT findings also correlate with stroke severity and outcome,^{8 9 10 12} but visual patterns have the advantage of being easy to use, reproducible,^{7 14 15} and rapidly applicable in evaluation of acute stroke patients.¹⁷

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 previously^{7 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 successful^{26 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

 

CNS = Canadian Neurological Scale HMPAO = hexamethylpropyleneamine oxime ICH = intracerebral hemorrhage ROC = receiver operating characteristic SPECT = single-photon emission computed tomography

	Acknowledgments

 
This work was supported by an operating grant from the Heart and Stroke Foundation of Ontario (A1610 for Drs Black and Ehrlich), the MacLaughlin Stroke Fund (Drs Alexandrov, Smurawska, and Pirisi), and the Sunnybrook Trust for Medical Research Foundation Fellowship (Dr Alexandrov). Dr Alexandrov is a recipient of the 1995 William Oldendorf Award of the American Society of Neuroimaging for this study. We gratefully acknowledge John W. Norris, MD, FRCP, for invaluable help and useful criticisms in preparation of the manuscript, and Joanne Lawrence, RN, and the technologists at the Department of Nuclear Medicine, Sunnybrook Health Science Centre, for their cooperation in obtaining the data.

	Footnotes

 
Presented in part at the 18th American Society of Neuroimaging Meeting, San Juan, Puerto Rico, March 9-11, 1995.

Received January 3, 1996; revision received April 24, 1996; accepted April 24, 1996.

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