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(Stroke. 1997;28:976-980.)
© 1997 American Heart Association, Inc.

Articles

Sensitivity and Specificity of ^99mTc-HMPAO SPECT Cerebral Perfusion Measurements During the First 48 Hours for the Localization of Cerebral Infarction

A.E. Baird, FRACP, PhD; M.C. Austin; Dip Appl Sci; W.J. McKay, FRACP; G.A. Donnan, MD, FRACP

From the Departments of Neurology (A.E.B., G.A.D.) and Nuclear Medicine (M.C.A., W.J.M.), Austin and Repatriation Medical Centre, Heidelberg; and the Department of Medicine, University of Melbourne (A.E.B., G.A.D.), Victoria, Australia.

Correspondence to Professor G.A. Donnan, Department of Neurology, Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose There is no routinely used method for imaging the location of the extent and severity of cerebral tissue perfusion changes during the first hours of ischemic stroke, the period during which therapeutic intervention is most likely to be successful. Cerebral perfusion measurements with single-photon emission CT (SPECT) may potentially provide this information rapidly and noninvasively. In this study, the sensitivity and specificity of ^99mTc–hexamethylpropyleneamine oxime (HMPAO) SPECT cerebral perfusion measurements during the first 48 hours of cerebral ischemia for the localization of cerebral infarction were determined.

Methods One hundred and four patients with acute ischemic stroke underwent ^99mTc-HMPAO SPECT and CT scanning during the first 48 hours. In each patient, the location of the SPECT perfusion abnormality was compared with the location of infarction on a second brain CT acquired at a mean of 8 days after stroke.

Results During the first 48 hours of ischemic stroke, the sensitivity of ^99mTc-HMPAO SPECT in locating the site of infarction was 79% (110/139), and the specificity was 95% (362/381). SPECT was more sensitive in the localization of the vascular territory of cortical infarction (sensitivity, 93%) than pure subcortical infarcts (sensitivity, 47%). During the first 48 hours, SPECT was significantly more sensitive than brain CT (sensitivity of brain CT during the first 48 hours, 35%; P<.001, Mann-Whitney U test).

Conclusions HMPAO SPECT measurement provides a widely available and practical technique of locating cerebral ischemia acutely and demonstrates high sensitivity and specificity within the first 48 hours for the localization of the vascular territory of cerebral infarction. It is most sensitive for cortical ischemia but is limited by its resolution in the subcortex, particularly of white matter perfusion changes.

Key Words: cerebral blood flow • cerebrovascular disorders • diagnostic imaging • perfusion • tomography, emission computed

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In human ischemic stroke, a potential window of uncertain duration (probably hours) exists, during which therapeutic intervention may limit infarct size and improve outcome.^{1 2 3} Locating the site and the severity of cerebral perfusion changes during the acute phase is likely to be important in guiding therapeutic intervention, since it is possible that some therapies will need to be targeted to specific stroke subtypes and patients in whom still-viable tissue is present. However, in current practice, acute cerebral ischemia is not routinely visualized because the structural images obtained from CT and MRI are usually normal or show minimal changes within the first few hours.

With functional imaging methods such as SPECT, it is now possible to visualize cerebral perfusion changes in the acute phase. Compared with other functional imaging techniques, this modality has the advantages of being widely available, practical, and relatively inexpensive. Several studies have demonstrated the ability of SPECT perfusion measurements to demonstrate the ischemic focus, but no large-scale study against a universally accepted gold standard of the sensitivity and specificity of ^99mTc-HMPAO SPECT in localizing cerebral ischemia within the first 48 hours (the time window during which it is believed that therapeutic intervention may potentially be effective) has been undertaken previously. Earlier studies had the following limitations: (1) small patient numbers,^{4 5} (2) heterogeneous examination times after the onset of ischemia,^{4 5} (3) the use of different radiopharmaceuticals^{6 7} such as ^99mTc-ECD or ¹²³I-IMP, (4) the use of clinical criteria for localization rather than a universally accepted or neuroimaging-based gold standard,^{6 8} (5) the absence of measurements of specificity except for one study,⁶ and (6) retrospective analysis in some studies. Three ^99mTc-HMPAO SPECT studies^{8 9 10} had fewer than 40 patients within the first 24 to 48 hours, and two other studies recruited patients within the first 4 to 6 days after stroke.^{11 12} Most other studies have involved the use of SPECT up to 5 days after stroke or beyond.

The aim of this study was to determine the sensitivity and specificity of ^99mTc-HMPAO SPECT cerebral perfusion measurements during the first 48 hours of cerebral ischemia for the localization of infarction on CT. A secondary aim was to compare the sensitivities of SPECT and CT during the first 48 hours.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study Establishment
The study was conducted prospectively from March 1991 through October 1993. Patients presenting to the Austin Hospital Stroke Unit¹³ within 48 hours of the onset of a focal neurological event consistent with ischemic stroke were eligible for inclusion in the study. Some patients were participants in other stroke trials in progress at the Austin and Repatriation Medical Centre, including the pilot and randomized phases of the Australian Streptokinase Trial.^{14 15} The study was approved by the ethics committee of the Austin and Repatriation Medical Centre and the Radiation Safety Section of the Health Department of Victoria.

Clinical Assessment
Patients were assessed in the emergency department. The following data were recorded: age, sex, time of symptom onset, neurological deficit, time of CT scanning, and ^99mTc-HMPAO administration. The following inclusion and exclusion criteria were applied. Inclusion criteria were CT and SPECT examination within 48 hours of the onset of symptoms, supratentorial ischemic stroke, CT exclusion of cerebral hemorrhage and other causes of pseudostroke, and informed consent (verbal or signed) obtained from the patient or closest relative if the patient was unable to give consent. Exclusion criteria were cerebral hemorrhage or pseudostroke, infratentorial ischemic stroke, or previous infarction in the clinically relevant vascular territory interfering with scan interpretation.

Neuroimaging
Each patient underwent noncontrast CT scanning on arrival in the emergency department with a Siemens DR3 scanner to exclude cerebral hemorrhage and other causes of pseudostroke. The slice thickness of the reconstructed images was 8 mm. The CT was repeated after 7 to 10 days, or earlier if clinically indicated. The second CT was performed to determine the topography of infarction, which was used as the gold standard in determining the sensitivity and specificity of SPECT. In cases where multiple CT scans were performed for clinical reasons, the scan that most clearly delineated the topography of the infarct was used as the "gold standard."

All SPECT scans were performed within 48 hours of the onset of symptoms and as soon after the patient's presentation as was possible. In some cases, two SPECT studies were performed during the first 48 hours (in patients entered into the Australian Streptokinase Trial^{14 15} ); in those cases, only the first ^99mTc-HMPAO SPECT study was evaluated.

^99mTc-HMPAO (15 to 25 mCi, Ceretec-Amersham Australasia) was injected as soon as possible after the CT scan had been performed, either in the emergency department or in the CT scanning suite. Scanning was performed when clinically convenient using a rotating General Electric 400 AC Starcam camera. Sixty-four images were acquired over 360° on a 128x128 matrix with a pixel size of 3.1 mm and acquisition time of 15 to 30 seconds per frame. After scatter correction and attenuation correction, 40 transaxial slices were reconstructed on a 64x64 matrix.

Analysis of Neuroimaging Studies
The neuroimaging studies were read visually by two observers blinded to the clinical localization (a neurologist and a neurology trainee) who classified the structural changes on the CT scans and the perfusion changes on the SPECT images by vascular territory. The categories of vascular territories were MCA, ACA, PCA, Ex WS, subcortical, and normal. Subcortical was defined as any region without cortical involvement.¹⁶ The subcortical categories included anterior choroidal territory,¹⁷ lacune,¹⁸ internal watershed,¹⁹ and striatocapsular²⁰ and white matter medullary infarcts.²¹ Subcortical infarcts and perfusion abnormalities were grouped because the resolution of our SPECT was 1.2 cm, measured in a resolution phantom. Because subcortical infarcts are often small (lacunae are defined as <1.5 cm), it was decided that it would be difficult to distinguish between the different categories of subcortical ischemia on SPECT. A total of 14 patients with clinical stroke (including 4 with reversible ischemic neurological deficits) were excluded because the late CT was normal.

Some patients had involvement of more than one vascular territory, which the readers recorded separately. Any discordant results were discussed and consensus reached. The interobserver agreement for late CT reading was overall =0.85 (MCA territory, =0.90; ACA territory, =0.82; PCA territory, =0.85; Ex WS, =0.49; subcortical, =0.65). The interobserver agreement for SPECT reading was overall =0.83 (MCA territory, =0.80; ACA territory, =0.79; PCA territory, =0.79; Ex WS, =-0.01; subcortical, =0.73).

Data Analysis and Statistical Analyses
The vascular territory of infarction on the second CT scan was used as the gold standard in determining the sensitivity and specificity of SPECT in localizing acute cerebral ischemia. In the overall data analysis, the perfusion abnormalities on the SPECT images in the first 48 hours were compared with the location of infarction on the late CT scan. For each patient and volunteer, a 6x6 contingency table was constructed with the CT location on one axis and the SPECT location of perfusion change on the other. The six categories were MCA cortical, ACA, PCA, Ex WS, subcortical, and normal.

In each patient, each of the five vascular territories was classified into true-positive, true-negative, false-positive, and false-negative categories (see below), giving a total of 520 vascular territories that were analyzed in 104 subjects. The cells of the 104 6x6 contingency tables were then summed to a 6x6 contingency table and then to an overall 2x2 contingency table that compared the HMPAO SPECT results with those of CT.

Definitions
The classifications were defined as follows.⁶

True-positive (TP). The location of ischemia on the SPECT study corresponded to the location of infarction on the late CT, eg, when the images were concordant for MCA territory infarction and hypoperfusion.

False-positive (FP). A perfusion abnormality was detected on the SPECT image in a vascular territory in a patient who had a normal CT (a control subject) or an extra perfusion abnormality was present on the SPECT study in an area that was not infarcted on the late CT scan. For example, if a perfusion defect was seen in the PCA territory and the MCA territory on the SPECT study in a patient with isolated cortical middle cerebral infarction on the CT, the PCA perfusion defect was defined as a false-positive.

False-negative (FN). The SPECT scan was reported as normal when there was an area of infarction on the late CT or the SPECT showed a perfusion abnormality in a different location to the site of infarction on CT, eg, if a patient with an ACA territory infarct on CT had a normal SPECT study.

True-negative (TN). This classification was used when the SPECT revealed no abnormality in a patient without infarction on CT.

The sensitivity, specificity, and positive and negative predictive values were determined using the following formulas: Sensitivity=TP/(TP+FN); Specificity=TN/(FP+TN); Positive Predictive Value=TP/(TP+FP); and Negative Predictive Value=TN/(FN+TN).

For statistical power in the final analysis, the cortical infarcts were grouped. The sensitivities of CT and HMPAO SPECT were compared by ² analysis. Comparisons between groups were analyzed using unpaired Student's t tests. A value of P<.05 was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
All Patients
A total of 104 patients were studied (Table 1). There were 53 men and 51 women (Table 1). The mean age of the patients was 69.3 years. The mean±SD time of ^99mTc-HMPAO administration was 16.4±2.3 hours after the onset of symptoms. The second CT scan was performed at a mean time of 8.0±4.3 days. There were 139 vascular territories of infarction (80 cortical, 59 subcortical) (Table 2) in the 104 patients. Eight patients had more than one cortical vascular territory involved. In 25 patients with cortical infarcts there was extension of the infarct into the lenticulostriate MCA territory.

View this table: [in this window] [in a new window]   Table 1. Demographics of Patients and Control Subjects in Study

View this table: [in this window] [in a new window]   Table 2. Vascular Territories of Infarction

Extra regions of hypoperfusion on SPECT in addition to the territory of infarction were identified in 19 patients: 1 patient with MCA infarction had additional PCA territory hypoperfusion; 7 patients with subcortical infarction had additional cortical hypoperfusion in the MCA territory; in another with an ACA territory infarct, there was cortical hypoperfusion in the MCA territory; and 10 patients with isolated cortical MCA infarcts also had subcortical hypoperfusion on SPECT. These extra regions may have represented areas of diaschisis or low flow or areas that were subsequently salvaged.

Sensitivity and Specificity of SPECT in Locating Ischemia During the First 48 Hours
SPECT was sensitive and specific in locating the site of ischemia during the first 48 hours (Table 3), with an overall sensitivity of 79% and specificity of 95%. SPECT was more sensitive in cortical ischemia, correctly localizing the site of the ischemia in 93% of infarcted cortical vascular territories, although it was less sensitive in pure subcortical infarcts, where the sensitivity was 47%. SPECT also demonstrated high positive and negative predictive values for the acute localization of the vascular territory of infarction (Table 3).

View this table: [in this window] [in a new window]   Table 3. Sensitivity, Specificity, and Positive and Negative Predictive Values of Brain HMPAO SPECT in Locating the Site of Cerebral Infarction During the First 48 Hours

Sensitivity of CT in the Localization of Ischemic Change During the First 48 Hours
As a corollary, the sensitivity of the acute (admission) CT scans performed during the first 48 hours were compared with that of SPECT in the cohort of 104 patients with acute stroke. In this cohort, the CT scans on average were performed significantly earlier than the SPECTs (mean time for CT was 8.6 hours compared with 16.4 hours for SPECT, P<.01, Student's t test). The overall sensitivity of CT in the acute phase was 34.5%, the sensitivity for detecting cortical lesions was 42%, and it was 18% for subcortical lesions. Therefore, during the first 48 hours of cerebral ischemia, SPECT was significantly more sensitive than CT in locating the site of eventual infarction (P<.01, ² analysis).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study confirmed the hypothesis that ^99mTc-HMPAO SPECT is sensitive and specific in detecting the location of cerebral ischemia during the first 48 hours. ^99mTc-HMPAO SPECT was also significantly more sensitive than CT scanning during the same time period. The study had the advantages that a large cohort was studied, the gold standard against which sensitivity and specificity were measured was based on the topography of infarction rather than on clinical criteria, and patients were recruited extremely early compared with previous studies, on average at 16.4 hours for the SPECT study. The early recruitment of our patients reflects the changing approach to stroke in recent years, in which the importance of the first few hours in the assessment and management of this condition has been recognized.²² The finding that ^99mTc-HMPAO is sensitive during the first 48 hours compares favorably with the results of previous studies using ¹²³I-IMP SPECT,^{7 11 133}Xe SPECT,²³ and ^99mTc-ECD SPECT.⁶ In ¹⁸F fluorodeoxyglucose positron emission tomography studies, higher detection rates in the first 48 hours of cerebral ischemia than CT have also been demonstrated.^{24 25 26 27} Beyond the first 48 hours, the sensitivity of CT approaches that of SPECT. In the subacute phase, SPECT may be even less sensitive because of the presence of spontaneous reperfusion. CT becomes more sensitive because of the evolution of tissue infarction.^{8 28} The importance of determining the sensitivity of SPECT in the acute phase, in the first 48 hours, is that this time window is most likely to be the most important for tissue rescue.

^99mTc-HMPAO SPECT was particularly sensitive in locating cortical ischemia acutely (93% of cases). It was less sensitive for subcortical ischemia because subcortical infarcts are often smaller and located in the white matter. White matter perfusion is poorly resolved on SPECT because white matter has only one quarter the blood flow of the gray matter.^{29 30} For cortical ischemia, SPECT might have been expected to be 100% sensitive. Reasons for this may be that small cortical infarcts were not located on blinded reading or that spontaneous reperfusion may have occurred in previously ischemic tissue. Perfusion defects were found in 4 patients with reversible ischemic neurological deficits who were excluded because their late CT scans were normal.

CT was less sensitive than SPECT within the first 48 hours because the structural changes of infarction evolve over hours to days: early hypodensity on CT is due to early edema.³¹ In previous studies, CT was found to be positive in 20% of cases in the first 6 hours³² and 50% of cases in the first 48 hours.³³ In this study, CT was 35% sensitive in the localization of infarction within the first 48 hours.

In studies of acute ischemic stroke using MRI,^{34 35 36} it was demonstrated that an abnormal signal could be detected within the first 2 to 4 hours in some cases. T2-weighted MRI has a higher sensitivity than CT but still detects only 30% of cases in the first 24 hours and 50% in the first 48 hours.^{34 35 36} Future improvements in sensitivity may be anticipated as higher resolution functional imaging technology becomes available, eg, multiple detector SPECT devices or functional MRI. However, functional MRI awaits full validation.³⁷

SPECT showed an overall specificity of 95%, which demonstrated the ease with which normal perfusion may be identified. In a previous study in which specificity was determined in a subgroup of patients, a high specificity was also found (98% in the study of Brass et al⁶ using ^99mTc-ECD). The 19 false-positives on SPECT reflect the fact that the extent of hypoperfusion on SPECT is often greater than the area of infarction delineated on CT, and they most likely arose from the changes of diaschisis or low flow or as a result of tissue salvage occurring after spontaneous reperfusion. For example, subcortical infarction may be associated with cortical hypoperfusion if there is subcortical diaschisis,³⁸ and cortical hypoperfusion may occur if there are significant internal carotid artery or MCA stenoses and exhausted autoregulatory reserves.³⁹ Early reperfusion of MCA territory ischemia may limit infarction to the structures, especially in the presence of a good collateral circulation,⁴⁰ as demonstrated in patients with spectacular shrinking deficits.⁴¹ Despite these false-positives, the specificity was high because of the high number of true-negative vascular territories (362); five vascular territories were analyzed per patient because a large number of patients had more than one vascular territory involved.

One possible limitation of using CT after 7 days as the gold standard should be acknowledged: infarcts may go through an isodense phase, which may mean that the true extent of infarction was not recognized in some cases.

This study appeared to represent a standard stroke population in terms of the frequency and type of supratentorial cortical infarction, although lacunae, which may account for up to 15% to 25% of infarcts, were underrepresented in this series because a large number of our cases had normal CT scans.¹⁸ The results in this study indicate that SPECT is sensitive and specific in detecting acute cerebral ischemia, particularly cortical ischemia, and that it will be useful in assessing perfusion in patients undergoing acute stroke reperfusion therapies during the time window of tissue viability.¹⁴

	Selected Abbreviations and Acronyms

 

ACA = anterior cerebral artery ECD = N,N1-1,2-ethylene-diylbis-L-cysteine diethylester dihydrochloride Ex WS = external watershed HMPAO = hexamethylpropyleneamine oxime IMP = N-isopropyl-p-iodoamphetamine MCA = middle cerebral artery PCA = posterior cerebral artery SPECT = single-photon emission computed tomography

	Acknowledgments

 
This work was supported by grants from the National Health and Medical Research Council of Australia and by Amersham Australasia. The staff of the Nuclear Medicine and Radiology Departments are gratefully acknowledged.

	Footnotes

 
Presented in part at the Scientific Meeting of the Australian Association of Neurologists, Canberra, Australia, May 22-25, 1994.

Received January 6, 1997; revision received February 13, 1997; accepted February 13, 1997.

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				P. A. Barber, S. M. Davis, B. Infeld, A. E. Baird, G. A. Donnan, D. Jolley, and M. Lichtenstein Spontaneous Reperfusion After Ischemic Stroke Is Associated With Improved Outcome Stroke, December 1, 1998; 29(12): 2522 - 2528. [Abstract] [Full Text] [PDF]

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