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(Stroke. 1998;29:2522-2528.)
© 1998 American Heart Association, Inc.

Original Contributions

Spontaneous Reperfusion After Ischemic Stroke Is Associated With Improved Outcome

P. Alan Barber, FRACP; Stephen M. Davis, MD, FRACP; Bernard Infeld, FRACP; Alison E. Baird, PhD, FRACP; Geoffrey A. Donnan, MD, FRACP; Damien Jolley, MSc Meir Lichtenstein, FRACP

From the Departments of Neurology (P.A.B., S.M.D., B.I.) and Nuclear Medicine (M.L.), Royal Melbourne Hospital; the Department of Neurology, Austin and Repatriation Medical Centre (A.E.B., G.A.D.); and the Department of Public Health and Community Medicine, University of Melbourne (D.J.), Australia.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—The rationale behind thrombolytic therapy in acute ischemic stroke is penumbral salvage by rapid restoration of cerebral blood flow. The relationship, however, between early reperfusion (potentially composed of both nutritional and nonnutritional components) and outcome remains unclear.

Methods—To establish the relationship between reperfusion parameters and outcome variables (Canadian Neurological Scale, Barthel Index, outcome CT scans), we used ⁹⁹Tc–hexamethylpropyleneamine oxime (⁹⁹Tc-HMPAO) single-photon emission CT (SPECT) to examine 41 acute ischemic stroke patients. All patients had at least 2 SPECT studies (24 with 3 studies), and none had been treated with thrombolytic or other acute investigational drugs.

Results—A total of 106 studies were performed. Mean time to acute study was 9.2 hours; that for subacute study was 42 hours and for outcome study was 150 days. Hypoperfusion (HP) volumes at each of the 3 time points correlated with outcome clinical state and final infarct size. Both early reperfusion (61% of patients) and nutritional reperfusion alone (56%), which is early reperfusion maintained at outcome, were associated with improvement in clinical state and better functional outcome. Early HP volume change (acute minus subacute HP volume) and total HP volume change (acute minus outcome HP volume) also correlated with clinical improvement and better outcome.

Conclusions—This study establishes the benefit of spontaneous reperfusion after ischemic stroke and emphasizes the prognostic value of HP deficit volumes. ⁹⁹Tc-HMPAO SPECT may be used to screen patients and group them according to perfusion deficit in acute stroke trials, thereby decreasing patient numbers required to show drug effect.

Key Words: cerebral blood flow • reperfusion • stroke, ischemic • tomography, emission computed

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In ischemic stroke, the degree and duration of hypoperfusion are key determinants of final infarct size.¹ Single-photon emission CT (SPECT) is rapidly able to identify regions of cerebral hypoperfusion (HP) using reliable, validated techniques.^{2 3} While conventional CT remains the investigation of choice for the triage of acute stroke patients, SPECT is more sensitive in detecting the location of acute cerebral ischemia and may show perfusion abnormalities while structural imaging is still normal.⁴ Other diagnostic techniques that can be used to study parenchymal perfusion include functional and Xe CT,^{5 6} MR perfusion imaging,^{7 8} and positron emission tomography (PET).^{9 10}

Serial studies in acute stroke patients using PET have shown that in the acute phase, regional perfusion is reduced to a greater extent than metabolism. This is followed by a period of excessive perfusion relative to metabolic needs consistent with the luxury perfusion syndrome of Lassen.¹¹ We prefer the term nonnutritional as opposed to luxury perfusion because this reperfusion is into nonviable tissue and is not maintained at outcome (Figure 1). Nutritional reperfusion, in contrast, rescues potentially viable tissue from infarction and is maintained at outcome (Figure 2). Previous work by our group has shown that acute reperfusion may consist of both nutritional and nonnutritional components, which can be delineated with the use of serial SPECT.¹²

View larger version (39K): [in this window] [in a new window]   Figure 1. Serial 99Tc-HMPAO SPECT studies showing nonnutritional reperfusion (patient 17). A, SPECT study at 10.5 hours showing left frontal HP deficit (arrow). B, At 30 hours the HP deficit has largely resolved, which is consistent with early reperfusion. C, At 95 days (outcome), the HP deficit has reappeared. Thus, the early reperfusion was not maintained, ie, was nonnutritional.

View larger version (36K): [in this window] [in a new window]   Figure 2. Serial 99Tc-HMPAO SPECT studies showing nutritional reperfusion (patient 18). A, SPECT study at 3.5 hours showing right middle cerebral artery territory HP deficit (arrow). B, At 100 hours the HP deficit has largely resolved, which is consistent with early reperfusion. C, At 99 days (outcome), the early reperfusion has been maintained, ie, was nutritional.

A number of studies have examined the relationship between perfusion changes and stroke outcome. Some report improved outcome with reperfusion,^{13 14 15 16 17 18} while others have found no such beneficial effect.^{19 20 21 22} Different methodological and technical approaches probably account for these discrepancies. In a systematic analysis, Baird et al²³ demonstrated that reperfusion within 48 hours of stroke onset was a powerful independent predictor of functional outcome; however, just over half of these patients were involved in trials of thrombolytic therapy.

In this study we used serial ⁹⁹Tc–hexamethylpropyleneamine oxime (HMPAO) SPECT to systematically examine the nature and degree of spontaneous reperfusion in a large group of acute hemispheric stroke patients not treated with thrombolytic or other investigational drugs. We aimed to clarify the individual effects of the nutritional and nonnutritional components of spontaneous reperfusion on stroke evolution and outcome by comparing these reperfusion parameters with acute changes in neurological state, clinical outcome, and final infarct size. Better delineation of these relationships may have important implications for clinical trials.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Forty-one patients (25 men, 16 women; mean age, 69.0±10.6 years; age range, 43.3 to 85.8 years) with sudden onset of focal neurological deficit consistent with hemispheric ischemic stroke were recruited from the Royal Melbourne Hospital (31 patients) and the Austin and Repatriation Medical Center (10 patients). Subjects were part of a larger group of 124 patients with a total of 294 SPECT studies investigated at our hospitals over the duration of the study. Patients who had received thrombolytic or other investigational stroke therapy were excluded, as were patients without a SPECT study within 24 hours of stroke onset or with only a single SPECT study. Other exclusion criteria included evidence of cerebral hemorrhage on the admission CT scan, a history of preexisting significant nonischemic neurological disease, or prior stroke, which would hinder interpretation of clinical, radiological, or SPECT data. This study was performed with the approval of the ethics committees at our institutions, and written informed consent was obtained from the patient or next of kin.

Stroke onset was defined as the time the patient was last known to be without neurological deficit. For the purposes of this investigation, acute studies were defined as those performed within 24 hours of stroke onset because there is evidence from PET^{10 24 25} and combined MR perfusion imaging and diffusion-weighted imaging^{26 27} studies that potentially viable tissue may still be present at this time. Subacute studies were defined as those performed between 24 hours and 12 days because the incidence of spontaneous reperfusion increases from 0% at the time of stroke onset to 77% over the first 2 weeks.¹⁷ Outcome studies were defined as those performed at or after 3 months.

A total of 106 ⁹⁹Tc-HMPAO SPECT studies were performed (Table 1). All 41 patients had acute studies. Twenty-four patients had 3 SPECT studies, and 17 patients had 2 studies (7 with acute and subacute SPECT studies and 10 with acute and outcome studies). Three patients died before the end of the study; 2 declined follow-up, and an additional 2 were lost to follow-up.

View this table: [in this window] [in a new window]   Table 1. Summary of Patient Results

Clinical Assessment
The modified Canadian Neurological Scale (CNS) (full normal score of 11.5),²⁸ a validated neurological impairment scale, was performed at the same time as each of the 3 SPECT studies. The Barthel Index (BI) (full normal score of 100),²⁹ a validated functional disability scale, was performed at the time of the outcome studies. The CNS and BI clinical scales were used because they measure different aspects of recovery after stroke.

Change in neurological state in the first days after stroke (early CNS) was defined as the subacute study CNS score minus the acute study CNS score. Change in neurological state over the duration of the study (total CNS) was defined as the outcome CNS score minus the acute CNS score. A worsening in neurological state between 2 study points therefore resulted in a negative CNS score. All clinical assessments were performed just before SPECT studies by a neurologist or neurology resident without knowledge of the SPECT or CT results. The 3 patients who died were assigned outcome CNS and BI scores of 0.

Imaging
⁹⁹Tc-HMPAO SPECT studies were obtained with the use of the triple-headed systems Siemens Multispect 3 (MS3) and Trionix Triad and the single-headed GE400 AC Starcam camera. Scans were performed with the same camera for each patient. ⁹⁹Tc-HMPAO (15 to 25 mCi, Ceretec-Amersham International) was injected as soon as possible after the initial CT scan had been performed, either in the emergency department or the CT scanning suite. SPECT studies were performed within 2 hours of injection. All SPECT studies were obtained with low-energy, high-resolution collimators with the following: 96 frames and a matrix of 128x128 pixels (1 pixel=2.46 mm) on the MS3 scanner; 64 frames and a matrix of 128x128 pixels (1 pixel=3.1 mm) with the GE400 system; and 120 frames and a matrix of 256x256 pixels (1 pixel=1.78 mm) with the Triad system. Images were reconstructed with the use of Chang's attenuation coefficient. Slice thickness was 2 pixels for the MS3 and GE400 systems and 3 pixels for the Triad system. The full-width half-maximum resolution was 7.13 mm for the MS3 system, 11.0 mm for the GE400 system, and 9.0 mm for the Triad system.

The cerebral HP volume was quantified by a nuclear medicine technician, with knowledge of the clinical localization of the stroke but not of the CT scan results, using a validated adaptation of the technique of Mountz.^{2 3} All involved transaxial slices were identified on a computerized video display. Regions of interest corresponding to the outline of the infarct and the corresponding region in the contralateral normal hemisphere were obtained with a cursor system. Counts from within the normal and lesion regions of interest for all involved slices were obtained and summed to produce total normal and lesion counts, respectively. A total brain count histogram was then generated. This is a plot of the frequency of all voxel count values within all cerebral slices of the brain image from which the count value of a normal voxel or the "normalized voxel count" can be obtained.³ The total volume of the regional hypoperfusion was then calculated according to the following formula: HP volume=[(normal counts-lesion counts)/ normalized voxel count]xvoxel volume

Changes in HP volume between studies were defined and calculated as follows: (1) Early HP volume change was defined as the acute HP volume minus the subacute HP volume in those patients who had SPECT scans at both of these time points. Early reperfusion would be indicated by a decrease in the HP volume between these 2 stages and would yield a positive early HP volume change. (2) Total HP volume change was defined as the acute HP volume minus the outcome HP volume. A positive total HP volume change would indicate reperfusion maintained at outcome, ie, nutritional reperfusion. (3) Late HP volume change was defined as the subacute HP volume minus the outcome HP volume.

Thirty patients had CT scans (GE9800 high-resolution CT scanner) on the same day as the outcome SPECT studies. Contiguous 1-cm-thick transaxial slices were obtained. Volumetric analysis was performed by a neuroradiologist without knowledge of the clinical scores or SPECT study results. The area of infarction on each slice was obtained by electronically tracing around the region of infarction with a semiautomated computer program and cursor system. The ventricles, prominent sulci, and low-attenuation artifacts were carefully excluded. The lesion areas were then multiplied by the slice thickness to obtain the final infarct volume.

Statistical Analysis
Demographic data are presented as mean±SD. Dependent variables are compared with nonparametric techniques except when normality could be proven, in which case parametric equivalents were used and presented as mean difference with 95% CI. Corrections were made for paired data and unequal variance when appropriate. Pearson's product moment correlation coefficient was used as an estimate of the strength of association between HP volumes and clinical measures (CNS, BI) and final infarct size. Results were considered statistically significant at the 5% level.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Changes in Hypoperfusion Volumes Over Time
There was a mean HP volume decrease of 14±67% in the 31 patients who had both acute and subacute SPECT studies (mean volume difference=7.0 cm³; CI, -4.6 to 18.5 cm³; P=0.23, paired Student's t test), consistent with early reperfusion. The mean HP volume then increased in the 24 patients who had both subacute and outcome studies; however, this change also failed to reach statistical significance (mean volume difference=-5.2 cm³; CI, -13.5 to 3.2 cm³; P=0.21, paired Student's t test).

Four patterns of HP volume change were seen between the acute and subacute studies and between the subacute and outcome studies: early reperfusion followed by late expansion (12 patients); reperfusion followed by further decrease in HP volume (2 patients); early HP volume expansion followed by reperfusion (6 patients); and both early and late HP volume expansion (4 patients). When the ² test was used to examine the null hypothesis that there is no difference in the pattern of HP volume changes between the 3 SPECT studies, the pattern of early HP volume shrinkage followed by late HP volume expansion differed from that expected by chance (²=9.34, 3 df, P<0.05).

Hypoperfusion Volume Correlations
Significant correlations were found between the acute HP volumes and the acute CNS scores (r=-0.42, P<0.05), outcome CNS scores (r=-0.59, P<0.05), outcome BI scores (r=-0.61, P<0.05), and final infarct size (r=0.81, P<0.0005). Subacute HP volumes correlated with the subacute CNS scores (r=-0.50, P<0.05), outcome CNS scores (r=-0.75, P<0.0005), outcome BI scores (r=-0.77, P<0.005), and final infarct size (r=0.94, P<0.0005). Outcome HP volumes correlated with the outcome CNS scores (r=-0.60, P<0.0005), outcome BI scores (r=-0.55, P<0.01), and final infarct size (r=0.92, P<0.0005). Hence, HP volumes at each of the studies correlated with clinical scores at that time point as well as with clinical outcome and eventual infarct size.

Early HP volume change (acute minus the subacute HP volume) correlated with the subacute CNS scores (r=0.42, P<0.05), outcome CNS scores (r=0.49, P<0.05), outcome BI scores (r=0.44, P<0.05), and final infarct size (r=-0.67, P<0.05). Early HP volume change also correlated with both early CNS (subacute minus acute CNS score) (r=0.63, P<0.005) and total CNS (outcome minus acute CNS score) (r=0.60, P<0.0005). Total HP volume change (acute minus outcome HP volume) correlated with the subacute CNS scores (r=0.47, P<0.05), outcome CNS scores (r=0.55, P<0.005), and final infarct size (r=0.58, P<0.05). Total HP volume change also correlated with early CNS (r=0.61, P<0.005) and total CNS (r=0.47, P<0.005). Late HP volume change (subacute minus outcome HP volume) did not correlate with any of the clinical outcome scores or final infarct size (outcome CNS score, P=0.91; outcome BI score, P=0.30; final infarct size, P=0.85).

Early Reperfusion
Patients were divided into those with reperfusion between the acute and subacute studies (early reperfusion), which might consist of both nutritional and nonnutritional components, and those with an early expansion of the HP volume (Table 2). Of the 31 patients with both acute and subacute SPECT studies, 19 (61%) had early reperfusion and 12 (39%) had an early expansion of the HP volume. In no case did full reperfusion occur. The 2 groups were well matched for age and time to acute and subacute scans. The group with early reperfusion had better outcome CNS scores, early and overall improvement in CNS scores, and smaller subacute and outcome HP deficit volumes. There were also trends toward improved outcome BI scores and smaller final infarct size, although these differences did not reach statistical significance, possibly because of small patient numbers.

View this table: [in this window] [in a new window]   Table 2. Comparison of Patients With and Without Both Early and Nutritional Reperfusion

Fourteen of 24 patients (58%) with SPECT studies at each of the 3 time points had early reperfusion (acute/subacute studies). At the outcome study, 31.4±97% of this early reperfusion had been maintained, ie, approximately one third of the early reperfusion was nutritional reperfusion.

Nutritional Reperfusion
Patients who had both acute and outcome SPECT studies were divided into those with nutritional reperfusion (positive total HP volume change) and into those in whom there had been an expansion in the HP volume between these 2 studies (negative total HP volume change). Of the 34 patients with both acute and outcome SPECT studies, 19 (56%) had nutritional reperfusion (Table 2). The 2 groups were well matched for age and time to acute scan and outcome scans. The group with nutritional reperfusion had better outcome CNS and BI scores, early and overall improvement in CNS scores, and smaller outcome HP deficit volumes. There were also trends toward smaller final infarct size (P=0.06). Thus, nutritional reperfusion was associated with improvement in clinical scores and better functional outcome.

Nonnutritional Reperfusion
Finally, we examined the relationship between nonnutritional reperfusion and outcome. There was no clinical evidence of recurrent stroke in any of the patients after the subacute study. Therefore, any subsequent late expansion of the HP volume (subacute/outcome studies) reflected early reperfusion that had not been maintained at outcome ie, nonnutritional or luxury reperfusion.^{11 12} Of the 24 patients who had both subacute and outcome SPECT studies, 12 (50%) had evidence of nonnutritional reperfusion. Patients with nonnutritional reperfusion were well matched with those with a contraction of the HP volume between the subacute and outcome studies for age (mean age difference=4.7 years; CI, -4.6 to 14.0 years; P=0.31), acute HP volume (mean volume difference=-4.6 cm³; CI, -32.6 to 23.4 cm³; P=0.74), and acute CNS score (6.25±2.6 [nonnutritional reperfusion group] versus 7.2±3.2; P=0.38, Mann-Whitney U test). There were no significant differences in outcome HP volume (mean volume difference=23.5 cm³; CI, -14.7 to 61.8 cm³; P=0.22), final infarct size (mean volume difference=23.3 cm³; CI, -29.1 to 75.8 cm³; P=0.36), CNS score (9.8±1.9 [nonnutritional reperfusion group] versus 8.0±3.2; P=0.26, Mann-Whitney U test), or BI (88.8±23.1 [nonnutritional reperfusion group] versus 77.7±35.4; P=0.35, Mann-Whitney U test). Thus, nonnutritional reperfusion was not associated with either an improved or an adverse outcome.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This natural history study emphasizes the correlation between acute and subacute HP deficit volumes and clinical and radiological outcome in ischemic stroke. Extending previous work by our group,^{21 23} we have also shown that spontaneous reperfusion is common after stroke and is usually incomplete. However, only approximately one third of this reperfusion is nutritional to ischemic tissues and hence maintained at outcome. Both early reperfusion (acute/subacute studies) and nutritional reperfusion (early reperfusion maintained at outcome) correlate with improving neurological state and better clinical and radiological outcome compared with those patients without reperfusion. Finally, this study has demonstrated the usefulness of ⁹⁹Tc-HMPAO SPECT in following perfusion changes over time in patients with ischemic stroke.

In this study the mean HP deficit volume decreased between the acute and subacute studies, consistent with spontaneous early reperfusion. The HP deficit then went on to expand between the subacute and outcome studies. We have previously noted this pattern of early reperfusion followed by subsequent late expansion of the HP deficit in a smaller group of patients.¹² Four patients had both early (acute/subacute study) and late (subacute/outcome study) HP deficit expansion. None of these patients had clinical evidence of recurrent stroke; indeed, CNS scores remained constant or improved between studies in all 4. While nonnutritional reperfusion may have occurred before the acute SPECT studies, other possible explanations for the late HP deficit expansion seen in this group include the presence of peri-infarct diaschisis at the time of the outcome study or the expansion of the ischemic zone beyond the initial HP deficit due to excitotoxic damage with spreading depression and/or recurrent depolarizations.^{30 31}

SPECT can be used to retrospectively determine the proportion of nutritional and nonnutritional reperfusion in stroke patients. However, few previous studies have looked specifically at the prognostic value of these components of reperfusion.¹² Early reperfusion (acute/subacute studies) was noted in 61% of patients. The patients with early reperfusion had better clinical outcome and improvement in the CNS score between the acute and outcome studies than those without early reperfusion. These findings are in accord with previous reports that spontaneous reperfusion after stroke is common, occurring in 52% to 77% of ischemic stroke patients,^{16 17} and is associated with improved outcome.^{14 15 16 17 18 23} In addition, a previous report has noted that the percent change in cerebral tissue perfusion at 24 to 48 hours correlates with functional outcome and provides independent prognostic information.²³ Approximately one third of the early reperfusion had been maintained at outcome and was therefore "nutritional." Patients with nutritional reperfusion also had better clinical outcome and improvement in CNS scores between the acute, subacute, and outcome studies.

In contrast, patients with nonnutritional reperfusion, as indicated by expansion of the HP volume between the subacute and outcome studies, did not fare any better or worse than those without nonnutritional reperfusion. In addition, late HP volume change (subacute minus outcome HP deficit) did not correlate with clinical or radiological outcome. This is of interest because in a subgroup of patients in the Australian Streptokinase Trial, we found that streptokinase given within 4 hours of stroke onset increased the nonnutritional component of early reperfusion and that this was associated with an adverse outcome, presumably because of hemorrhagic transformation, edema, and reperfusion injury.¹² A more recent study found that tissue plasminogen activator administered within 3 hours of stroke onset improved perfusion and that this was associated with improvement in clinical score.³² When streptokinase is given within 3 hours of stroke onset, there is a trend to beneficial effect.^{33 34} In another report of patients treated with tissue plasminogen activator, of those patients who had evidence of reperfusion by 24 hours, the earlier tissue plasminogen activator had been given, the greater was the clinical improvement.¹⁵ This suggests that the earlier thrombolytic treatment is given, the greater is the proportion of nutritional reperfusion.

One of the limitations of SPECT is that the proportions of nutritional and nonnutritional perfusion cannot be determined on the basis of a single study. This important prognostic information is therefore unavailable when a patient first presents and can only be inferred in retrospect from subsequent studies. Three-dimensional functional CT⁵ and Xe CT,⁶ which can identify regions of abnormal perfusion and be combined with conventional CT and CT angiography in the same brief examination, are also unable to determine whether perfusion is nutritional in the acute setting. Stable Xe also has the disadvantage of having a mild, short-acting anesthetic effect. In contrast, PET can demonstrate regions of hypoperfusion with concomitant demonstration of the ischemic core.^{9 10} However, PET is only available in a small number of research centers, and practical difficulties and safety considerations limit its routine use. In addition, combined MR perfusion imaging and diffusion-weighted imaging may identify hypoperfused but potentially viable tissue,^{26 27 35 36} although more research is required to determine its exact role in the investigation of acute stroke patients.

Image degradation and distortion due to photon attenuation and scatter, inadequate spatial resolution, and partial volume effects are the major limitations to accurate quantification of HP lesions on SPECT images. The volumetric analysis algorithm we used, as previously described,³ has attempted to take these effects into account. Although inevitable errors in region of interest placement occur, we have found that the interobserver variability for this analysis algorithm was not significantly different from zero.³ In addition, the same protocol was used in each patient for all studies, and therefore these effects are constant between studies. We believe that the changes in HP volume reflect true changes in perfusion and are not due to limitations in spatial resolution and partial volume effects.

In summary, this study has shown that reperfusion after stroke in a group of patients not receiving any acute interventional stroke therapy is beneficial and is composed of both nutritional and nonnutritional components. In addition, both early reperfusion and nutritional reperfusion alone correlate with stroke outcome. We suggest that ⁹⁹Tc-HMPAO SPECT may be used to screen acute stroke patients to determine the likelihood of potential response to or risk of side effects from thrombolysis. ⁹⁹Tc-HMPAO SPECT may also have a role in acute stroke trials, where it may be used to group patients according to perfusion deficit, which may decrease the number of patients required to show drug effect.

	Acknowledgments

 
This study was supported by the National Health and Medical Research Council of Australia, the National Stroke Foundation, and the Neurological Foundation of New Zealand, V.J. Chapman Research Fellowship (Dr Barber). We wish to thank Dr David Darby for his helpful comments in the preparation of this manuscript.

	Footnotes

 
Reprint requests to Stephen M. Davis MD, FRACP, Department of Neurology, Royal Melbourne Hospital, Grattan St, Parkville, Victoria 3050, Australia.

Received July 6, 1998; revision received September 24, 1998; accepted September 24, 1998.

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