Prospective Value of Perfusion and X-Ray Attenuation
Imaging With Single-Photon Emission and Transmission
Computed Tomography in Acute Cerebral Ischemia
Henryk Barthel, MD; Swen Hesse, MD; Claudia Dannenberg, MD; Annegret Rössler, MD;
Dietmar Schneider, MD; Wolfram H. Knapp, MD; Jürgen Dietrich, MD; Jörg Berrouschot, MD
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
Background and Purpose—The aim of the present study was to test the hypothesis that perfusion single-photon emission
computed tomography (SPECT), carried out in addition to transmission computed tomography (TCT), improves the
predictive value of brain imaging within the therapeutically relevant time window after acute cerebral ischemia.
Methods—Using TCT and [99mTc]ethyl cysteinate dimer (ECD)-SPECT within 6 hours after symptom onset, we examined
108 patients (44 women, 64 men; mean age 65⫾13 years) with acute ischemic stroke attributed to the territory of the
middle cerebral artery (MCA). In each case, 3 experts prospectively evaluated the early SPECT and TCT images. We
correlated these ratings with follow-up TCT findings for the final infarction as well as with clinical outcome
(Scandinavian Stroke Scale, Barthel Index, Modified Rankin Scale) after 30 and 90 days.
Results—Severe activity deficits on SPECT, not caused by local atrophy on TCT, were the best predictors (positive
predictive value [PPV ]94%, 95% CI 89% to 99%; negative predictive value [NPV] 90%, 95% CI 78% to 100%;
P⬍0.001) for evolving cerebral infarction. Complete MCA infarctions were predicted with significantly higher accuracy
with early SPECT (area under receiver operating characteristic curve [AUC] index 0.91) compared with early TCT
(AUC index 0.77) and clinical parameters (AUC index 0.73, P⬍0.05). Logistic regression analysis revealed 1
independent predictor for completed MCA territory infarction: SPECT activity deficits in the corresponding areas (PPV
88%, 95% CI 65% to 100%; NPV 96%, 95% CI 92% to 100%; P⬍0.001). Furthermore, death after stroke was optimally
predicted by [99mTc]ECD-SPECT. Clinical outcome up to 90 days after the stroke event best correlated with the degree
of activity deficits in early SPECT (r⫽0.53, P⬍0.001).
Conclusions—[99mTc]ECD brain perfusion SPECT that completes TCT definitely improves the predictive value of brain
imaging after acute cerebral ischemia. Thus, the combined imaging of brain edema and of cerebral perfusion early after
stroke is recommended for clinical use. (Stroke. 2001;32:1588-1597.)
Key Words: cerebral ischemia 䡲 stroke, acute 䡲 tomography, emission computed 䡲 tomography, x-ray computed
N
Because these entire therapeutic approaches involve the
preservation of jeopardized but viable brain tissue with
functional relevance, a diagnostic tool is required that is able
to predict the presence of salvageable brain tissue.8,9 Transmission computed tomography (TCT) has been the routine
brain-imaging method of choice for cases of acute stroke.10,11
TCT allows the exclusion of hemorrhagic stroke with high
accuracy.12 In addition, a number of TCT findings provide
evidence for an ischemic course of the stroke event: hyperdense middle cerebral artery (MCA) sign,13 focal hypoattenuation,14 and focal brain swelling.15 TCT performed early after
stroke onset is able to evaluate brain tissue viability with high
specificity16: the presence of “early signs” in TCT provides
strong evidence for an evolving infarction and reliably
excludes reversible ischemia. However, the sensitivity of
ew therapies for acute cerebral infarction have been
tested for several years. Among them, intravenous
thrombolysis within 3 hours after symptom onset represents
the first therapeutical approach that can effectively treat acute
ischemic stroke.1 Although adequate treatment should be
started as early as possible, most patients still arrive at the
hospital too late to receive the maximum benefit from this
emerging therapy.2 It is evident, however, that viable brain
tissue may persist beyond this time. 3,4 Therefore,
thrombolysis was also tested up to 6 hours after symptom
onset.5–7 Despite the recently published PROACT II trial that
first demonstrated the efficiency of intra-arterial
thrombolysis,7 up until now, thrombolysis has not been
approved for intravenous administration ⬎3 hours after
stroke onset.
Received October 19, 2000; final revision received February 2, 2001; accepted March 8, 2001.
From the Departments of Nuclear Medicine (H.B., S.H.), Radiology (C.D., J.D.), and Neurology (A.R., D.S., J.B.), University of Leipzig, Leipzig,
Germany; and Department of Nuclear Medicine (W.H.K.), Hanover Medical School, Hanover, Germany.
Presented in part at the 45th meeting of the Society of Nuclear Medicine, Toronto, Canada, June 1998, and at the 7th World Congress of Nuclear
Medicine and Biology, Berlin, Germany, September 1998.
Correspondence to Dr Henryk Barthel, PET Oncology Group, MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Du
Cane Road, London W12 0NN, UK. E-mail [email protected]
© 2001 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
1588
Barthel et al
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TCT, especially at very early time points after the stroke, is
controversial, as discussed in the literature,16,17 and must be
further investigated. There also is evidence from the literature
that the predictive value of brain imaging in acute ischemia
could be improved by the addition of information regarding
blood flow to information regarding early ischemic edema,
which is obtained with TCT.9,18
In a previous study, we demonstrated that single-photon
emission computed tomography (SPECT) of the brain with
[99mTc]ethyl cysteinate dimer ([99mTc]ECD) within 6 hours
after the onset of stroke symptoms is able to differentiate
between reversible cerebral ischemia and evolving cerebral
infarction.19 In the case of evolving infarction within the
MCA territory, [99mTc]ECD-SPECT, performed at the acute
stage, allows a prediction of complete (“malignant”) infarction.20 Even clinical outcome can be reliably predicted with
early [99mTc]ECD-SPECT.21
Until now, no studies have compared brain TCT with
[99mTc]ECD-SPECT within the therapeutically relevant time
window of 6 hours, particularly with respect to the identification of (1) patients with spontaneously good prognosis,
who do not need specific treatment, (2) patients with evolving
infarctions, who would profit from adequate therapy, and
(3) patients with the risk of complete (malignant) MCA
territory infarctions,22 in whom clinical outcome probably
could be improved by alternative treatment strategies such as
decompressive hemicraniectomy or hypothermia.23,24 Thus,
in the present study, we prospectively tested the hypothesis
that [99mTc]ECD-SPECT, performed in combination with
TCT, can improve the predictive value of non– contrastenhanced TCT alone early after stroke.
Subjects and Methods
Subjects
In this study of combined TCT and SPECT, 108 consecutive patients
(44 women, 64 men; mean age 65⫾13 years) were prospectively
enrolled. All patients had acute neurological deficits attributed to
ischemia within the MCA territory, no stroke history, Scandinavian
Stroke Scale (SSS)25 score of ⬍40 points on admission, and TCT as
well as SPECT imaging within 6 hours after the time point at which
the acute neurological deficit was first observed. Exclusion criteria
were presence of coma, rapid improvement in symptoms during the
TCT and SPECT investigations, signs of intracerebral hemorrhage
on acute TCT, and symptoms of vertebrobasilar stroke. The study
was approved by the Ethics Committee of the University of Leipzig.
Of the 108 patients, 39 represent the first group of patients, who were
included at the University of Leipzig in an ongoing double-blind,
placebo-controlled trial (ECASS II [Second European-Australian
Acute Stroke Study]26) and were treated in a randomized manner
with recombinant tissue plasminogen activator (n⫽20) or placebo
(n⫽19). The SPECT results for the patients who were included in the
ECASS II trial at the University of Leipzig were recently
published.27
Protocol and Clinical Investigation
Immediately after admission to the hospital, all patients were
clinically examined, including blood pressure measurement, evaluation of consciousness, eye inspection with respect to putative gaze
palsy or conjugate eye deviation, cardiac examination, and SSS (46
points maximum, without “gait”). Clinical examination was followed by TCT and SPECT imaging. To save time, in 43 patients the
radiopharmaceutical agent for SPECT imaging was administered
directly before TCT. TCT was repeated 7 days after the stroke to
[99mTc]ECD-SPECT and CT in Acute Stroke
1589
evaluate extent and localization of definitive infarctions. SSS was
assessed again 30 and 90 days after stroke. Additional functional and
disability outcomes were scored after 90 days using the Barthel
Activity of Daily Living Index (0 to 100 points)28 and the Modified
Rankin Disability Scale (0 to 6 points).29
Brain Imaging
For TCT, all patients underwent non– contrast-enhanced cranial TCT
with a Somatom Plus S scanner (Siemens Inc). Axial slices of the
whole brain were obtained parallel to the orbitomeatal line. The slice
thickness was 5 mm (lower part of brain up to sellar region) and
10 mm (upper part of brain), respectively. Window width equaled
128 Hounsfield units, with the center level at 36 Hounsfield units.
For SPECT, all patients were injected intravenously with 400 to
600 MBq [99mTc]ECD.30 SPECT acquisition was begun 15 minutes
after the injection. Photons were registered with a brain-dedicated
SPECT camera (Ceraspect; DSI) with 3 rotating parallel-hole collimators.31 The SPECT data were acquired, reconstructed, attenuationcorrected, and reoriented according to a standard protocol that has
been described elsewhere.32
Image Analysis
Interpretation of the acute TCT and SPECT images was performed
visually.
Separate Analysis of Early TCT Images
The TCT images were independently evaluated by 3 experienced
interpreters. The extent of putative hypodensity and brain swelling in
MCA territory (⬍33%, 33% to 66%, or ⬎66% of MCA territory)
was rated, as well as the additional involvement of anterior or
posterior cerebral artery territories. On the basis of the TCT findings,
the outcome was rated as “transient ischemia,” “nontotal MCA
infarction,“ or “total MCA infarction.” The experts were aware of the
affected side but blinded to the severity of symptoms.
Separate Analysis of Early SPECT Images
In the same manner as for the TCT images, the SPECT images
(transverse, coronal, and sagittal slices) were independently evaluated by 3 experienced interpreters. These interpreters were also
aware of the side of the symptoms but were blinded to the results of
the TCT scoring and symptom severity. Extent of local activity
deficits within the MCA territory (⬍33%, 33 to 66%, to ⬎66%
subtotal and total MCA territory) was scored, as well as severity
(0⫽no, 1⫽mild, 2⫽moderate, 3⫽severe decrease in activity). Outcome was predicted as described for TCT images.
Combined Analysis of Early SPECT and TCT Images
The SPECT images were reinterpreted as described together with the
corresponding individual TCT images.
Categorization
The follow-up TCT images were analyzed by 1 of the experts, who
was blinded to the ratings of the initial TCT and SPECT images,
concerning the occurrence of hypodensities. According to these
findings, the patients were separated into 3 groups: group A (n⫽24)
had no hypodensities, group B (n⫽73) had hypodensities in subtotal
MCA territory, and group C (n⫽11) had hypodensities in total MCA
territory. This grouping was performed with consideration for
possible subsequent pooling of the study population according to the
different hypotheses to be tested: prediction of evolving subtotal
(groups B plus C versus group A) or total (group C versus groups A
plus B) MCA territory infarctions.
Statistical Analysis
Differences between the patient groups in the number of SPECT and
TCT findings were tested for significance using the Student’s t test
for independent samples after verification of normal distribution with
the statistical software package SPSS. Normal values were given
with 1 SD. Significance levels for differences were set at P⬍0.05,
P⬍0.01, and P⬍0.001. Interobserver variability of the visual SPECT
1590
Stroke
TABLE 1.
July 2001
Clinical Data for the Different Patient Groups
Group A
(No Final
Infarction)
Parameter
Age, y*
Group B
(Final Subtotal MCA
Territory Infarction)
Group C
(Final Total MCA
Territory Infarction)
P
(Group A vs
Group B)
P
(Group B vs
Group C)
NS
66⫾14
65⫾12
67⫾14
NS
Sex, % female (F/M)
42 (10/24)
38 (28/73)
55 (6/11)
NS
NS
Side of ischemia, % left hemisphere
46 (11/24)
64 (47/73)
27 (3/11)
NS
⬍0.05
Time of SPECT,* h†
4.2⫾1.9
4.0⫾1.6
3.7⫾1.3
NS
NS
SSS score, points*‡
36⫾3
29⫾8
25⫾7
⬍0.001
NS
Systolic BP, mm Hg*‡
155⫾20
161⫾24
170⫾25
NS
NS
Diastolic BP, mm Hg*‡
89⫾10
87⫾13
89⫾11
NS
NS
Impaired consciousness, % (n)‡
4 (1/24)
15 (11/73)
36 (4/11)
NS
⬍0.05
Eye signs, % (n)‡§
4 (1/24)
25 (18/73)
55 (6/11)
⬍0.05
NS
Cardiac arrhythmia, % (n)‡
17 (4/24)
36 (26/73)
50 (5/10)
NS
NS
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BP indicates blood pressure.
*Values are mean⫾SD.
†Duration between onset of stroke symptoms and injection of radiopharmaceutical agent.
‡Status on admission.
§Gaze palsy/conjugate eye deviation.
and TCT analyses was assessed by calculating the ␬ statistics for the
ratings of each of the 3 independent experts. Receiver operating
characteristic (ROC) parameters for results of SPECT and TCT
image analyses, as well as clinical findings, were calculated with the
software CLABROC for continuously distributed variables and
CORROC2 for categorical rating-scale variables. ROC curves were
fitted by application of the software ROCFIT. Accuracy, positive
predictive value (PPV), negative predictive value (NPV), and relative risk were calculated after cutoff values were defined with the
help of the corresponding ROC data and that of cross-tables,
respectively. Proportions were presented with 95% CI values. After
these univariate analyses, multivariate analyses were performed to
identify independent parameters for the prediction of infarction, total
MCA territory infarction, or death after stroke. For that, logistic
regression analysis was carried out using stepwise forward selection
of variables with Wald’s testing. Correlations between clinical, TCT,
and SPECT data on admission and clinical follow-up parameters
were characterized by calculation of Kendall’s ␶ rank correlation
coefficients and (linear) regression analyses.
Results
Patient Characteristics
Group characteristics concerning individual and clinical data
for the patients are listed in Table 1. No significant differences were found between groups A (no hypodensities on
final TCT), B (subtotal MCA territory hypodensities on final
TCT), and C (total MCA territory hypodensities on final
TCT) with respect to age and sex distribution or regarding
systolic and diastolic blood pressure and occurrence of
cardiac arrhythmia. SSS score on admission was significantly
higher in group A patients than in group B and C patients
(mean⫾SD 36⫾3 versus 29⫾8 and 25⫾7, respectively),
whereas the difference between groups B and C was insignificant. Impairment of consciousness, evaluated on admission, was observed significantly more often in group C than
in group B. Gaze palsy/conjugate eye deviation occurred in
only 4% of patients in group A in comparison to 25% of
patients in group B (Table 1).
Analysis of Early TCT and Perfusion
SPECT Images
In early TCT, hyperdense MCA sign was observed significantly more often in group B than in group A (10% versus
0%, P⬍0.05), as well as focal hypodensities (64% versus 8%,
P⬍0.001) and brain swelling (51% versus 4%, P⬍0.001). In
a comparison of the findings between groups B and C, a
highly significant group difference was found regarding the
Figure 1. Early TCT (left), SPECT
(middle), and follow-up TCT
(right) images of a patient with a
final infarction in the total right
MCA territory. Early hypodensities and brain swelling are
shown in the complete right
MCA territory (arrows) on acute
TCT, with corresponding activity
deficit in the total MCA territory
on acute SPECT. The patient
underwent decompressive hemicraniectomy 2 days after the
stroke event.
Barthel et al
[99mTc]ECD-SPECT and CT in Acute Stroke
1591
Figure 2. Results of early TCT,
SPECT, and follow-up TCT in a
patient with a final infarction in
the total left MCA territory. In
acute TCT, early signs of evolving infarction were rated only in
left putaminal area (arrow). Acute
SPECT imaging, however,
revealed an activity deficit in the
complete left MCA territory.
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
occurrence of focal hypodensities/brain swelling in ⬎66% of
the MCA territory (3% versus 36%, P⬍0.001). Interobserver
variability concerning the early TCT analysis, defined as
mean variation among the ratings of the 3 experts, was 17.1%
(␬⫽0.33, P⬍0.001), and that of early SPECT analysis was
4.4% (␬⫽0.75, P⬍0.001). SPECT imaging was carried out
1.3 to 6.0 hours (mean 4.0⫾1.6 hours) after the onset of
stroke symptoms, without significant differences within that
period, defined as duration between symptom onset and
injection of the radiopharmaceutical agent, among the 3
patient groups (Table 1). With respect to the early SPECT
findings, highly significant differences were found between
all patient groups: Activity deficits with an extent of ⬎33%
of the MCA territory were more often observed in group B
than in group A (76% versus 21%, P⬍0.001), and those in the
total MCA territory were more often observed in group C
than in group B (64% versus 1%, P⬍0.001). Highly signifiTABLE 2.
cant differences between groups A and B were further
found concerning the frequency of activity deficits with a
degree of ⬎1 in the visual scoring (17% versus 97%,
P⬍0.001). Figures 1 and 2 give examples of early imaging
results of 2 patients from group C: although in the case of
the patient in Figure 1, early TCT revealed hypodensities
and brain swelling in the total MCA territory, in the case
of the patient in Figure 2, hypodensities were rated only in
the left putaminal area. Early SPECT imaging, however,
showed activity deficits in complete MCA territories in
both patients.
Prediction of Evolving Infarction
Patients with final infarctions (groups B and C) were pooled and
compared with the patients without final infarction (group A).
Predictive values, calculated relative risk in case of the presence
of clinical signs on admission, and TCT and SPECT findings for
Impact of Clinical Data on Admission and Early Imaging Data for Prediction of Infarction
Groups B and C
(n⫽84)
Group A
(n⫽24)
PPV, %
(95% CI)
NPV, %
(95% CI)
Relative Risk
for Infarction
P*
P†
SSS‡ ⬍33 points (n⫽60)
56
4
93 (87–100)
42 (28–56)
1.60
⬍0.001
⬍0.05
Eye signs‡§ (n⫽25)
24
1
96 (88–100)
28 (18–37)
1.33
0.012
NS
At least 1 “early sign”㛳 in TCT (n⫽65)
62
3
95 (90–100)
49 (34–64)
1.86
⬍0.001
NS
Focal hypodensity in TCT (n⫽58)
56
2
97 (92–100)
44 (30–58)
1.72
⬍0.001
NS
Hypodensity in basal ganglia in TCT (n⫽21)
20
1
95 (86–100)
26 (17–36)
1.29
0.032
NS
Parameter
Brain swelling in TCT (n⫽46)
45
1
98 (94–100)
37 (25–49)
1.56
⬍0.001
0.059
Focal hypodensity/swelling ⬎33% MCA
territory in TCT (n⫽13)
13
0
100 (100–100)
25 (17–34)
1.34
0.04
NS
SPECT activity deficit of any extent (n⫽102)
84
18
82 (75–90)
100 (100–100)
¶
⬍0.001
NS
SPECT activity deficit extent ⬎33% MCA
territory (n⫽72)
67
5
93 (87–99)
53 (36–69)
1.97
⬍0.001
NS
SPECT activity deficit severity ⬎1 (n⫽88)
82
6
93 (88–98)
90 (77–100)
9.32
⬍0.001
NS
SPECT activity deficit severity ⬎1, not
caused by local atrophy in TCT (n⫽87)
82
5
94 (89–99)
90 (78–100)
9.90
⬍0.001
⬍0.001
All relevant parameters with significant P values after univariate ␹2 testing are listed.
*Univariate ␹2 testing.
†Multivariate logistic regression analysis.
‡Status on admission.
§Gaze palsy/conjugate eye deviation.
㛳Hyperdense MCA sign, focal hypodensity, or brain swelling.
¶Not calculated, because no false-negative cases were observed.
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July 2001
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Figure 3. False-positive prediction of evolving infarction on early
SPECT (right) in a patient with acute right hemiparesis and
aphasia. There is no activity uptake in left temporal area
(arrows), caused by local trophy on early TCT (left). Combined
interpretation of early TCT and SPECT resulted in the correct
prediction of reversible ischemia.
the prediction of evolving cerebral infarction are listed in Table
2. The highest PPVs and NPVs were found for a parameter of
combined interpretation of early TCT and SPECT images:
activity deficits in SPECT with a severity of ⬎1 in visual
scoring, which were not caused by local atrophy (PPV 94%,
NPV 90%). An example of false-positive scoring in the separate
interpretation of the early SPECT images due to local atrophy is
illustrated in Figure 3. Multivariate logistic regression analysis
revealed both SSS scoring on admission and severity of activity
deficits in SPECT to be independent predictors of evolving
infarction. Combination of information from these 2 independent predictors resulted in an accuracy of 91% for the prediction
of evolving infarction (Table 3). The application of the optimal
clinical, TCT, and SPECT predictors and the combination of
their predictive impact according to the course of events within
the clinical setting (clinical examination, TCT, brain perfusion
SPECT) resulted in stepwise improvement in accuracy from
70% to 83% and 93%. This improvement in accuracy was
attributed to an improvement in NPV (Figure 4).
Prediction of Total MCA Territory Infarction
The group of patients with a final total MCA territory
infarction (group C) was compared with a pool of patients
without a final total MCA territory infarction (groups A and
B). The highest impact on the prediction of total MCA
territory infarction among all clinical and early TCT and
SPECT parameters was calculated for the extent of activity
deficits in SPECT. Deficits with an extent of 100% of the
MCA territory were found in 7 of 11 group C patients and in
only 1 of 97 group A and B patients. Multivariate analysis
revealed the extent of SPECT defects to be the only independent predictor of total MCA territory infarction (Tables 3 and
4). ROC analysis resulted in a significant larger area under
the ROC curve (AUC) concerning the extent of the activity
deficit scored in the early SPECT images (AUC index 0.91)
compared with that concerning SSS scoring on admission
(AUC index 0.73) and the extent of hypodensities/brain
swelling rated on early TCT images (AUC index 0.77,
P⬍0.05) (Figure 5). The combination of optimal clinical and
early TCT predictors resulted in an improvement in accuracy
from 58% to 92%, with further improvement after the
addition of SPECT information (94%). This stepwise improvement was the result of substantially higher PPV by adding the
parameters of brain imaging to the clinical score (Figure 6).
Prediction of Clinical Outcome
Death after stroke occurred in 12 patients (11%). Among all
clinical, TCT, and SPECT parameters, it was optimally
predicted with the information on the extent of activity
deficits in SPECT (PPV 88%, NPV 95%, P⬍0.001). Activity
deficits on SPECT in the total MCA territory, as well as
coinvolvement of the territories of the anterior and posterior
cerebral arteries to the MCA territory, were revealed to be
independent predictors of death after stroke (P⬍0.001 and
⬍0.012 after multivariate logistic regression analysis). The
combination of these 2 independent predictors resulted in an
accuracy of 93% (Table 3). Correlations between parameters
of clinical outcome (SSS after 30 and 90 days, Barthel Index
after 90 days, and Modified Rankin Scale after 90 days) and
clinical parameters on admission as well as early TCT and
SPECT parameters are shown in Table 5: whereas in the case
of SSS scoring after both 30 and 90 days, the highest
coefficients were calculated for correlation with SSS scoring
on admission (r⫽0.50 and 0.52), with respect to the Barthel
Index after 90 days and the Modified Rankin Scale after 90
days, the highest coefficients were found for the correlation
with the degree of activity deficits on early SPECT (r⫽0.46
and 0.53).
Discussion
The present study was initiated to test whether brain SPECT
with [99mTc]ECD, carried out in combination with TCT, can
improve the prospective value of brain imaging within 6
TABLE 3. Optimal Predictive Values of Combined Information on Clinical Status on Admission
and Early TCT and Perfusion SPECT Imaging
Event
Parameter
Accuracy, %
(95% CI)
PPV, %
(95% CI)
NPV, %
(95% CI)
P*
90 (80–96)
94 (82–100)
⬍0.001
Infarction
SPECT/TCT⫹CD
91 (85–96)
Total MCA territory infarction
SPECT1
95 (91–99)
88 (65–100)
96 (92–100)
⬍0.001
Death after stroke
SPECT1⫹SPECT2
93 (88–98)
100 (100–100)
92 (87–97)
⬍0.001
Combinations of all independent parameters (result of multivariate logistic regression analyses) were tested.
*␹2 testing.
SPECT/TCT, activity deficit severity ⬎1 in SPECT, not caused by local atrophy in TCT; CD, SSS scoring ⬍33 points;
SPECT1, activity deficit in total MCA territory; SPECT2, coinvolvement of ACA and PCA territory.
Barthel et al
[99mTc]ECD-SPECT and CT in Acute Stroke
1593
Figure 4. Prediction of evolving infarction corresponding to the course of events in the clinical
setting. There is improvement after the stepwise
addition of information on early TCT and SPECT
imaging to information on clinical symptomatology
on admission.
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
hours after the onset of stroke symptoms. Both imaging
modalities were first applied in a time window in which
decisions regarding treatment can be derived from the obtained diagnosis. Previous studies that compared brain perfusion SPECT and TCT in early stages (within 48 hours) of
stroke were carried out, with the only exception being a study
by Giubilei et al33 of 32 patients, ⬎6 hours after stroke
symptom onset.34 –39 Because until now optimal treatment
strategy beyond the 6-hour time window has not been found,
diagnosis at this time after stroke in most cases lacks
therapeutical relevance. Therefore, in the present study, we
included only patients (n⫽108) who underwent both TCT
and [99mTc]ECD-SPECT imaging within 6 hours after the
onset of symptoms.
Furthermore, we compared TCT with SPECT images
obtained using the radiopharmaceutical agent [99mTc]ECD in
the acute stage after stroke. The cited studies were exclusively carried out using the local cerebral blood flow (lCBF)
TABLE 4.
tracer [99mTc]hexylmethylpropylene amineoxine (HMPAO)
or 133Xe,35 respectively. SPECT studies with 133Xe have lower
spatial resolution than 99mTc studies (6 to 7 mm with highresolution SPECT systems31) due to physical characteristics
of the isotope. Two brain perfusion radiopharmaceutical
agents labeled with 99mTc are available: in comparison to the
originally introduced [ 99m Tc]HMPAO, 40 the secondgeneration lCBF tracer [99mTc]ECD41 offers a number of
advantages. First, there is a stronger correlation between the
uptake of the radiopharmaceutical agent and cerebral blood
flow in lower flow rates, which results in higher sensitivity
for the detection of smaller infarctions.42 Second, in contrast
to the brain uptake of [99mTc]HMPAO, that of [99mTc]ECD is
codetermined by metabolic integrity and viability of the brain
tissue.43,44 Third, as reported by our group, image quality and
radiochemical stability are higher with the use of [99mTc]ECD,
even compared with the recently introduced stabilized
[99mTc]HMPAO compounds.45
Impact of Clinical Data on Admission and Early Imaging Data for Prediction of Total MCA Territory Infarction
Parameter
Ischemia of right hemisphere (n⫽47)
SSS‡ ⬍32 points (n⫽54)
Conjugate eye deviation‡ (n⫽4)
Group C
(n⫽11)
Groups A and B
(n⫽97)
8
39
10
2
PPV, %
(95% CI)
NPV, %
(95% CI)
Relative Risk for Total
MCA Territory Infarction
17 (6–28)
95 (90–100)
3.46
44
19 (8–29)
98 (95–100)
10.00
0.004
NS
2
50 (1–99)
91 (86–97)
5.78
0.007
NS
P*
P†
0.039
NS
Systolic BP‡ ⬎165 mm Hg (n⫽39)
7
32
18 (6–30)
94 (89–100)
3.10
0.045
NS
Impaired consciousness‡ (n⫽16)
4
12
25 (4–46)
92 (84–98)
3.29
0.034
NS
All “early signs”§ in TCT (n⫽6)
3
3
50 (10–90)
92 (87–97)
6.38
0.001
NS
Focal hypodensity/swelling ⬎33%
MCA territory in TCT (n⫽13)
5
8
38 (12–65)
94 (89–99)
6.09
⬍0.001
NS
Focal hypodensity/swelling ⬎66%
MCA territory in TCT (n⫽6)
4
2
67 (29–100)
93 (88–98)
9.71
⬍0.001
NS
SPECT activity deficit extent ⬎66%
MCA territory (n⫽42)
9
33
21 (9–34)
97 (93–100)
7.07
0.002
NS
SPECT activity deficit extent 100%
MCA territory (n⫽8)
7
1
88 (65–100)
96 (92–100)
21.88
⬍0.001
⬍0.001
SPECT activity deficit MCA⫹ACA/PCA
territory (n⫽11)
6
5
55 (25–84)
95 (90–100)
10.58
⬍0.001
NS
All relevant parameters with significant P values after univariate ␹2 testing are listed.
*Univariate ␹2 testing.
†Multivariate logistic regression analysis.
‡Status on admission.
§Focal hypodensity, brain swelling, or hyperdense MCA sign.
1594
Stroke
July 2001
Figure 5. ROC curves of clinical parameters on admission, as
well as early TCT (*focal hypodensity or brain swelling) and
SPECT, for the prediction of total MCA territory infarction. FPF
indicates false-positive fraction; TPF, true-positive fraction.
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
By using [99mTc]ECD for high-resolution SPECT and
comparing its prognostic impact with that of parameters of
clinical status on admission and early TCT, an improvement
in the prediction of evolving infarction was achieved. This is
particularly evident in borderline situations concerning therapeutical decisions. The combination of admission symptomatology and information obtained with TCT and SPECT
allows the prediction of evolving cerebral infarctions with an
accuracy of 93% (95% CI 88% to 98%). Symptom severity
and severity of perfusion deficits in SPECT were revealed to
be the only independent predictors of evolving infarction.
However, in cases of an infarction, involvement of the total
MCA territory is predicted with a similar accuracy of 94%
(95% CI 89% to 98%). Multivariate regression analysis
showed potential to independently predict total MCA territory infarction only for SPECT perfusion defects in total
MCA territory, not for any early signs of infarction on TCT
or clinical data. This advantage of early [99mTc]ECD-SPECT
was clearly confirmed by additional ROC analysis.
Despite the limited comparability to the above studies, our
results of higher predictive values of early SPECT compared
with those of early TCT for the prediction of infarction
correspond with the results of Giubilei et al,33 who published
the only available study that systematically compared brain
perfusion SPECT and TCT within 6 hours after acute stroke.
They used [99mTc]HMPAO as the lCBF tracer in 32 patients
and found that 7 of 8 patients (88%) with large infarctions on
follow-up TCT, but without early signs of infarction on acute
TCT, had severe perfusion defects in SPECT (asymmetry
⬎40% compared with contralateral hemisphere). Furthermore, 10 of 11 patients (91%) with smaller final infarctions
had accordingly milder perfusion disturbances.33 These results are paralleled by studies that compare brain perfusion
SPECT and TCT for the diagnosis of infarction within time
windows of 36 to 48 hours.34,37,39 However, we were able to
reproduce these findings for the newer radiopharmaceutical
agent [99mTc]ECD and, of more importance, for the therapeutically relevant time window of 6 hours.
In a comparison of the 2 imaging modalities during the
acute stage of cerebral ischemia, it should not be disregarded
that the information obtained with [99mTc]ECD-SPECT substantially differs from that obtained with TCT: Although in
the case of cerebral infarction [99mTc]ECD-SPECT directly
detects local perfusion abnormalities, TCT reveals changes in
brain tissue density due to ischemic edema. However, this
edema develops as a consequence of the initial ischemia,
which means there is a varying time delay, and it occurs only
when brain perfusion decreases under the critical threshold of
15 mL · 100 g⫺1 · min⫺1 (Pulsinelli46) (normal 50 mL · 100 g⫺1
· min⫺1). However, a comparison of the predictive values of
brain perfusion SPECT and TCT is appropriate, because both
procedures are applied within an identical clinical context
after acute ischemic stroke.
Our results of a higher predictive value with brain perfusion SPECT compared with TCT are not hampered by a lack
of quality in early TCT evaluation: Fiorelli et al47 evaluated
the occurrence of early signs of cerebral infarction in TCT
(within 5 hours after symptom onset) in a study of 158
patients and reported a PPV of 97% (95% CI 93% to 100%;
present results, 95% to 100%) and an NPV of 40% (95% CI
29% to 51%; present results, 25% to 49%) for focal parenchymal changes. In addition, von Kummer et al14 reported a PPV of
70% to 85% and an NPV of 83% to 88% of hypodensities and
focal brain swelling covering ⬎50% of the MCA territory for
the prediction of fatal clinical outcome (Oxford Handicap Scale
⬎3). In the present study, focal brain swelling/hypodensities in
⬎66% of MCA territory predicted total MCA territory infarction
with a PPV of 67% (95% CI 29% to 100%) and an NPV of 93%
(95% CI 88% to 98%). However, the PPV and NPV of our early
TCT evaluation are in accordance with those of Fiorelli et al47
and von Kummer et al.14
Figure 6. Stepwise improvement in the prediction
of total MCA territory infarction after rating of the
early TCT and SPECT images in addition to clinical
evaluation on admission, corresponding to the
sequence of event in the clinical setting.
Barthel et al
[99mTc]ECD-SPECT and CT in Acute Stroke
1595
TABLE 5. Coefficients for Correlation of Clinical and Imaging Data on Admission With
Parameters of Clinical Outcome
Parameter
Age
SSS After 30 d
⫺0.032
SSS After 90 d
⫺0.034
Barthel Index
After 90 d
⫺0.132
Modified Rankin
Scale After 90 d
0.080
0.501㛳
0.520㛳
0.414㛳
⫺0.460㛳
Impaired consciousness*
⫺0.277§
⫺0.283§
⫺0.265§
0.286§
Eye signs*
⫺0.242§
⫺0.270§
⫺0.278§
0.288§
Systolic BP*
⫺0.126
⫺0.120
⫺0.170‡
0.141
Diastolic BP*
⫺0.074
⫺0.070
⫺0.056
0.062
Extent of hypodensity in TCT
⫺0.361㛳
⫺0.359㛳
⫺0.341§
0.361㛳
Extent of brain swelling in TCT
⫺0.324㛳
⫺0.314㛳
⫺0.305§
0.318㛳
Number of “early signs”† in TCT
⫺0.380㛳
⫺0.372㛳
⫺0.311§
0.356㛳
Degree of activity deficit in SPECT
⫺0.475㛳
⫺0.475㛳
⫺0.457§
0.527㛳
Extent of activity deficit in SPECT
⫺0.441㛳
⫺0.431㛳
⫺0.410§
0.432㛳
SSS*
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
BP indicates blood pressure.
*Status on admission.
†Hyperdense MCA sign, focal hypodensity, or brain swelling.
‡P⬍0.05, §P⬍0.01, and 㛳P⬍0.001 (Kendall ␶ testing).
An interesting finding resulted from the analyses of predictive
values of early TCT and [99mTc]ECD-SPECT for the prediction of
evolving cerebral infarctions. Optimal PPV and NPV were calculated for perfusion defects that were not caused by local atrophy,
whereby this information was obtained from the combined TCT
and SPECT image interpretation. In the future, such combined
measurements of different pathophysiological parameters could
play an important role, particularly in the determination of ischemic
penumbra,48 which represents the target of most stroke therapies49
and could be diagnosed by combining evaluations of brain tissue
viability and blood flow/oxygen concentration.18,9,50
Weir et al51 investigated a subgroup of 28 stroke patients
within 16 hours of symptom onset by using [99mTc]HMPAOSPECT and concluded that the accuracy of clinical follow-up
prediction decreases the longer the SPECT imaging is delayed, so we focused on the prediction of clinical outcome of
the stroke patients within the early time window of 6 hours.
In the comparison of early brain perfusion SPECT with TCT
and clinical data on admission, only 2 SPECT parameters
regarding the extent of lCBF defects, and no early TCT
parameters or clinical data on admission, were found to be
independent predictors of death after the stroke (overall
accuracy 93%, 95% CI 88% to 98%). Among all clinical and
early TCT and SPECT parameters, the functional and disability outcome after 3 months was best correlated with the
degree of the initial perfusion defect (r⫽0.06 and 0.53,
P⬍0.001). Our results are paralleled by studies of Lees et al52
and Laloux et al,37 who reported the volume of SPECT, but
not of TCT defects or Canadian Neurological Score on
admission, to be a significant predictor of clinical outcome. In
contrast to our study, these authors exclusively compared
SPECT and TCT results, which were acquired later than the
therapeutical relevant time window of 6 hours.52,37
In present study study, the interobserver variability of
[99mTc]ECD-SPECT interpretation was revealed to be substantially lower than that of TCT interpretation. Only moderate
interobserver agreement for TCT analyses was confirmed by
von Kummer et al.53 This problem with the quality of TCT
analysis resulted, for example, in the inclusion of 52 patients in
the ECASS I trial (8.4% of the ECASS I population) despite
extended hypoattenuation in early TCT, which was detected by
additional retrospective evaluation.54 It can be speculated that in
the future, not only diagnosis of acute cerebral ischemia but also
quality of studies for the testing of new therapeutical strategies
of acute stroke can be improved by including such additional
diagnostic information, which can be obtained with lower
interobserver variability.
A possible limitation of the present study must be considered. Discrimination of the patient groups was performed
depending on the results of a follow-up TCT examination
after 7 days. Because Baron and Marchal55 noted that TCT
within this period after stroke onset is not optimum for
assessment of the extent of the final infarction due to
vasogenic edema and mass effects, it cannot be guaranteed
that all patients were correctly grouped. In addition, it cannot
be completely excluded that the “fogging” effect, in which
initially hypodense ischemic areas become isodense compared with normal brain tissue,56 could have compromised the
quality of the follow-up TCT evaluation. However, literature
shows that many stroke investigators schedule the follow-up
TCT to evaluate the final infarction within the time range of
⬇5 to 7 days,36,39,57 even in large multicenter trials.6,26
In conclusion, the hypothesis that the prospective value of
brain imaging within 6 hours after the onset of cerebral
ischemia is improved by the application of [99mTc]ECD brain
perfusion SPECT in addition to TCT can be confirmed by our
results. In the case of irreversible cerebral ischemia, total
MCA infarction is predicted with high reliability. Furthermore, the prediction of clinical outcome after acute stroke is
improved. Thus, early brain perfusion SPECT in combination
with TCT has the potential to become a valuable diagnostic
tool in the acute phase after stroke.
1596
Stroke
July 2001
Acknowledgments
This work was supported by DuPont Pharmaceuticals Co. The
authors are also grateful to Jochen Halpick for the acquisition of a
number of the acute brain perfusion SPECT studies, to Johannes
Köster for his support in preparation of the analyses of the early TCT
images, and to Hisham Taha for his careful correction of the
manuscript. Furthermore, the important suggestions of Rüdiger von
Kummer during the preparation of the manuscript are acknowledged.
References
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke
Study Group. Tissue plasminogen activator for acute ischemic stroke.
N Engl J Med. 1995;333:1581–1587.
2. Smith MA, Doliszny KM, Shahar E, McGovern PG, Arnett DK, Luepker
RV. Delayed hospital arrival for acute stroke: the Minnesota Stroke
Survey. Ann Intern Med. 1998;129:190 –196.
3. Marchal G, Beaudouin V, Rioux P, de la Sayette V, Le Doze F, Viader
F, Derlon JM, Baron JC. Prolonged persistence of substantial volumes of
potentially viable brain tissue after stroke: a correlative PET-CT study
with voxel-based data analysis. Stroke. 1996;27:599 – 606.
4. Barber PA, Darby DG, Desmond PM, Yang Q, Gerraty RP, Jolley D, Donnan
GA, Tress BM, Davis SM. Prediction of stroke outcome with echoplanar
perfusion- and diffusion-weighted MRI. Neurology. 1998;51:418–426.
5. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D,
Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E,
Trouillas P. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative
Acute Stroke Study (ECASS). JAMA. 1995;274:1017–1025.
6. The Multicenter Acute Stroke Trial-Europe Study Group. Thrombolytic
therapy with streptokinase in acute ischemic stroke. N Engl J Med.
1996;335:145–150.
7. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin
M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial
prourokinase for acute ischemic stroke. JAMA. 1999;282:2003–2011.
8. Brass LM. Brain SPECT in clinical neurology: stroke. Neurology. 1997;
48(suppl 1).
9. Hurst RW. Imaging of pathophysiology of infarction in the clinical
setting. AJNR Am J Neuroradiol. 1998;19:1947–1948.
10. Culebras A, Kase CS, Masdeu JC. Practice guidelines for the use of imaging
in transient ischemic attacks and acute stroke: a report of the Stroke Council,
American Heart Association. Stroke. 1997;28:1480–1497.
11. Vuadens P, Bogousslavsky J. Diagnosis as a guide to stroke therapy.
Lancet. 1998;352:5–9.
12. Gilman S. Imaging the brain. N Engl J Med. 1998;338:812– 820.
13. Yock DH Jr. CT demonstration of cerebral emboli. J Comput Assist
Tomogr. 1981;5:190 –196.
14. von Kummer R, Meyding-Lamade U, Forsting M, Rosin L, Rieke K,
Hacke W, Sartor K. Sensitivity and prognostic value of early computed
tomography in middle cerebral artery trunk occlusion. AJNR Am J Neuroradiol. 1994;15:9 –15.
15. Tomura N, Uemura K, Inugami A, Fujita H, Higano S, Shishido F. Early
CT findings in cerebral infarction. Radiology. 1988;168:463– 467.
16. Wardlaw JM, Dorman PJ, Lewis SC, Sandercock P. Can stroke physicians and neuroradiologists identify signs of early cerebral infarction on
CT? J Neurol Neurosurg Psychiatry. 1999;67:651– 653.
17. von Kummer R. CT of acute cerebral ischemia. Radiology. 2000;216:611.
Reply.
18. Rowley HA. Noninvasive imaging of the ischemic penumbra. Ann
Neurol. 1997;42:539 –541.
19. Berrouschot J, Barthel H, Hesse S, Köster J, Knapp WH, Schneider D.
Early differentiation between TIA and ischemic stroke within the first six
hours after onset of symptoms by using Tc-99m-ECD-SPECT. J Cereb
Blood Flow Metab. 1998;18:921–929.
20. Berrouschot J, Barthel H, von Kummer R, Knapp WH, Hesse S,
Schneider D. 99m Technetium-ethyl-cysteinate-dimer single-photon
emission CT can predict fatal ischemic brain edema. Stroke. 1998;29:
2556 –2562.
21. Barthel H, Berrouschot J, Hesse S, Dannenberg C, Schneider D, Knapp
WH, Burchert W. Prognostic potential of Tc-99m-ECD-SPECT within 6
hours after onset of stroke symptoms. In: Höfer R, Bergmann H, eds.
Radioactive Isotopes in Clinical Medicine and Research XXIII. Stuttgart/New York: Schatthauer; 1999:37– 42.
22. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer
R. “Malignant” middle cerebral artery territory infarction: clinical course
and prognostic signs. Arch Neurol. 1996;53:309 –315.
23. Schwab S, Steiner T, Aschoff A, Schwarz S, Steiner HH, Jansen O,
Hacke W. Early hemicraniectomy in patients with complete middle
cerebral artery infraction. Stroke. 1998;29:1888 –1893.
24. Ginsberg MD, Sternau LL, Globus MY, Dietrich WD, Busto R. Therapeutic modulation of brain temperature: relevance to ischemic brain
injury. Cerebrovasc Brain Metab Rev. 1992;4:189 –225.
25. Scandinavian Stroke Study Group. Multicenter trial of hemodilution in ischemic stroke: background and study protocol. Stroke. 1985;16:885–890.
26. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D,
Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E,
Trouillas P. Randomised double-blind placebo-controlled trial of
thrombolytic therapy with intravenous alteplase in acute ischemic stroke
(ECASS II). Second European-Australian Acute Stroke Study Investigators. Lancet. 1998;352:1245–1251.
27. Berrouschot J, Barthel H, Hesse S, Knapp WH, Schneider D, von
Kummer R. Reperfusion and metabolic recovery of brain tissue and
clinical outcome after ischemic stroke and thrombolytic therapy. Stroke.
2000;31:1545–1551.
28. Mahoni FI, Barthel DW. Functional evaluation: the Barthel Index. Md
State Med J. 1965;14:61– 65.
29. Rankin J. Cerebral vascular accidents in patients over the age of 60, II:
prognosis. Scott Med J. 1957;2:200 –215.
30. Walovitch RC, Hill TC, Garrity ST, Cheesman EH, Burgess BA, O’Leary
DH, Watson AD, Ganey MV, Morgan RA, Williams SJ. Characterization
of 99mTc-L,L-ECD for brain perfusion imaging, part 1: pharmacology of
99m
Tc-ECD in non-human primates. J Nucl Med. 1989;30:1892–1901.
31. Holman BL, Carvalho PA, Zimmerman RE, Johnson KA, Tumeh SS,
Smith AP, Genna S. Brain perfusion SPECT using annular single cristal
camera: initial clinical experience. J Nucl Med. 1990;31:1456 –1561.
32. Barthel H, Wiener M, Dannenberg C, Bettin S, Sattler B, Knapp WH.
Age-specific cerebral perfusion in 4 to 15 years old children: a high
resolution brain SPECT study using Tc-99m-ECD. Eur J Nucl Med.
1997;24:1245–1252.
33. Giubilei F, Lenzi GL, Di Piero V, Pozzilli C, Pantano P, Bastianello S,
Argentino C, Fieschi C. Predictive value of brain perfusion single-photon
emission computed tomography in acute ischemic stroke. Stroke. 1990;
21:895–900.
34. Yeh SH, Liu RS, Hu HH, Wong WJ, Lo YK, Lai ZY, Huang JC, Chang
SL, Wang SJ, Chu FL. Brain SPECT imaging with Tc-99m-hexamethylpropyleneamine oxime in the early detection of cerebral infarction:
comparison with transmission computed tomography. Nucl Med
Commun. 1986;7:873– 878.
35. Kurokawa H, Iino K, Kojima H, Saito H, Suzuki M, Watanabe K, Kato
T. Regional cerebral blood flow in the acute stage with ischemic cerebrovascular disease studies by xenon-133 inhalation and single photon
emission computerized tomography. No To Shinkei. 1987;39:437– 446.
36. Feldmann M, Voth E, Dressler D, Henze T, Felgenhauer K. Tc-99mHexamethylpropylene amine oxime SPECT and x-ray CT in acute
cerebral infarction. J Neurol. 1990;237:475– 479.
37. Laloux P, Richelle F, Jamart J, De Coster P, Laterre C. Comparative correlations of HMPAO SPECT indices, neurological score, and stroke subtypes
with clinical outcome in acute carotid infarcts. Stroke. 1995;26:816–821.
38. Laloux P, Jamart J, Meurisse H, De Coster P, Laterre C. Persisting
perfusion defects in transient ischemic attacks: a new clinically useful
subgroup? Stroke. 1996;27:425– 430.
39. Baird AE, Austin MC, McKay WJ, Donnan GA. Sensitivity and specificity of 99mTc-HMPAO SPECT cerebral perfusion measurements during
the first 48 hours for the localization of cerebral infarction. Stroke.
1997;28:976 –980.
40. Ell PJ, Jarritt PH, Cullum I, Hocknell JM, Costa DC, Lui D, Jewkes RF,
Steiner TJ, Nowotnik DP, Pickett RD, et al. A new regional cerebral blood
flow mapping with Tc-99m-labelled compound. Lancet. 1985;2:50–51.
41. Leveille J, Demonceau G, De Roo M, Rigo P, Taillefer R, Morgan RA,
Kupranick D, Walovitch RC. Characterization of technetium-99mL,L-ECD for brain perfusion imaging, part 2: biodistribution and brain
imaging in humans. J Nucl Med. 1989;30:1902–1910.
42. Matsuda H, Li YM, Higashi S, Sumiya H, Tsuji S, Kinuya K, Hisada K,
Yamashita J. Comparative SPECT study of stroke using Tc-99m ECD,
I-123 IMP, and Tc-99m HMPAO. Clin Nucl Med. 1993;18(9):754 –758.
43. Ogasawara K, Mizoi K, Fujiwara S, Yoshimoto T. 99mTc-Bicisate and
99m
Tc-HMPAO SPECT imaging in early spontaneous reperfusion of
cerebral embolism. Am J Neuroradiol. 1999;20:626 – 628.
Barthel et al
44. Jacquier-Sarlin M, Polla B, Siosman D. Cellular basis of ECD brain
retention. J Nucl Med. 1996;37:1694 –1697.
45. Barthel H, Kämpfer I, Seese A, Dannenberg C, Kluge R, Burchert W,
Knapp WH. Improvement of brain SPECT by stabilization of
Tc-99m-HMPAO with methylene blue or cobalt chloride: comparison
with Tc-99m-ECD. Nuklearmedizin. 1999;38:80 – 84.
46. Pulsinelli W. Pathophysiology of acute cerebral ischemia. Lancet. 1992;
359:533–536.
47. Fiorelli M, Toni D, Bastianello S, Sacchetti ML, Sette G, Falcou A,
Argentino C, Lorenzano S, Di Angelantonio E, Bozzao L. Computed
tomography findings in the first few hours of ischemic stroke: implications for the clinician. J Neurol Sci. 2000;173:10 –17.
48. Astrup J, Siesjö BK, Symon L. Threshold in cerebral ischemia: the
ischemic penumbra. Stroke. 1981;12:723–725.
49. Fisher M. Characterizing the target of acute stroke therapy. Stroke. 1997;
28:866 – 872.
50. Lythgoe MF, Williams SR, Busza AL, Wiebe L, McEwan AJ, Gadian
DG, Gordon I. The relationship between magnetic resonance diffusion
imaging and autoradiographic markers of cerebral blood flow and hypoxia in an animal stroke model. Magn Reson Med. 1999;41:706 –714.
[99mTc]ECD-SPECT and CT in Acute Stroke
1597
51. Weir CJ, Bolster AA, Tytler S, Murray GD, Corrigall RS, Adams FG,
Lees KR. Prognostic value of single-photon emission tomography in
acute ischaemic stroke. Eur J Nucl Med. 1997;24:21–26.
52. Lees KR, Weir CJ, Gillen GJ, Taylor AK, Ritchie C. Comparison of mean
cerebral transit time and single-photon emission tomography for estimation of stroke outcome. Eur J Nucl Med. 1995;22:1261–1267.
53. von Kummer R, Holle R, Gizyska U, Hofmann E, Jansen O, Petersen D,
Schumacher M, Sartor K. Interobserver agreement in assessing early CT
signs of middle cerebral artery infarction. AJNR Am J Neuroradiol.
1996;17:1743–1748.
54. von Kummer R. Effect of training in reading CT scans on patient
selection for ECASS II. Neurology. 1998;51(suppl 3):50 –52.
55. Baron JC, Marchal G. What is the predictive value of increased technetium-99m-HMPAO uptake for brain survival/necrosis in the acute stage
of ischemic stroke? J Nucl Med. 1995;36:2392. Letter to the Editor.
56. Becker H, Desch H, Hacker H, Pencz A. CT fogging effect with ischemic
cerebral infarcts. Neuroradiology. 1979;18:185–192.
57. Alexandrov AV, Black SE, Ehrlich LE, Bladin CF, Smurawska LT, Pirisi A,
Caldwell CB. Simple visual analysis of brain perfusion on HMPAO SPECT
predicts early outcome in acute stroke. Stroke. 1996;27:1537–1542.
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
Prospective Value of Perfusion and X-Ray Attenuation Imaging With Single-Photon
Emission and Transmission Computed Tomography in Acute Cerebral Ischemia
Henryk Barthel, Swen Hesse, Claudia Dannenberg, Annegret Rössler, Dietmar Schneider,
Wolfram H. Knapp, Jürgen Dietrich and Jörg Berrouschot
Downloaded from http://stroke.ahajournals.org/ by guest on July 28, 2017
Stroke. 2001;32:1588-1597
doi: 10.1161/01.STR.32.7.1588
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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