1733
99m
Tc-HMPAO-SPECT With Acetazolamide
Challenge to Detect Hemodynamic Compromise
in Occlusive Cerebrovascular Disease
J. Knop, MD; A. Thie, MD; C. Fuchs, MD; G. Siepmann, MD; and H. Zeumer, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose: Insufficiency of collateral supply may lead to low-flow infarcts in severe
occlusive cerebrovascular disease. The aim of this study was to evaluate the feasibility of technetium99m-labeled hexamethylpropyleneamine oxime ("Tc-HMPAO) single-photon emission computed tomography (SPECT) to assess hemodynamic compromise in the anterior circulation.
Methods: Cerebral bloodflowbefore and after 1 g acetazolamide was analyzed by "Tc-HMPAO-SPECT
in 21 symptomatic patients with documented extracranial obstructions. SPECT findings were correlated
with the results of angiography, transcranial Doppler sonography, and computed tomographic scan.
Results: The acetazolamide-induced increase of cerebral blood flow could be reliably monitored by
increase of cerebral "Tc-HMPAO uptake, which varied between 11.4% and 47.6% in the less-affected
hemisphere. Increment of hemispheric side-to-side asymmetry of tracer uptake after drug challenge
revealed significant restriction of regional vasoreactivity in 11 patients. Agreement in assessing hemodynamic compromise was reached in 81% of patients with ophthalmic artery collaterals on angiography
(p<0.001), in 76% with low-flow infarcts on computed tomographic scan (p<0.01), and in 91% with
markedly reduced flow velocities on transcranial Doppler (p<0.0001). One patient developed a low-flow
infarct in the area predicted by SPECT during follow up.
Conclusions: We conclude that Tc-HMPAO-SPECT with acetazolamide challenge is a useful method
for assessment of the adequacy of hemispheric collateral pathways in patients with severe occlusive
cerebrovascular disease. (Stroke 1992;23:1733-1742)
KEY WORDS • acetazolamide • cerebrovascular disorders • tomography, emission computed •
ultrasonics
O
bstructive disease of the cerebral arteries may
produce brain ischemia by different mechanisms. The pattern of ischemic lesions on
computed tomographic (CT) scan or magnetic resonance imaging (MRI) may suggest embolic or hemodynamic pathogenesis.1-2 While embolic risk increases with
degree of vessel stenosis,3-4 assessment of hemodynamic
risk is more difficult. Its diagnosis would be clinically
most useful if cerebral infarction had not yet occurred.
Degree of vessel occlusion does not correlate well with
the hemodynamic status of the ipsilateral hemisphere,
which depends on the functional capacity of collateral
channels.5 Evaluation of this cerebrovascular reserve
capacity in stroke patients might have major impact on
their management. Angiography, CT scan, MRI, and
measurements of regional cerebral blood flow (rCBF) at
rest are incapable of providing information on the
perfusion reserve provided by collaterals. By pathophysiological rationale, hemodynamic compromise in occlusive cerebrovascular disease can be estimated by funcFrom the Departments of Nuclear Medicine (J.K., C.F.), Neurology (A.T.), and Neuroradiology (G.S., H.Z.), University Hospital Eppendorf, Hamburg, FRG.
Address for reprints: Priv. Doz. Dr. Joachim Knop, Department
of Nuclear Medicine, University Hospital Eppendorf, D-2000
Hamburg 20, Martinistrasse 52, FRG.
Received April 24, 1992; final revision received July 27, 1992;
accepted August 4, 1992.
tional evaluation of the compensatory response to a
decrease in perfusion pressure. The compensatory vasodilation is measurable either directly by simultaneous
imaging of cerebral blood volume and rCBF2-5-9 or
indirectly by testing of the functional response to vasodilatory stimuli by single-photon emission computed
tomography (SPECT).10-13
Acetazolamide (ACZ; Diamox) induces increase of
cerebral blood flow without additional effect in areas of
compensatory vasodilation.14 This discriminating ACZ
response has been studied previously with 133Xe-SPECT
using dedicated SPECT systems15-28 but only recently
with 123I- or """Tc-labeled brain blood flow imaging
agents using conventional rotating camera systems.29"35
The aim of this study was to investigate the feasibility
of 99mTc-labeled hexamethylpropyleneamine oxime
(HMPAO) SPECT to monitor the vasodilatory response to ACZ in patients with symptomatic occlusive
cerebrovascular disease. Results are compared with
angiographic, CT, and transcranial Doppler (TCD)
findings to address the question of whether SPECT
provided additional useful information in patients
whose vascular pathology was already known.36
Subjects and Methods
We studied 21 patients (three women and 18 men,
aged 44-75 years) after transient ischemic attack or
minor stroke with documented extracranial obstructive
1734
Stroke
Vol 23, No 12 December 1992
TABLE 1. Clinical, Angiographic, Computed Tomographic, TCD, and Pre-ACZ/Post-ACZ Tc-HMPAO-SPECT Findings
Patient/sex/age
(years)
l/F/43
2/M/62
3/M/50
4/M/75
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Signs and symptoms
R brachial ischemia
Vascular lesions
IA stenosis with R VA steal
Collaterals
AComA L>R
CT
Normal
Recurrent transient L
hemiparesis
Recurrent transient L
hemiparesis
Dysphasia, recurrent
transient R hemiparesis
R ICA stenosis 90%
ROA
AComA L>R
None
R LFI (parietal)
None
L LFI (parietal)
ROA
R PComA
R TI (PCA)
L TI (PCA)
None
Normal
AComA L>R
R LFI (parietal)
LOA
AComA R>L
PComA R
AComA R>L
L PComA (weak)
ROA
AComA L>R
LOA
Normal
R OA (weak)
R PComA
L OA (weak)
AComA R>L
AComA R>L
RaBZ
RTI(PCA)
LaBZ
LpBZ
L LFI (parietal)
LpBZ
L LFI (frontal)
L ICA stenosis
R ICA stenosis+floating thrombus
R ICA stenosis <80%
R ECA stenosis <80%
L ICA stenosis >80%
R ICA stenosis (subtotal)
L ICA stenosis 50%
L VA stenosis 50% (origin)
B ICA stenosis 70% (siphon)
R VA occlusion
L VA stenosis >80%
R ICA occlusion (siphon)
5/M/68
Recurrent R amaurosis fugax
6/M/62
Recurrent transient R
paresthesia+aphasia
7/M/55
8/M/61
Recurrent transient R
hemiparesis+dysphasia
Recurrent L amaurosis fugax
9/M/55
Acute slight R hemiparesis
L ICA occlusion
Acute L hemiparesis
(fluctuating)
Recurrent transient R
hemiparesis
Recurrent L hemiparesis
R ICA occlusion
10/M/72
ll/M/63
12/M/54
13/M/65
14/M/44
Dysphasia, slight R
hemiparesis
Transient R hemiparesis
15/M/52
Recurrent transient dysphasia
16/F/60
Transient L hemiparesis
17/M/51
Acute L amaurosis, transient
L hemiparesis
18/M/64
19/M/67
Recurrent L amaurosis fugax,
recurrent transient aphasia
Transient R arm paresis
20/F/72
Acute R hemiparesis, aphasia
21/M/60
Acute R amaurosis
L ICA occlusion
L ICA occlusion
L VA stenosis <50% (origin)
R ICA occlusion
R VA tandem stenosis (intracranial, origin)
L ICA occlusion
L VA hypoplastic
L ICA occlusion (siphon)
L P2 stenosis
L ICA occlusion
ACoA hypoplastic
R ICA occlusion
L ICA stenosis 60%
L ECA stenosis >80%
R ICA occlusion
L ICA stenosis 90%
R ICA occlusion
L ICA stenosis >80%
L CCA occlusion
R ICA stenosis 80%
R VA hypoplastic
B ICA occlusion
L VA stenosis <80% (origin)
R CCA occlusion
L ICA occlusion
L ECA stenosis
R VA occlusion
LOA
L PComA
ROA
AComA L>R
Normal
L multiple LFI
(parietal)
R LFI (MCA)
RpBZ
LaBZ
RTI (MCA)
ROA
AComA L>R
B PComA
ROA
R TI (MCA)
R OA (weak)
AComA R>L
R PComA
BOA
L PComA
AComA R>L
LOA
R OA (weak)
L PComA
R LFI (parietal)
L LFI (parietal)
R LFI (parietal)
Normal
Normal
CT, computed tomographic; TCD, transcranial Doppler ultrasonography, ACZ, acetazolamide; Tc-HMPAO-SPECT, technetium-99mlabeled hexamethylpropyteneamine oxime single-photon emission computed tomography, AU, increase of cortical "Tc-HMPAO uptake; SAI,
side-to-side asymmetry index; hSAL hemispherical side-to-side asymmetry index (positive value left> right); rms, fractional root-mean-square
uncertainty, L, left; R,right;B, bilateral; IA, innominate artery, VA, vertebral artery, ICA, internal carotid artery, ECA, external carotid artery,
CCA, common carotid artery, OA, ophthalmic artery; P2, P2 segment of posterior cerebral artery, AComA, anterior communicating artery,
PComA, posterior communicating artery, aMCA, mMCA, pMCA; anterkjr, middle, and posterior branch groups of middle cerebral artery,
respectively; LFI, low-flow infarct; TI, territorial infarct; aBZ, infarct of anterior border zone of MCA; pBZ, infarct of posterior border zone of
MCA; AComA L>R, crossflow from left to right in AComA; PI-, marked reduction of pulsatility index (see text for details).
* Sector=sector angle <180°, a 18°; significant asymmetry increment
tHemisphcric=sector angle 180°).
Knop et al Acetazolamide HMPAO-SPECT
TABLE 1.
1735
Continued
Meanflowvelocities
(cm/sec)
TCD diagnosis
R MCA 40-50
L MCA 60-70
No compromise of
MCA
R MCA 60
L MCA 90-100
B MCA 50
Possible compromise
of R MCA
No compromise of
MCA
TCD not done
Post-ACZ
T c - H M P A O Uptake
(AU [%])
R cortex
L cortex
Hemispheric side-to-side
asymmetry (hSAI±2 rms [%])
Pre-ACZ
Post-ACZ
38.0
35.6
3.4±3.5
1.7±2.9
3.0
11.4
4.2±2.5
11.4±2.5t
30.3
25.4
2.1±3.5
-1.7±3.1
31.0
42.4
-5.4±3.2
2.8±2.9
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R MCA 30, P I L MCA 30-35, P I -
Probable compromise
of B MCA
15.5
29.1
6.4±3.5
16.2±3.1t
L MCA 40-50
R MCA 40-50
No compromise of
MCA
32.6
40.5
l.l±3.0
6.6±2.6
10.1
12.3
4.1 ±3.5
6.0±3.3
TCD not done
Regional SAI
increment*
R aBZ parietal
RpBZ
B MCA 50
No compromise of
MCA
47.1
47.6
-1.2±3.3
-0.8±2.8
L MCA 40-50
R MCA 60
R MCA 20-25, P I L MCA 50-60
L MCA 30, P I R MCA 40
R MCA 15-20, P I L MCA 60-70
TCD not done
No compromise of
MCA
Probable compromise
of R MCA
Possible compromise
of L MCA
Probable compromise
of R MCA
19.0
14.9
0.5±4.1
2.9±3.8
10.0
16.7
10.9±2.9
15.4±2.7
RpMCA
26.6
15.5
-7.4+3.4
-15J±3.1t
LmMCA
6.0
11.9
32.2±3.5
35.6±3.5
29.0
24.0
-18.9±3.4
-22.1±2.8
L MCA 40-50, P I R MCA 60-70
TCD not done
Possible compromise
of L MCA
28.1
4.2
-10.1±2.8
-26.9±2.7t
LmMCA
13.0
1.0
-1.1±3.5
-11.7±3.4t
LmMCA
R MCA 30, P I L MCA 50
Probable compromise
of R MCA
6.7
11.6
13.8±2J
17.5±2.2
RpMCA
B MCA 40-50
No compromise of
MCA
13.7
12.5
2.8 ±2.9
1.8±2.7
B MCA 30, P I -
Probable compromise
of B MCA
Probable compromise
of L MCA
15.8
4.6
2.7±4.1
-7.2±3.5
46.9
36.1
-3.0±2.9
-10.1 ±2 J t
LmMCA
31.3
32.0
11J±3J
11.7±2.7
RmMCA
26.0
9.8
0.6±3.1
-12.4±2.9t
LaMCA
L MCA 20-30, P I R MCA 50
TCD not done
L MCA 30-40, P I R MCA 40-50
Possible compromise
of L MCA
cerebrovascular disease in the anterior circulation.
Nineteen patients underwent intra-arterial selective
arteriography that revealed unilateral or bilateral internal carotid artery occlusion in 13 patients and
unilateral or bilateral internal carotid artery stenosis
in five cases; stenosis of the innominate artery was
found in one patient. Intracranial collateral flow
through the anterior or posterior communicating ar-
RaBZ
teries was observed in 16 patients. Extracranial-intracranial collaterals through the ophthalmic artery
were depicted angiographically in 14 cases. In patients
10 and 17, Doppler sonogTaphy revealed unilateral
internal carotid artery occlusion with intracranial
and extracranial-intracranial collaterals. Clinical
symptoms and angiologic findings are presented in
Table 1.
1736
Stroke
Vol 23, No 12 December 1992
fJP JHL
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All but five patients were examined with a transcranial
Doppler device (model TC 2-64 B, EME, Uberlingen,
FRG) using a hand-held 2-MHz-probe. We measured
mean blood flow velocity (MBFV) in centimeters per
second at rest and pulsatility index (PI) in the middle
cerebral artery (MCA).37 PI denotes systolic minus diastolic blood flow velocity divided by MBFV.38 To account
for spontaneous variation, MBFV values are given in
ranges (e.g., 40-50 cm/sec) unless only minor fluctuations
(2-4 cm/sec) occurred. Diagnosis of hemodynamic com-
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HMPAO 2 7 / 9 0
Sector
3i
LIFT
RI0HT
Si:.*
9
FIGURE 1, continued. Panel D: Cortical activity profiles of the pre-ACZ ""TcHMPAO-SPECT shown in panel A (notations as in panel C; error bars±l
root-mean-square). Regional side-to-side asymmetry (rSAI) is shown below (white
profile), with respective ±10% intervals (light blue). Profiles indicate congruent
rCBF distribution (mean rSAI, 5.4%) except for a small right temporooccipital area
(rSAI, 14.6%). Panel E: Cortical activity profiles and regional side-to-side asymmetry (rSAI) of the post-ACZ ""Tc-HMPAO-SPECT in panel B (notations as in
panel D) showing asymmetric side-to-side rCBF distribution in left prefrontal and
precentral sectors (mean rSAI, 24.6%; rSAI increment, +19.3%) and congruent
rCBF distribution in remaining sectors (mean rSAI, 5.6%; rSAI increment, <.9%).
Panel F: Corresponding pre-ACZIpost-ACZ cortical activity profiles of the left and
right cerebral cortexes shown in panels D and E (red, pre-ACZ activity profiles;
yellow, post-ACZ activity profiles). Sectorial change of"mTc-HMPAO uptake (rbU)
in percent is shown below (white columns), with respective ±10% intervals (light
blue). Profiles indicate reduced or absent rCBF response to ACZ in right frontal and
left prefrontal/precentral sectors (mean rAU, +5.9%), with adequate ACZ effect in
other areas (mean rAU, +28.6%).
S»ctor
HHPAO 27. 99
,-vST AC!
573.4 Coounti:
1738
Stroke
Vol 23, No 12 December 1992
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promise by TCD alone was tried by using the following
criteria: 1) in unilateral lesions, if on the affected side
MBFV was <40 cm/sec and the side-to-side difference of
MBFV was at least 20 cm/sec, or if the side-to-side
difference of PI was at least 0.4; 2) in unilateral or bilateral
lesions, if MBFV was below 40 cm/sec on either side; and
3) in bilateral lesions, if difference of PI between posterior
and anterior circulation was 0.4 or more on either side.
Probable hemodynamic compromise was diagnosed if two
of the above criteria applied in bilateral lesions or if all
criteria applied in unilateral lesions. Possible hemodynamic compromise was diagnosed if at least one criterion
was fulfilled. MBFV in the MCA and TCD diagnosis are
included in Table 1. Cranial computed tomography (Somatom DR, Siemens, Erlangen, FRG) was performed in
all patients for assessment of site and pattern of infarct
We classified infarcts as hemodynamic or nonhemodynamic according to the criteria of Ringelstein and coworkers.1-2 Thus, border zone infarcts and low-flow infarcts
were considered to be generated by hemodynamic hemispheric compromise, and territorial infarcts to have occurred by embolic branch occlusions. Individual results of
CT scans are also given in Table 1.
We performed SPECT with a conventional single-head
rotating camera system (Gamma Diagnost, Philips, Hamburg, FRG) combined with our standard SPECT hardware and software (Philips model 6P673, nps release 5 and
user-written software). Patients were placed in a Supine
position with the head fixed in a hemicylindrical plastic
head holder. The canthomeatal line served as reference
for patient position with the aid of position lights. During
the examination, variations in the relative position of the
patient's head were carefully checked.
We prepared T c - H M P A O from a nonradioactive
kit (Ceretec, Amersham, UK) according to the recommendations of the manufacturer. After ligand preparation, a solution of 370 MBq was withdrawn from the vial
and immediately injected into the patient after completion of quality control. Radiochemical purity exceeded
95%. Injections were carried out with the patient's eyes
closed but not blindfolded in an examination room with
dimmed light. Residual activity in the administrative
syringe was measured. Sodium perchlorate (500 mg)
was given before T c - H M P A O administration.
Scanning was started 5 minutes after tracer injection
with a Philips low-energy slanthole collimator, and 64
projections were acquired within 32 minutes (30 seconds per angle). After completion of data acquisition of
the baseline examination (pre-ACZ), 1 g i.v. ACZ
(Diamox, Lederer, FRG) was injected. After 15 minutes, a fresh T c - H M P A O solution was prepared from
a new kit of the same batch, and 370 MBq of the
solution was injected immediately. Scanning was restarted 5 minutes later without change in the patient's
head position, which resulted in combined pre-ACZ/
post-ACZ acquisition data. Decay-corrected subtraction of the pre-ACZ acquisition data from the combined
pre-ACZ/post-ACZ data yielded post-ACZ data. Image
processing involved prereconstruction filtering using a
count-dependent Metz filter for reduction of Poisson
noise.39 A sinogram was created by reconstruction of the
filtered projections for quality control, and 6-mm-thick
transaxial slices (64x64 matrices) were reconstructed by
filtered back projection (ramp filter). Final SPECT
slices were reoriented to the skull base to correspond to
CT scans, resulting in a slice thickness of approximately
12 mm. Visual analysis of slices included localization
and extent of cortical low-activity areas outside infarcts
as visualized on corresponding CT scans. For quantification of the cortical 9! Tc-HMPAO uptake and distribution, circumferential-profile analysis was applied to
the most relevant transaxial tomogram. Briefly, for each
patient an operator-defined elliptical region-of-interest
(ROI) (width, 8 pixels) was drawn around the contour
of the cortex on the pre-ACZ slices. Care was taken to
ensure identical repositioning of the ROI for the postACZ examination using identical sets of coordinates.
The cortical ROI was subdivided into 62 sectors, each
emanating from the center of the tomogram. All 62
sectors were of equal angle, which began at 12 o'clock
(frontopolar) and proceeded clockwise and counterclockwise for the right and left hemispheres, respectively, to 6 o'clock (occipitopolar). Each sector corresponded to a 12-mm-thick, 6° ROI (31 per hemisphere)
covering an area of at least 12 pixels (Figure 1C). To
confirm a global response of rCBF to ACZ, all 31
sectors over the cerebral cortex were averaged for each
hemisphere and normalized to the administered dose to
obtain an estimated mean cortical activity per pixel.
The change of cortical uptake (U) of ""Tc-HMPAO
into each hemisphere (h) after ACZ challenge was
expressed as the percentage of change of post-ACZ
uptake compared with pre-ACZ uptake (h AU%).
Calculation of hemispherical and sectorial pre-ACZ/
post-ACZ side-to-side asymmetry indexes (SAI=[100x
(1—r)/maximum (l,r)]) from paired right-sided (r) and
left-sided (1) sectors was performed to evaluate global
and regional effects of ACZ on cortical T c - H M P A O
distribution, respectively.
Statistical uncertainty (fractional root-mean-square
uncertainty) of U and SAI was determined in each
sector and each hemisphere for evaluation of the significance of changes.40 A significant response to ACZ was
assumed if post-ACZ T c - H M P A O h AU% exceeded
the twofold root-mean-square uncertainty ranges of
pre-ACZ and post-ACZ uptake measurements. Hemispheric and regional (^3 adjacent sectors) hemodynamic compromise was diagnosed if the respective SAIs
after ACZ challenge exceeded the twofold root-meansquare uncertainty ranges of pre-ACZ and post-ACZ
indexes.
Scintigraphic response to ACZ was compared with
the results of angiography, CT scan, and TCD to
determine the overall agreement (fraction of coincident
results), positive agreement (fraction of coincident abnormal results), and negative agreement (fraction of
coincident normal results). Agreement was tested with
X2 analysis of a 2x2 contingency table. Spearman's rank
correlation coefficients were calculated for correlation
between paired values. A two-tailed value ofp<0.05 was
regarded as significant.
Results
Results of pre-ACZ/post-ACZ " T c - H M P A O SPECT are given in Table 1. Fifteen minutes after ACZ
injection, a significant global increase of cortical " T c HMPAO uptake was detected in 20 patients, indicating
an ACZ-induced increase of rCBF. In one patient
without global response to ACZ, a significant change of
h AU was shown in a second study 2 weeks later. For all
Chopp et al
Hypothermia Reduces HSP-72 Induction
105
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FIGURE 1. Panel a: Intensive 72-kDa heat-shock protein (HSP-72) immunoreactivity was present in CA1-CA2, CA3, and CA4
areas of the hippocampus in five of seven rats from group 1 (normothcrmic group). Magnification, x21. Panel b: CA1-CA2
hippocampal areas containing damaged or necrotic neurons were devoid of or low in HSP-72 immunoreactivity in two of seven rats
from group 1 (normothermic group). Magnification, x21.
induction of ischemia (n=2). Because the peak of
forebrain HSP-72 immunoreactivity has been reported to occur at 48 hours of recirculation in
gerbils,3 we killed the rats at 48 hours of recirculation
with the assumption that HSP-72 immunoreactivity
in rats was similar to that in gerbils.
In group 2 (hypothermia without ischemia), wholebody hypothermia (30°C rectal temperature) was
maintained for 3 hours (n=9). No surgical procedures were performed on these rats. Hypothermia
was induced using evaporation cooling (alcohol and a
fan), and the core temperature was regulated as
described in group 1. The animals were anesthetized
with halothane and 70% N2O-30% O2, using a face
mask. The hypothermic rats were killed at 48 hours
(n=2) or 24 hours (n=7) after hypothermic induction. The 24-hour time point was selected because no
HSP-72 staining was detected at 48 hours, and we
sought an earlier time point at which to detect
HSP-72. Two additional control rats, not subjected to
surgical procedures, were killed 48 hours after induction of anesthesia.
In group 3 (hypothermic forebrain ischemia), ischemia and surgical procedures were identical to those
performed in group 1, except that hypothermia (30°C)
was instituted and maintained 1 hour before and during
ischemia and for 2 hours of reperfusion (n=5). Hypothermia was induced and regulated as in group 2. These
rats were killed 48 hours after ischemia.
The HSP-72 immunohistochemical technique was
essentially as described in detail by Vass et al.3 All
rats were given an overdose of pentobarbital and
fixed by transcardial perfusion with 100 mM sodium
phosphate buffer (pH 7.4), followed by 4% paraformaldehyde in the buffer. Brains were removed and
kept in the same fixative overnight at 4°C, then
transferred to 10 mM phosphate buffered saline.
Coronal slices (3 mm) were made using a rodent
brain matrix. Coronal sections (50 /xm) were cut on a
vibratome and reacted immunohistochemically using
a mouse monoclonal antibody C92 to HSP-72 (RPN
1197; Amersham, Cleveland, Ohio). Biotinylated
sheep anti-mouse immunoglobin G was used as the
second antibody. Sections were incubated with
streptavidin "bridge" 1:200 in phosphate buffered
saline for 1 hour, followed by biotinylated horseradish peroxidase 1:400 in phosphate buffered saline for
1 hour. Peroxidase was detected with diaminobenzidine. Sections were gelatin-mounted on slides for
light microscopic evaluation. Control sections were
run in each experiment without primary antibody to
Knopetal
Acetazolamide HMPAO-SPECT
1739
FIGURE 2. Computed tomographic (CT)
scans performed 2 weeks before (panel A)
and 4 weeks after (panel B) pre-acetazolamide
(ACZ)lpost-ACZ
technetium-99mlabeled hexamethylpropyleneamine oxime single-photon emission computed tomography
(""Tc-HMPAO-SPECT) in the same plane.
Panel A: Normal CT scan. Panel B: Subcortical, low-flow infarct in territory of left middle cerebral artery corresponding to area of
restricted vascular response to ACZ (see Figure IB).
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patients, the increase of h AU in the less-affected
hemisphere averaged 26% (range, 11.4-47.6%). The
degree of cerebrovascular obstruction and level of baseline "Tc-HMPAO uptake, however, did not correlate
with the extent of ACZ response (p>0.05). Cortical
T c - H M P A O uptake was asymmetrical in seven patients, yielding a significant increment of interhemispheric SAI after ACZ with a mean increase of hSAI of
10.2% (range, 7.1-16.8%;/><0.05). In fourteen patients,
the cortical flow response to ACZ was symmetrical, with
a mean asymmetry increment of 3.1% (range, 0.45.5%) in eight cases and a small decrease of hSAI in
three patients (mean, -1.0%; range, -1.7% to -0.4%).
In three patients, side-to-side asymmetry inverted after
ACZ challenge. Sectorial analysis of cortical T c HMPAO distribution in four of these patients revealed
significant increments of SAI in more than three consecutive sectors (angle £ 18°). Thus, eleven patients had
a regionally impaired vasodilatory response to ACZ
corresponding topographically to the anterior or posterior border zones of the MCA in four cases and the
territory of the MCA or posterior cerebral artery (PCA)
in seven patients. Two of six patients with normal CT
scans had a pathological SPECT with focal impairment
of an ACZ-induced rCBF increase. Two of three patients with isolated territorial infarcts on CT scan had
evidence of focally decreased collateral flow on SPECT
after ACZ challenge in addition to infarct areas as
visualized on CT scan. Thus, SPECT provided additional pathological results compared with CT scan in
four of nine patients.
An illustrative case of pre-ACZ/post-ACZ T c - H M PAO-SPECT is shown in Figures 1A-1F and Figure 2,
which depict impaired focal vasodilatory capacity to
ACZ in a patient who eventually developed a low-flow
infarct in the appropriate area.
Results of pre-ACZ/post-ACZ T c - H M P A O SPECT compared with angiologic data and CT scan
and TCD findings are presented in Table 2.
Blood flow reversal through ophthalmic artery collaterals, suggesting restricted intracranial collateral capacity, was shown in 15 hemispheres of 14 patients. PreACZ and post-ACZ Tc-HMPAO-SPECT exhibited
an impaired vasodilatory response in only nine of these
hemispheres. In contrast, two of 27 hemispheres without collateral blood flow through the ophthalmic artery
revealed a focally decreased vasoreactrvity to ACZ.
Thus, the agreement between angiologic results and
pre-ACZ/post-ACZ Tc-HMPAO-SPECT was moderate (positive correspondence, 82%; negative correspondence, 81%; contingency coefficient c=0.497;
/><;0.0005).
CT scan depicted territorial infarcts in the MCA or
PCA territory in four patients, but low-flow infarcts in
twelve patients indicating a hemodynamic pathogenesis.
In six patients, CT scan was normal. Correlation of CT
results and pre-ACZ/post-ACZ Tc-HMPAO-SPECT
yielded low rates of diagnostic agreement (positive
correspondence, 64%; negative correspondence, 81%;
contingency coefficient c=0.388; p^O.Ol). Of eleven
hemispheres with a focally impaired ACZ reactivity, CT
displayed low-flow infarcts in only seven. In contrast,
TABLE 2. Overall, Positive, and Negative Agreement of Pre-ACZ/Post-ACZ Tc-HMPAO-SPECT for Assessment
of Hemodynamk Compromise With Angiographlc, CT, and TCD Findings
Parameter
Ophthalmic artery collaterals
(angiography)
Low-flow infarctions (CT scan)
Reduced flow velocities (TCD)
Contingency
coefficient
Overall
agreement
Positive
agreement
Negative
agreement
P
0.497
0388
0.628
0.81 (34/42)
0.76 (32/42)
0.91 (29/32)
0.82 (9/11)
0.64 (7/11)
1.00 (9/9)
0.81 (25/31)
0.81 (25/31)
0.87 (20/23)
0.0005
0.01
0.0001
ACZ, acetazolamide; Tc-HMPAO-SPECT, technetium-99m-labeled hexamethylpropyleneamine oxime singlephoton emission computed tomography; CT, computed tomographic; TCD, transcranial Doppler ultrasonography.
1740
Stroke Vol 23, No 12 December 1992
hemodynamic infarcts were present in six of 31 hemispheres with good response to ACZ.
The vasodilator response to ACZ correlated best with
the results of TCD, which were available in 16 patients
(positive correspondence, 100%; negative correspondence, 87%; contingency coefficient c=0.628; /?£0.0001).
MBFV or PI in the MCA were reduced (i.e., hemodynamic compromise was diagnosed) in all but one hemisphere, demonstrating focalry decreased vasoreactivity to
ACZ. On the other hand, TCD findings were normal in
20 of 23 hemispheres without significant increment of
side-to-side asymmetry after ACZ challenge.
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Discussion
Tc-HMPAO-SPECT is used for tomographicalry
portraying rCBF distribution.4142 Due to flow-limited
extraction efficacy of T c - H M P A O , absolute measurement of rCBF is not feasible; thus, T c - H M P A O SPECT represents a semiquantitative rCBF study.43-44
The amount and distribution of the tracer in the brain
depend essentially on the variable flow-dependent local
uptake and release rates of the tracer, with stable
long-term retention when the early back-diffusion has
ceased.45 However, in vitro instability of the tracer
solution, level of sensorimotor activation, state of consciousness, respiratory function, timing of measurement, patient's head position, and size of the ROI can
contribute markedly to the level of cortical tracer uptake and side-to-side asymmetry.41-46'47
Because of these interfering variables, we employed a
strictly standardized data acquisition protocol and evaluation technique. Assuming neglectable tracer loss after
completion of the baseline examination, baseline data
were subtracted from data after ACZ challenge for
assessment of ACZ's effect on T c - H M P A O brain
uptake. Results were quantified by side-to-side scintimetry to allow regional comparison of pre-ACZ/postACZ rCBF distribution. The use of hemispheric ratios
takes advantage of the basic symmetry of the brain to
improve sensitivity for identifying focal abnormalities.
This technique, however, allows only one hemisphere to
be classified as abnormal and permits no conclusion to
the hemodynamic status of the opposite hemisphere.7
Because age-matched healthy controls were not available for pre-ACZ/post-ACZ Tc-HMPAO-SPECT,
individual statistical precision of the image data was
defined as a decision criterion. Based on this approach,
significant increment of the side-to-side asymmetry was
considered if pre-ACZ/post-ACZ asymmetry increment
exceeded a mean of 6.2% (range, 4.5-7.9%) for the
whole cortex and 16.1% (range, 11.7-20.6%) for three
adjacent sectors (18° segment) considered to be a
minimum resolution element, respectively. At 15 minutes after ACZ challenge, cortical uptake increased
significantly in all patients in our sample. Its degree
varied between 11.4% and 47.6% in the less hemodynamicalry affected hemisphere. This is in agreement
with results of pre-ACZ/post-ACZ 1MXe-dynamic (D)SPECT in healthy subjects, which varied between 5%
and 64%.17-21-2«s-4«-49 Using Tc-HMPAO-SPECT, a
mean increase of 17% and 23% in cerebral HMPAO
retention after ACZ challenge was found in 40 of 65
patients (62%) and 14 of 19 patients (74%),3<w4 respectively. Increase of T c - H M P A O uptake, however, did
not con-elate with the level of pre-ACZ retention. This
is in contrast to results of Kreisig et al,21 who detected
an inverse correlation between baseline and post-ACZ
cerebral blood flow using 133Xe-D-SPECT. Response to
ACZ was asymmetrical in seven of our patients, yielding
a significant increment of the hemispherical asymmetry
indexes. Diagnostic efficacy was improved by sectorial
analysis of cortical "Tc-HMPAO uptake, which additionally revealed focally restricted vasodilation in four
patients. Areas of compromised flow increase included
the border zones of the MCA supply territory in four
patients and the MCA or PCA territory in seven.
Our SPECT findings did not correlate with the degree of ipsilateral vascular obstruction, confirming previous results.5-31 Most patients with hemodynamic compromise had multiple vascular lesions. However,
presence of multiple angiographic lesions did not predict SPECT findings. Retrograde flow through the
ophthalmic artery, presumably reflecting insufficient
intracranial collaterals,7 was detected in nine of 11
hemispheres (82%) with regionally impaired ACZ vasoreactivity. Correspondingly, low-flow infarcts demonstrated on CT scan were found in 64% (7 of 11) of these
hemispheres. On the other hand, ophthalmic artery
collateral flow and low-flow infarcts were present in 6 of
31 hemispheres (19%) with intact ACZ vasoreactivity,
which suggests effective recruitment of supplementary
collaterals over time. This is corroborated by follow-up
studies that revealed almost complete improvement of
vasodilatory capacity 1 year after the initial assessment
in some patients.33
Pre-ACZ/post-ACZ Tc-HMPAO-SPECT showed
more impairment than did CT scan in four of nine
patients with either normal scans or isolated territorial
infarcts, which indicates that hemodynamic compromise
was pending in some patients. This point is illustrated in
patient 21, who had acute right amaurosis and multiple
cerebral artery occlusions. Initial CT scan was normal,
but pre-ACZ/post-ACZ T c - H M P A O - S P E C T revealed absent response to ACZ in the left prefrontal/
precentral area. The patient suffered a symptomatic
infarct in this area during follow-up 4 weeks later
(Figure 2).
Pre-ACZ/post-ACZ T c - H M P A O - S P E C T corresponded best with TCD findings. Ultrasonic diagnosis of
possible or probable hemodynamic compromise had
been made in all hemispheres with markedly reduced
focal vasoreactivity on SPECT. However, in one patient
with bilaterally reduced MBFV in the MCA, unilateral
retrograde flow in the ophthalmic artery, and low-flow
infarct on CT scan, pre-ACZ/post-ACZ T c - H M P A O SPECT failed to show an increment of side-to-side
asymmetries, thus uncovering the limits of this method.
TCD diagnosis was based on reduced MBFV and
dampened PI. As suggested by recent results,50 vasomotor reactivity testing with CO2 inhalation might enable
better prediction of the hemodynamic effect of vessel
occlusion than these basic parameters. In addition,
Kleiser et al51 showed that markedly reduced CO2
reactivity as measured by TCD is frequently associated
with low-flow infarcts on CT scan. Thus, ACZ-induced
vasoreactivity with SPECT should be compared with
ultrasonic vasoreactivity testing in the future.
We conclude at this point that in patients after
transient ischemic attack or minor stroke, pre-ACZ/
post-ACZ Tc-HMPAO-SPECT 1) allows an objective
Knop et al
assessment of regional vasoreactivity to ACZ; 2) is a
feasible method to detect noninvasively the efficacy of
collateral channels in cerebrovascular obstructions; and
3) provides supplementary information for CT, angiographic, and TCD findings. In particular, it may help to
confirm equivocal ultrasonic findings of hemodynamic
compromise distal to vessel occlusion or detect improved collateral flow in patients with chronic low-flow
infarcts demonstrated on CT scan.
Acknowledgment
The authors thank Dr. Louis R. Caplan, Boston, for his
review of the manuscript.
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99mTc-HMPAO-SPECT with acetazolamide challenge to detect hemodynamic
compromise in occlusive cerebrovascular disease.
J Knop, A Thie, C Fuchs, G Siepmann and H Zeumer
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Stroke. 1992;23:1733-1742
doi: 10.1161/01.STR.23.12.1733
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