Increased Blood–Brain Barrier Permeability on Perfusion
CT Might Predict Malignant Middle Cerebral
Artery Infarction
Hesna Bektas, MD; Tzu-Ching Wu, MD; Mallikarjunarao Kasam, PhD; Nusrat Harun, MS;
Clark W. Sitton, MD; James C. Grotta, MD; Sean I. Savitz, MD
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Background and Purpose—Perfusion CT has been used to assess the extent of blood– brain barrier breakdown. The
purpose of this study was to determine the predictive value of blood– brain barrier permeability measured using
perfusion CT for development of malignant middle cerebral artery infarction requiring hemicraniectomy (HC).
Methods—We retrospectively identified patients from our stroke registry who had middle cerebral artery infarction and
were evaluated with admission perfusion CT. Blood– brain barrier permeability and cerebral blood volume maps were
generated and infarct volumes calculated. Clinical and radiographic characteristics were compared between those who
underwent HC versus those who did not undergo HC.
Results—One hundred twenty-two patients (12 HC, 110 no HC) were identified. Twelve patients who underwent HC had
developed edema, midline shift, or infarct expansion. Infarct permeability area, infarct cerebral blood volume area, and
infarct volumes were significantly different (P⬍0.018, P⬍0.0211, P⬍0.0001, P⬍0.0014) between HC and no HC
groups. Age (P⫽0.03) and admission National Institutes of Health Stroke Scale (P⫽0.0029) were found to be
independent predictors for HC. Using logistic regression modeling, there was an association between increased infarct
permeability area and HC. The OR for HC based on a 5-, 10-, 15-, or 20-cm2 increase in infarct permeability area were
1.179, 1.390, 1.638, or 1.932, respectively (95% CI, 1.035 to 1.343, 1.071 to 1.804, 1.108 to 2.423, 1.146 to 3.255,
respectively).
Conclusion—Increased infarct permeability area is associated with an increased likelihood for undergoing HC. Because
early HC for malignant middle cerebral artery infarction has been associated with better outcomes, the infarct
permeability area on admission perfusion CT might be a useful tool to predict malignant middle cerebral artery
infarction and need for HC. (Stroke. 2010;41:2539-2544.)
Key Words: acute stroke 䡲 blood– brain barrier 䡲 diffusion-weighted imaging 䡲 hemicraniectomy
䡲 malignant middle cerebral infarction 䡲 neuroradiology 䡲 perfusion CT 䡲 treatment
A
pproximately 10% to 15% of all patients with cerebral
infarction in the territory of the middle cerebral artery
(MCA) have progressive clinical deterioration because of
increasing brain swelling, raised intracranial pressure, and
brain herniation. This patient population constitutes a particularly difficult challenge for clinicians charged with their
care.1–3 Because of the limitations of medical therapies,
decompressive surgery is an option for patients with neurological deterioration due to large hemispheric infarction and
edema. The rationale of this therapy is to prevent brain tissue
shifts and to normalize intracranial pressure and thereby
preserve cerebral blood flow and prevent secondary damage.4
Hemicraniectomy (HC) for malignant middle cerebral artery
infarctions (MMCA) has been shown to be an effective
treatment.5 Currently, clinical data and early cranial tomog-
raphy does not reliably identify patients who will develop
MMCA. Prognostic criteria that might permit early identification of patients at risk for such “malignant” infarction are
important.6 – 8
Perfusion CT (PCT) is a modern imaging technique that
has been proposed for evaluating patients with acute stroke at
the time of their emergent evaluation. PCT involves the
sequential acquisition of CT images performed in cine mode
during the intravenous administration of iodinated contrast
material and has been reported to allow for accurate quantitative assessment of cerebral blood flow and cerebral blood
volume (CBV).9 It also has been validated in determining
final infarct volumes and measuring potentially salvageable
tissue using different PCT maps.10 By extending the PCT
acquisition time window, blood– brain barrier permeability
Received May 22, 2010; final revision received June 22, 2010; accepted June 29, 2010.
From the Departments of Neurology (H.B., T.-C.W., M.K., N.H., J.C.G., S.I.S.) and Radiology (C.W.S.), University of Texas–Houston Medical
School, Houston, Texas.
Correspondence to Sean I. Savitz, MD, Department of Neurology, Stroke Team, The University of Texas–Houston Medical School, 6431 Fannin Street,
Houston, TX 77030. E-mail [email protected]
© 2010 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.110.591362
2539
2540
Stroke
November 2010
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Figure 1. A 75-year-old right-handed man who presented with sudden onset of left hemiparesis and dysarthria. A, Admission CT; (B)
admission CBV color maps showing hypoperfusion with right MCA acute ischemic stroke (AIS). C, Admission permeability color maps
showed permeability abnormality with right MCA AIS. D, Subsequent head CT before HC showing malignant MCA infarction.
(BBBP) can also be obtained.11 PCT techniques for measuring BBBP have been shown to be achievable in tumor models
in animals12,13 and in a small human series,14 but only
recently has it been applied to acute stroke imaging.15
The aim of this retrospective study was to determine
whether permeability maps, generated from admission PCT,
can be used to predict MMCA. We hypothesized that patients
with an increased area of permeability defect would be at
higher risk for development of MMCA.
Methods
We retrospectively reviewed our registry from August 2007 to
August 2009 and identified 268 consecutive patients diagnosed with
MCA infarctions (18 patients in the HC group and 250 patients in
nonhemicraniectomy [NHC] group). We included in our analysis
patients who underwent PCT on admission with interpretable permeability maps. Two patients in the HC and 31 patients in NHC
group had uninterpretable PCT maps. Three patients in the HC and
76 patients in the NHC groups did not have PCT. Patients who had
their care withdrawn were also excluded from the analysis. In total,
122 patients fit our criteria: 12 underwent HC and 110 in the NHC
group. Demographic characteristics and baseline clinical information
including admission National Institutes of Health Stroke Scale
(NIHSS), admission glucose level, HbA1c, lipids, the timing of MRI
acquisition, and PCT were extracted from the medical records.
Clinical, laboratory, and radiographic characteristics were analyzed
between the 2 groups.
Calculation of Infarct Volumes
All MRI scans were performed before decompression in the HC
group. One of the investigators was blinded to clinical outcomes and
independently reviewed all the diffusion-weighted images (DWIs) to
verify infarct volumes. Infarct volumes were measured by handdrawn regions of interest around each area of infarct in every slice
separately. The regions of interest area was calculated automatically
by the Picture Archiving and Communication Systems software
(General Electric Centricity workstation) and then multiplied by the
slice thickness (5 mm for DWI). Seven patients (58.3%) in the HC
group and 85 patients (77.3%) in the NHC group had DWI.
Calculation of Permeability and CBV Volume
Permeability color maps was retrospectively generated from PCT
data using a modified Patlak method. PCT was performed on a
Siemens Somatom Sensation 40 scanner. After intravenous administration of 40 mL iodinated contrast at 8 mL/s by a power injector
into an antecubital vein (Omnipaque, 350/40 mL), images were
acquired without delay. PCT imaging parameters were 80 kVp, 270
mAs, and 1.2-mm section collimation. Slice thickness was 9.6-mm
acquired 3 slices at a time for 75 seconds. The modified Patlak model
(in Siemens Syngo Neuro PCT) calculates vascular permeability
(PS) with CT enhancement values after the peak contrast enhancement has been reached and using a built-in delay correction algo-
Bektas et al
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rithm. This allows estimation of PS during the end of the first
passage of contrast but avoids erroneous elevation of PS values
secondary to delayed arrival of contrast, which would occur in a
standard application of the Patlak model to PCT data in the setting of
acute cerebral ischemia.16 From the PCT data, permeability maps
were calculated using Syngo Neuro PCT software, which sets the
threshold for generating the permeability maps at 0.5 mL/10 mL/
min. We defined the perfusion abnormality as the region analyzed on
the permeability maps, IP as the weighted mean of the permeability
value, and IParea as the area of the region that had perfusion
abnormality. Each permeability map was analyzed by demarcating
trace lines around the area of perfusion abnormality on each of the 3
slices. IP and IParea values were measured by hand-drawn regions of
interest in every slice separately. The weighted mean of IP and IParea
of the 3 slices was calculated, respectively, and used for statistical
analysis. Contralateral nonischemic hemisphere was used as a
control.
Using the Siemens Syngo Neuro software, CBV was calculated
along with cerebral blood flow using the maximal slope model,
which has been shown to yield lesion volumes that are similar to
delay-insensitive deconvolution techniques.17The hypoperfused areas on CBV maps were defined as volume abnormality. The infarct
core was outlined on CBV maps as a severely hypoperfused area
displayed by 2 colors in the color bar (eg, purple and blue). The CBV
threshold was defined at 2.0 mL⫻100 g⫺1. Each CBV map was
analyzed by demarcating trace lines around the area of volume
abnormality on each of the 3 slices by hand-drawn regions of
interest. The area of volume abnormality was defined as CBVarea.
The weighted mean of CBV and CBVarea was calculated in each of
the 3 slices, respectively, and used for statistical analysis. Representative images of CBV and permeability are shown in Figure 1 from
a patient who developed malignant infarction and underwent HC.
Statistical Analysis
Means with SDs or medians for continuous variables and proportions
for categorical variables were used. The differences were assessed
using t tests, ␹2 tests, Fisher exact test, or Mann-Whitney U test. A
significance level of 0.05 was used to assess statistical difference.
We used multivariate analysis using logistic regression to obtain ORs
to determine associations controlling for potential confounders. The
statistical analysis was performed using SAS 9.2.
Results
Patients
We included 122 patients in total, 12 HC and 110 NHC. Of
the baseline characteristics analyzed, mean age (56.08⫾13.20
versus 65.40⫾13.66 years; P⬍0.03) was statistically different between the HC and NHC groups. Patients in the HC
group were significantly younger than the NHC group. Other
baseline characteristics such as gender, race, and risk factors
were not statistically different between the 2 groups (Table 1).
Laboratory parameters (mean serum glucose at admission,
HbA1c level, serum total cholesterol level, triglyceride,
high-density lipoprotein, low-density lipoprotein) assessed at
baseline were not significantly different between HC and
NHC groups.
Clinical Factors
Baseline stroke severity, as measured by median NIHSS
scores, was significantly higher in the HC group than the
NHC group (19 [range, 11 to 29] versus 11 [range, 0 to 40];
P⬍0.0029). The mean time from stroke onset to PCT in
minutes in the HC and NHC groups were 310.55⫾306.75 and
502.56⫾845.90, respectively. There was no significant difference in time to PCT scanning between 2 groups (P⫽0.19).
Increased BBBP Predicts MMCA Infarction
Table 1.
2541
Demographics and Pre-Existing Conditions
HC Group
(n⫽12)
NHC Group
(n⫽110)
P
56.08⫾13.20
65.40⫾13.66
0.03*
Female (%)
7 (58.33)
57 (51.82)
Male (%)
5 (41.67)
53 (48.18)
Black (%)
4 (33.33)
27 (25.71)
Hispanic (%)
4 (33.33)
12 (11.43)
White (%)
4 (33.33)
63 (60)
Other (%)
0 (0)
Age, years (mean⫾SD)
Gender
0.66†
Race
0.11‡
3 (2.86)
Risk factors
Hypertension (%)
9 (75)
77 (70)
0.71†
Diabetes mellitus (%)
2 (16.67)
29 (26.36)
0.72‡
Coroner disease (%)
3 (25)
24 (21.82)
0.72‡
Atrial fibrillation (%)
4 (33.33)
18 (16.36)
0.22‡
Smoking (%)
3 (25)
37 (33.64)
0.74‡
*Student t test.
†␹2 test.
‡Fisher exact test.
Seven (58.3%) patients in the HC group and 85 (77.3%)
patients in the NHC group had DWI (P⬍0.0035). Onset to
acquired DWIs was not statistically different (877.6⫾712.7
versus 975.5⫾709.4 minutes, P⫽0.7680; Table 2).
Radiographic Characteristics
Mean DWI infarct volume was significantly larger in the HC
group compared with the NHC group (162.206⫾81.20 versus
43.62⫾55.33 mL; P⬍0.0014). Patients with infarct volumes
⬎145 mL were more likely to receive HC (62.5% versus
37.5%; P⬍0.0001).
No significant differences in IP were observed between the
2 groups (7.26⫾2.95 mL 䡠 min⫺1 䡠 [100 g]⫺1 versus 8.44⫾
7.42 mL 䡠 min⫺1 䡠 [100 g] ⫺1; P⫽0.2950). Similarly, no
significant differences in mean CBV were observed between
HC and NHC groups (13.72⫾12.89 mL 䡠 [100 g]⫺1) versus
16.5512.15 mL 䡠 [100 g]⫺1, P⫽0.4487; Table 3). The mean
IParea was significantly different between the 2 groups
Table 2.
Clinical Characteristics
HC Group
(n⫽12)
NHC Group
(n⫽110)
P
19 (11–29)
11 (0 – 40)
0.0029†
Onset to PCT, minutes
(mean⫾SD)
310.55⫾306.75
502.56⫾845.90
0.19*
Onset to DWI, minutes
(mean⫾SD)
877.6⫾712.7
975.5⫾709.4
0.76*
Intravenous tissue
plasminogen activator
given (%)
4 (33.33)
60 (54.55)
0.22‡
Clinical Features
Admission NIHSS median
(minimum to maximum)
*Student t test.
†Two-sample test.
‡Fisher exact test.
2542
Stroke
Table 3.
November 2010
Radiographic Measurements
Radiographic Measurements
DWI infarct volumes (mean⫾SD), cm3
DWI infarct volumes ⱖ145 cm3 (%)
Infarct permeability
HC Group (n⫽12)
NHC Group (n⫽110)
P
162.20⫾81.20 (n⫽7)
43.62⫾55.33 (n⫽85)
0.0014‡
5 (83.33%)
1 (16.67%)
0.0001†
7.26 mL 䡠 min
⫺1
⫺1
䡠 关100 g兴 ⫾2.95
⫺1
8.44 mL 䡠 min
⫺1
䡠 关100 g兴 ⫾7.42
0.29*
Infarct permeability area
61.97 cm2⫾27.10
41.48 cm2⫾32.27
Contralateral permeability
2.80 mL 䡠 min1 䡠 关100 g兴⫺1⫾1.88
2.71 mL 䡠 min⫺1 䡠 关100 g兴⫺1⫾3.11
0.92*
13.72 mL 䡠 关100 g兴⫺1⫾12.89
16.55 mL 䡠 关100 g兴⫺1⫾12.15
0.44*
48.36 cm ⫾24.23
29.14 cm ⫾27.33
29.80 mL 䡠 关100 g兴⫺1⫾10.04
28.86 mL 䡠 关100 g兴⫺1⫾10.72
Infarct CBV
Infarct CBV area
Contralateral cerebral blood volume
2
2
0.018‡
0.0211*
0.77*
*Student t test.
†␹2 test.
‡Two-sample test.
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(61.97⫾27.10 versus 41.485⫾32.270; P⬍0.018). We used a
logistic regression model to determine whether IParea is
associated with the probability of having a HC, controlling
for potential confounders. We found that the odds of receiving a HC was higher for patients with larger IParea (OR,
1.018; 1.001 to 1.036; P⫽0.0432). The ORs and 95% CI for
HC based on a 5-, 10-, 15-, or 20-cm2 increase in IParea were
1.179 (1.035 to 1.343), 1.390 (1.071 to 1.804), 1.638 (1.108
to 2.423), and 1.932 (1.146 to 3.255), respectively. Thus, a
patient with IParea of 50 would have a 39% higher odds of
having HC compared with a patient with IParea 40 (Figure 2).
The positive predictive value of IParea for HC was 10.4% and
the negative predictive value 100%. There was a significant
association between receiving HC and DWI volume (OR,
1.019 [1.007 to 1.031]; P⫽0.0016) but not with CBV lesion
volume (OR, 0.976 [0.916 to 1.040]; P⫽0.4513). However,
when controlling for the DWI volume, there was no association between receiving HC and IParea (OR, 1.008 [0.975 to
1.041]; P⫽0.6391). There was no correlation between DWI
volume and IParea (P⫽0.5219). We also did not find a
correlation between IParea and admission NIHSS (P⫽0.0817),
HbA1c levels (P⫽0.9072), or admission glucose levels.
(P⫽0.6542).
Discussion
Progressive deterioration of clinical status due to massive
hemispheric edema occurs in 10% of patients and is described
as the “MMCA.” Ischemic edema occurs within hours after
stroke onset18 and is initially cytotoxic characterized by
intracellular water accumulation, and later vasogenic, in
Figure 2. Change in IParea versus OR.
which water moves across the blood– brain barrier (BBB) into
the extracellular interstitial space. The disruption of the BBB
can be demonstrated as early as 20 minutes after brain
ischemia in rats.18,19
Over the past 15 years, several studies have shown that
decompressive surgery is a possible treatment strategy for
increased intracranial pressure after severe hemispheric
stroke and can reduce the mortality to ⬍50%.3,20 –23 The
clinical course of many patients with severe MCA stroke is
predictable. Therefore, waiting for pupillary dilatation causes
an unnecessary delay.24,25 However, there is little information
to guide clinicians in selecting which patients are most
suitable for this aggressive intervention.
The aim of this study was to define radiographic predictors
of malignant MCA infarct in retrospectively evaluated patients with MCA stroke and to provide early prognostic
factors that may affect treatment decisions of clinicians.
Patients who underwent HC were significantly younger than
the NHC group. Wijdicks and colleagues26 suggested that
intracranial pressure in younger patients might rise rather
quickly due to less reserve to compensate for the increase in
volume. Certain degrees of age-related cerebral atrophy
might protect older patients from space-occupying brain
swelling.2,7,8,27 Age is an important factor for deciding to
pursue surgery and clinicians focus on younger patients
before signs of herniation appear such as stroke severity.
Krieger et al reported that patients with malignant MCA
strokes had higher NIHSS scores at admission and no single
item or cluster of items in the NIHSS was a predictor of fatal
brain edema than the total NIHSS score.8 Higher NIHSS
scores at admission were found in our HC group as well.
DWI is increasingly being used for the early management
of acute stroke.28 Oppenheim et al28 had used DWI to study
patients with impending malignant MCA infarction and
found a mean DWI volume of 244 cm3 in patients with
malignant MCA infarction and a cutoff value of 145 cm3 to
predict massive brain edema within the first 14 hours after
stroke.28 We identified a mean volume of infarct of 162.20
cm3 and a cutoff value of 100 cm3 in the HC population.
Quantitative measurement of DWI volumes is a reliable
factor to decide for HC.
Other radiographic factors may play a role in determining
the population at risk for subsequent fatal ischemic brain
Bektas et al
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swelling.8 PCT is an imaging technique currently used to
evaluate patients with acute stroke at the time of their
emergency evaluation.9 Dittrich et al have even reported that
the blood flow and volume parameters of PCT might permit
identifying patients at risk for malignant infarction.29 More
recently, PCT has been used to characterize the BBBP.15,30,31
A relatively simple and frequently applied model to calculate
BBBP is the Patlak model.32,33 Applying this model to PCT
data15,34 –36 requires using arterial and parenchymal contrast
enhancement curves to calculate the rate of contrast transfer
from the intravascular to the extravascular compartment,
which is a measure of BBBP. Microvascular permeability
(expressed as the transendothelial transfer constant or PS area
product) is a metric of BBB integrity. Similar to the standard
perfusion metrics, PS can also be calculated using dynamic
imaging by measuring the leakage of an intravascular tracer
into the extravascular (interstitial) space.33,37,38
In the normal brain parenchyma, PS is 0 for relatively large
hydrophilic molecules (such as a peripherally injected iodinated contrast agent), which reflects the tight regulation of the
BBB.39 – 42 Evidence from animal and human studies suggests
that increased permeability can occur in the first 2 to 4 hours
of acute ischemia.43– 45 In our study, the infarct permeability
area and infarct cerebral blood volume area of the ischemic
region determined by PCT were shown to be significantly
larger in patients in the HC group. This result can be
explained by the fact that the patients with larger infarct
permeability developed malignant brain edema. Recently
PCT data were also used to characterize the BBBP in an effort
to predict which patients with stroke develop hemorrhagic
transformation.15 Lin et al showed that elevated PS had been
detectable during the hyperacute period using first-pass
dynamic CT data and was predictive for hemorrhagic transformation in patients who received tissue plasminogen activator.15 Aviv et al evaluated the admission PS measurements
of patients with acute stroke and reported that a PS threshold
of 0.23 mL 䡠 (100 g)⫺1 had high sensitivity and specificity for
predicting hemorrhagic transformation.46 Taken together,
these studies along with our results underscore the fact that a
compromise in the BBB is a necessary but not sufficient
criterion for hemorrhagic transformation. If the permeability
of the BBB is not large enough for blood cellular elements
(red blood cells, platelets) to pass, hemorrhage will not occur,
but the BBB only needs to be permeable to much smaller
molecules such as albumin for water to follow it into the
interstitial space and cause edema. BBB permeability maps
may therefore have even more use than just predicting
hemorrhage by showing which patients may develop malignant edema.
This study is limited by its retrospective design and small
sample number in the HC group. There could also have been
variations in the gravity of the MCA infarcts (eg, internal
carotid artery infarct with involvement of the anterior cerebral artery), which may have favored HC and thus may have
introduced a systematic difference between the HC and NHC
groups. In addition, we found that in multivariate regression,
IParea was no longer predictive of HC when controlling for
DWI lesion volume. Although DWI lesion size may be more
predictive for HC, MRI is not always available or feasible for
Increased BBBP Predicts MMCA Infarction
2543
all patients in the initial management period, particularly for
patients with large strokes who are susceptible to malignant
edema (as shown by our data in which patients with deterioration were less likely to have DWI follow-up). Thus, the
BBB permeability map might be useful in predicting patients
who will develop MMCA, especially in light of the result that
the CBV (core) lesion area was not predictive of deterioration. Thus, the modified Patlak permeability map uniquely
offers novel information over the conventional perfusion CT
maps and PCT can be obtained rapidly when the patient first
presents to the emergency department.
In conclusion, the IParea on admission PCT might be a
useful tool to predict MMCA and need for HC. Given that
studies suggest early rather than delayed HC for MMCA is
associated with better outcomes,20,46,47 further prospective
studies are needed to validate our findings.
Sources of Funding
This work was supported by National Institutes of Health training
grant T32NS04712 and P50 NS04422, the Notsew Orm Sands
Foundation, and the Howard Hughes Medical Institute.
Disclosures
None.
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Increased Blood−Brain Barrier Permeability on Perfusion CT Might Predict Malignant
Middle Cerebral Artery Infarction
Hesna Bektas, Tzu-Ching Wu, Mallikarjunarao Kasam, Nusrat Harun, Clark W. Sitton, James
C. Grotta and Sean I. Savitz
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Stroke. 2010;41:2539-2544; originally published online September 16, 2010;
doi: 10.1161/STROKEAHA.110.591362
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