Radiol Oncol 2019; 53(1): 25-30. doi: 10.2478/raon-2018-0048
25
research article
Infarct-core CT perfusion parameters in 
predicting post-thrombolysis hemorrhagic 
transformation of acute ischemic stroke 
Crt Langel1, Katarina Surlan Popovic2 
1 Novo Mesto General Hospital, Slovenia
2 Institute of Radiology, University Medical Centre Ljubljana, Slovenia
Radiol Oncol 2019; 53(1): 25-30.
Received 26 August 2018
Accepted 11 November 2018
Correspondence to: Assoc. Prof. Šurlan Popović Katarina, M.D., Ph.D., Institute of Radiology, University Medical Centre Ljubljana, Zaloška 
cesta 7, SI-1000 Ljubljana, Slovenia. Phone: +386 1 522 85 30; E-mail: katarina.surlan@gmail.com
Disclosure: No potential conflicts of interest were disclosed. 
Background. Intravenous thrombolysis (IVT) is the method of choice in reperfusion treatment of patients with signs 
and symptoms of acute ischemic stroke (AIS) lasting less than 4.5 hours. Hemorrhagic transformation (HT) of acute 
ischemic stroke is a serious complication of IVT and occurs in 4.5–68.0% of clinical cases. The aim of our study was to 
determine the infarct core CT perfusion parameter (CTPP) most predictive of HT.
Patients and methods. Seventy-five patients with AIS who had undergone CT perfusion (CTP) imaging and were 
treated with IVT were enrolled in this retrospective study. Patients with and without HT after IVT were defined as cases 
and controls, respectively. Controls were found by matching for time from AIS symptom onset to IVT ± 0.5 h. The follow-
ing CTPPs were measured: cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), relative 
CBF (rCBF) and relative CBV (rCBV). Receiver operating characteristic analysis curves of significant CTPPs determined 
cut-off values that best predict HT.
Results. There was a significant difference between cases and controls for CBF (p = 0.004), CBV (p = 0.009), rCBF (p 
< 0.001) and rCBV (p = 0.001). Receiver operating characteristic analysis revealed that rCBF < 4.5% of the contralat-
eral mean (area under the curve = 0.736) allowed prediction of HT with a sensitivity of 71.0% and specificity of 52.5%.
Conclusions. CTP imaging has a considerable role in HT prediction, assisting in selection of patients that are likely to 
benefit from IVT. rCBF proved to have the highest HT predictive value.
Key words: acute ischemic stroke; computed tomography perfusion; infarct core; hemorrhagic transformation
Introduction
Ischemic stroke is defined as an episode of neuro-
logical dysfunction caused by focal cerebral, spinal 
or retinal infarction accompanied by overt symp-
toms.1 About 90% of all strokes are ischemic, while 
roughly 10% are hemorrhagic (including intracer-
ebral and subarachnoid hemorrhage).2
Patients presenting signs and symptoms of 
acute ischemic stroke (AIS) undergo a series of CT 
imaging procedures, including non-contrast CT to 
exclude pre-treatment intracranial hemorrhage, 
CT angiography (CTA) to determine the precise lo-
cation of vessel occlusion, CT perfusion (CTP) to 
differentiate between potentially salvageable and 
irreversibly damaged brain tissue, and post-treat-
ment non-contrast CT to exclude thrombolysis-
related hemorrhage.3–6
The standard AIS treatment method within 4.5 
hours of symptom onset is intravenous thromboly-
sis (IVT) with tissue plasminogen activator (tPA) 
injection.7, 8 Patients with IVT-therapy contraindi-
cations or ineffectiveness may be eligible for endo-
vascular mechanical thrombectomy (MT).8, 9
Hemorrhagic transformation (HT) is a conver-
sion of ischemic brain tissue into a hemorrhagic le-
sion due to blood-brain barrier disruption. It may 
occur spontaneously in ischemic brain tissue but 
Radiol Oncol 2019; 53(1): 25-30.
Langel C et al./ Infarct core CT perfusion parameters of acute ischemic stroke26
may also be triggered by reperfusion.10, 11 HT oc-
curs in 4.5 - 68.0% of AIS clinical cases and has a 
higher incidence in patients treated with IVT than 
in patients without such treatment.12–14 While mild 
to moderate HT may not seriously impact the clin-
ical outcome, severe HT is a significant predictor 
of neurological deterioration and higher mortal-
ity.14, 15
CTP is an imaging technique that measures 
brain tissue blood perfusion by analyzing time-at-
tenuation curves of contrast agent in input artery 
and parenchyma, generating maps of CT perfusion 
parameters (CTPPs). CTPPs are cerebral blood vol-
ume (CBV), mean transit time (MTT) and cerebral 
blood flow (CBF). CBV is defined as the total vol-
ume of flowing blood in a given volume of brain. 
MTT is defined as the average transit time of blood 
through a given brain region. CBF is defined as the 
volume of flowing blood moving through a given 
volume of brain in a specific amount of time. The 
three CTPPs are associated by the equation: CBF = 
CBV / MTT.16 
Absolute CTPPs are values of a certain brain re-
gion while relative CTPPs are values of a certain 
brain region divided by values of the contralateral 
brain region. In the context of AIS, relative CTPPs 
are values measured in the pathological hemisphere 
expressed as a percentage of the values measured 
in the contralateral normal hemisphere.17
Previous studies have shown that CTPPs of the 
whole infarct area (penumbra and infarct core as a 
single region) could be used to predict HT, finding 
relative CBV (rCBV) ≤ 1.09 and Tmax > 14 s , respec-
tively, to be the most predictive of HT, with relative 
CBF (rCBF) < 30% also being of considerable utility 
in predicting HT.18, 19 One study found neither CBF 
nor CBV to be significantly different between cases 
and controls, while not examining relative CTPPs.20 
Another study examined infarct-core CTPPs, find-
ing CBV ≤ 0.5 mL/100 g to be predictive of symp-
tomatic intra-cerebral hemorrhage, while also not 
investigating relative CTPPs.21 One study initially 
proposed separate analysis of infarct-core CTPPs 
but eventually dismissed the idea due to insuffi-
cient sample size.18 
The rationale for separate analysis of the infarct 
core subregion is that it may provide a different 
insight into HT prediction than a whole-infarct 
approach, due to the elimination of the “average-
out” effect.21 The reasoning behind the use of rela-
tive rather than absolute CTPPs is to account for 
potential interpatient variability, while also avoid-
ing the inter-vendor variability of postprocessing 
software.18,22 Our study thus aimed to investigate 
CTPPs of the infarct core in predicting HT, with an 
emphasis on relative CTPPs
Patients and methods
Patients
This single-centre retrospective study enrolled 
75 patients (47 males, 37 females, mean age ± SD 
72.63 ± 11.7 years) who had been admitted to neu-
rological emergency, with AIS symptoms lasting 
less than 4.5 hours. Patients underwent admission 
non-contrast CT, CTA and CTP imaging, and were 
treated with IVT according to guidelines, in the 
period from January 2012 – April 2015. The study 
was performed in accordance with the Declaration 
of Helsinki and was approved by the National 
Medical Ethics Committee (Trial registration num-
ber: 0120-453/2017-3). 
Methods
CT, CTA and CTP imaging were performed with 
a Siemens Sensation Open 40 (Siemens Medical 
Systems, Erlangen, Germany). CTP was performed 
using 40 mL of iodinated contrast medium at a flow 
rate of 6 mL/s, followed by 40 mL of saline flush at 
the same rate, injected into the cubital vein. Four s 
after initiation of the injection, a continuous (cine) 
scan was initiated using the following parameters: 
80 kVp, 209 mAs, 4 × 5 mm sections, 1-second per 
rotation for a duration of 40 s.
The images were loaded onto a worksta-
tion (Syngo MultiModality Workplace; Siemens 
Healthcare, Erlangen, Germany). CTPPs - cerebral 
blood flow (CBF), cerebral blood volume (CBV) 
and mean transit time (MTT) - were automatically 
calculated from CTP data using commercial soft-
ware (Neuro PCT; Siemens Healthcare, Erlangen, 
Germany). A single circular region of interest (ROI) 
measuring 15–20 mm in diameter was placed in the 
region of the infarct core. Mirror ROI was automati-
cally placed by the software in the contralateral (i.e., 
asymptomatic) hemisphere. Region-specific CTPPs 
of both ROIs were measured. Relative CTPPs were 
calculated by dividing the CTPP values of infarct 
core ROI by asymptomatic hemisphere ROI.
The development of HT was documented by 
follow-up non-contrast CT 24 h after initial imag-
ing. Patients who developed HT were assigned to 
the cases group (n=35), while patients that did not 
develop HT were assigned to the controls group 
(n=40), matching the cases based on time from AIS 
symptom onset to IVT ± 0.5 h. The matching was 
Radiol Oncol 2019; 53(1): 25-30.
Langel C et al./ Infarct core CT perfusion parameters of acute ischemic stroke 27
carried out by first obtaining the data regarding the 
time period from AIS symptom onset to the start 
of the IVT procedure for each patient, then select-
ing those patients from the pool of controls group 
candidates that most closely matched each cases 
group patient’s time period, ± 0.5 h being the cut-
off point beyond which a controls group candidate 
would not be considered for matching. Adhering 
to these conditions 40 cases were assigned controls, 
however due to technical inadequacies of some of 
the imaging studies (e.g. patient movement) cases 
group was later reduced to 35 patients.
Statistical analysis
All numerical data were reported as means ± 
standard deviation. The normality of data distribu-
tion was evaluated by the Shapiro-Wilk test. The 
Mann-Whitney U-test was used to determine the 
existence of a statistically significant difference in 
CTPPs between cases and controls. A p value < 0.05 
was regarded as statistically significant. The area of 
the receiver operating characteristic (ROC) curve 
under the curve (AUC) determined the ability of 
CTPPs to differentiate between the occurrence and 
non-occurrence of HT. ROC curve analysis identi-
fied optimal cut-off values of CTPPs that predict 
the onset of HT with the highest sensitivity and 
specificity. IBM SPSS Statistics (version 20.0, SPSS 
Inc., Chicago, IL, USA) was used to perform statis-
tical analyses.
Results
Seventy-five patients with AIS who had undergone 
CTP imaging and had been treated with IVT were 
included in the study. Significant differences in 
mean values between cases and controls were ob-
served (p = < 0.000–0.009) for CBF, CBV, rCBF and 
rCBV.
The area under the curve (AUC) of the receiv-
er operating characteristic (ROC) of rCBF (0.736) 
showed a satisfactory ability to differentiate be-
tween the occurrence and non-occurrence of HT, 
while AUCs of CBF, CBV and rCBV showed com-
paratively inferior differentiation abilities (0.704–
0.676).
Discussion
HT is a potentially grave complication of IVT, oc-
curring in 4.5–68.0% of clinical AIS cases. Severe 
FIGURE 1. CT perfusion (CTP) in a 64-year old patient with acute ischemic stroke 
(AIS) in the territory supplied by the right middle cerebral artery (MCA). Four 
radiological slices correspond to different anatomical levels of image acquisition. (A) 
Hand-drawn region of interest (ROI) in the region of infarct core. (B) Automatically 
generated ROI of the asymptomatic contralateral hemisphere. 
FIGURE 2. CT perfusion (CTP) in a 64-year old patient with acute ischemic stroke (AIS) 
in the territory supplied by the right middle cerebral artery (MCA). (A) Infarct core. 
(B) Penumbra. (C) Intact brain parenchyma.
A
A
A
A
A
B
B
B
B
B
C
Radiol Oncol 2019; 53(1): 25-30.
Langel C et al./ Infarct core CT perfusion parameters of acute ischemic stroke28
HT is a significant predictor of neurological dete-
rioration and higher mortality.15 Various HT pre-
diction methods have been investigated, including 
CT, CTP, SPECT and diffusion- and perfusion-
weighted MR imaging.21-26 According to previously 
published data, CTPPs of the whole infarct area ef-
fectively predict HT. Jain et al. and Yassi et al. found 
relative CTPPs – rCBV and rCBF, respectively, – to 
be the most predictive of HT.18,19
To the best of our knowledge, this study is the 
first to analyze relative CTPPs of infarct core in 
predicting HT. On the one hand, the infarct core 
itself seems not to have been the main focal point of 
investigations so far, due to various circumstances, 
including limited sample size, as was the case with 
Jain et al.18 On the other hand, the sole study that 
did analyze infarct core, carried out by Lin et al., 
investigated absolute CTPPs only. The findings of 
Zussman et al. cautioned against using absolute 
CTPPs due to inter-vendor variability of post-
processing software, while Jain et al. also warned of 
possible interpatient variability of absolute CTPPs, 
encouraging the use of relative CTPPs instead.21,22
The above arguments prompted us to focus on 
analyzing relative CTPPs of the infarct core, with 
the full knowledge that there might currently be no 
point of reference to compare our results directly. 
We found additional reasoning for an infarct-core 
approach in the fact that our attempts at free-hand 
whole-infarct designation with image segmenta-
tion to eliminate structures that were irrelevant for 
CTP (e.g., large vessels and sulci) proved futile in 
many cases; eliminating a large vessel completely 
often required such a large Hounsfield units (HU) 
exclusion interval that it inadvertently also dese-
lected the majority of tissue viable for CTP analy-
sis. Additionally, we found the non-segmentation 
single-ROI infarct-core approach to be fast and 
straightforward – a potential advantage when us-
ing CTPPs in an emergency clinical setting.
Our study of infarct-core CTPPs demonstrates 
that rCBF < 4.5% of the contralateral mean best 
predicts the occurrence of HT (sensitivity 71.0%, 
specificity 52.5%). Considering studies that opted 
for whole-infarct measurement of relative CTPPs, 
it should be noted that our approach offered con-
siderably inferior sensitivity but better specificity 
than whole-infarct rCBF < 30% (sensitivity 100%, 
specificity 39.0%) studied by Yassi et al., while 
whole-infarct rCBV < 1.09 (sensitivity 100%, speci-
ficity 58.3%) researched by Jain et al. proved to 
be superior to both infarct-core rCBF and whole-
infarct rCBF. Infarct-core rCBV < 8.5% (sensitivity 
71.4%, specificity 42.5%) examined by our study 
TABLE 1. Characteristics of study cohort
Parameter Cases Controls p value
CBF (mean (SD)) [mL/100 g/min] 0.38 (0.47) 0.98 (1.37) 0.004
CBV (mean (SD)) [mL/100 g] 1.45 (1.7) 3.06 (2.99) 0.009
MTT (mean (SD)) [s] 4.27 (4.00) 4.22 (3.26) 0.718
rCBF (mean (SD)) 0.03 (0.05) 0.10 (0.12) < 0.000
rCBV (mean (SD)) 0.07 (0.09) 0.10 (0.12) 0.001
rMTT (mean (SD)) 2.47 (2.05) 2.36 (1.65) 0.948
CBF = cerebral blood flow; CBV = cerebral blood volume; MTT = mean transit time; rCBF = relative 
cerebral blood flow; rCBV = relative cerebral blood volume); rMTT = relative mean transit time
TABLE 2. Region of interest (ROI) curve analysis results
AUC cut-off value sensitivity specificity
CBF [mL/100 g/min] 0.691 0.35 62.0% 35.0%
CBV [mL/ 100g] 0.676 1.65 68.6% 40.0%
rCBF 0.736 4.5% 71.0% 52.5%
rCBV 0.704 8.5% 71.4% 42.5%
CBF = cerebral blood flow); CBV = cerebral blood volume); rCBF = relative cerebral blood flow; 
rCBV = relative cerebral blood volume
FIGURE 3. Region of interest (ROI) curve of relative cerebral blood flow (rCBF) in 
patients with and without hemorrhagic transformation (HT). rCBF represents the 
CBF of the infarct core region normalized to the intact contralateral side. The cut-
off point marks the threshold at which relative cerebral blood volume (rCBV) can 
predict HT with optimal sensitivity and specificity. Diagonal segments are produced 
by ties.
Radiol Oncol 2019; 53(1): 25-30.
Langel C et al./ Infarct core CT perfusion parameters of acute ischemic stroke 29
proved to be inferior in HT prediction to the afore-
mentioned CTPPs but might be considered as an 
additional parameter to rCBF when evaluating the 
infarct core due to similar sensitivity.
A possible reason for the extremely low infarct-
core rCBF examined in our study being less sensi-
tive in prediction of HT than the moderately low 
whole-infarct rCBF examined by Yassi et al. might 
be that the severe hypo-perfused stroke region con-
tains very low levels of contrast, which in certain 
cases could be undetectable by CTP.19 Additionally, 
our ROI placement protocol limited the maximum 
diameter of circular ROI to 20 mm, and while 
smaller ROIs help eliminate the “average-out” ef-
fect that is associated with large, whole-infarct 
freehand ROIs, they may also be more susceptible 
to the effect of random pixel noise.21 Another pos-
sible source of the comparatively higher data het-
erogeneity in our study may be the potential tem-
poral truncation of the contrast bolus in the infarct 
region.27, 28
Our study has several limitations. It was a ret-
rospective study. The effects of stroke severity and 
anatomical location were not controlled by match-
ing, nor was the anatomical location of HT. HT was 
not stratified into subtypes. The time to treatment 
was controlled by matching; this, however, de-
creased the final cohort size. ROI placement was 
performed by a single experienced operator but 
no estimation of the intra-observer reproducibility 
of this procedure was made. Our results represent 
only a single-institution experience.
In conclusion, our analysis indicates that infarct-
core CTPPs - low rCBF in particular - can predict 
HT in patients with AIS. Should this be further 
verified by larger multi-centre studies, CTP imag-
ing could become the method of choice for identi-
fication of patients at low risk of HT, thus helping 
decide on IVT treatment.
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