Interleaving cerebral CT perfusion with neck CT angiography part I. Proof of concept and accuracy of cerebral perfusion values
Interleaving cerebral CT perfusion with neck CT angiography part I. Proof of concept and accuracy of cerebral perfusion values
Marcel T. H. Oei 0
Frederick J. A. Meijer 0
Willem-Jan van der Woude 0
Ewoud J. Smit 0
Bram van Ginneken 0
Mathias Prokop 0
Rashindra Manniesing 0
0 Department of Radiology and Nuclear Medicine, Radboud University Medical Center , P.O. Box 9101, 6500 HB Nijmegen , The Netherlands
Objectives We present a novel One-Step-Stroke protocol for wide-detector CT scanners that interleaves cerebral CTP with volumetric neck CTA (vCTA). We evaluate whether the resulting time gap in CTP affects the accuracy of CTP values. Methods Cerebral CTP maps were retrospectively obtained from 20 patients with suspicion of acute ischemic stroke and served as the reference standard. To simulate a 4 s gap for interleaving CTP with vCTA, we eliminated one acquisition at various time points of CTP starting from the bolus-arrivaltime(BAT). Optimal timing of the vCTA was evaluated. At the time point with least errors, we evaluated elimination of a second time point (6 s gap). Results Mean absolute percentage errors of all perfusion values remained below 10 % in all patients when eliminating any one time point in the CTP sequence starting from the BAT. Acquiring the vCTA 2 s after reaching a threshold of 70HU resulted in the lowest errors (mean <3.0 %). Eliminating a second time point still resulted in mean errors <3.5 %. CBF/ CBV showed no significant differences in perfusion values except MTT. However, the percentage errors were always below 10 % compared to the original protocol.
Multidetector computed tomography; Angiography; Perfusion; Brain; Stroke
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* Frederick J. A. Meijer
Conclusion Interleaving cerebral CTP with neck CTA is
feasible with minor effects on the perfusion values.
Key Points
Removing a single CTP acquisition has minor effects on
calculated perfusion values
Calculated perfusion values errors depend on timing of
skipping a CTP acquisition
Qualitative evaluation of CTP was not influenced by
removing two time points
Neck CTA is optimally timed in the upslope of arterial
enhancement
A separate head and neck CT angiography (CTA) and cerebral
CT perfusion (CTP) acquisition in addition to cerebral
noncontrast CT (NCCT) is commonly performed in the diagnostic
workup of patients presenting with acute ischemic stroke
[1–4]. This implies that the combination of CTA and CTP
requires two doses of contrast agent. Since CTP can be used
to provide excellent cerebral CTA as well [5–7], the technique
can be optimized by only covering the region of the neck
vessels in a separate CTA acquisition [8].
If the cerebral CTP acquisition sequence could be
interleaved with the neck CTA acquisition, no additional contrast
injection would be necessary and the total exam time would be
reduced in a clinical setting where rapid treatment decisions
are of paramount importance. We present a novel scanning
technique for wide-detector CT scanners that obviates the
need for a separate head and neck CTA acquisition, which
we therefore consider a One-Step-Stroke protocol. This
technique relies on a wide detector coverage and a rapid table
movement to interleave a whole brain CTP with neck CTA in
one sequence using a single dose of contrast agent. The
sequence begins with CTP acquisitions of the brain. At a
suitable time point, a volumetric neck CTA is acquired by rapidly
moving the table to the adjacent neck region. Then, the table
moves back to the brain, where the CTP acquisition is
continued. By using a single exam imaging time, radiation exposure
and amount of contrast material can be reduced. A prerequisite
for this technique is that the perfusion maps resulting from
such an interleaved sequence remain diagnostic. Ideally, the
quantitative perfusion values should remain unaffected by the
time gap introduced by performing the neck CTA within the
CTP sequence.
The purpose of this study is to evaluate whether the
resulting time gap in the CTP sequence affects the accuracy
of the perfusion values.
Materials and methods
Two authors (R.M. and M.P.) received a research grant from
Toshiba Medical Systems Corporation (TMSC, Japan).
Toshiba Medical Systems Corporation did not have any
influence on the concept of the One-Step-Stroke protocol, the
execution of this study, the analysis of the data, nor on the
writing of this manuscript.
This retrospective study was approved by the ethics
committee of our institution, and informed consent was waived.
Initially, 34 consecutive subjects were included who
underwent CTP scanning at the emergency department of
our hospital. Inclusion criteria were: patients with clinical
symptoms of acute ischemic stroke, with onset of symptoms
within 9 hours, without a history of kidney failure and a
minimum age of 18 years. Exclusion criteria were: non-standard
CTP acquisition protocol (4), severe patient movement
artefacts in CTP (2), incidental finding of a tumour lesion (1), late
or poor contrast enhancement (3), intra-arterial contrast
injection (1), the presence of a drainage tube (1), clipped or coiled
cerebral aneurysm (2). The remaining 20 patients consisted of
eight male and 12 female patients (mean age 65 years, median
66 years and age range 36 - 93 years).
In eight out of 20 patients, signs of acute ischemic stroke
were seen on the NCCT, CTA and/or CTP images by the
attending neuroradiologist.
CT imaging was performed on a 320-row CT scanner
(Toshiba, Aquilion ONE, Toshiba Medical Systems
Corporation, TMSC, Otawara, Japan). The scan protocol
consisted of a cerebral NCCT, cerebral CTP, and head and
neck CTA. In all patients two contrast injections were
performed, one for CTP and one for the CTA. Only the CTP
acquisitions were used in the present study.
For CTP, 50 mL nonionic contrast agent (300 mg iodine/
mL Xenetix 300, Guerbet, Villepinte, France) was injected
into an antecubital vein with an injection rate of 5 mL/s
followed by a 40 mL saline flush at 5 mL/s. Whole brain
volumetric acquisitions with 16 cm z-coverage were acquired
with 0.5 mm slice thickness, 0.5 s rotation time, and 80 kV
tube voltage. A cerebral CTP protocol was used, which started
5 s after contrast agent injection with the first volumetric
acquisition at 200 mAs, followed after 4 s by 13 scans at
100 mAs with a 2 s interval, followed after 5 s by five scans
at 75 mAs with a 5 s interval. The total number of scans was
19 and total scan duration was 60 s (Fig. 1). Image
reconstruction was done using a smooth convolution kernel FC41 and
standard AIDR3D (adaptive iterative dose reduction in
threedimensions, TMSC).
A publicly available software program, Perfusion Mismatch
Analyzer (PMA) developed by the Acute Stroke Imaging
Standardization Group (ASIST), version 5.0.0.0, was used to
calculate perfusion maps of cerebral blood flow (CBF), cerebral
blood volume (CBV), and mean transit time (MTT). The
software automatically selects ten arterial input functions (AIFs) in
one slice, which was set at the level of the Circle of Willis. The
venous output function (VOF) was automatically chosen in the
intracranial veins above the skull base. The perfusion maps
were calculated with a delay-insensitive deconvolution
algorithm, the block-circulant Singular Value Decomposition
(bSVD) [9]. Calculations were performed on a 256 × 256
matrix with smoothing enabled, on 5 mm slabs of the original CTP
data; other parameters of PMA were kept at default values.
Simulating the one-step-stroke protocol
The One-Step-Stroke protocol was simulated by eliminating
specific acquisitions from a CTP sequence in order to study
the optimal time gaps between subsequent acquisitions,
similar to a previous study published in the literature [10]. The
perfusion values derived from the original sequence served
as the reference standard. One observer experienced in CTP
analyses (M.O.) selected a region of interest (ROI) in the
(unaffected) proximal M1-portion of the middle cerebral
artery (M1-MCA) to visually determine the bolus arrival time
(BAT). For every patient one volumetric acquisition was
deleted, starting from the BAT up to the fifth time point after the
arterial peak (see Fig. 1). Because the number of volumetric
acquisitions between these two markers may differ per patient,
Fig. 1 Graphical overview of the clinical CTP protocol. The vertical bars
denote the individual time points of the protocol; the height of each bar
represents the tube current at that time point. The red line is the
attenuation curve in the middle cerebral artery in the proximal M1
segment (MCA). For every patient bolus arrival time and peak
the number of deleted time points and, therefore, the number
of simulated One-Step-Stroke protocols differ per patient.
Perfusion maps were calculated for the original CTP
acquisition and for each One-Step-Stroke protocol. The locations of
the automatically chosen AIF and VOF of these simulated
One-Step-Stroke protocols were compared to the locations
in the original protocol and manually corrected if they were
not at identical locations. The ROI in the MCA was also used
to estimate arterial enhancement to estimate the enhancement
of the carotid arteries.
Perfusion values in normal-appearing white matter (WM) and
normal-appearing gray matter in the basal ganglia (GM) were
estimated by drawing multiple ROIs (M.O.) and averaging
perfusion values across these ROIs for each patient and tissue
type. White matter ROI’s included the centrum semiovale and
cortical spinal tract. Subcortical gray matter ROI’s included
the caudate nucleus, putamen and globus pallidus. The size
and location of the ROIs were kept constant within the patient,
while the size of the ROI’s differed between patients (freehand
ROI’s were applied). The total number of voxels included was
6,922 ± 3,674 (mean ± standard deviation) for NAWM and
547 ± 244 for NABG.
For each skipped time point, percentage errors of the
perfusion values were calculated per tissue type and patient. The
percentage error was calculated by taking the difference of the
perfusion values between the original CTP protocol and the
simulated One-Step-Stroke protocol divided by the perfusion
value of the original CTP protocol multiplied by 100. Since
these percentage errors can be positive or negative, we used
the absolute percentage error |% error| for further analysis.
enhancement in the MCA were determined. The One-Step-Stroke
protocol was simulated by eliminating one volumetric acquisition starting
from the bolus arrival time up to the fifth time point after peak
enhancement of the M1-MCA. These are denoted by the orange bars
First, to estimate the magnitude of the absolute percentage
errors, we determined the mean and standard deviation of all
patients and all simulated One-Step-Stroke protocols, for
CBV, CBF, and MTT in WM and GM. Thus, in total six mean
absolute percentage errors and corresponding standard
deviations were calculated. Furthermore, we report the maximum
absolute percentage errors.
Next, we determined the optimal timing of the neck CTA.
Since we aimed to evaluate which time point could be deleted
without having a major influence on any of the three perfusion
parameters, for each patient we selected the maximum
percentage error across the three perfusion parameters CBV,
CBF, and MTT in WM and GM per deleted time point.
Thus, per patient and per simulated One-Step-Stroke protocol
(i.e., per deleted time point), one maximum percentage error is
selected for further analyses.
In order to determine the optimal timing of the neck CTA,
we simulated bolus tracking by determining the first time point
T0 in which the enhancement in the M1-MCA exceeded a given
relative threshold value. Relative thresholds, i.e., enhancement
above the baseline pre-contrast scan, were varied between 40
HU and 100 HU in steps of 10 HU. Every deleted time point
was reported in seconds relative to T0, for up to 10 s after T0.
Therefore, each threshold defines a T0 (which may
differ per patient in absolute time) and each simulated
OneStep-Stroke protocol results in a maximum percentage
error per patient. The mean (maximum percentage error) of
all patients was then calculated. We calculated the mean
maximum percentage error as a function of the relative
threshold (a trigger for bolus tracking) and as a function
of the deleted time points from T0.
To estimate how often the selected timing would lead
to larger errors, we reported the number of patients in
whom the absolute percentage error exceeded 10 % in at
Mean, standard deviation and maximum absolute percentage
least one perfusion parameter. The time point and
threshold with the lowest average maximum percentage error
and the lowest number of patients with more than 10 %
errors in combination with the highest enhancement in the
MCA (which served as proxy for carotid enhancement)
was chosen as the optimal timing.
Finally, after determining the optimal time point for neck
CTA the analysis was repeated but with two time points
deleted to simulate a 6 s gap at the optimal timing only.
Visual assessment of the perfusion maps
A subsequent observer study was performed in order to
evaluate the influence of skipping two CT perfusion time points on
the qualitative evaluation of perfusion maps. An experienced
observer (F.J.A.M.) evaluated the original perfusion maps and
perfusion maps with a 6 s time gap randomly. The CT
perfusion maps were scored for: 1) The presence or absence of a
perfusion deficit. 2) Absence or presence of infarct core. 3)
Absence or presence of penumbra. and 4) Size of infarct core
or penumbra. The sizes were described as either small or large
relative to the vascular territory affected. Infarct core was
defined by a perfusion deficit with increased MTT, decreased
CBF, and decreased CBV. Penumbra was defined as the
presence of a perfusion deficit in relation with normal or slight
elevated CBV. The observer was blinded to perfusion maps
shown (original or with a 6 s gap), clinical information and
diagnoses.
Statistical analyses were performed using the Statistical
Package of Social Sciences version 20.0 for Windows
(SPSS Inc., Chicago, USA). A Wilcoxon signed rank test
was used to show significant differences between the original
CTP protocol and the One-Step-Stroke protocol at the optimal
time point with 4 s and 6 s gaps. A P value < 0.05 was
considered significant. By examining the slope of a linear fit
intersecting the origin, the linear relationship between the
original CTP protocol and the One-Step-Stroke protocol with
4 s and 6 s gaps were assessed. A linear fit of 1 was considered
ideal. Spearman correlation coefficients were reported.
BlandAltman analyses were performed to compare the original CTP
and the simulated One-Step-Stroke with 4 s and 6 s time gaps.
Absolute percentage errors
Table 1 gives an overview of the absolute percentage errors. In
WM, the mean absolute percentage errors were 3.1 % for
CBF, 2.7 % for CBV, and 1.6 % for MTT. In GM, we found
3.5 ± 3.5 (30.1)
2.8 ± 3.2 (24.6)
2.6 ± 2.4 (13.8)
Note - Absolute percentage error of CT perfusion values in white matter
and gray matter if one time point of the CTP sequence is skipped,
averaged for all patients and for all deleted time points. Values shown are the
mean ± standard deviations and maximum absolute percentage error in
parentheses. Note that despite a low mean across all time points and
patients, the maximum error may be substantial
an average absolute percentage error of 3.5 % for CBF, 2.8 %
for CBV, and 2.6 % for MTT of all patients and time points.
However, the maximum errors that could occur were
substantially larger: 22.2 % for CBF, 18.5 % for CBV, and 7.4 %
for MTT in WM, and 30.1 % for CBF, 24.6 % for CBV, and
13.8 % for MTT in GM. The absolute percentage errors
exceeded 10 % in 16 instances in CBF (seven in GM and nine
in WM), 14 instances in CBV (five in GM and nine in WM),
and two instances in MTT (GM).
Supplementary Figure 4 gives an example of a patient in
whom the percentage errors exceeded 10 % in all perfusion
maps if an unsuitable time point was chosen.
The results of optimization are summarized in Tables 2 and 3.
Table 2 displays the mean maximum absolute percentage error
across all perfusion parameters, and provides the number of
patients in whom the absolute percentage error exceeded
10 %. Given a threshold in the range of 40–70 HU, the
percentage errors never exceeded 10 % if the neck CTA was
acquired 2 s after the first scan in which enhancement
exceeded the threshold. A relative threshold of 70 HU gave
the lowest percentage errors.
Table 3 provides the absolute percentage errors for
CBV, CBF, and MTT for the case of optimal timing with
a 4 s gap and with a 6 s gap. For optimal timing with a 4 s
gap, all errors were below 7.5 %. At that time point, the
average HU value in the M1 segment of the MCA were
302 ± 57.4 HU (range, 198 – 408 HU). For optimal timing
with a 6 s gap, all errors were below 9.2 %, except for one
patient for which CBF showed an error 13.9 %. On
average, the percentage errors were below 3.5 %.
Bland-Altman plots are shown in Fig. 2. Spearman
correlations are shown in Table 4. There was no significant
difference between the perfusion values of the One-Step-Stroke
protocol at the optimal time point and the original CTP
protocol, for both 4 s and 6 s time gaps, except for MTT in WM (see
Table 4). Although MTT in WM showed a significant
Optimization of timing and threshold for bolus tracking
Note - For each patient the maximum of the errors of CBV, CBF and MTT was calculated for each combination of enhancement threshold (horizontally)
and post-threshold delay (vertically). The table displays the mean ± standard deviation and the range for each combination averaged over all patients. In
addition, the number of patients in whom the maximum error exceeded 10 % is listed. Note that the lowest error occurred for a threshold of 70 HU above
baseline (green box), which is selected as the optimal timing (one deleted time point, 4 s time gap)
difference in perfusion values, the absolute perfusion values
stayed within the 10 % (9.2 % for a 6 s time gap, and even
5.2 % for a 4 s time gap) compared to the original protocol.
Visual assessment of the perfusion maps
In eight of 20 patients, a perfusion deficit was visible. All
perfusion deficits were visible in the middle cerebral artery
(MCA) territory. Two patients showed an infarct core of one
third of the MCA territory with no penumbra and two patients
showed small infarct core lesions in less than one third of the
MCA territory with no penumbra. Two patients showed only
penumbra of less than one third of the MCA territory. Two
patients showed only penumbra which was more than two
thirds of the MCA territory.
The study showed full agreement between the original
perfusion maps and the perfusion maps with a 6 s time
gap in the detection of a perfusion deficit. However, in
one case a possible small cortical perfusion deficit was
Table 3 Absolute percentage
error of the perfusion values at the
optimal timing
noted in the original perfusion maps, while not rated in
the perfusion maps with a 6 s gap; after reviewing the
images next to each other, this was rather due to observer
variability than to the imaging technique. At follow-up,
no infarct was demonstrated in this area. No perfusion
deficits were missed and the sizes of penumbra and infarct
core were described similar in both perfusion maps. An
example is shown in Fig. 3.
Our study shows that a One-Step Stroke protocol is
feasible with only minor differences in CTP values and good
arterial enhancement for the neck CTA, if a suitable time
point is used for skipping one volumetric CTP acquisition
and performing the neck CTA instead. In fact, the
absolute percentage errors for CBV, CBF or MTT then never
exceeded 7.5 %. Eliminating a second time point still
Optimal Time with 4 s Gap
Optimal Time with 6 s Gap
Note – Data are shown in mean ± standard deviation, with the maximum value in parentheses. The mean across all
patients remains low, and the maximum error is ≤7.5 % at optimal time with a 4 s gap and ≤9.2 % at optimal time
with a 6 s gap (except for one patient for whom the CBF reached 13.9 %)
Bland Altman CBF
Mean One-Step-Stroke and conventional CTA
Bland Altman CBV
Bland Altman MTT
perfusion values resulting from selection of AIF and
VOF was 27.1 % for manual selection and 10.4 % for
automatic selection [13]. Two studies reported that it is
unlikely that clinical decisions alter with qualitative visual
assessment of the perfusion maps, if an overall variability
around 10 % is achieved [14, 15]. We, therefore, chose a
10 % limit for absolute percentage errors as an indicator
of errors that might become clinically relevant. With the
optimal timing suggested in this article, the errors always
remain below 7.5 %.
A comparable study showed that CTP with a 3 s (if
50 ml contrast agent was given) or 4 s (if 60 ml contrast
agent was given) temporal sampling interval over the first
60 s does not significantly over- or underestimate the
perfusion values relative to protocols with 1 s sampling
intervals [10]. In concordance with their findings, the
average absolute percentage errors reported in this study
ranged between 1.6 % for MTT in WM and 3.5 % for
CBF in GM across all time points and patients. We found,
however, substantially higher errors in certain patients and
time points that ranged between a maximum of 7.4 % for
MTT in WM to 30.1 % for CBF in GM. We believe that
such errors are not acceptable, if they can be avoided by
an optimal timing of the excluded time point for the neck
CTA. Nonetheless, even with maximum errors up to
17 %, the perfusion maps of the One-Step-Stroke protocol
have strong visual resemblance with perfusion maps of
the original protocol (Supplementary Fig. 4, see also
Fig. 3), with persistence of relative differences in
perfusion between white matter and gray matter.
In current literature, scan durations longer than 60 to
90 s are advised to avoid truncation of the tissue curves
[16]. The scan duration of our CTP protocol is 60 s,
which in our experience is sufficient for the enhancement
of collateral vessels and to avoid truncation of the tissue
curves which may affect perfusion values [7]. Our data
verified that there was no truncation of the tissue curves
in all patients.
Our study has some limitations. First, the sample size
is relatively small. However, mean percentage errors
remain small independent of timing, and in none of the 20
patients the error exceeded 7.5 % for the suggested
timing. In addition, visual analysis on CTP maps will
probably still provide sufficient information to detect
cerebral perfusion deficits as relative differences in
perfusion values are probably not affected. The observer study
showed full agreement between the original perfusion
maps and the perfusion maps with two missing time
points. Second, only perfusion values of ROIs in normal
appearing white matter and basal ganglia were
investigated. In each patient we kept all ROIs constant during the
experiments of removing one time point from the CTP
dataset in order not to introduce another source of
Mean One-Step-Stroke and conventional CTA
Fig. 2 Bland Altman plots showing the perfusion values (CBF, CBVand
MTT) between the original CTP protocol (the reference standard) and the
One-Step-Stroke protocol 6 s time gap
resulted in average errors <3.5 % and maximum
percentage errors <10 %. Arterial enhancement in the MCA was
on average above 300 HU if the neck CTA was performed
2 s after a threshold of 70 HU was reached in the MCA.
Given that the timing is in the upslope of the arterial
enhancement curve, the enhancement in the carotid artery
can be expected to be even higher because the
enhancement in the MCA tails enhancement in the carotids.
Generally, perfusion values have high variability due to
differences in, e.g., acquisition protocol, post-processing
software and the manual selection of AIF and VOF [11].
A previous study assessed the effect of manually outlining
ROIs in various flow territories and found that the
observer variability for perfusion values was 11-18 % for CBV,
15-19 % for CBF, and 6-9 % for MTT [12]. Another
study showed that the inter-observer variability of
Table 4 Comparison of
perfusion values of the
One-StepStroke Protocol at optimal time
with a 4 s gap with the original
protocol
Optimal Time with 4 s Gap
Optimal Time with 6 s Gap
Note – All correlations were found to be significant. Wilcoxon signed ranked test showed no significant
differences between the means of the One-Step-Stroke protocol and the original protocol except for MTT in white
matter. Despite this significance, the percentage errors remained below 9.2 % for a 6 s time gap, and even 5.2 %
for a 4 s time gap (see Table 3)
variation. We choose not to annotate infarct core or
penumbra because of the subjectivity of determining those
areas and because such areas were not present in all
patients. Third, it is known that perfusion values are also
dependent on the software package used [17, 18].
Therefore we used only one software package for
evaluation, which is publicly available and vendor independent.
We f o u n d t h a t ou r a v e r a g e p e r c e n t a g e e r r o r s a r e
consistent with values reported by another study [10]
who used a different software package.
In conclusion, our study showed that the One-Step-Stroke
protocol has only minor effects on the calculated perfusion
values, if the neck CTA is acquired 2 s after a relative
threshold of 70 HU is observed in the MCA. Visual assessment of
the perfusion maps with a 6 s gap did not affect the detection
of a perfusion deficit.
Fig. 3 CT perfusion maps of a 41-year-old female with an infarct in the
right MCA territory presented with weakness in left arm and legs and a
right-sided face droop. In the upper row perfusion maps of the original
CTP protocol are shown (a, b, and c). The lower row (d, e, and f) shows
perfusion maps of the same patient in which the second time point was
deleted. The perfusion images show an increased MTT with a small area
of reduced CBV and CBF in the right MCA territory. Note that the
perfusion maps are similar of the original and the perfusion maps with a 6 s
gap. WL settings were not changed since the observer was shown the
images as the perfusion software calculated the perfusion maps with these
WL settings
Acknowledgments The scientific guarantor of this publication is
Prof. Dr. M. Prokop. The authors of this manuscript declare
relationships with the following companies: Two authors (R.M. and
M.P.) received a grant from Toshiba Medical Systems Corporation
(TMSC, Otawara, Japan) to carry out this research. Toshiba
Medical Systems Corporation did not have any influence on the
execution of this study, the analysis of the data, nor on the
writing of this manuscript. The authors of this manuscript declare no
relationships with any companies, whose products or services may
be related to the subject matter of the article. One of the authors
has significant statistical expertise and no complex statistical
methods were necessary for this paper. Institutional Review
Board approval was obtained. Written informed consent was
waived by the Institutional Review Board. None of study subjects
or cohorts have been previously reported. Methodology:
retrospective, experimental, performed at one institution.
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