CT PERFUSION IN NEUROIMAGING

Zainul Ibrahim Zainuddin (B.Sc Diagnostic Radiography, UK)[a]

INTRODUCTION
Several modalities in neuroimaging provide structural or functional information or both.
Positron Emission Tomography (PET) has established itself as the gold standard in
brain functional imaging
1
. But it involves radiation risks from the use of radionuclides
and has limited accessibility. Functional Magnetic Resonance Imaging (fMRI) is an
emerging alternative which is gaining prominence in functional brain studies. It does not
pose any radiation risk and is becoming more readily accessible. However, fMRI has
limitations in its long examination time and contraindications for its use in certain
patients.
In order to circumvent the limitations of these two modalities, Computed Tomography
Perfusion (CT Perfusion) presents an alternative method for functional neuroimaging as it
can depict functional aspects of the brain. A theoretical analysis of this functional
capability was put forward by Axel in 1980, in the form of cerebral blood flow
determination using CT
2
.
This review serves to explore and describe the role of CT Perfusion in neuroimaging,
with an emphasis on its functional capabilities in brain studies. The relevant
technological, methodological and clinical application, and probable future developments
with respect to the modality are discussed.
HISTORICAL BACKGROUND.
Computed Tomography is able to show not just structural information but, through CT
Perfusion, can provide functional information. In this aspect it shares a common
characteristic with PET and fMRI. All these modalities make use of changes in cerebral
blood flow (CBF) in presenting functional information following brain activity, or lack of
it, both in healthy or diseased conditions. Quantitative measurement of CBF using PET is
considered a standard of reference
3
. However PET has a limitation with accessibility. The
need for a cyclotron that synthesizes the radionuclide to be nearby, and the cost
associated with it makes the modality available only in a few centers. Functional MRI
requires specialized hardware in the form of rapid imaging gradients and other Magnetic
Resonance (MR) compatible accessories to perform MR Perfusion studies. Therefore, the
capability to perform quantitative perfusion imaging using the more widely available CT
scanner would be a valuable option
4
.
Historically, Cerebral CT Perfusion was described more than 20 years ago by Drayer,
Gur, Wolfson and Dujovuy
5
who used non-radioactive Xenon-133 in their study of
regional blood flow in the posterior fossa. This was followed by perfusion studies that
made use of bolus intravenous administration of contrast media
2
. The later technique
permitted the values of cerebral blood flow (CBF) and cerebral blood volume (CBV) to
be determined. However these capabilities did not receive much support due to the
limited scanning frequency of CT scanners then
7
. With continuous advancement in CT
technology and increase in accessibility of the modality, CT Perfusion could play a role
in functional imaging particularly in cerebral studies.
CT PERFUSION TECHNIQUES.
Basically there are two CT perfusion techniques. One makes use of Xenon gas while the
other uses intravenous contrast media. The two techniques are described below:
Xenon CT
Blood flow determination using Xenon CT was proposed in late the 1970s
8
. Xenon-133 is
used in perfusion studies as it possesses several desirable characteristics that are
conducive for these studies. Being stable, non radioactive, freely diffusable, able to
penetrate the blood brain barrier and having an atomic number close to iodine, makes it
ideal to be used through inhalation in combination with oxygen. Its distribution, which
depends on cerebral blood flow, is more rapid in gray matter. This causes changes in
Hounsfield units which are displayed as colour maps. As Xenon washout occurs rapidly,
repeat examination is possible after fifteen to twenty minutes
9
.
This technique is associated with long sequential acquisition time of about six minutes.
Other limitations include the need for specialised and expensive equipment and
associated discomfort to patients in the form of headaches and nausea. There were
reasons to believe that Xenon may be responsible for decreasing respiratory rate and
causing hallucinations in some patients
10
.
Intravenous contrast enhanced CT Perfusion
This technique makes use of a peripherally administered venous bolus contrast media.
Transient changes in blood vessels density can be represented by contrast media as it
makes its first pass in the perfused tissue. Any increase in Hounsfield units is directly
proportional to the iodine concentration in the region
9
. Data acquisition is made at a
preselected level in the brain and the dynamic sequential acquisition led to the technique
to be known as Dynamic CT Perfusion. Currently the preselected level is the basal
ganglia, encompassing the areas of the Anterior, Posterior and Middle Cerebral
Arteries
11
, where there exists vascular territories which are frequently affected by
perfusion impairment in acute stroke
12
. The information gathered can be used to calculate
CBF parameters
13
. These parameters are presented in colour using suitable CT perfusion
software to facilitate fast interpretation of data
14
.
This technique experienced changes with improving technology which resulted in the
applications gaining prominence as compared to Xenon CT. Initially, a high flow rate of
up to 20ml/sec was used and this is uncomfortable for the patients. Using suitable
deconvolution software, contrast administration has been modified to a more manageable
and tolerable rate of 4-8ml per second
15
. This is also attributable to advances in contrast
media technology with the delivery of contrast with higher iodine content per milliliter.
Single section dynamic scanning has also been replaced with dual contiguous slices
which permit data acquisition of about 20mm slice thickness, with new multidetector CT
systems. It is now possible to use 80 KVp at constant mAs to perform the perfusion
studies with better contrast enhancement in gray and white matter while reducing
radiation dose to the patient by a factor of 2.8
16
.
PERFUSION PARAMETERS AND IMAGE INTERPRETATION.
The data generated in perfusion studies are analysed using commercially available
Perfusion software. The three most common parameters described in the literature are
CBF, CBV and Time to Peak (TTP). CBF was defined as the flow of blood
(ml/min/100g) through a given vascular network in the brain, while CBV is the volume
of blood (ml/100g) within the vessels
17
. TTP is defined as the time lag between first
arrival of the contrast agent within major arterial vessels included in the section and the
local bolus peak in the brain tissue.
11


There are differences of opinion as to whether these perfusion parameters should be
quantified as absolute or relative for clinical interpretation. Koenig et al
11
recognised that
absolute values of CBF, CBV and TTP do not correctly reflect the perfusion status of
ischemic tissues. They attributed this to the fact that there exists inter-modality and inter-
individual variability. Inter-modality variability with respect to CBF, for example, can be
seen in the differences between Xenon CT and Dynamic CT Perfusion. Xenon CT uses
an equilibrating indicator model, while Dynamic CT Perfusion uses central volume
principle. Inter-individual variability of more than 20% and variability due to age factors
in healthy volunteers have also been noted. The cardiovascular status of the patient and
contrast injection protocol can influence TTP values. To overcome these, a semi-
quantitative assessment of the above parameters using results from adjacent or mirrored
regions within the contralateral hemisphere was adopted. The ratio of affected brain
tissue to the normally perfused contralateral hemisphere gives a relative CBF (rCBF) [Fig
1] and relative CBV (rCBV) [Fig. 2]. Relative TTP was calculated based on the
differences in TTP values between the corresponding regions in the two hemispheres
11
. A
limitation to this approach exists in cases of bilateral disease
3
.


Fig. 1: The determination of relative
Cerebral Blood Flow (rCBF) based on ratio
obtained from readings in the contralateral
hemispheres (Green circles).
Fig. 2: A colour coded representation of
differences in relative Cerebral Blood
Volume. In this software vascular areas are
designated in red.

Variations in perfusion parameters have been used to describe several pathological
conditions. In hyperacute stroke, perfusion impairment was demonstrated by severe
reduction in rCBF, followed by decrease in rCBV, indicating the core of infarction while
prolonged TTP indicates flow via collateral pathways or sluggish flow
11
. In the
monitoring of subarachnoid haemorrhage, lower mean CBF values were registered in
patients with delayed cerebral infarcts compared to patients with early or without cerebral
infarcts. Overall CBV values were noted to be higher in patients with early infarcts,
compared to those with delayed infarcts indicating impaired cerebral autoregulation in
the latter
18
. In predicting the extent of cerebral infarct, CBF showed good sensitivity
(93%) and specificity (98%), while CBF and TTP together were 100% sensitive for
cerebral infarction relative to patients as well as territories
19
.
CLINICAL APPLICATIONS.
Perfusion studies are predominantly used in cases of cerebral ischemia and stroke. It is
recognised that adequate brain perfusion is fundamental for the integrity of the central
nervous system and dysfunction or death of neuronal cells occur if the cerebral blood
flow falls below a certain threshold
7
. The ability of CT Perfusion to observe and quantify
contrast media transit in the brain can be used to assess asymmetric changes in cerebral
perfusion or ischaemic effects
3
. This would be useful in determining management
strategies. Early diagnosis of perfusion deficits could improve prognosis
20
.
One of the most fundamental advantages of CT Perfusion is the ability to detect ischemic
changes before any morphological changes can be observed on non-contrast enhanced
CT scans
20
. Once detection is made, the severity and extent of ischemia can be
determined
21
and by using perfusion parameters, prediction of tissue outcome can be
made
11
. In the characterisation of ischaemia, the degree of hypoperfusion is an indicator
in determining whether an ischaemic lesion becomes an infarct or represents viable
tissue
11
. Severe perfusion deficit can be present in the ischemic core while the ischemic
penumbra exhibits a zone of moderate perfusion deficit
22
. Mayer et al
19
estimated that
infarction will occur in all vascular territories exhibiting loss in perfusion of more than
70%.
CT perfusion is recognised as a fast and practical technique that provides substantial and
important information for devising treatment strategies for patients with hyperacute
stroke
23
. The perfusion information in these cases can provide a more accurate picture of
acute stroke pathophysiology, as well as providing information about the extent of
infarction and vascular anatomy
24
. Determination of appropriate treatment options such
as intravenous fibrinolysis, angiography and intra arterial recanalisation, heparinisation,
neuroprotective medication, hypothermia or early decompression craniotomy can be
made
19
.
Not limiting its use in ischaemia and stroke management, perfusion parameters can
provide useful information in the detection and characterisation of entities such as
tumours, infection and inflammation
25
. CBF maps from dynamic CT Perfusion can be
used to depict areas of different blood flow in tumours and surrounding tissue, separating
low perfusion necrotic areas from elevated cerebral blood flow in neoplastic areas
26
.
Perfusion CT has its role in monitoring treatment effects such as carotid
revascularisation
3
, cerebral angioplasty and in the characterisation of cerebral infarcts
after subarachnoid haemorrhage
18
.
METHODOLOGICAL ISSUES IN CLINICAL APPLICATIONS.
While Xenon CT is proven to be accurate in providing quantitative cerebral blood flow
maps
10
, its use in the emergency setting is limited because of the need for specialised
equipment, associated side effects and longer examination time that can adversely affect
patient management. Dynamic CT perfusion can provide an alternative technique in these
situations.
The high flow rate of about 8ml/sec contrast medium administration can be a limiting
factor in Dynamic CT perfusion. Some approaches that may be taken include the use of
two sites of simultaneous contrast administration, for example both antecubital veins,
each with a rate of 4ml/sec. This delivers the same amount of iodine concentration as the
higher flow rate through a single intravenous site. Warming of the contrast media to body
temperature or using contrast media with higher iodine content but applied at a slower
rate are other alternative measures to facilitate contrast delivery. A lower injection rate of
5ml/sec has given results that correlate accurately with those of Xenon CT
10
.
In the imaging of ischaemic stroke a protocol has been developed that combines both
structural and functional information
27
. First, non-enhanced CT imaging is done to
provide structural information, making use of its proven excellence in depicting
haemorrhagic stroke. This is then followed by Dynamic CT Perfusion, which can show
hemodynamic status, type and extent of ischaemic process and quality of collateral flow.
CT Angiography is then performed to provide information concerning vascular
pathology, occlusion type and location, which can improve planning of potential
intervention. An additional advantage made possible with this protocol is that the
information can be acquired in a fast, well tolerated examination with a modality that is
easily accessible. Concern over the sensitivity to contrast medium can be overcome by
using non-ionic contrast media
10
. The use of steroid cover can also reduce the probability
of reaction to contrast media.
Radiation dose considerations in Dynamic CT Perfusion was addressed by Nabavi et al
28

who found that the overall effective dose equivalent for Dynamic CT Perfusion (2-
2.5mSv) was only slightly higher than for routine CT (1.5 mSv), and even less than the
dose delivered by similar blood flow studies using PET or Single Photon Emission
Computed Tomography (SPECT). Wintermark et al
16
recorded cerebral effective dose
that was lower than the reference dose level for standard cerebral CT examination. The
differences that exist in the literature can be attributed to different scan protocols used in
the respective studies.
CT PERFUSION IN COGNITIVE STUDIES.
Cerebral blood flow changes are also associated with brain activation with cognitive
tasks. Imaging modalities such as PET and fMRI have established themselves in imaging
cognitive studies. However, CT Perfusion has yet to find its place in this area. This is
evident from the lack of literature describing its use as a functional modality in cognition
research. This could be attributed to several reasons:
i) CT perfusion in cerebral studies is predominantly used in the detection of
hypoperfusion areas. This is in contrast to the demonstration of areas of increased brain
activity in cognition, with associated increase of CBF within that area. Hence the use of
the perfusion software would be limited as the colour coded data presentation highlight
areas of hypoperfusion.
ii) Contrast media used in Dynamic CT Perfusion do not attach themselves to agents
that take part in metabolism, such as glucose or oxygen. This is in contrast to PET and
SPECT which both use these agents to outline cerebral areas where brain activation,
characterised by increased metabolism, takes place. Future development of contrast
agents, which are metabolised in the same manner, for use with CT may be beneficial.
However these would need to be tagged to iodine-containing contrast agents detectable
by CT.
iii) Current data acquisition in Dynamic CT Perfusion is limited to a single 10mm slice
or the double contiguous slices of 20mm. This coverage is insufficient to image areas of
cognition outside the preselected plane. Furthermore the limited data cannot be
reconstructed into the coronal and sagittal planes for further assessment. The volumetric
data acquisition in PET and fMRI do not present these problems; hence they are more
conducive for cognitive studies. However there could be some new developments in the
role of Dynamic CT Perfusion in cognitive studies with the existence of volumetric
data acquisition with multi-slice capabilities of new systems such as the 16 slice CT
scanners. Research in this area could make use of the rapid data acquisition with other
modifications necessary for cognitive studies to be conducted.
iv) In a study on functional anatomy of visual mental imagery, Mazard et al
29
showed
that noise from the imaging system may affect both the performance and the neural
activation pattern in the cognition area. The researchers felt that while cognitive studies
that use simple and minimal cognitive demands may not be too badly affected by this
factor, the noise could disrupt the subjects attention and thus impair performance during
complex cognition studies. In CT perfusion, besides system noise, there are other external
factors that could impair the findings in these cognitive studies. They include the sight of
the movement of the rotating x-ray tube, movement of the couch into the scanning plane,
and the uncomfortable sensation at the site of injection. The high flow rate of contrast
media usually administered may be uncomfortable to some subjects. The existence of risk
of contrast media sensitivity adds to the list of limitations.
v) It can be argued that Xenon CT can acquire data covering the whole brain with its
sequential mode. Although this looks promising, its use in cognitive studies could be
hampered by the fact that the gas mixture of Xenon and oxygen can cause discomfort in
subjects, as described above. It is also believed that the face mask needed to deliver the
gas mixture may influence results. Its limited accessibility due to the need for specialised
and expensive equipment is another reason that the modality is not widely used in
cognitive studies.
It is possible to generate some cognitive information with the data acquired from CT
Perfusion. Though limited to the areas around the basal ganglia, the colour coded
information may be correlated with existing brain atlases such as the Talairach and
Tournoux
30
. Cognitive impairment may then be inferred from abnormal areas based on
the colour-coded maps.
COMPARATIVE IMAGING
Positive correlations between results obtained by CT Perfusion and other imaging
methods have been shown. Comparable CBF maps by CT Perfusion and SPECT have
been obtained in the detection of ischaemic stroke
12
. CT perfusion results were also
comparable to Diffusion-weighted and Perfusion-weighted imaging using MRI in the
identification of cerebral penumbra in acute stroke patient
31
. In subarachnoid
haemorrhage monitoring, CBF and CBV values in the perfusion study were in agreement
with PET studies. These imply that CT Perfusion is a reliable tool in functional brain
imaging.
LIMITATIONS OF CT PERFUSION.
The limitations and disadvantages of Xenon CT have been discussed above. The limited
sequential brain coverage with Dynamic CT Perfusion, has resulted in reduced sensitivity
when perfusion deficits exist outside the preselected plane
9
. The limited coverage cannot
display the full extent of an infarction, for example, in all three spatial dimensions
20
. This
limitation has yet to be overcome even with multidetector systems. Other attempts to
increase the coverage necessitate an increase in contrast medium dose
32
.
Other shortcomings of Dynamic CT Perfusion include radiation risks and potential
hypersensitivity to contrast medium, making MR imaging a more appropriate choice.
However, these shortcomings should be viewed by balancing the benefits of acquiring
tissue perfusion status in an emergency situation where monitoring of patients vital
parameters may not permit MR imaging. Poor history from patients in these situations
will not help establish whether patient-related contraindications to MR imaging may be
present.
At least one system vendor did not integrate the Perfusion software into the main console
set-up. This software is installed in a personal computer. Although this may be
advantageous, it necessitates more post processing time as the images generated will have
to be transferred from the main console. It would be advantageous if the data generated
can be displayed real-time, especially in the stroke protocol in order to reduce data
processing time.
CONCLUSION
It can be seen that CT Perfusion has an important role in imaging cerebrovascular
conditions. Its advantages include easy accessibility, fast and non-invasive data
acquisition, and results that are comparable to other modalities. However it is still
hampered by some technological limitations which may be overcome by future
technological advancements. Radiation dose and other methodological issues should be
addressed in the proper perspectives. Future research could lead to its use in other
neuroimaging applications such as cognition imaging.
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[a] Department of Radiology, IIUM