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INTRODUCTIONStroke is the third-most-common cause of death in adults
and is a leading cause of morbidity in Australia.1 Conventional
structural imaging typically comprises CT to exclude intra-
cerebral haemorrhage. However, 85% of strokes are the result
of ischaemic infarcts for which, in the majority of patients
imaged in the first 6 h, CT is either normal or demonstrates
only subtle abnormalities that are easy to misinterpret. Even
conventional MR images are commonly normal in this early
period.
The development of thrombolytic and neuroprotective
agents for the treatment of acute stroke has created an
imperative for improved imaging techniques in the evaluation of
acute stroke. The National Institute for Neurological Diseases
and Stroke trial was the first study to demonstrate that
thrombolysis in patients with no intracerebral haemorrhage
leads to a one-third increase in clinical outcomes if
administered within 3 hours of the onset of ictus.2 However, for
patients treated beyond the 3 h of onset, it carries a substantial
risk of intracranial bleeding. This setback in the use of
thrombolysis has prompted the realization that a more rigorous
selection of patients might reduce the risk of intracranial
bleeding, and that the use of thrombolysis might have a bene-
fit in selected patients extending beyond the current 3-h
therapeutic window.3 There have been several studies to
suggest that the level of residual blood flow in the ischaemic
zone is a useful indicator of the risk of intracranial bleeding.4–7
There are distinct thresholds of cerebral blood flow for various
functions of the brain. It is possible to use these thresholds to
determine whether a particular brain region is salvageable.
Perfusion CT offers the ability to positively identify patients
with non-haemorrhagic stroke, to select those cases where
thrombolysis is appropriate, and to provide an indication as to
prognosis.
Pictorial Essay
Computed tomography perfusion imaging in acute strokeCJ Keith,1,2 M Griffiths,2,3 B Petersen,1 RJ Anderson1 and KA Miles1,3
1Southern X-ray Clinics, 2Wesley Research Institute, The Wesley Hospital, and 3Centre for Medical Health and Environmental Physics,
School of Physical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
SUMMARY
The development of thrombolytic and neuroprotective agents for the treatment of acute stroke has created animperative for improved imaging techniques in the assessment of acute stroke. Five cases are presented to illustratethe value of perfusion CT in the evaluation of suspected acute stroke. To obtain the perfusion data, a rapid series ofimages was acquired without table movement following a bolus of contrast medium. Cerebral blood flow, cerebralblood volume and mean transit time were determined by mathematically modelling the temporal changes in contrastenhancement in the brain and vascular system. Pixel-by-pixel analysis allowed generation of perfusion maps. In twocases, CT-perfusion imaging usefully excluded acute stroke, including one patient in whom a low-density area onconventional CT was subsequently proven to be tumour. Cerebral ischaemia was confirmed in three cases, one with anold and a new infarction, one with a large conventional CT abnormality but only a small perfusion defect, and onedemonstrating infarct and penumbra. Perfusion CT offers the ability to positively identify patients with non-haemorrhagic stroke in the presence of a normal conventional CT, to select those cases where thrombolysis isappropriate, and to provide an indication for prognosis.
Key words: computed tomography, functional imaging, stroke.
CJ Keith MB BS; M Griffiths BSc, MAppSci; B Petersen Radiographer; RJ Anderson MB, ChB, FRANZCR; KA Miles MB BS, FRCR, MSc, MD.
Correspondence: Carolyn Keith, Southern X-ray Clinics, 2nd Floor, Day Centre, The Wesley Hospital, 45 Coronation Drive, Auchenflower, Queensland
4066, Australia. Email: [email protected]
Submitted 24 August 2001; accepted 24 September 2001.
Australasian Radiology (2002) 46, 221–230
Measurements of cerebral perfusion can be made with
CT using conventional contrast agents as tracers. Perfusion
measurements using conventional contrast agents benefit
from wide availability and can be easily incorporated into the
conventional CT examination that is routinely performed to
exclude intracranial haemorrhage. By avoiding the need to
transfer the patient to another imaging device, perfusion CT can
save a significant amount of time in a situation where early
administration of thrombolysis is critical.
Five cases are presented that illustrate the application of
perfusion CT in suspected acute stroke.
Pathophysiology of acute strokeBasic physiological functions, such as synaptic transmission,
the membrane ion pump and energy metabolism, are critically
dependent on blood flow, and will fail at distinct blood-flow
levels. Normal cerebral perfusion is in the range of 50–60
mL/min per 100 g.When cerebral perfusion pressure decreases,
the brain has an intricate system of control that attempts to
maintain cerebral blood flow. The mildest impairment in the
cerebral circulation is associated with an autoregulatory
dilatation of cerebral arterioles resulting in a reduction in
vascular resistance and an increase in cerebral blood volume
(CBV) that is able to maintain cerebral perfusion at normal
levels (Table 1). With worsening ischaemia, vasodilatation is
insufficient to maintain perfusion, and perfusion then falls
below normal levels. At approximately 20 mL/min per 100 g,
electrical activity and water homeostasis are disrupted, which
is associated with abolition of somatosensory evoked potentials
and electroencephalogram (EEG).8,9 At this threshold, ischae-
mic impairment of tissue function is reversible and there is an
increased CBV and a prolonged mean transit time (MTT).
At 10–15 mL/min per 100 g, synthesis of adenosine triphos-
phate (ATP) is outstripped by demand resulting in disruption
of the membrane ion pump. Failure of the membrane ion
pump leads to an efflux of potassium from, and an influx of
calcium, sodium and water into cells resulting in membrane
depolarization and cytotoxic oedema.9 Later, the capillaries
become leaky, resulting in an accumulation of extracellular
water (vasogenic oedema). Both cytotoxic and vasogenic
oedema cause further compression of the microcirculation,
worsening the level of ischaemia.
Failure of the integrity of the cell membrane precedes the
irreversible destruction of the cell (infarction), and it is therefore
justified to associate the threshold of irreversible damage with
the threshold for ion-pump failure. However, it has been shown
that disturbed energy metabolism and ion-pump failure can fully
recover,10,11 which suggests that membrane failure might trigger
processes causing infarction without being the direct cause
of these processes.12 The cerebral blood-flow threshold for
membrane failure is therefore close to that of infarction, but the
development of necrosis and infarction is not only dependent
upon the level of perfusion but also the time for which the tissue
has been ischaemic. Heiss and Rosner13 found that the duration
of ischaemia required to induce permanent loss of neuronal
activity became progressively shorter as blood flow decreased.
In summary, for ischaemic non-viable tissue, both the
cerebral blood flow (CBF) and CBV are reduced, but MTT might
remain normal or slightly elevated. It is the mismatch between
CBF and CBV that discriminates between salvageable and
infarcted tissue. An area of infarction is frequently surrounded
by brain tissue that is ischaemic but viable. This surrounding
tissue is known as the penumbra and represents tissue at risk of
infarction that is potentially recoverable on re-establishment of
the circulation.The size of the perfusion defect has been shown
to correlate closely with the clinical outcome, and follow-up
studies have shown that recoverable tissue exhibits relatively
preserved blood volume.14
METHODSPerfusion computed tomographyTo obtain the perfusion data, a rapid series of images is
acquired without table movement following a bolus of contrast
medium. The protocol adopted for this study consisted of
60 acquisitions of 1-s duration with a 1-s interval following the
injection of 40 mL of non-ionic iodinated contrast material
(Isovue 370, 370 mg iodine/mL; Bracco, Milan, Italy) at a rate of
4 mL/s. The section chosen for study was at the level of the
basal ganglia as this level includes those vascular territories of
the brain that are frequently affected by acute stroke in the
carotid arterial territory. Cerebral perfusion, cerebral blood
volume and mean transit time are determined by mathemat-
ically modelling the temporal changes in contrast enhancement
in the brain and vascular system, and pixel-by-pixel analysis
222 CJ KEITH ET AL.
Table 1. Summary of the changes in cerebral vascular physiology with worsening circulatory impairment. (Note that transit time is proportional to
blood volume/perfusion)
Perfusion Blood volume Transit time
Autoregulatory range N ↑ ↑
Oligaemia (misery perfusion) ↓ ↑↑ ↑↑
Ischaemia (metabolic impairment) ↓ ↑ ↑↑
Irreversible damage (necrosis) ↓↓ ↓ ↓↑
allows generation of perfusion maps. A number of commercial
perfusion CT software packages are now available. In this study,
data were transferred to a workstation and then evaluated with
‘CT Perfusion 2’ that uses a deconvolution-based method.
Imaging techniquesThere have been a number of methods developed for the
measurement of tissue perfusion using CT. These various
methods can be grouped under two classes: compartmental
analysis and deconvolution-based methods. The mathematics
for these methods has been described in detail elsewhere.15
Compartmental analysis-based methodsFor compartmental analysis, a single compartmental model is
used where arterial blood flows into the vascular compartment
and leaves via a single draining vein. Based on the Fick
principle, perfusion can be determined from the maximum rate
of accumulation of contrast agent within the tissue divided by
the peak arterial concentration of contrast agent. Blood-volume
measurements are obtained from the ratio of the areas under
the tissue and arterial time-attenuation curves.
Deconvolution-based methodsDeconvolution analysis mathematically calculates the tissue
time-attenuation curve that would have been obtained had
the arterial bolus arrived instantaneously. The height of this
idealized tissue curve (also known as the impulse response
function) is determined by perfusion whereas the area under
the idealized curve gives the relative blood volume (Fig. 1).
Both methods require time-attenuation data from the
vascular system to correct for interpatient variation in bolus
geometry. Although identification of some arterial vessels, such
as branches of the anterior and middle cerebral arteries, might
generally be possible on an axial scan through the basal
ganglia, arterial-enhancement values tend to be markedly
reduced due to partial volume effects.Therefore, measurement
of the maximum value in the superior sagittal sinus is used to
rescale the arterial enhancement curve. Cerebral CT perfusion
imaging has been validated against microspheres16 and H215O
PET17 with good reproducibility.
CASE REPORTSCase 1An 82-year-old man presented to the emergency department
having awoken from sleep with slurred speech and difficulty
walking. On examination, the patient’s speech was dysarthric
but there were no other cranial nerve abnormalities.There were
left cerebellar signs of incoordination and tremor, with marked
truncal and gait ataxia; however, power, tone and reflexes
were all normal, and sensation was also reported as normal.
An acute CT scan showed no abnormalities on conventional
scan, and there was no perfusion defect on CT-perfusion study
(Fig. 2). The patient’s condition improved throughout the
week. A follow-up conventional CT scan 1-week later was again
normal for age, with no evidence of a recent ischaemic event.
Case 2A 63-year-old man was admitted to another hospital with a
subacute bowel obstruction. On the third day of his stay, the
patient was found with a decreased level of consciousness and
dense right-sided weakness. On examination, there was both
receptive and expressive dysphasia. Muscular tone was normal
on the left and increased on both the right upper and lower
limbs, there was markedly reduced power on the right (1/5).
There were also abnormally brisk reflexes on examination of the
right lower limb, with a positive Babinski sign. A conventional CT
of the head performed on the same day was normal for age.The
patient was transferred to the hospital where this study was
conducted. A repeat CT in another 4 days showed a large low-
density area in the left cerebral hemisphere in the territory
supplied by the left middle cerebral artery. Perfusion CT
performed at the same time demonstrated a substantial
reduction in blood flow to a much smaller area, with a mild
reduction in blood volume and a greatly increased MTT in the
corresponding small area (Fig. 3). It was thought then that the
large lesion seen on conventional scan was in fact a small
infarct with surrounding oedema.Clinically, the patient improved
markedly. At the end of 2 weeks, he was speaking in full
sentences and understanding commands, power had returned
to his right upper limb and there was minimal return of power to
his right lower limb.
Case 3A 79-year-old man was brought into the emergency depart-
ment following a collapse while walking. On arrival, the patient
was alert and orientated to his surroundings. There were no
223PERFUSION CT IN STROKE
Fig. 1. Graphical representation of the deconvolution analysis
method, the height of this idealized tissue curve (also known as the
impulse response function) is determined by perfusion whereas the
area under the idealized curve gives the relative blood volume. AUC,
area under curve; CBF, cerebral blood flow; CBV, cerebral blood
volume; MTT, mean transit time.
difficulties with speech. The only finding was some mild left
lower-limb weakness, reflexes were all normal. The patient had
a past history of left-sided occipital stroke. A conventional CT
performed 3 days after onset of symptoms showed a large
low-attenuation area occupying the right occipital lobe,
consistent with an old cerebral infarct.The CT-perfusion images
showed a large area of greatly decreased CBF, CBV and
MTT corresponding to the old infarct demonstrated on the
conventional images. The perfusion images also show a small
area of reduced perfusion and blood volume with preserved
MTT in the right temporoparietal region just anterior to the old
infarct (Fig. 4). This perfusion abnormality is consistent with a
recent infarct.
Case 4A 56-year-old man presented with a sudden onset of expressive
dysphasia, followed in 5–10 min by a headache. While in the
emergency department, the patient was observed to have
some focal right-sided motor-seizure activity. The patient was
sent for a conventional CT scan that demonstrated a
hypodense area in the left hemisphere, which was reported
as likely to be an early infarct. There was no evidence of
224 CJ KEITH ET AL.
Fig. 2. Case 1. (a) Mean transit time. (b) Cerebral blood volume. (c) Cerebral blood flow. (d) Follow-up conventional CT image performed 1 week
later.
intracranial haemorrhage. The CT perfusion images dem-
onstrated a slight increase in blood flow in the area
corresponding to the hypodense lesion in the left hemisphere
consistent with a low-grade tumour (Fig. 5). The MRI of the
head, including T1- and T2-weighted images, diffusion-
weighted images and a gradient-echo sequence, performed at
the same time and after 1 month demonstrated a focal
abnormality involving the left insula and adjacent frontal lobe.
There was apparent thickening of the grey matter with some
reactive oedema around the lesion. Post-gadolinium images
displayed no enhancement and no abnormal blood vessels.
The morphology on MR was consistent with a low-grade glioma
rather than an infarct.
Case 5A 78-year-old woman suffered a brief loss of consciousness
and was noted to have a right hemiplegia thereafter. She was
brought into the emergency department where examination
revealed aphasia with right-sided neglect and a complete right
hemiplegia. The right-sided reflexes were brisker and the
plantar response was extensor. A CT brain scan performed
within 4 h of the onset of ictus demonstrated reduced density
225PERFUSION CT IN STROKE
Fig. 3. Case 2. (a) Mean transit time. (b) Cerebral blood volume. (c) Cerebral blood flow. (d) Conventional CT image performed 4 days postictus.
and loss of clarity of the basal ganglia, and there was also
subtle loss of clarity of the grey–white interface in the left
temporoparietal region. A CT-perfusion brain scan performed
at the same time demonstrated markedly decreased blood
flow to the left temporoparietal region and reduced blood
volume predominately in the basal ganglia with preservation
of blood volume in the cortex (i.e. there was a mismatch
between CBF and CBV). This indicated that although there
was some infarction in the left temporoparietal region in
the territory supplied by the left middle cerebral artery,
some of the ischaemic changes were likely to be reversible
(Fig. 6). The patient was transferred to another hospital.
Conventional CT imaging of the head performed the following
day to investigate a marked deterioration in consciousness
revealed an extensive intraparenchymal bleed with intra-
ventricular and subarachnoid extension. The patient died the
next day.
DISCUSSIONA range of physiological brain-imaging techniques have been
used in the assessment of acute stroke including perfusion
CT, perfusion and diffusion weighted MR, MR spectroscopy,
226 CJ KEITH ET AL.
Fig. 4. Case 3. (a) Mean transit time. (b) Cerebral blood volume. (c) Cerebral blood flow. (d) Conventional CT.
positron emission tomography (PET), single photon emission
tomography (SPECT) and transcranial Doppler ultrasound.
Xenon CT requires specialized equipment that is not widely
available and the technique is associated with adverse side-
effects in a significant number of patients. Perfusion MR is
directly analogous to perfusion CT but MR has the advantage
of obtaining dynamic contrast-enhanced images over a larger
volume of brain tissue with no radiation burden. Further-
more, perfusion MR can be combined with diffusion-weighted
MR (DWI) to define more clearly the areas of infarction and
penumbra. At present, perfusion MR is relatively time-
consuming, and the availability is relatively limited, although
future advances in MR technology and availability can be
expected. The use of MR within the first few hours of stroke
also poses a problem regarding patient cooperation, and the
adequate monitoring of vital parameters in patients receiving
emergent care remains a challenge while patients are placed
inside the magnet. Magnetic resonance spectroscopy
estimates the concentration of normal and abnormal metab-
olites in brain tissue. Early cerebral ischaemia is associated
with increased levels of lactate, while levels of N-acetyl-
aspartate (NAA) fall in the later stages. However, as well as
227PERFUSION CT IN STROKE
Fig. 5. Case 4. (a) Mean transit time. (b) Cerebral blood volume. (c) Cerebral blood flow. (d) Conventional CT.
the other drawbacks mentioned for perfusion MR, a relatively
large volume of tissue is required for analysis, thereby
constraining the spatial resolution of the biochemical data. By
using radiotracers such as 15O-water, 15O-carbon dioxide and15O-oxygen, PET can provide quantitative information about
blood flow, blood volume and oxygen extraction while 18F-MISO
can depict ischaemic tissue. However, PET is largely used as a
research tool, and its limited availability prevents routine clinical
use. Single photon emission tomography can provide an image
of relative cerebral perfusion and blood volume but is non-
quantitative. Transcranial Doppler can access patency and flow
within the middle cerebral artery but is unable to evaluate
perfusion at tissue level.
This pictorial essay demonstrates the use of perfusion CT in
the delineation of suspected cerebral ischaemia. The potential
benefits of perfusion CT in the evaluation of stroke include
the ability to rapidly demonstrate and aid in the correct
diagnosis of non-haemorrhagic stroke, to identify those patients
whom treatment will benefit and those to which it might be
detrimental, and to indicate the likely clinical outcome.
Perfusion CT is an effective imaging technique for the
evaluation of stroke because it can reliably demonstrate
228 CJ KEITH ET AL.
Fig. 6. Case 5. (a) Mean transit time. (b) Cerebral blood volume. (c) Cerebral blood flow. (d) Conventional CT.
ischaemia within 1–2 h after symptom onset, thereby allowing
initiation of therapeutic strategies.14,18,19 This ability to aid in early
diagnosis is shown in several of the cases presented here.
Case 1, in which the CT-perfusion study was able to help
exclude stroke as a possible cause for the patient’s signs and
symptoms, was confirmed as accurate by the follow-up images
after 1 week. These results could have saved the patient
unnecessary treatment that carries with it a risk of increased
morbidity and mortality. In case 2, the conventional CT images
demonstrated a large area of hypoattenuation and were
reported as showing a large infarct. However, the CT-perfusion
images demonstrated a much smaller area of infarction and it
was thought the larger area seen on conventional imaging was
predominantly the result of surrounding oedema. In case 3,
conventional CT images revealed an old infarct whereas CT-
perfusion images are able to demonstrate both old and recent
infarcts. In case 4, perfusion CT changed the clinical diagnosis
of stroke to tumour. Perfusion CT has the additional benefit of
defining abnormal regions of blood flow in brain tumours.
Neoplasms of the brain develop abnormal capillaries that are
fenestrated and allow the free passage of contrast agents. Also,
neovascularization within tumours results in an increased
vessel density and abnormally dilated venous channels, which
is reflected in an increase in the relative blood volume of the
tumours.20
Clinical outcome has been shown to correlate with the size
of the perfusion defect. Mayer et al., using CT perfusion, found
in their study of 70 patients for whom CBF maps predicted
the extent of the infarct with a sensitivity of 93% and a specificity
of 98%.14 Another study by a second group using the same
technique in 75 patients confirmed these findings.15 The
prognostic value of perfusion CT is demonstrated in this review
by case 2, in which the conventional CT images demonstrated a
large area of hypoattenuation and were reported as showing a
large infarct.However, the CT perfusion images demonstrated a
much smaller area of infarction and it was thought the larger
area seen on conventional imaging was predominantly the
result of surrounding oedema.This is supported by the fact that
the patient’s clinical status improved dramatically over the
following weeks with recovery of both speech and much of the
motor deficit he originally presented with.
A range of new therapy approaches directed at thromboly-
sis and reversing or minimizing ischaemic damage are cur-
rently undergoing investigation. Salvage of tissue at risk
(i.e. penumbra) is the target of many of these treatment options.
However, restoration of blood flow will not always result in a
clinical benefit because therapy will not rescue brain tissue if
the level of cerebral perfusion is below the viability thresholds
of ischaemia. An imaging technique that could identify and
characterize the potentially reversible ischaemic tissue would
be invaluable in the selection of patients for new therapies.
Presently, the best and most quantifiable technique for
determining the penumbra is xenon CT, although for the
reasons mentioned previously, this technique has limitations.
Recently, Wintermark et al.21 demonstrated a good correlation
of CBF measured by perfusion CT and xenon CT. Jansen et al.
showed that tissue at risk, defined by MR perfusion-weighted
imaging that exceeded tissue with diffusion abnormality,
could be salvaged by recanalization.22 Koenig et al.,23 using CT
perfusion, demonstrated significantly lower values for cerebral
blood flow in infarcted areas compared with those suffering
reversible ischaemia, and that a severe reduction of CBF is
followed by a reduction in CBV and indicates the core of the
infarction, while in the border zone with only moderate hypo-
perfusion the CBV was maintained or only slightly reduced.
Case 5, in which the CT perfusion images showed a mismatch
between CBF and CBV, demonstrated the potential for
perfusion CT to define the penumbra and identify patients
suitable for thrombolysis.
Perfusion CT adds only a few minutes to the duration of
a conventional CT scan, and it is easily performed using
current CT technology and readily available computer soft-
ware. The amount of contrast material used and the short
examination time easily allow repetition of the procedure to
obtain a second and, if required, a third CT section if the
standard section does not provide conclusive information.
Furthermore, future developments in CT technology, including
dynamic scanning with multisection data acquisition,24,25 might
further increase the value of this technique and provide
information about the 3-D extent of cerebral ischaemia for the
assessment of stroke.
In conclusion, perfusion CT can demonstrate abnormalities
in patients with acute stroke, even when conventional images
are normal. Perfusion CT in acute stroke can depict brain tissue
at-risk and provide prognostic information, and is a useful tool
for the selection of patients for thrombolytic therapy.
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