The goal of prompt treatment following a stroke is to rescue the ischemic penumbra and to prevent the death of additional brain tissue. The authors review computed tomography (CT), magnetic resonance (MR) imaging, and MR angiography techniques for hyperacute stroke imaging. With the proper selection of imaging techniques and the timely administration of thrombolytic therapy, it is hoped that more stroke patients will have improved outcomes.
is an Assistant Professor of Radiology, Department of Radiology,
Neuroradiology Section, University of California, San Francisco,
is a Private Lecturer and a Specialist in Diagnostic Radiology,
Institute for Diagnostic and Interventional Radiology and
Neuroradiology, University Hospital of Essen, Germany.
The central premise of acute stroke treatment is to rescue the
ischemic penumbra. When a cerebral artery is occluded, a core of
brain tissue dies rapidly. Surrounding this infarct core is an area
of brain that is hypoperfused but does not die quickly, because of
collateral blood flow. This area is called the ischemic penumbra.
The fate of the penumbra depends upon reperfusion of the
ischemic brain. In the case of persistent arterial occlusion, the
infarct core will grow and progressively replace the penumbra. In
the case of early recanalization-either spontaneous or resulting
from thrombolysis-the penumbra will be salvaged from infarction.
The presence and extent of the ischemic penumbra is
time-dependent, but especially patient-dependent. Indeed, from
patient to patient, survival of the penumbra can vary from <3
hours to well beyond 48 hours. Approximately 90% to 100% of
patients with supratentorial arterial occlusion show ischemic
penumbra in the first 3 hours of a stroke, but, interestingly
enough, 75% to 80% of patients still have penumbral tissue 6 hours
after stroke onset.
The relatively negative results to date of thrombolysis trials
between 3 and 6 hours,
in spite of the high percentage of patients with penumbra within
this time window, relate to the fact that these trials did not use
any method of penumbral imaging to select patients for therapy,
despite the fact that the penumbra area was the target for
treatment. Thus, a tissue clock, where both the extent of infarct
and penumbra are determined, would seem an ideal guide to patient
selection for thrombolysis, rather than a rigid time window, as in
the current thrombolysis guidelines.
Extension of the therapeutic window beyond 3 hours could
substantially increase the number of patients who are able to
receive thrombolysis. However, for this to occur with improved
outcomes, a rapid and accessible neuroimaging technique able to
assess the ischemic penumbra is required.
The advent of new magnetic resonance imaging (MRI) techniques
such as diffusion-weighted imaging (DWI) and perfusion MRI
(perfusion-weighted imaging [PWI]) in the early 1990s added a new
dimension to diagnostic imaging in stroke.
In the late 1990s, improved gradient hardware that was needed for
echoplanar imaging was implemented in clinical MRI scanners. Deep
brain ischemia leads to a shortage of metabolites. This causes a
Na+/K+ channel failure in each ischemic cell. This membrane channel
failure causes a subsequent cytotoxic edema. Without any net water
uptake in the affected brain, the tissue water content remains
unchanged and, therefore, X-ray attenuation does not change. During
this early stage, native CT does not show any changes in tissue
contrast. Cytotoxic edema leads to a narrowing of the extracellular
matrix and, thus, to a reduction of Brownian molecular motion in
the extracellular space. This phenomenon can be measured with DWI.
It was first described in 1965 and can be measured quantitatively
in the form of the apparent diffusion coefficient (ADC).
Kucinski and coworkers
presented clinical data from ischemic stroke pa-tients who were
imaged with CT and DWI. They measured ADC and X-ray attenuation
changes in infarcted tissue. In a cohort of 25 patients, they
observed mean ADC changes of 170 × 10
/sec in the infarcted tissue 1.3 to 5.4 hours after symptom onset.
This ADC decrease caused a strong contrast between infarcted and
unaffected brain tissue (ADC 803 × 10
/sec) on DWI. In contrast to the ADC changes, Kucinski observed a
time-dependent X-ray attenuation decrease of 0.4 HU per hour. Based
on these data, CT appears to be less sensitive for early brain
infarction as compared with DWI.
A stroke MRI protocol consists of T2-weighted (T2W) imaging,
T2*-weighted (T2*W) imaging, DWI, and PWI as well as MR angiography
(MRA). On T2W and fluid-attenuated inversion recovery (FLAIR)
images, ischemic infarction appears as a hyperintense lesion that
is seen--at the earliest--6 to 8 hours after stroke onset, in
Diffusion-weighted imaging allows the depiction of ischemic tissue
changes within minutes after vessel occlusion with a reduction of
A net shift of extracellular water into the intracellular
compartment (cytotoxic edema) with a consecutive reduction of free
water diffusion is the main underlying mechanism for the ADC
The use of DWI leads to a significantly improved detection of early
infarction compared with CT (91% versus 64%).
Perfusion-weighted imaging allows the measurement of capillary
perfusion of the brain. The contrast bolus passage causes a
nonlinear signal decrease in proportion to the perfused cerebral
blood volume (CBV). It is not yet clear which PWI parameter gives
the optimum approximation to critical hypoperfusion and allows the
differentiation of infarct from penumbra and penumbra from
In clinical practice, however, most authors agree that mean transit
time (MTT) gives the best results. The calculation of the
quantitative cerebral blood flow (CBF) requires knowledge of the
arterial input function (AIF), which in clinical practice is
estimated from a major artery, such as the middle cerebral artery
(MCA) or internal carotid artery. Thijs et al
evaluated the impact of different AIFs measured at 4 different
locations in 13 ischemic stroke patients. The curves of AIF were
measured near both of the MCAs in MCA branches adjacent to the
largest DWI abnormality and in the contralateral tissue to the
lesion that is seen on DWI. The largest PWI lesion was measured
based on the AIF of the unaffected MCA. The other 3 measurements of
AIF led to an underestimation of the infarct size on follow-up
The attempt to differentiate infarction from penumbra by imaging
techniques was made by introducing DWI and PWI into the clinical
setting. In a simplified approach, it has been hypothesized that
DWI more or less reflects the irreversibly damaged infarct, and PWI
reflects the complete area of hypoperfusion.
The volume difference between these 2, which is also known as the
PWI/DWI-mismatch (ie PWI volume minus DWI volume), would,
therefore, be the stroke MRI correlate of the ischemic penumbra
(Figure 1). On the other hand, if there is no difference in PWI and
DWI volumes or even a negative difference (PWI < DWI), this is
considered to be a PWI/ DWI match (Figure 2) and, according to the
model is equivalent to the condition of a patient who does not have
penumbral tissue because of normalization of prior hypoperfusion or
completion of infarction and total loss of penumbra.
This model might be criticized because it does not take into
account that the PWI lesion also assesses areas of oligemia that
are not in danger and that DWI abnormalities do not necessarily
turn into infarction.
Fiehler and coworkers
analyzed the frequency of ADC normalization in 68 acute stroke
patients. They reported that 19.7% of their cohort had ADC
normalization in >5 mL brain tissue. In those patients imaged
within 3 hours after symptom onset, ADC normalization was seen in
35.5%, while it was 7.5% in patients imaged between 3 and 6 hours
after onset. Apparent diffusion coefficient normalization was
predominantly seen in the basal ganglia and white matter in
patients with distally located vessel occlusions, and it was
associated with a trend toward a better clinical outcome.
Thus, patients presenting with a PWI/DWI match with-in 3 hours
after symptom onset might have salvageable tissue at risk and may
benefit from fibrinolysis. However, it is still not known whether
the absence of hyperintensities on follow-up T2W images indicates
neuronal integrity in humans. DeLaPaz and coworkers
and Li and coworkers
observed neuronal damage in histologic examinations of tissue
showing ADC normalization after reperfusion in a rat stroke
Stroke MRI was investigated under a routine clinical setting.
Based on an open, nonrandomized patient cohort of 139 patients
treated at 6 different academic hospitals, Röther et al
compared the results of 76 patients treated with recombinant
tissue-type plasminogen activator (rtPA) with 63 control subjects.
Presenting with a slightly more severe stroke score, similar DWI
lesions, and a larger mismatch ratio, the treated patients showed
early vessel recanalization more frequently and had better clinical
outcome after 90 days than did the controls. The recently published
Desmoteplase In Acute Stroke (DIAS) trial used a new fibrinolytic
drug similar to a peptide from the salivaria of
, a vampire bat. Patient screening was based on clinical
examination and medical history and was guided by the stroke MRI.
Only patients presenting with a clear DWI/PWI mismatch were
randomized. Besides the safety and dose-finding aspects of the
trial, it also proved the usefulness of this imaging approach
during the first 9 hours after symptom onset in ischemic stroke.
Those patients who received a placebo or an ineffective dosage
showed a low recanalization rate and, thus, an unfavorable outcome.
In patients who achieved an early vessel recanalization and, thus,
a reperfusion of penumbra tissue, a significant clinical benefit
was observed, and 60% of the patients from the most effective dose
tier had an excellent clinical outcome.
Hyperacute stroke imaging demands the differentiation between
ischemic stroke and intracranial hemorrhage (ICH), which is
impossible by clinical means only. The diagnosis of ICH is still in
the domain of CT. Performing both-CT for the exclusion of ICH and
stroke MRI to guide therapeutic efforts-is time-consuming and
The appearance of ICH at MRI primarily depends on the age of the
hematoma and the type of MR contrast used. The key substrate for
early MRI visualization of hemorrhage is deoxyhemoglobin, a blood
degradation product with paramagnetic properties due to unpaired
electrons. The typical appearance of ICH on MRI images is a
heterogeneous focal lesion. With increasing susceptibility
weighting, the central area of hypointensity became more
pronounced. On T2*W images, no or few areas of hyperintensity are
visible in the lesion's core, which is surrounded by a hypointense
rim. There is a surrounding hyperintensity on T2W and T2*W images
and a hypointensity on T1-weighted images that represent perifocal
vasogenic edema. One randomized, blinded pro-spective multicenter
trial recently investigated the role of stroke MRI in ICH.
Images from 62 ICH patients and 62 nonhemorrhagic stroke patients
all acquired within the first 6 hours after symptom onset (mean 3
hours 18 minutes) were analyzed after randomization for the order
of presentation. The size of ICH ranged from 1 to 101.5 mL (mean
17.3 mL). Three readers who were experienced in stroke imaging and
3 senior medical students each separately evaluated sets of DW,
T2W, and T2*W images (all were unaware of the clinical details).
The experienced readers identified ICH with a 100% sensitivity
(confidence interval: 97.1% to 100%) and a 100% overall accuracy.
The medical students achieved a mean sensitivity of 95.16% (90.32%
to 98.39%). Thus, hyperacute ICH is detectable with excellent
accuracy even if the raters have only limited experience.
Modern CT studies--including noncontrast CT (NCCT), perfusion CT
(PCT), and CT angiography (CTA)
--fulfill all the requirements for hyperacute stroke imaging.
Noncontrast CT has classically been used as the standard initial
imaging examination for acute stroke patients because of its
convenience and its high sensitivity for the detection of
intracranial hemorrhage, which represents an absolute
contraindication to thrombolytic therapy. Occasionally, NCCT can
provide information that is supportive of the diagnosis of evolving
infarction (eg, the hyperdense artery sign, indicating arterial
thrombus), even when ischemic changes in the brain parenchyma, such
as hypodensity, are not visible. Unfortunately, NCCT provides
solely anatomic and not physiologic information and has thus very
low sensitivity for acute stroke detection.
Sensitive and specific functional CT imaging, including CTA and
PCT (Figure 3), provide complementary information about vessel
patency and the hemodynamic repercussions of a possible vessel
occlusion, respectively. Perfusion CT and CTA can be obtained
immediately after NCCT, during the same CT examination, obviating
moving the patient to another imaging device for the physiologic
information needed for making treatment decisions. The total
duration of an NCCT, 2 series of PCT, and a CTA is approximately 10
Perfusion CT imaging, using standard nonionic iodinated
contrast, relies on the speed of modern helical CT scanners that
can sequentially trace the entry and wash-out of a bolus of
contrast injected into an arm vein through an intravenous line.
The relationship between contrast concentration and signal
intensity of CT data is linear. Thereby, analysis of the signal
intensity increasing and then decreasing during the passage of the
contrast pro-vides information about brain perfusion. More
specifically, PCT description of brain perfusion consists of 3
types of parametric maps that relate to regional cerebral blood
volume (rCBV), MTT, and regional cerebral blood flow (rCBF),
respectively. Regional cerebral blood volume reflects the blood
content of each pixel. Mean transit time designates the average
time required by a bolus of blood to cross the capillary network in
each pixel. Finally, rCBF relates to the amount of blood flowing
through each pixel during a 1-minute interval.
Recently, blood flow values from PCT imaging have been shown to be
highly accurate in humans when compared with the gold standard,
By combining MTT and rCBV results, PCT has the ability to
reliably identify the ischemic reversible penumbra and the
irretrievable infarct core in acute stroke patients, immediately on
admission. In the infarct core, both MTT and rCBV values are
lowered, whereas in the penumbra, cerebral vascular autoregulation
attempts to compensate for decreased rCBF by a local
vasodilatation, which results in increased rCBV values.
Commercial PCT software currently offers the real-time automatic
calculation of infarct and penumbra maps according to the
PCT/CTA or MRI: Which one to choose?
CT and MRI provide similar information. The DWI lesion
corresponds to the infarct core, whereas the DWI/PWI mismatch is
representative of the ischemic penumbra.
The infarct core and the ischemic penumbra, as exhibited by DWI/PWI
and by PCT, respectively, are comparable (Figure 4).
Similarly, CTA and MRA results are very much alike (Figure 3).
Besides the similarity of their results, both CT and MRI techniques
show respective advantages and drawbacks to be considered in the
special settings of acute stroke.
Stroke MRI is still available only in a limited number of
hospitals. Despite the advantages of stroke MRI, there are still
doubts whether it is a safe approach in severely affected patients
and, depending on each individual setting, it is hard to conduct
stroke MRI without losing too much time before the onset of
treatment. The main advantages are, first, direct visualization on
DWI of the full extent of infarction and, second, whole-brain
coverage that can be achieved with PWI at a time resolution of 1.4
seconds per frame; thus, even small but clinically relevant
hypoperfusion can be visualized. Visualization of the circle of
Willis can be performed within 3 minutes with a time-of-flight MRA.
If a patient moves his or her head during image acquisition, a
sequence can be easily repeated. No additional X-ray dosage or
iodinated contrast agent is needed, and, therefore, no
nephrotoxicity or relevant allergic reactions are expected. In
contrast to iodinated contrast media, MRI perfusion measurement
does not cause a feeling of heat, and, therefore, movement
artifacts are less likely during perfusion imaging. However, the
control of vital signs and the access to the patient during the
10-minute scan procedure is limited by the magnet. In addition, it
takes some effort to train staff and technicians to conduct stroke
MRI in a short period of time and to establish an adequate workflow
during the hyperacute phase of ischemic stroke.
CT is often criticized, without reason, for its use of X-rays
and iodinated contrast material. However, the radiation dose
involved in PCT imaging is less than that of conventional cerebral
and, to the authors' knowledge, no renal failure has yet been
reported following a PCT examination.
Because of limited spatial resolution, PCT cannot detect small
lacunes, whereas NCCT is not as sensitive to microbleeds as
gradient-echo MRI. Perfusion CT has a limited spatial coverage (20-
to 48-mm thickness). The issue of spatial coverage will, however,
be addressed in the near future through the development of larger
multidetector CT scanners with greater arrays of elements, and,
even at present, PCT has been shown to have 95% accuracy in the
delineation of the extent of supratentorial strokes, despite its
limited spatial coverage.
Perfusion CT has also been proven to be as useful in the evaluation
of vertebrobasilar ischemia.
The low requirements for performing PCT/CTA technology and its
wide availability are keys to its taking over MRI in the imaging of
acute stroke patients. Indeed, because of their relatively low cost
and utility in other areas of medicine-particularly emergency
medicine and trauma-CT scanners are becoming very widely available.
In contrast to MRI, it is foreseeable that every major emergency
center will eventually be able to complete this form of imaging
within minutes of the patient presenting to the emergency
department. Another major advantage of PCT over MRI relates to its
quantitative accuracy, whereas MRI perfusion imaging offers only
semiquantitative comparison of one hemisphere with the other. The
quantitative accuracy of PCT makes it a potential surrogate marker
to monitor the efficiency of acute reperfusion therapy, which is a
decisive element when it comes to finding and validating new
individualized therapeutic strategies for acute stroke
Both CT and MRI fulfill all the requirements for hyperacute
stroke imaging. CT angiography and MRA can define the occlusion
site, depict arterial dissection, grade collateral blood flow, and
characterize atherosclerotic disease. Perfusion CT and DWI/PWI
accurately delineate the infarct core and the ischemic penumbra. CT
and MRI both have their own advantages and drawbacks. The selection
of one technique over another depends on the intrinsic
characteristics of each imaging technique but also on the settings
and on the knowledge and experience of the institution's staff.
Controversies regarding the superiority of either CT or MRI for
acute stroke imaging should not obscure the ultimate goal, which is
to increase the availability and improve the efficiency of
thrombolytic therapy. From that standpoint, CT and MRI must be
considered to be equivalent tools. It is hoped that the use of CT
and/or MRI to define new individualized strategies for acute
reperfusion will allow the number of acute stroke patients
benefiting from thrombolytic therapy to be significantly