is a fourth-year Radiology Resident at the University of
California, San Francisco. He received his MD in 1996 and his PhD
in biophysics in 1997, both at the University of Illinois at
Urbana-Champaign. He will begin a Neuroradiology fellowship at UCSF
after completing his residency.
Brain ischemia is a clinical emergency, and immediate
neuroimaging is necessary to confirm stroke and to exclude
alternative diagnoses. Magnetic resonance (MR) imaging offers
considerable diagnostic and prognostic information, although
practical difficulties have limited its role to this point. This
review includes a brief summary of the clinical issues of acute
cerebral infarction, a description of common MR methods and
findings, and the use of MR to direct therapy and to predict
Brain ischemia is a clinical emergency because neurons die
rapidly when deprived of oxygen and metabolic substrates. Although
the use of thrombolytic agents has recently become available for
the treatment of stroke, this potentially curative therapy must be
administered expeditiously to be effective. Moreover, since
thrombolytics increase the incidence and severity of intracranial
hemorrhage (ICH), this complication must be excluded before these
agents are administered. Therefore, immediate neuro-imaging is
necessary to confirm the diagnosis of acute cerebral ischemia and
to exclude alternative diagnoses for stroke-like clinical
syndromes. While computed tomography (CT) remains the standard for
imaging patients with acute stroke, magnetic resonance (MR) imaging
offers considerably more diagnostic and prognostic information. At
this point, however, practical difficulties have limited the role
of MR. Recent extensive research into the benefits and practicality
of MR in the evaluation of stroke has indicated significant
potential for improving stroke management and patient outcome.
This review summarizes the clinical issues of cerebral
infarction and describes common MR methods for imaging the
condition. It discusses the significance of MR findings and their
use for selecting appropriate therapies and predicting clinical
outcome. It also outlines proposed protocols for the application of
MR in acute stroke.
The clinical impact of stroke
The potential benefit of developing techniques for the rapid
diagnosis and treatment of stroke is clear--stroke is the third
leading cause of death in the United States and results in an
annual cost of $30 billion.
Within 6 months after a stroke, 20% to 30% of patients die, 20% to
30% are moderately to severely disabled, and very few recover
There has been considerable effort recently to elucidate the
pathophysiology of stroke and to develop treatments aimed at
effectively improving functional outcome. Several major trials have
investigated the benefit of early pharmacologic intervention with
thrombolytic agents, and recombinant tissue plasminogen activator
(rtPA) has been approved by the Food and Drug Administration for
the treatment of acute stroke.
Because intravenous rtPA thrombolysis has been proven to be
beneficial only when administered within 3 hours of the onset of
symptoms, rapid clinical diagnosis and imaging confirmation is
The integrity of collateral flow to the ischemic region may be a
critical factor that determines the outcome of an ischemic episode.
Given this and other variables that influence the outcome of
patients with stroke, it is necessary to stratify patients
according to the likelihood of successful intervention; MR can
accomplish this rapidly and effectively. The unique diagnostic and
prognostic information quickly obtainable by new MR imaging
techniques promises to have a substantial impact on stroke
Brain attack: The pathophysiology of stroke
Distinct pathophysiologic stages of cerebral ischemia can be
identified, and each one can be investigated with MR techniques.
The cascade begins with a blood flow abnormality, which may be
focal, from embolism or in situ thrombosis; or from global
hypoperfusion. Autoregulation of cerebral blood flow may compensate
for a focal insult in several ways. It may increase cerebrovascular
resistance to counteract decreased cerebral perfusion pressure or
recruit collateral blood flow from the circle of Willis or from
leptomeningeal vessels. It may also compensate by increasing oxygen
extraction efficiency. If there are insufficient avenues of
collateral flow, the affected tissue can switch from oxidative to
glycolytic metabolism. This may lead to lactate accumulation and
acidosis. Hypoperfusion below a critical level (approximately 10 to
20 mL/min/100 g tissue), however, causes electrical and cellular
dysfunction, with release of cytotoxic levels of glutamate and
failure of the Na
Pump failure allows accumulation of sodium, calcium, and water
within the cell, a process known as cytotoxic edema. Finally, after
approximately 6 hours of ischemia, cellular structural integrity
fails, causing the breakdown of the blood-brain barrier and
subsequently vasogenic edema.
Physical principles of MR stroke imaging
Several complementary MR techniques are useful in the evaluation
of the various stages of acute stroke. A brief discussion of these
Diffusion-weighted imaging (DWI) derives image contrast from the
random, microscopic (Brownian) motion of water molecules in tissue.
The DWI pulse sequence includes magnetic field gradients before and
after a 180° radiofrequency (RF) pulse, and image readout is
generally accomplished with a rapid echoplanar imaging (EPI)
technique. During the first gradient period, both static and moving
spins acquire a phase shift. The second diffusion-weighting
gradient is identical to the first, but is effectively reversed
because it follows the 180° RF pulse. For stationary spins, the net
phase shift after the two diffusion gradient pulses is zero. For
spins moving in the direction of the diffusion gradient during the
time interval between the two gradient pulses, the dephasing caused
by the first diffusion gradient pulse is not reversed by the second
pulse, and thus moving spins are suppressed. Diffusion-weighted
images therefore show higher signal intensity for spins in which
diffusion is reduced, whereas freely diffusing spins are lower in
By varying the direction of the diffusion gradients over
repeated acquisitions, diffusion anisotropy effects are minimized
by averaging. By varying the magnitude of diffusion gradients, an
apparent diffusion coefficient (ADC) can be calculated for each
voxel--with high ADC values indicating freely diffusible spins, and
low values signifying spins with reduced diffusion. One potential
pitfall of DWI is that the EPI readout in common diffusion
sequences introduces inherent T2-weighting, and increased signal in
DWI may be due to "T2 shine-through" rather than to true reduced
diffusion. Calculating an ADC map, however, eliminates this
confounding effect (Figure 1).
Ischemic and infarcted tissue is associated with restricted
motion of intracellular and/or extracellular water molecules
causing increased signal on diffusion-weighted images. This finding
by itself is nonspecific because other pathologies, such as
abscesses and certain tumors, may show reduction of water
diffusion. In the proper clinical setting, however, the diagnostic
accuracy of diffusion imaging is quite high, with sensitivity and
specificity for acute stroke approaching 100%.
Normal DWI in the face of clinical symptoms suggestive of acute
stroke should provoke consideration of alternative diagnoses such
as transient ischemic attack, migraine, seizure, ICH, or metabolic
Critically decreased regional perfusion of brain tissue is the
inciting physiologic abnormality leading to infarction and,
therefore, visualization of this deficit with MR perfusion-weighted
imaging (PWI) is highly valuable. Although there are noninvasive MR
perfusion techniques that use MR spin tagging of inflowing blood
("arterial spin-labeling") and obviate the need for an exogenous
contrast agent, the most common PWI technique uses a bolus
injection of 0.1 to 0.2 mmol/kg gadolinium and T2*
susceptibility-weighted EPI during its first pass.
Images per slice can be acquired in about 50 to 100 milliseconds.
The passage of paramagnetic gadolinium chelate through the image
slice causes a transient and focal decrease of signal. The amount
of signal loss measured is proportional to the concentration of
contrast agent within the microvasculature. With the arterial input
function, the following information can be calculated: relative
cerebral blood flow (rCBF, volume of contrast agent to the
microvasculature per unit time); mean transit time (MTT, time for
bolus of contrast agent to travel through the microvasculature);
and relative cerebral blood volume (rCBV, volume of contrast agent
in the microvasculature during first pass).
Time to peak (TTP) of contrast concentration in the imaging slice
can be determined directly from the images. Possible
pathophysiologic implications of abnormalities of these parameters
will be discussed later.
Magnetic resonance angiography
Magnetic resonance angiography (MRA) evaluates the luminal
anatomy of blood vessels by visualizing the spins in flowing blood.
This can be accomplished with a number of techniques, the most
common of which is two-dimensional (2D) or three-dimensional (3D)
time of flight (TOF). With these sequences, a selected imaging
volume is repeatedly excited with a train of rapid RF pulses that
saturates the signal from stationary tissue; the signal from
inflowing blood, which has not received the pulse train, is bright
(Figure 2). Because of the saturation effect, slowly forming blood
can be poorly visualized with 3D TOF, and 2D TOF may show
stepladder artifacts on maximum-intensity projections. A
combination technique called multiple overlapping thin-slab
acquisitions (MOTSA) improves on these limitations. Using an
intravascular contrast agent can decrease acquisition time
angiographic effect by reducing the saturation of intravascular
Magnetic resonance spectroscopy
The magnetic resonance spectros-copy (MRS) experiment is based
on principles similar to those of MR imaging. However, the data
acquired are resonance peaks in which signal frequencies depend on
the local magnetic microenvironment and thus differ for each
compound, and peak areas are directly related to metabolite
concentrations. Spectra can be obtained from spatially limited
volumes of interest using one of a variety of single-volume-element
(single-voxel) sequences or 2D or 3D spectroscopic imaging
techniques. Proton (
H) spectroscopy is most common, but other nuclei, such as
P), are MRS-visible but suffer from poor signal-to-noise ratio.
Metabolites frequently identified in
H spectra of healthy brain tissue include cholines, creatines, and
N-acetylaspartate (NAA). Decreased NAA can be seen within hours of
stroke onset, presumably indicating neuronal death. Increased
lactate can often be detected in ischemic brain areas, indicating
glycolytic metabolism, or, when chronic, the presence of
macrophages and leukocytes (Figure 3).
Numerous amino acids, which may be globally or focally increased in
a variety of diseases, can be detected in
H spectra obtained with short echo times. With
P spectroscopy, pH can be determined readily, and ischemic areas
are often acutely acidotic.
The use of MRS in acute stroke has not yet been proven in
widespread studies. However, MRS has been shown to be helpful in
early reports of neonatal ischemia, which is often difficult to
assess on anatomic MR imaging studies.
MR findings in acute stroke
The MR imaging findings in the first 24 hours of stroke are
summarized in Table 1. Due to its high sensitivity for ischemia and
speed in acquisition, DWI is the current workhorse for MR imaging
of acute stroke. Diffusion-weighted MR images show prompt increase
in the ischemic tissue signal, even within minutes of vessel
occlusion. This finding is thought to reflect primarily cytotoxic
edema, with shift of extracellular water into the cell, where
diffusion is constrained. Additional mechanisms for reduced
diffusion, such as increased tortuosity of the extracellular
compartment and increased viscosity of the intracellular
compartment, have also been proposed.
The temporal evolution of the diffusion abnormality in
territorial stroke has been shown to follow a reproducible time
course. After an initial low ADC in the ischemic lesion, the ADC
increases gradually until about a week after symptom onset, at
which point it starts to pseudonormalize. Then it remains
The observed pattern has been described to represent initial
reduced diffusion due to cytotoxic edema, then increasing ADC
secondary to subsequent membrane disruption and vasogenic edema,
and, finally, elevated ADC indefinitely due to gliosis and further
increase in lesion water content.
Without early intervention, ischemic tissue showing severe early
ADC decreases has been shown to proceed almost invariably to
infarction, and this tissue is considered by many to represent an
ischemic core. However, surrounding tissue showing more modest
diffusion abnormalities may be potentially viable.
In fact, with early recanalization, even severe ADC reductions have
been shown to be reversible in both animal models
and patients with stroke.
This so-called "ischemic penumbra" of potentially viable tissue,
which surrounds a core of tissue doomed to infarct, is seen in a
majority (65% to 95%) of patients with stroke who were imaged
within 24 hours of symptom onset.
This concept has been the subject of numerous recent studies
comparing perfusion and diffusion abnormalities in acute stroke.
Within the core of the lesion defined by a severe diffusion
abnormality, perfusion imaging generally shows increased relative
MTT and significantly decreased rCBV and rCBF.
Very often, the volume of the perfusion abnormalities on PWI is
larger than the diffusion abnormality on DWI. While this lesion
volume mismatch between DWI and PWI may represent peripheral
ischemic, it could very well be viable tissue, and, as such, has
the potential of being saved with early therapeutic intervention
and recanalization. In untreated patients, the presence of a
perfusion-diffusion mismatch in initial imaging has been shown to
correlate with subsequent lesion growth.
In contrast, if the DWI and PWI lesion volumes are similar, there
is generally no significant increase of lesion size.
Increased rCBV in the penumbra region
may represent reactive vasodilation, while prolonged MTT and TTP
may represent indirect blood flow via collateral pathways (Figure
Patient selection for thrombolytic therapy
Potentially, the identification of a DWI-PWI mismatch can be
exploited to select a subset of patients with stroke who would most
likely benefit from thrombolysis (Figure 5), possibly even after
the currently accepted time window for rtPA has expired. The
benefit of expanding the window for thrombolytic therapy is
substantial; the most common reason for intravenous rtPA
ineligibility is patient presentation beyond 3 hours from symptom
Indeed, studies have indicated that the penumbra region may remain
viable up to, and even beyond, 48 hours. The viability may also
vary among individuals due to differences in location of ischemic
insult and the adequacy of collateral flow.
Conversely, MR DWI/PWI imaging may identify those patients with
matched lesions for whom thrombolytic therapy is unlikely to be
effective, sparing them the attendant risks. Verification of the
existence of potentially viable tissue could also be useful in
selecting patients who may benefit from other therapeutic measures,
such as angioplasty, or promising neuroprotective agents, such as
MR angiography and MRS evaluation may also prove helpful in
selecting patients for whom immediate treatment is indicated.
Although patients with proximal middle cerebral artery (MCA) branch
occlusions often recanalize with thrombolysis,
it has been shown that patients with distal internal carotid artery
(ICA) occlusions are less likely to benefit from thrombolytic
Additionally, normal MRA in the setting of acute territorial stroke
suggests spontaneous recanalization, in which case thrombolytic
therapy would be superfluous and potentially dangerous. In a study
evaluating the ability of
H MRS to predict infarct growth, expansion of the initial diffusion
abnormality was seen in patients in whom peri-infarct
lactate/choline ratios were increased.
This finding suggests that elevated lactate may indicate tissue at
risk to infarct, for which thrombolytic therapy may be
Prediction of functional outcome
Whether or not thrombolytic therapy is administered, it is
important to obtain timely information about the likely outcome of
the stroke patient. There is a strong positive correlation of
neurologic deficit with volume of the initial DWI lesion, as well
as with the severity of the initial ADC abnormality.
Lesion volume at early DWI was combined into a single indicator
using two clinical measures of stroke severity (the National
Institutes of Health stroke scale score, a measure of neurologic
deficit, and the Barthel Index, an assessment of the ability to
perform 10 specific activities of daily life) and then calculated.
The resultant measure correlated with final functional outcome
better than any of the individual components.
Several groups have reported that mismatches of volume between
the early DWI lesion and the lesions on rCBV and MTT maps correlate
with growth in DWI lesion volume on follow-up studies.
This finding suggests that although cerebral vascular
autoregulation may preserve viability in the penumbra region early
in the process, compensation is tenuous, and eventually will fail
and lead to infarct. Also, although DWI and PWI lesion volumes at
early imaging correlate individually with clinical outcome, the
size of the mismatch between DWI and rCBV was best at predicting
lesion growth and functional outcome.
Since both critical hypoperfusion and benign oligemia may create
the perfusion abnormality, correlations of perfusion abnormalities
with functional outcome may be improved if thresholds of severity
are used to define the spatial extent of the lesion. For example,
the mismatch volume between the DWI abnormality and a PWI
abnormality defined by a mild prolongation of MTT or TTP does not
correlate as strongly to final infarct volume as it does when
defined by a more pronounced delay.
Pixel-by-pixel analyses, more robust than simple volumetric
thresholding, are also being investigated to account for the
occasional appearance of PWI lesion heterogeneity.
Metabolite concentrations as measured by MRS have also been
shown to correlate with final infarct size and with the degree of
neurologic impairment. Although the concentrations of both NAA and
lactate within the ischemic core at initial imaging have been shown
to be independently linked to functional outcome, several studies
suggest that there is a stronger correlation between lactate and
Lactate levels in the chronic state continued to correlate with
Intravascular enhancement due to slow flow is an early sign of
ischemia. However, the initial area of intravascular enhancement
does not seem to predict final infarct size, even if the area of
initial intravascular enhancement is larger than that of the
initial DWI abnormality.
Nonetheless, a tendency toward poor clinical condition in patients
showing the hyperintense vessel sign within the full MCA territory
on fluid-attenuated inversion recovery imaging has been described.
Additionally, the absence of MCA flow on MRA in patients with
DWI-PWI mismatch may serve as an independent predictor of DWI
lesion expansion and worse clinical outcome.
Evaluation of future risk for stroke
Stratification of relative risk of future ischemic events in
patients after initial stroke, or in patients without prior stroke
but with flow-limiting carotid disease, would be beneficial in
directing therapy. A multifunctional MR imaging study (MR imaging,
MRA, MRS) evaluated 115 patients with angiographically confirmed
ICA occlusion presenting with transient or mild ischemic symptoms
and with 4-year follow-up. A low ratio of NAA/choline in the white
matter of the ipsilateral centrum semiovale was associated with a
yearly risk of recurrent ischemic event of nearly 4 times that of
patients with normal ratios. This finding suggests a possible
increased benefit of external-internal carotid bypass in this
subset of patients.
In studies in the United States, Japan, and Europe, MR evidence
of clinically silent prior infarcts was found in approximately 25%
of thousands of elderly volunteers without a history of stroke, and
was associated with hypertension.
Annual incidence of stroke was 1.5 to 13 times higher in patients
with silent infarcts than in those without. This association
remained even after adjusting for age, sex, and other (multiple)
risk factors for stroke. These findings may eventually lead to MR
screening in certain high-risk patient populations.
Investigating stroke etiologies
Because advanced MR imaging techniques are fast and repeatable,
they can be very effective in elucidating the pathophysiologic
mechanisms of secondary stroke. In subarachnoid hemorrhage (SAH),
acute or delayed ischemia secondary to vasospasm is an important
cause of morbidity and mortality.
The natural history of ischemia secondary to vasospasm differs from
that caused by occlusive disease, because vasospasm represents a
protracted low-flow state with eventual reperfusion. In an animal
model of acute SAH in which the circle of Willis of anesthetized
rats was perforated during repeated DWI acquisitions, there was
rapid decline in ADC in the ipsilateral somatosensory cortex in the
distribution of the distal MCA. This finding suggests acute
vasospasm as the likely etiology, with the time course and spatial
extent of the ADC abnormalities related to the severity of SAH.
In serial DWI studies of patients with SAH, all patients with
vasospasm suggested by transcranial Doppler ultrasound had
associated DWI abnormalities, despite the fact that some patients
were asymptomatic. However, DWI was normal in patients with SAH
In some patients with vasospasm, the associated ADC decreases were
In a retrospective study of posttraumatic cerebral infarction,
which complicates 2% to 10% of head-trauma cases, focal mass effect
or brain herniation was the most common cause.
The investigators noted, however, that because the angiography was
not performed in these cases, the impact of vasospasm could not be
evaluated. Also, outcomes were worse in the patients with
posttraumatic SAH than in those without.
Feasibility of MR imaging for acute stroke
The critical time constraints for identifying patients with
ischemic stroke who could benefit from therapy demand that the
imaging protocol be both accurate and efficient. Additionally, the
test must also rule out hemorrhage to prevent the administration of
thrombolytics or anticoagulants in these patients. Ideally, an
imaging protocol for acute stroke must exclude ICH, verify the
presence of ischemic disease, and take no more than 20 minutes to
If MR is to replace CT as the standard of care for imaging acute
stroke, its superiority must be definitively established. In a
direct comparison between MR and CT performed within 6 hours of
onset in patients with clinically suspected acute hemispheric
stroke, DWI/MRA was found to be superior to CT in diagnosing acute
infarction, revealing occluded MCAs, and disclosing subtle
hemorrhage. Additionally, MR was found to be more accurate than CT
in revealing infarction in >33% of the MCA territory, whereas
intravenous rtPA is relatively contraindicated.
The identification of acute ICH has been the domain of CT,
although the sensitivity of MR for acute hemorrhage has been
questioned. The sensitivity of MR imaging for hyperacute ICH was
investigated in a study of 5 patients with hyperacute-to-acute ICH.
Susceptibility-weighted EPI identified ICH in all 5 patients as
early as 23 minutes after symptom onset.
Similar sensitivity has been reported by other investigators.
An additional concern that conventionally favors CT over MR
concerns efficiency as it relates to the time between patient
arrival and imaging completion. However, the results of a 2-year
study of this issue showed that MR was competitive with CT in this
regard, at least in larger institutions with stroke centers.
The availability of MR imaging on an emergent basis in smaller
facilities may be more limited. Considering the duration of the MR
examination, Sunshine and colleagues
have detailed a protocol for the emergency MR evaluation of acute
stroke that is performed routinely in <15 minutes. The sequences
include sagittal T1 scout, axial T2 turbo gradient and spin echo
(GRASE), axial EPI DWI, and gadolinium-bolus PWI, which is
routinely performed in <15 minutes. Difusion-weighted and
perfusion-weighted images are postprocessed automatically, with ADC
and TTP maps immediately available at the console.
Other considerations for the application of MR to acute stroke
are body movements in the acutely ill patient (who is often
uncooperative), patient monitoring that requires specialized
MR-compatible equipment, and the unique requirement to screen for
contraindications to the MR examination, such as metal fragments
and MR-incompatible implants. More research is needed to determine
the practical significance of these issues.
Early reports of the use of novel MR techniques in the diagnosis
and treatment of various brain pathologies indicate the increasing
use of this modality for evaluating and managing stroke.
Preliminary research with a MR contrast agent, which was created by
conjugating iron oxide particles with a protein known to bind to
membrane phospholipids of apoptotic cells, has demonstrated the
ability of an MR technique, used in both in vitro and tumor models,
to detect cells destined to die. This type of research may lead to
a specific early MR indicator of brain tissue certain to infarct in
Significant research is also under way on the use of MR in guiding
neurointerventional procedures directly, such as the coil
embolization of aneurysms.
In stroke, such a system could provide real-time monitoring of the
patency of occluded vessels, as well as territorial perfusion
during thrombolysis or angioplasty.
By providing superior anatomic and physiometabolic information,
MR imaging clearly offers substantial benefit for rapidly and
accurately evaluating the extent, severity, etiology, and
chronicity of cerebral ischemia. These capabilities promise to
improve the clinical management and outcome for patients with
strokes. These capabilities are compelling motives for increasing
the use of MR imaging in acute stroke.