REVIEW ARTICLE
Diffusion and Perfusion MR Imaging in Acute Stroke: Clinical
Utility and Potential Limitations for Treatment Selection
Mathew Bateman, MBChB, FRANZCR,  Lee-Anne Slater, MBBS, FRANZCR, y
Thabele Leslie-Mazwi, MD, z Claus Z. Simonsen, MD, PhD, § Stephen Stuckey, MBBS, MD, FRANZCR, y
and Ronil V. Chandra, MBBS, FRANZCR y
Abstract: Magnetic resonance (MR) diffusion-weighted imaging (DWI)
and perfusion-weighted imaging (PWI) offer unique insight into acute
ischemic stroke pathophysiology. These techniques may offer the ability to
apply pathophysiology to accurately individualize acute stroke reperfusion
treatment, including extending the opportunity of reperfusion treatment to
well beyond the current time-based treatment windows.
This review examines the use of DWI and PWI in the major stroke trials, their
current clinical utility, and potential limitations for reperfusion treatment
selection. DWI and PWI continue to be investigated in ongoing randomized
controlled trials, and continued research into these techniques will help
achieve the goal of tissue-based decision making and individualized acute
stroke treatment.
Key Words: diffusion imaging, MRI, perfusion imaging, reperfusion,
stroke, thrombolysis
(Top Magn Reson Imaging 2017;26:77–82)
S troke is the second highest cause of mortality in the world and is
a cause of significant morbidity. Globally, there were an esti-
mated 16.9 million strokes in 2010 that resulted in nearly 6 million
deaths.1 In the United States, a stroke occurs every 40 seconds, and a
death from stroke occurs every 4 minutes.1 Up until the turn of the
century, the only management options were supportive therapy,
rehabilitation, and risk factor modification. In 1995, the benefit of
intravenous thrombolysis for acute stroke was established by the
National Institute of Neurological Disorders and Stroke (NINDS)
tPA trial.2 This led to the U.S. Food and Drug Administration
approving intravenous tissue plasminogen activator (IVtPA) for
use within 3 hours of stroke onset. Further trials extended the time
window for treatment from 3.0 to 4.5 hours in select populations.3
IVtPA remained the only proven effective treatment for ischemic
stroke for the next 2 decades.
In early 2015, 5 landmark studies demonstrated the efficacy of
endovascular therapy (ET) for ischemic stroke caused by large artery
occlusion.4–8 There was a significant benefit for use of IVtPA and ET
for patients with a small established infarct, a proximal occlusion, a
significant neurological deficit, and ability to achieve recanalization
by ET within 6 hours of onset compared with IVtPA alone. All of
these landmark stroke trials utilized brain imaging to select patients.9
From the Neuroradiology Service, Monash Imaging, Monash Health; ySchool of
Clinical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash
University, Melbourne, Victoria, Australia; zNeuroEndovascular Service,
Massachusetts General Hospital, Harvard Medical School, Boston, MA;
and §Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
Address correspondence to Ronil V. Chandra, MBBS, MMed, FRANZCR, Diag-
nostic and Interventional Neuroradiology, Monash Health, Monash University,
Melbourne, VIC 3168, Australia.
(e-mail: ronil.chandra@monash.edu; ronilvchandra@gmail.com).
The authors report no conflicts of interest.
Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/RMR.0000000000000124
Topics in Magnetic Resonance Imaging  Volume 26, Number 2, April 2017
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Although the initial goals of imaging were to exclude intracranial
hemorrhage (ICH) and major established infarct in the early IVtPA
trials, imaging goals evolved to include parenchymal and vascular
imaging to identify patients with a small infarct core and large vessel
occlusion for the major ET stroke trials.10 Computed tomography
(CT) imaging was widely utilized to achieve these imaging goals,
and worldwide, remains the most widely utilized imaging modality
in acute stroke due to availability and speed of use.
However, there is potential novel information that magnetic
resonance imaging (MRI) and perfusion imaging techniques could
provide to better select patients for reperfusion. This stems from the
observation that current time treatment windows are based on
epidemiologic population studies, and that the treatment benefit
for the population declines over time. However, this ‘‘time-clock’’
does not always correlate with stroke physiology for an individual
patient. Thus, the goal of stroke therapy patient selection is to create a
treatment paradigm that individualizes stroke treatment toward a
‘‘tissue-clock.’’ In this review, we initially discuss the hemodynamics
in acute stroke that form the foundation for understanding individ-
ualized stroke physiology, and then examine current data for the use
of MRI diffusion-weighted imaging (DWI) and perfusion-weighted
imaging (PWI) to achieve the goal of individualized tissue based
acute reperfusion stroke treatment.
HEMODYNAMICS IN ACUTE STROKE
Cerebral infarction occurs when there is insufficient blood flow
to perfuse cerebral tissue, most commonly due to arterial occlusion.
This is driven by a focal reduction in local cerebral perfusion pressure
(CPP). If there is only a minor reduction in CPP, autoregulatory
responses cause local arteriolar vasodilation that allows maintenance
of normal cerebral blood flow (CBF). This vasodilation increases
mean transit time (MTT; the time that red blood cells remain within a
volume of tissue) as well as cerebral blood volume (CBV; the total
volume of blood within a volume of brain tissue). This small increase
in CBV may be difficult to detect with PWI. However, if local CPP
falls further, CBF begins to reduce. If there is only a mild reduction in
CBF, further compensatory mechanisms such as an increase in local
oxygen extraction from the red blood cells can still sustain brain
electrical function, and tissue viability may not be compromised.
This state of hypoperfusion is referred to as benign oligemia.11
With further reduction in CBF, there is insufficient delivery of
oxygen to brain tissues leading to electrical dysfunction and neuro-
logical deficit. CBF becomes pressure dependent, that is, autoregu-
lation mechanisms have been overwhelmed, and with further
reduction in CPP, there is corresponding reduction in CBF. The
greater the severity of the ischemia, the more likely ischemic injury
will be irreversible. Thus, although brain tissue dies within minutes
without any blood flow, if the reduction in CBF is only moderate, the
brain tissue may remain viable for many hours.12 One of the holy
grails of acute stroke imaging is to reliably identify brain tissue that is
irreversibly injured, that is, the ‘‘core’’ infarct, and the brain tissue
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Bateman et al
that has electrical dysfunction from moderate reduction of CBF, but
remains viable. This tissue that remains viable forms a ring-like
shape around the core, and is referred to as the ‘‘penumbra.’’12 This is
the target for acute reperfusion treatment, as this tissue is potentially
salvageable with timely return of adequate CBF, resulting in arrest of
infarct growth and return of neurological function to that
threatened tissue.
There are many factors that influence the likelihood of irre-
versible injury, including the size of the occluded blood vessel, the
consequent severity and duration of ischemia, the adequacy of
collateral circulation, and other factors including blood glucose level
and temperature. Notably, when reperfusion occurs, either spon-
taneously or through reperfusion therapies, CPP is normalized.
However, local arteriolar vasodilation may persist resulting in
elevation of CBF and CBV in the previously ischemic tissue bed,
including in the infarcted tissue bed. This state is referred to as luxury
perfusion,13 as greater blood flow than required to meet the tissue
metabolic needs is being delivered.
Ultimately depending on when acute imaging is performed
during an ischemic stroke, a snapshot of the patient’s individual
physiology based on these fundamental hemodynamic concepts, and
operationalized concepts of infarct ‘‘core’’ and ischemic ‘‘penum-
bra’’ is obtained. If imaging can reliably determine between infarct
core and penumbra, it could guide and individualize reperfusion
treatment. The patients with the greatest potential to benefit could be
those with the greatest difference between the core and penumbra,
that is, a cohort of patients with a target ‘‘mismatch’’ profile.14 MRI
DWI and PWI offers the greatest promise in reliably identifying core,
penumbra, and mismatch, and these imaging techniques and the
potential clinical applications are discussed in the following sections.
MR DIFFUSION-WEIGHTED IMAGING
With advanced ischemic injury, failure of energy-dependent ion
exchange pumps results in shift of interstitial water into the intra-
cellular compartment, increased intracellular viscosity, and increased
extracellular space tortuosity. This disruption of the normal random
movement (diffusion) of water molecules causes reduction in the
apparent diffusion coefficient (ADC) of water in injured tissues and
increased signal intensity on DWI. DWI is currently considered the
most sensitive method for detecting ischemic stroke; injury is
manifested minutes after infarction,15 with peak changes between
24 and 48 hours.16 In general, the acquisition sequences for DWI
generate b-1000 DWI, b-0 DWI, and ADC maps, all of which contain
useful information in acute stroke. The b-1000 DWI lesion is
typically utilized as the infarct core and has been considered for
reperfusion treatment selection.
HAVE MAJOR STROKE TRIALS USED DWI FOR
REPERFUSION TREATMENT SELECTION?
Overall, no major stroke trial has relied on DWI for patient
selection for reperfusion treatment. Although the NINDS IV tPA
study did not utilize MRI screening, ECASS III trial allowed both CT
and MRI to screen for enrolment in the 3 to 4.5-hour treatment
window. Only 6% of patients in this trial were screened with MRI
before randomization; thus, the benefits of these 2 landmark trials
were confirmed largely using screening with noncontrast CT head
alone to exclude hemorrhage and major established infarct. The
largest study of IVtPA, the third International Stroke trial,17 also
permitted CT or MR screening before randomization; however, the
use of MRI DWI and results of the imaging substudies are yet to be
reported.18 The major ET trials for acute stroke also largely utilized
CT-based paradigms—less than 5% of patients received MRI for
selection. Additional advanced imaging included vascular imaging
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Topics in Magnetic Resonance Imaging  Volume 26, Number 2, April 2017
with single-phase CT angiography (CTA),4 multiphase CTA,6 or
perfusion imaging5,8 also typically with CT.
CLINICAL UTILITY OF DWI FOR REPERFUSION
TREATMENT SELECTION
Although the major stroke trials have not utilized MRI as their
major selection tool, many centers have developed rapid MRI work-
flow and integrate routine MR DWI as the primary imaging strategy
or part of a multimodal CT and MRI strategy for acute stroke.19– 21
The primary goal for early parenchymal imaging prior to
commencement of IVtPA is exclusion of hemorrhage. Most com-
prehensive stroke centers performing MRI only before IVtPA utilize
additional susceptibility-weighted imaging or T2-weighted to
exclude hemorrhage, a strategy with similar sensitivity to noncon-
trast CT.22 Some have advocated that a stand-alone DWI screening
protocol before IVtPA could reduce time to treatment by reducing
overall imaging time. The sensitivity of routine b1000 DWI for
parenchymal hemorrhage has received little attention in the liter-
ature, but probably is similar to noncontrast CT23 and T2-weighted
MRI.24
The main advantage of acute DWI for stroke patients is the
greater sensitivity and higher inter-rater reliability for infarct detec-
tion than noncontrast CT for acute stroke.25 Overall signs of stroke
including parenchymal abnormality as well as hyperattenuating
vessels are detectible in approximately 60% of CT scans, with
overall poor to moderate inter-rater agreement.26,27 This is in contrast
to DWI with a sensitivity of approximately 90% with an excellent
inter-rater agreement.28–30
Moreover, characterization of the DWI lesion could have
prognostic information that can be utilized in treatment decisions.
In particular, it has been postulated that DWI lesion volumes more
than 70 mL are associated with poor outcome regardless of reperfu-
sion treatment.31 Moreover, DWI lesion volumes more than 100 mL
have been considered a ‘‘malignant’’ imaging profile associated with
symptomatic ICH and poor outcome even after reperfusion.14 This
led to the exclusion of these patients in some of the recent ET trials—
in particular, both SWIFT PRIME and EXTEND IA excluded
patients with infarct core volumes more than 50 mL and more than
70 mL, respectively.8,32 However, this concept has been increasingly
challenged with recent reports of 1 in 3 patients with pre-treatment
DWI volumes more than 70 mL and successful reperfusion with
either IVtPA or ET achieving good functional outcome.33,34 Future
research is required to define more robust DWI volume thresholds
beyond which reperfusion would be considered futile.
There is also increasing interest in assessing ADC maps for
prognostic information. The probability of infarct is inversely pro-
portional to the ADC level. Thus, there is utility in identifying ADC
thresholds that could predict irreversible injury.35 Moreover, ADC
thresholds could be used to identify infarct core and penumbra,36 as
well as stratify the risk of hemorrhage after reperfusion therapy.37
However, at this time, there remains no consensus on such ADC
thresholds. Moreover, there may be a significant overlap in ADC
values for tissues of various fate after reperfusion treatment, limiting
clinical utility at this time.37
POTENTIAL LIMITATIONS OF ROUTINE DWI FOR
REPERFUSION TREATMENT SELECTION
Practicality of a MRI Paradigm
The main limitations regarding routine MRI use as the primary
imaging modality before reperfusion treatment are the practicalities
of MR availability, patient MR safety, and persisting questions about
treatment delay. Although access to MRI is variable in emergency
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Topics in Magnetic Resonance Imaging  Volume 26, Number 2, April 2017
departments across the United States, 24/7 onsite MRI is now a
requirement for comprehensive stroke center designation, which
should increase access to MRI for acute stroke patients. Nonetheless,
use of MRI as a primary imaging modality for acute stroke is feasible
in only 80% to 85% of patients.20,38,39 Approximately 10% of stroke
patients have contraindications to MRI, while others may be unable
to tolerate MRI due to unstable medical conditions or agitation.39
Moreover, no publications using MRI have emerged with the ultra-
short time to IVtPA delivery (median 20 minutes) that is feasible with
CT-based paradigms.40,41 This is of importance given the powerful
interaction between time and treatment effect—every 15-minute
reduction to IVtPA treatment could provide an extra month of
additional disability-free life.42 Thus, some centers use a multimodal
imaging strategy with initial CT and CTA, followed by MRI DWI
imaging in select patients.19,43
Sensitivity for Intracranial Hemorrhage
There remain persisting questions regarding the sensitivity of
MR techniques including DWI for ICH. Hyperacute blood products
contain oxyhemoglobin, which is diamagnetic and thus has a min-
imal susceptibility effect, and thus small amounts of ICH could be
occult on T2 and susceptibility-weighted imaging (SWI) sequen-
ces.44 This is generally not a practical issue for large intraparenchy-
mal hemorrhages, which often have a T2 hypointense rim due to a
greater concentration of deoxyhemoglobin at the periphery of the
hematoma. However, the higher oxygen tension in the subarachnoid
spaces, and mixing of subarachnoid blood with CSF reduces the
sensitivity of T2 and SWI for small amounts of SAH.44 This could
be potentially overcome by use of both fluid-attenuated inversion
recovery (FLAIR) sequences and SWI for hemorrhage detection.45
Does DWI Represent Irreversible Injury?
There also remains debate about the extent and clinical correlate
of DWI reversibility. In rodent models, DWI lesions have been
demonstrated to resolve completely within an hour of reperfusion,
but develop again after 12 hours. DWI reversal in stroke patients has
also been reported, but the clinical significance is unclear. A pooled
analysis of the EPITHET and DEFUSE patients treated with IVtPA
between 3 and 6 hours found the volume of permanent DWI reversal
to be less than 5 mL.46 Moreover, most areas of transient DWI
reversal at 3 to 6-hour MRI were abnormal on follow-up FLAIR
imaging. However, with earlier and more effective reperfusion, DWI
reversal is increasingly identified. Despite this, even after IVtPA
reperfusion within 4.5 hours, median volumes of DWI reversal
remain less than 5 mL, with only 10% of patients experiencing more
than 10 mL DWI reversal.47 After ET, DWI reversal is more com-
mon; one-third of patients may experience DWI reversal more than
10 cc when reimaged within 12 hours of ET. However, most of this is
transient, with permanent DWI reversal commonly less than 5 mL.48
The mechanism of this transient DWI reversal with reperfusion is
unclear, but is thought to be related to vasogenic edema, rather than
true tissue salvage.48
MR PERFUSION IMAGING
Although DWI is useful in assessing for infarct core, PWI is
useful to identify areas of potentially reversible ischemia, the
penumbra. The most widely used technique is dynamic susceptibility
contrast (DSC) imaging, which relies on administration of a gado-
linium-based contrast agent. As the gadolinium passes through the
large vessels, the capillaries, and then into the veins, there is local
signal loss due to the T2 effects of the contrast. By rapidly imaging
at multiple time points during contrast passage through the blood
vessels, a time-signal intensity curve is created. This then undergoes
mathematical post-processing to yield perfusion maps of the brain,
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Diffusion and Perfusion MR Imaging in Acute Stroke
which provide information of clinical utility. The time-to-peak (TTP)
map is a representation of the time taken for the T2 effects from the
gadolinium to reach their maximum in each voxel. This is likely the
most reproducible map given that the remainder of the maps require
greater mathematical post-processing. To calculate the remainder of
the maps, the time signal-intensity curve must be converted to a time-
concentration curve and then further post processed to create CBV,
CBF, MTT, and time to maximum (TMax) maps. These maps can
then be used to assess the core, penumbra, and assess for mismatch.
PWI also offers a way to assess the core infarct using CBV.
Although CBV has been shown to offer good correlation with DWI
and final infarct volume,49 it is rarely used in clinical practice for core
infarct, as lesions are easier to identify on DWI, and DWI is less
likely to miss small lesions.49 Accurate assessment of the penumbra
is challenging due to the requirement to accurately determine the
interface between the core and penumbra, as well as penumbra and
areas of benign oligemia. There is no consensus as to which PWI
parameter best identifies penumbral tissue. Currently, the most
widely utilized threshold to determine penumbral tissue is TMax
in the range of 4 to 6 seconds. 50 Other PWI measures, in particular
MTT, are prone to error with overestimation of the penumbra.51
There is much active research in the accurate determination of core
and penumbra, due to interest in the mismatch hypothesis. If there is a
significant difference between the imaging core and penumbra, that
is, DWI/PWI mismatch, restoration of perfusion to this penumbral
tissue results in clinical recovery.52 In general, a mismatch volume of
more than 20% is generally accepted as an indicator of penumbral
presence. Moreover, mismatch can persist to at least 48 hours in some
patients,52 and thus could facilitate treatment outside traditional time
based windows of 4.5 hours from onset for IVtPA and 6 to 8 hours
from onset for ET, thus extending the opportunity of reperfusion
treatment to more stroke patients.
In addition, PWI parameters may also be able to identify
patients unlikely to benefit and to be potentially harmed by reperfu-
sion therapy. A pooled analysis of the DEFUSE and EPITHET cohort
identified patients with a TMax more than 8 seconds volume more
than 85 mL who had a ‘‘malignant’’ profile.53 After reperfusion,
almost 70% of patients developed parenchymal hemorrhage, and
90% had a poor outcome. Moreover, this PWI threshold outper-
formed DWI to predict outcome.53 PWI could perhaps be a better
predictor of harm than DWI, as it may more readily identify severely
hypoperfused microvasculature that may be prone to blood-brain
barrier breakdown and postreperfusion hemorrhage. Notably, these
patients were selected for reperfusion treatment in the 3 to 6-hour
time window. In the sub-3-hour time window, the incidence of the
malignant profile is not clear, but is probably close to 10%.54
However, with improving ET reperfusion efficiency and ongoing
reductions in symptom onset to complete reperfusion time, the
malignant profile will be redefined. In patients with rapid and
complete reperfusion, there were no differences in outcome for
patients with TMax > 10-second lesion > 100 mL compared with
those without this malignant imaging profile.55
HAVE MAJOR STROKE TRIALS USED PWI FOR
REPERFUSION TREATMENT SELECTION?
Within 3 hours from onset, no major IVtPA stroke trial has
used mismatch for patient treatment selection. Beyond traditional
time windows, there is growing interest in mismatch to guide
treatment selection. Between 3 and 6 hours, patients with mismatch
in the DEFUSE 2 trial benefited from reperfusion treatment,
whereas those without mismatch did not.14 This hypothesis is
currently being further tested with the ECASS-4:EXTEND IVtPA
stroke trial for patients 4.5 to 9 hours after stroke onset or with
wake-up stroke.56
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Bateman et al
The MR-RESCUE study was an ET trial that used mismatch for
patient selection.57 However, the methodology was more complex,
involving ADC and PWI parameters. Although this trial was not
positive, a significant component of the inability to show benefit
related to the ET device used, which did not achieve reliable or
adequate reperfusion rates (compared with the more recent ET trials).
In the recent positive ET trials, the size of treatment effect was
greater for the trials that used perfusion or collateral imaging to select
patients for treatment, than those that treated based on large vessel
occlusion alone. SWIFT PRIME and EXTEND IA utilized penum-
bral imaging for patient selection.5,8 The majority of patients were
selected with CT and not MR PWI; however, both were processed
using RAPID (iSchemaView, California) automated perfusion soft-
ware to select patients with a favorable imaging profile, that is, less
than 50-cc core and more than 1.8 mismatch ratio in SWIFT PRIME
and less than 70-cc core infarct and more than 1.2 mismatch ratio in
EXTEND IA. Ongoing trials of ET using mismatch for treatment
selection include Trevo and Medical Management Versus Medical
Management Alone in Wake Up and Late Presenting Strokes
(DAWN)58 and Endovascular Therapy Following Imaging Evalu-
ation for Ischemic Stroke 3 (DEFUSE 3).59
CLINICAL UTILITY OF PWI FOR REPERFUSION
TREATMENT SELECTION
Currently, there are insufficient data to support routine use of
PWI selection for reperfusion treatment within traditional time
windows. Early after onset, patients with a significant neurological
deficit and large vessel occlusion will have a significant mismatch if
DWI core volume is small, thus rendering acquisition of additional
PWI data less useful.60 There is promise in patient treatment
selection more than 4.5 hours or in wake-up strokes, who are
currently being enrolled into trials of both IVtPA and ET.56,58,59
Moreover, early data also suggest that patients with large core
infarcts and large areas of mismatch could still benefit from ET.61
This benefit may be even greater with different outcome goals (eg,
reperfusion to reduce need for hemicraniectomy, reduce overall
morbidity and mortality, as opposed to achieve functional independ-
ence). Further prospective studies are required.
Nonetheless, in routine clinical practice, the use of PWI does
improve rates of stroke diagnosis compared to use of DWI alone.
When PWI is combined with DWI, the diagnostic sensitivity for
stroke rises to close to 97%.29 Small subcortical and perforator
infarcts are likely to be the cause for initial imaging negative studies.
Moreover, PWI could detect small peripheral perfusion abnormal-
ities caused by distal occlusion that may not be identified by MR
angiography, and these patients may still benefit from IVtPA.62
Finally, most stroke mimics are likely to have normal DWI and
PWI examinations.63 These strengths of PWI could aid in refining
treatment to those with definite stroke and minimizing treatment of
stroke mimics.
POTENTIAL LIMITATIONS OF ROUTINE PWI FOR
REPERFUSION TREATMENT SELECTION
Variability in Acquisition, Processing, Thresholding,
and Definitions
There is significant variability in PWI acquisition and process-
ing making it challenging to standardize across centers and extrap-
olate from trials. One of the major variables relates to acquisition
time and truncation errors. In the setting of ischemic stroke, bolus
contrast injections in the arm need to travel to the brain, possibly
through stenotic arterial vessels, and through the pial collateral
circulation in the setting of major intracranial occlusion. This can
significantly increase time taken for contrast to travel to the brain,
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Topics in Magnetic Resonance Imaging  Volume 26, Number 2, April 2017
pass through the ischemic tissue bed and into the venous system,
which can be compounded by the presence of impaired cardiac
function or severe cervical vessel stenosis. Thus, PWI acquisitions
that are not long enough may result in truncation effects in the time-
signal intensity curve that underestimate CBV, MTT, TMax, and
potentially CBF.64 Additional factors reducing transit time of con-
trast from arm to brain, such as contrast injection rate and volume,
cardiac output, and body habitus may also create or exacerbate
truncation errors if PWI acquisitions are not long enough.64 Simple
variation in placement of the arterial input function (AIF) required to
generate perfusion maps can also impact on PWI volumes65; decon-
volution methods used for post-processing may also be variable.
Initial thresholding of penumbra was based on a TMax threshold of at
least 2 seconds, which was overly inclusive in identifying penumbral
tissue in the EPITHET and DEFUSE cohorts.14,66 Subsequent
research has suggested stricter definitions of TMax more than
6 seconds, which has been utilized in the recent ET trials.5,8 More-
over, the initial definitions of mismatch ratio of greater than 1.2 to
identify a penumbral state are arbitrary50; subsequent trials such as
the DEFUSE 2 and 3 trials, as well as the SWIFT PRIME ET trial
used a mismatch ratio of 1.8,8 while EXTEND IA used a mismatch
ratio of 1.2.5 These variable definitions in the trials make it challeng-
ing to uniformly implement PWI into robust and reproducible
multicenter pathways.
Future solutions include the use of automated postprocessing
solutions to standardize for these issues. Various platforms are
available commercially, but one of the more prominent is RAPID
(iSchemaView, CA), which was utilized in routinely in 2 of the recent
endovascular trials5,8 and is being further applied in DEFUSE 3 and
DAWN. The significant effect on the variability in thresholding and
definitions was highlighted with RAPID software applied to the
EPITHET and DEFUSE cohorts.67 The original EPITHET PWI
volumes were 55% larger than the corresponding RAPID volumes;
the original DEFUSE PWI volumes were 25% larger than the RAPID
volumes. This is likely related to the differences in TMax thresholds
(EPITHET TMax 2; DEFUSE TMax >2, and RAPID TMax
>6 seconds and the differences in AIF and postprocessing). This
highlights the importance of input variables for these programs and
subsequent decisions based upon them.
The Dynamic Nature of Stroke
Variability in processing and thresholds is compounded by the
dynamic nature of stroke, characterized by arterial occlusion,
patient-dependent collateral flow, occlusive clot migration/fragmen-
tation, and reperfusion, which can all occur in rapid succession in a
stroke patient. PWI captures an imaging snapshot in time of these
related phenomena. The most effective means of maintaining the
relevance of this imaging snapshot is to maintain hemodynamics in
stable condition in the period between imaging and reperfusion, and
shortening that time interval as aggressively as possible.
Potential Alternative Definitions of Mismatch
Apart from PWI-DWI mismatch that has limitations as high-
lighted, there is increasing interest in alternate definitions of mis-
match, such as clinical diffusion mismatch (CDM). CDM is
generally defined as NIHSS score of at least 8 and DWI of 25 mL
or less on arrival, and identifies a cohort of patients at risk of infarct
growth and early neurological deterioration.68 ET of patients with a
large vessel occlusion based on similar clinical and MRI criteria
results in favorable outcomes.19 Proponents of this alternative mis-
match definition suggest that additional assessment of PWI mis-
match is not necessary. Further alternate mismatch definitions,
including MR angiogram-DWI mismatch,69 MRI DWI-FLAIR mis-
match,70 MRI FLAIR vascular hyperintensities-DWI mismatch,71
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Topics in Magnetic Resonance Imaging  Volume 26, Number 2, April 2017
and SWI-DWI mismatch,72 are all being investigated as alternatives
to PWI-DWI mismatch. Furthermore, all current definitions of
mismatch often do not consider eloquence of territory involved.
Mismatch involving a less eloquent territory may be less important
compared with involvement of the cortical motor strip. Although
visual assessment can consider these variations, future perfusion-
based paradigms that can incorporate anatomical with functional
information will help further individualize stroke treatment in
the future.
CONCLUSION
DWI and PWI in acute stroke offer unique insight into the
pathophysiology of ischemic stroke in the individual patient.
Although not routinely utilized in major reperfusion trials, they
may offer the ability to extend the opportunity of reperfusion treat-
ment to well beyond the current time-based windows. DWI and PWI
continue to be investigated in ongoing randomized controlled trials,
and clinical use of these imaging techniques for routine patient
treatment selection should consider the known limitations. None-
theless, continued research into DWI and PWI for treatment selection
will help achieve the goal of tissue-based decision making and
individualized acute stroke reperfusion treatment.
REFERENCES
1. Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional
burden of stroke during 1990-2010: findings from the Global Burden of
Disease Study 2010. Lancet. 2014;383:245–254.
2. The National Institute of Neurological Disorders and Stroke rt-PA Stroke
Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. N
Engl J Med. 1995;333:1581–1587.
3. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to
4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329.
4. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of
intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11–
20.
5. Campbell BCV, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for
ischemic stroke with perfusion-imaging selection. N Engl J Med.
2015;372:1009–1018.
6. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid
endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019–
1030.
7. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after
symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296–2306.
8. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after
intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285–2295.
9. Cougo-Pinto PT, Chandra RV, Simonsen CZ, et al. Intra-arterial therapy for
acute ischemic stroke: a golden age. Curr Treat Options Neurol. 2015;17:360.
10. Akbik F, Hirsch JA, Cougo-Pinto PT, et al. The evolution of mechanical
thrombectomy for acute stroke. Curr Treat Options Cardiovasc Med.
2016;18:32.
11. Parsons MW, Yang Q, Barber PA, et al. Perfusion magnetic resonance imaging
maps in hyperacute stroke: relative cerebral blood flow most accurately
identifies tissue destined to infarct. Stroke. 2001;32:1581–1587.
12. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia: the ischemic
penumbra. Stroke. 1981;12:723–725.
13. Lassen NA. The luxury-perfusion syndrome and its possible relation to acute
metabolic acidosis localised within the brain. Lancet. 1966;2:1113–1115.
14. Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging profiles
predict clinical response to early reperfusion: the diffusion and perfusion
imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann
Neurol. 2006;60:508–517.
ß 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Diffusion and Perfusion MR Imaging in Acute Stroke
15. Hjort N, Christensen S, Solling C, et al. Ischemic injury detected by diffusion
imaging 11 minutes after stroke. Ann Neurol. 2005;58:462–465.
16. Schwamm LH, Koroshetz WJ, Sorensen AG, et al. Time course of lesion
development in patients with acute stroke: serial diffusion- and hemodynamic-
weighted magnetic resonance imaging. Stroke. 1998;29:2268–2276.
17. group ISTc, Sandercock P, Wardlaw JM, et al. The benefits and harms of
intravenous thrombolysis with recombinant tissue plasminogen activator
within 6 h of acute ischaemic stroke (the third international stroke trial [IST-
3]): a randomised controlled trial. Lancet. 2012;379:2352–2363.
18. Wardlaw JM, von Kummer R, Carpenter T, et al. Protocol for the perfusion and
angiography imaging sub-study of the Third International Stroke Trial (IST-3)
of alteplase treatment within six-hours of acute ischemic stroke. Int J Stroke.
2015;10:956–968.
19. Leslie-Mazwi TM, Hirsch JA, Falcone GJ, et al. Endovascular stroke treatment
outcomes after patient selection based on magnetic resonance imaging and
clinical criteria. JAMA Neurol. 2016;73:43–49.
20. Shah S, Luby M, Poole K, et al. Screening with MRI for accurate and rapid
stroke treatment: SMART. Neurology. 2015;84:2438–2444.
21. Simonsen CZ, Schmitz ML, Madsen MH, et al. Early neurological
deterioration after thrombolysis: clinical and imaging predictors. Int J Stroke.
2016;11:776–782.
22. Fiebach JB, Schellinger PD, Gass A, et al. Stroke magnetic resonance imaging
is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the
validity of stroke imaging. Stroke. 2004;35:502–506.
23. Keigler G, Goldberg I, Eichel R, et al. Diffusion-weighted imaging at b1000
for identifying intracerebral hemorrhage: preliminary sensitivity,
specificity, and inter-rater variability. J Stroke Cerebrovasc Dis.
2014;23:1934–1938.
24. Oppenheim C, Touze E, Hernalsteen D, et al. Comparison of five MR
sequences for the detection of acute intracranial hemorrhage. Cerebrovasc
Dis. 2005;20:388–394.
25. Gonzalez RG, Schaefer PW, Buonanno FS, et al. Diffusion-weighted MR
imaging: diagnostic accuracy in patients imaged within 6 hours of stroke
symptom onset. Radiology. 1999;210:155–162.
26. Wardlaw JM, Mielke O. Early signs of brain infarction at CT: observer
reliability and outcome after thrombolytic treatment–systematic review.
Radiology. 2005;235:444–453.
27. Gupta AC, Schaefer PW, Chaudhry ZA, et al. Interobserver reliability of
baseline noncontrast CT Alberta Stroke Program Early CT Score for intra-
arterial stroke treatment selection. AJNR Am J Neuroradiol. 2012;33:1046–
1049.
28. Saur D, Kucinski T, Grzyska U, et al. Sensitivity and interrater agreement of
CT and diffusion-weighted MR imaging in hyperacute stroke. AJNR Am J
Neuroradiol. 2003;24:878–885.
29. Simonsen CZ, Madsen MH, Schmitz ML, et al. Sensitivity of diffusion- and
perfusion-weighted imaging for diagnosing acute ischemic stroke is 97.5%.
Stroke. 2015;46:98–101.
30. Yoo AJ, Chaudhry ZA, Leslie-Mazwi TM, et al. Endovascular treatment of
acute ischemic stroke: current indications. Tech Vasc Interv Radiol.
2012;15:33–40.
31. Yoo AJ, Verduzco LA, Schaefer PW, et al. MRI-based selection for intra-
arterial stroke therapy: value of pretreatment diffusion-weighted imaging
lesion volume in selecting patients with acute stroke who will benefit from
early recanalization. Stroke. 2009;40:2046–2054.
32. Campbell BC, Mitchell PJ, Yan B, et al. A multicenter, randomized, controlled
study to investigate EXtending the time for Thrombolysis in Emergency
Neurological Deficits with Intra-Arterial therapy (EXTEND-IA). Int J Stroke.
2014;9:126–132.
33. Gilgen MD, Klimek D, Liesirova KT, et al. Younger stroke patients with large
pretreatment diffusion-weighted imaging lesions may benefit from
endovascular treatment. Stroke. 2015;46:2510–2516.
www.topicsinmri.com | 81
Bateman et al
34. Tisserand M, Turc G, Charron S, et al. Does diffusion lesion volume above
70 ml preclude favorable outcome despite post-thrombolysis recanalization?
Stroke. 2016;47:1005–1011.
35. Purushotham A, Campbell BC, Straka M, et al. Apparent diffusion coefficient
threshold for delineation of ischemic core. Int J Stroke. 2015;10:348–353.
36. Lopez-Mejia M, Roldan-Valadez E. Comparisons of Apparent Diffusion
Coefficient Values in Penumbra, Infarct, and Normal Brain Regions in Acute
Ischemic Stroke: Confirmatory Data Using Bootstrap Confidence Intervals,
Analysis of Variance, and Analysis of Means. J Stroke Cerebrovasc Dis.
2016;25:515–522.
37. Kidwell CS, Alger JR, Saver JL. Beyond mismatch: evolving paradigms in
imaging the ischemic penumbra with multimodal magnetic resonance
imaging. Stroke. 2003;34:2729–2735.
38. Sakamoto Y, Tanabe M, Masuda K, et al. Feasibility of using magnetic
resonance imaging as a screening tool for acute stroke thrombolysis. J Neurol
Sci. 2016;368:168–172.
39. Singer OC, Sitzer M, du Mesnil de Rochemont R, Neumann-Haefelin T.
Practical limitations of acute stroke MRI due to patient-related problems.
Neurology. 2004;62:1848–1849.
40. Meretoja A, Strbian D, Mustanoja S, et al. Reducing in-hospital delay to 20
minutes in stroke thrombolysis. Neurology. 2012;79:306–313.
41. Meretoja A, Weir L, Ugalde M, et al. Helsinki model cut stroke thrombolysis delays
to 25 minutes in Melbourne in only 4 months. Neurology. 2013;81:1071–1076.
42. Meretoja A, Keshtkaran M, Saver JL, et al. Stroke thrombolysis: save a
minute, save a day. Stroke. 2014;45:1053–1058.
43. Mehta BP, Leslie-Mazwi TM, Chandra RV, et al. Reducing door-to-puncture
times for intra-arterial stroke therapy: a pilot quality improvement project.
J Am Heart Assoc. 2014;3:e000963.
44. Whang JS, Kolber M, Powell DK, Libfeld E. Diffusion-weighted signal
patterns of intracranial haemorrhage. Clin Radiol. 2015;70:909–916.
45. Verma RK, Kottke R, Andereggen L, et al. Detecting subarachnoid
hemorrhage: comparison of combined FLAIR/SWI versus CT. Eur J Radiol.
2013;82:1539–1545.
46. Campbell BC, Purushotham A, Christensen S, et al. The infarct core is well
represented by the acute diffusion lesion: sustained reversal is infrequent.
J Cereb Blood Flow Metab. 2012;32:50–56.
47. Soize S, Tisserand M, Charron S, et al. How sustained is 24-hour diffusion-
weighted imaging lesion reversal? Serial magnetic resonance imaging in a patient
cohort thrombolyzed within 4.5 hours of stroke onset. Stroke. 2015;46:704–710.
48. Inoue M, Mlynash M, Christensen S, et al. Early diffusion-weighted imaging
reversal after endovascular reperfusion is typically transient in patients imaged
3 to 6 hours after onset. Stroke. 2014;45:1024–1028.
49. Schaefer PW, Hunter GJ, He J, et al. Predicting cerebral ischemic infarct
volume with diffusion and perfusion MR imaging. AJNR Am J Neuroradiol.
2002;23:1785–1794.
50. Campbell BC, Macrae IM. Translational perspectives on perfusion-diffusion
mismatch in ischemic stroke. Int J Stroke. 2015;10:153–162.
51. Butcher KS, Parsons M, MacGregor L, et al. Refining the perfusion-diffusion
mismatch hypothesis. Stroke. 2005;36:1153–1159.
52. Ma H, Wright P, Allport L, et al. Salvage of the PWI/DWI mismatch up to 48 h from
stroke onset leads to favorable clinical outcome. Int J Stroke. 2015;10:565–570.
53. Mlynash M, Lansberg MG, De Silva DA, et al. Refining the definition of the
malignant profile: insights from the DEFUSE-EPITHET pooled data set.
Stroke. 2011;42:1270–1275.
54. Inoue M, Mlynash M, Straka M, et al. Patients with the malignant profile
within 3 hours of symptom onset have very poor outcomes after
intravenous tissue-type plasminogen activator therapy. Stroke.
2012;43:2494–2496.
82 | www.topicsinmri.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Topics in Magnetic Resonance Imaging  Volume 26, Number 2, April 2017
55. Nogueira RG, Haussen DC, Dehkharghani S, et al. Large volumes of
critically hypoperfused penumbral tissue do not preclude good outcomes
after complete endovascular reperfusion: redefining malignant profile.
Stroke. 2016;47:94–98.
56. Amiri H, Bluhmki E, Bendszus M, et al. European Cooperative Acute Stroke
Study-4: extending the time for thrombolysis in emergency neurological
deficits ECASS-4: ExTEND. Int J Stroke. 2016;11:260–267.
57. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection
and endovascular treatment for ischemic stroke. N Engl J Med.
2013;368:914–923.
58. Trevo and Medical Management Versus Medical Management Alone in Wake
Up and Late Presenting Strokes (DAWN) [Internet]; 2014. Web site http://
clinicaltrials.gov/ct2/show/NCT02142283.
59. Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3
(DEFUSE 3) [Internet]; 2015. Website https://clinicaltrials.gov/ct2/show/
NCT02586415.
60. Hakimelahi R, Yoo AJ, He J, et al. Rapid identification of a major diffusion/
perfusion mismatch in distal internal carotid artery or middle cerebral artery
ischemic stroke. BMC Neurol. 2012;12:132.
61. Rebello LC, Bouslama M, Haussen DC, et al. Endovascular treatment for
patients with acute stroke who have a large ischemic core and large mismatch
imaging profile. JAMA Neurol. 2017;74:34–40.
62. Sillanpaa N, Saarinen JT, Rusanen H, et al. Location of the clot and outcome of
perfusion defects in acute anterior circulation stroke treated with intravenous
thrombolysis. AJNR Am J Neuroradiol. 2013;34:100–106.
63. Campbell BC, Weir L, Desmond PM, et al. CT perfusion improves diagnostic
accuracy and confidence in acute ischaemic stroke. J Neurol Neurosurg
Psychiatry. 2013;84:613–618.
64. Copen WA, Deipolyi AR, Schaefer PW, et al. Exposing hidden truncation-
related errors in acute stroke perfusion imaging. AJNR Am J Neuroradiol.
2015;36:638–645.
65. Thijs VN, Somford DM, Bammer R, et al. Influence of arterial input function
on hypoperfusion volumes measured with perfusion-weighted imaging.
Stroke. 2004;35:94–98.
66. Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3 h
after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial
(EPITHET): a placebo-controlled randomised trial. Lancet Neurol.
2008;7:299–309.
67. Lansberg MG, Lee J, Christensen S, et al. RAPID automated patient selection
for reperfusion therapy: a pooled analysis of the Echoplanar Imaging
Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion
Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study.
Stroke. 2011;42:1608–1614.
68. Davalos A, Blanco M, Pedraza S, et al. The clinical-DWI mismatch: a new
diagnostic approach to the brain tissue at risk of infarction. Neurology.
2004;62:2187–2192.
69. Lansberg MG, Thijs VN, Bammer R, et al. The MRA-DWI mismatch
identifies patients with stroke who are likely to benefit from reperfusion.
Stroke. 2008;39:2491–2496.
70. Thomalla G, Cheng B, Ebinger M, et al. DWI-FLAIR mismatch for the
identification of patients with acute ischaemic stroke within 4.5 h of symptom
onset (PRE-FLAIR): a multicentre observational study. Lancet Neurol.
2011;10:978–986.
71. Legrand L, Tisserand M, Turc G, et al. Do FLAIR vascular hyperintensities
beyond the DWI lesion represent the ischemic penumbra? AJNR Am J
Neuroradiol. 2015;36:269–274.
72. Lou M, Chen Z, Wan J, et al. Susceptibility-diffusion mismatch predicts
thrombolytic outcomes: a retrospective cohort study. AJNR Am J Neuroradiol.
2014;35:2061–2067.
ß 2017 Wolters Kluwer Health, Inc. All rights reserved.