Systematic Review

International Journal of Stroke

2021, Vol. 16(5) 497–509
The ischemic penumbra: From concept ! 2020 World Stroke Organization
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DOI: 10.1177/1747493020975229
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Charlotte M Ermine1 , Andrew Bivard2,3, Mark W Parsons2,3,*

and Jean-Claude Baron4,5,*

Abstract
The discovery that brain tissue could potentially be salvaged from ischaemia due to stroke, has led to major advances in
the development of therapies for ischemic stroke. In this review, we detail the advances in the understanding of this area
termed the ischaemic penumbra, from its discovery to the evolution of imaging techniques, and finally some of the
treatments developed. Evolving from animal studies from the 70s and 80s and translated to clinical practice, the field of
ischemic reperfusion therapy has largely been guided by an array of imaging techniques developed to positively identify
the ischemic penumbra, including positron emission tomography, computed tomography and magnetic resonance ima-
ging. More recently, numerous penumbral identification imaging studies have allowed for a better understanding of the
progression of the ischaemic core at the expense of the penumbra, and identification of patients than can benefit from
reperfusion therapies in the acute phase. Importantly, 40 years of critical imaging research on the ischaemic penumbra
have allowed for considerable extension of the treatment time window and better patient selection for reperfusion
therapy. The translation of the penumbra concept into routine clinical practice has shown that ‘‘tissue is at least as
important as time.’’

Keywords
Stroke, ischemic stroke, penumbra, positron emission tomography, computed tomography scan, magnetic resonance
imaging

Received: 18 May 2020; accepted: 3 September 2020

Introduction baboons, that in ischemic tissue, there were large vari-

A major scientific discovery underpinning modern
treatment for ischemic stroke was made four decades
ago, with the identification of a region around the irre-
versibly injured core of infarction, where neurons were
not functioning but could still be saved if perfusion was
restored promptly. This region was coined the ‘‘ische-
mic penumbra’’.1 In this review, we will describe the
evolution of our understanding of the ischemic penum-
bra from its discovery to the treatments currently
available.
Ischemic penumbra: Discovery and
definition
Animal studies have played a major role in understand-
ing the evolution of brain tissue following ischemia. In
1973, Hossmann and Kleihues demonstrated following
global ischemia in cats and monkeys that neuronal
function could recover and survive an extended time
past total oxygen depletion under suitable conditions.2
In 1974, Symon et al. showed in a middle cerebral
artery occlusion (MCAo) model of focal stroke in
ations in the reduction of cerebral blood flow (CBF),
suggesting that brain tissue was being supplied with
blood from more than one route (subsequently
termed collaterals). This finding gave the first indication
that a treatment post-stroke was possible, through sal-
vaging the tissue at risk of infarction.3 In 1977, Astrup
et al. using the same model showed that failure of
1
Florey Institute of Neuroscience and Mental Health, Melbourne,
Australia
2
Department of Medicine, Melbourne Brain Centre at The Royal
Melbourne Hospital, Parkville, Australia
3
Department of Neurology, Melbourne Brain Centre at The Royal
Melbourne Hospital, Parkville, Australia
4
Institute of Psychiatry and Neuroscience of Paris (IPNP), Université de
Paris, Paris, France
5
GHU Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, Paris,
France
*
These authors contributed equally to this study.
Corresponding author:
Charlotte M Ermine, The Florey Institute of Neuroscience and Mental
Health, 30 Royal Parade, Parkville, Victoria 3052, Australia.
Email: charlotte.ermine@florey.edu.au

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498 International Journal of Stroke 16(5)

Figure 1. Representation of the ischaemic thresholds from two studies: (a) Figure modified from Astrup et al. (1977), represents
ischaemic thresholds for electrical failure and K+ release. (b) Cartoon modified from Jones et al. (1981), illustrating the CBF x
Time interaction, where paralysis represents the ischaemic penumbra and infarction representing the core.
Source: reproduced with permission from Astrup et al., 19774 and Jones et al., 1981.7

electrical activity was not uniform across an ischemic
region, suggesting that some tissue remained electrically
active despite severe ischemia, and defined ischemic
thresholds based on CBF levels.4 They identified three
regions: (i) below 20 ml/100 g/min, where electrical
function of the tissue is affected; (ii) below 15 ml/
100 g/min, where electrical failure is complete; and
(iii) below 5 ml/100 g/min, where release of extracellular
Kþ attests to impending cell death (Figure 1(a)).
Furthermore, they showed that increasing CBF could
restore evoked potential and normalize extracellular
Kþ. Additional animal studies have confirmed the
presence of salvageable tissue (subsequently called the
penumbra) and have further refined the CBF threshold
corresponding to the infarct core and to the ischemic
penumbra5–7 (Figure 1(b)). One of those studies by
Jones et al. in 1981 used histological evidences corre-
lated with electrode recording sites to validate the pen-
umbra threshold of 20 ml/100 g/min. They further
showed that the core threshold, in contrast to the pen-
umbra threshold was time dependent, which was later
confirmed in three recent clinical studies.8–11 It is
important to note that throughout this review, we will
be referring to both infarct and ischemic core. These
terms may not be strictly equivalent, as they differ
from their mode of acquisition, namely histology and
perfusion/diffusion/cerebral metabolic rate of oxygen
(CMRO2) imaging respectively.
The first definition of the ischemic penumbra was
given by Astrup and Symon in 1981 as: ‘‘the region of
reduced CBF with absent spontaneous or induced elec-
trical potentials that still maintained ionic homeostasis
and transmembrane electrical potentials’’.12 From
there, it was suggested that the penumbra was ischemic
tissue that was potentially reversible with timely restor-
ation of perfusion, with the key point that treatment of
stroke should focus on salvaging this tissue.13 CBF in
the penumbral region is gradually increased as we move
away from the core, which explains the progressive
death of tissue with time, and therefore the possibility
of successful treatment being time-dependent.7,14–16
This was shown by positron emission tomography
(PET) where CBF, CMRO2, oxygen extraction fraction
(OEF), and cerebral metabolic rate of glucose
(CMRglc) were directly measured few hours post
MCAo in baboons and later repeatedly measured
over 24 h following MCAo in another study in
cats.15,17 This revealed initially a reduction in CBF
and an increase of OEF in the ischemic core, and a
decrease in CBF, CMRglc, CMRo2, and OEF in the
periphery, with sequential studies showing that the
core expands to the outer regions of the penumbra.15
This was confirmed one year later in a baboon
model, where the volume of severely hypometabolic
tissue measured via sequential PET was shown to be
stable for the first few hours following insult, but

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Ermine et al. 499

then had enlarged at 24 h post-ischemia and continued
to grow in subsequent days.16 Consistent with the
penumbra concept, reperfusion at 6 h reversed this
process.18
Thus, animal studies permitted the discovery of the
existence of the ischemic penumbra, a tissue that was
destined to die with time, but that did not immediately
die in the first hours after vessel occlusion. These
advances were crucial in identifying targets for rational
treatment of stroke.
Identifying the ischemic penumbra:
Evolution of imaging techniques
Following the discovery in animal studies of the ische-
mic penumbra, the next step was to document the exist-
ence of, and map the penumbra in man, as it was widely
considered at that time that animal studies did not
apply to human stroke. To work toward this goal,
researchers investigated various methods of imaging
the penumbra, from combined perfusion and metabolic
imaging using PET to sole perfusion imaging including
computed tomography (CT) and magnetic resonance
(MR). When reviewing the historical evolution of ima-
ging to define core and penumbra in humans, it is
important to note that the penumbra threshold does
not significantly vary with time after stroke onset.19,20
However, the infarction (core) threshold is time-depen-
dent and by definition has varied from study to study
given the variability (and uncertainty) in timing of
reperfusion historically. Indeed, only with thrombec-
tomy (and hence known time and extent of reperfusion)
it was established in human studies that earlier reperfu-
sion can salvage more severely hypoperfused tissue. The
current definitions of the ischemic penumbra according
to each imaging techniques are summarized in Table 1.
Positron emission tomography
PET is a quantitative imaging technique that uses
radiotracers to measure regional cerebral blood
volume (CBV), CBF, OEF, CMRglc, and CMRO2, as

Table 1. Summary of the definitions of the ischemic core and penumbra according to the different imaging techniques presented in
this review.
Techniques Ischemic core Ischemic penumbra Advantages Disadvantages

PET Very low CBFa and CBF <20 ml/100 g/min, Accuracy thanks to quantita- Technically challenging
CMRO2 and variable increased OEF, but rela- tive measures of both Expensive
OEF tively preserved CMRO2 perfusion and metabolism Radiation
Limited availability

SPECT >70% reduction in tracer 40–70% reduction of tracer Lower cost Use of radioactive agents
signal compared to the signal compared to Good availability Difficult data analysis
contralateral side contralateral side Coarse spatial
resolution
Inaccurate in case of
partial reperfusion

MRI: DWI lesion ¼ PWI lesion (Tmax > 6 s or Most accurate way to map Limited access to MRI
‘‘Perfusion–diffusion hyperintensity delay time > 3 s) – DWI the penumbra and core in Contraindications
mismatch’’ lesion the clinical setting (e.g. pacemakers,
(MTT less precise than delay claustrophobia)
measures)

MRI: DWI lesion ASL–CBF threshold of Rapid Poor spatial resolution

‘‘ASL–DWI 40%—DWI lesion Non-invasive Loss of signal due to low
mismatch’’ Quantitative measures perfusion
Artifacts due to slow
collateral flow

CTP Low CBF (<30%) Tmax > 6 s or delay time- Low cost Less reliable than MRI
>3s Good availability Radiation exposure
(MTT less precise than delay Artifacts in case of low
measures) cardiac ejection
fraction
a
The core may partially reperfuse early after stroke onset, in which case, its perfusion may be normal or even increased, together with very low OEF
and CMRO2.
PET: positron emission tomography; SPECT: single photon emission computer tomography; CBF: cerebral blood flow; CMRO2: cerebral metabolic rate
of oxygen; OEF: oxygen extraction fraction; DWI: diffusion-weighted imaging; PWI: perfusion-weighted imaging; ASL: arterial spin labeling; CTP:
computed tomography perfusion.

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500 International Journal of Stroke 16(5)

Figure 2. Identification of the ischaemic penumbra using different imaging techniques. (a) Using PET measurement of CBF, OEF
and CMRO2, where the penumbra (red arrow) is identified by reduced CBF, increased OEF but relatively preserved CMRO2 apart
from a moderate reduction in the basal ganglia area. Image from Heiss et al. 2017100. (b) Using DWI-PWI mismatch (image from
Ebinger et al. 2009), the lesion from DWI is shown by the arrow, the perfusion deficit on PWI is shown in red and the ischeamic
penumbra defined by the DWI/PWI mismatch is shown in blue101. (c) Using CTP (image from Bivard et al. 2013), which allows the
creation of maps for CBF, CBF, MTT, TTP, Tmax and delay-time, to identify the infarction core in red and the ischaemic penumbra
in green9.
Source: reproduced with permission from Heiss and Weber, 2017.,100 Ebinger et al., 2009,101 and Bivard et al., 2013.9
PET: positron emission tomography; CBF: cerebral blood flow; OEF: oxygen extraction fraction; CMRO2: cerebral metabolic rate
of oxygen; DWI: diffusion-weighted imaging; PWI: perfusion-weighted imaging; CBV: cerebral blood volume; CBF: cerebral blood
flow; MTT: mean transit time; TTP: time to peak; Tmax: time to maximum.

well as regional binding of radioligands to neurorecep-
tors.21 These parameters allow the identification of the
penumbra and its distinction from the core and from
oligemia for instance, the moderately hypoperfused
tissue that is functional and normally survives the
insult (Figure 2(a)). The physiologic profiles of
penumbral tissue after stroke have been characterized
using CBF, OEF, and CMRO2.22–24
The use of PET in the early 1980s allowed the iden-
tification of a hypoperfused region called ‘‘misery per-
fusion’’, with preserved CMRO2 and increased
OEF.25–27 Using quantitative voxel-based mapping of

International Journal of Stroke, 16(5)

Ermine et al.
these variables, this region was later validated as the
ischemic penumbra. The quantitative regional measure-
ments of CMRO2 and of CBF were found to accurately
distinguish viable from non-viable tissue. The penum-
bra threshold, which separates the penumbra from the
oligemia, was found to be around 20 ml/100 g/min28
and the threshold for core, which separates the penum-
bra from the core, has been found to sit around
8 ml/100 g/min, which were carried out generally > 3 h
from onset. However, lower thresholds characterize the
core at earlier timepoints, as it was in the animal stu-
dies. For instance, Heiss et al. showed that the volume
of tissue with CBF < 12 ml/100 g/min was still salvage-
able within 3 h from onset, and the volume of salvaged
penumbra correlated with neurological improvement
(shown earlier by Furlan et al.).29 Baron and his
group used a cohort of 30 patients with first ever
middle cerebral artery stroke and performed PET
within 18 h of onset and at one month, with co-regis-
tration of follow-up infarct from one-month CT scan.
They replicated in man the Astrup and Symon model
with identification of three distinct tissue types: the
core, the ischemic penumbra, and the oligemia.28,30,31
Using their paradigm and applying the classical thresh-
old of CMRO2 for irreversible damage set at 1.4 ml/
100 g/min, they determined the penumbra CBF thresh-
old in man and successfully mapped the penumbra.32
The identification of the penumbra using PET was
further refined to include three criteria: (1) have misery
perfusion, which is defined with a high OEF value, and
a partially preserved CMRO2; (2) an undetermined out-
come of the affected tissue, toward necrosis or survival;
and (3) clinical correlation, namely initial neurological
deficit proportional to volume of (core þ penumbra),
and neurological recovery at one month correlated with
the volume of surviving penumbra.33 These two clinical
correlations are of utmost importance, as they indicate
that (i) the volume of core expresses the already irrecu-
perable neurological deficit, regardless of any sort of
therapy including recanalization; and (ii) targeting the
penumbra with appropriate therapy, namely timely
recanalization, is the key to improve the outcome of
acute stroke patients. Baron’s group further identified
four PET patterns of increasing severity that character-
ized the ischemic brain: (1) an isolated increase in CBV,
maintaining the CBF; (2) an increase in OEF in
response to the reduction of CBF but with a maintained
CMRO2, which corresponds to the oligemia; (3) a
marked increase in OEF in regions with reduced CBF
and CMRO2, maintaining tissue metabolism, which
corresponds to the ischemic penumbra; and (4) very
low CBF and CMRO2 with variable OEF, which cor-
responds to the ischemic core.33 Furthermore, while the
presence of extensive penumbra was not associated
with functional outcome (reflecting the uncertain fate
501
of the penumbra), the pattern of extensive core invari-
ably predicts poor functional outcome, and the pattern
of extensive hyperperfusion invariably predicts excel-
lent spontaneous outcome.31 This key finding led the
authors to advocate the use of core/penumbra imaging
to triage stroke patients for individualized management
and treatment.31,34 Finally, PET studies documented
that substantial volumes of penumbra persisted up to
18 h32 and perhaps even beyond,35 suggesting that
delayed treatment targeting the penumbra, including
recanalization, could be considered in some patients
selected based on core/penumbra imaging.36
Additionally, PET can also map the binding of spe-
cific radioligands to neuroreceptors, which proved
useful in identifying the ischemic penumbra. For exam-
ple, 11C-Flumazenil (FMZ), which labels the benzodi-
azepine receptor, has been successfully used to
differentiate infarcted from penumbral tissue within
3 h of stroke onset.37–39 FMZ binding was reduced
to < 3.4 times the mean value of normal tissue for
tissue that did not benefit from reperfusion, thus allow-
ing prediction of irreversible tissue damage. Another
radiotracer, 18F-fluoromisonidazole (FMISO), which
irreversibly binds to hypoxic cells, was validated in a
rat model of MCAo for use in PET imaging to define
penumbral tissue.40,41 FMISO was able to identify hyp-
oxic tissue in the first 48 h following stroke onset.42,43
However, a recent pilot study has suggested that
FMISO is unable to differentiate the penumbra from
the (still hypoxic) core.44
PET imaging is a very powerful research tool for
mapping the penumbral region and the core, and the
original PET studies laid the platform for the advances
we see now in routine acute stroke imaging and treat-
ment. However, PET has limitations, including the
complexity of execution, relatively poor spatial reso-
lution, the cost, limited access, and the long time neces-
sary to produce the tracers with a cyclotron and
dedicated hot chemistry due to the short half-lives of
the positron emitters, and perform the measurements,
making the use of PET in acute clinical settings imprac-
tical and is rarely used clinically today.
Single photon emission computer tomography
Single photon emission computer tomography
(SPECT) uses gamma rays to detect radiotracers
injected, most commonly 99m-Technetium hexamethyl-
propyleneamineoxime (99mTc-HMPAO), and renders a
3D mapping of cerebral perfusion. Its advantages over
PET are the ease of production and transport of the
tracers, and its disadvantages the inaccurate quantifica-
tion and poorer spatial resolution due to scattering.
The ischemic penumbra was identified with SPECT
within 3–6 h of stroke insult, as the region with a signal
International Journal of Stroke, 16(5)
502
tracer of 40–70% that of the contralateral side.21,45 The
final infarct size was also accurately predicted by a
SPECT imaging within 6 h of symptoms.46–48
However, while the penumbra was identifiable using
SPECT technology, early studies found that SPECT
imaging of regional hypoperfusion failed to show any
advantages in prediction of stroke outcome over the
initial clinical evaluation.49,50 Nevertheless, one study
found that SPECT imaging within 3–6 h of stroke
onset using 99mTc-HMPAO was useful to identify
patients at high risk of symptomatic hemorrhagic trans-
formation before reperfusion treatment.51 Later studies
did show that 99mTc-HMPAO-SPECT was capable of
predicting clinical outcome, and the use of 99mTc-ECD,
another radiotracer, was useful in distinguishing tran-
sient ischemic attacks from stroke and patients with
massive infarction.52–54 However, it became clear that
using CBF mapping alone with SPECT was insufficient
to distinguish the penumbra from the core.
Accordingly, it was subsequently reported that the
combination of SPECT imaging for detection of hypo-
perfused volumes around the core and magnetic reson-
ance imaging (MRI) for detection of infarcted tissue
was able to predict infarct growth and clinical
outcome.55
SPECT is cheaper and more available than PET;
however, it is not used in routine clinical care due to
limitations, including the limited availability of the
radiotracers, the length of data acquisition, the difficul-
ties in data analysis, and the coarse spatial resolution.
Perfusion weighted and diffusion weighted MRI
MRI is widely used in acute stroke in clinical practice,
including to image the penumbra. This technique
applies powerful magnetic fields to identify molecular
signatures, notably from hydrogen. Various images can
be generated, including: (i) structural T1- and T2-
weighted; (ii) MR angiography of the intracranial ves-
sels; (iii) T2* imaging, which allows the detection of
recent or old hemorrhages; (iv) diffusion-weighted ima-
ging (DWI), which uses the movement of hydrogen in
water molecules to generate maps of the apparent dif-
fusion coefficient (ADC); and (v) perfusion-weighted
imaging (PWI), which is a bolus tracking technique
that uses the injection of a contrast agent (generally
gadolinium), to produce CBV, CBF, and other perfu-
sion maps.56 These acquisitions only take few minutes,
but are highly sensitive to patient motion, and MRI in
general requires extensive pre-screening for safety
making them less ideal in the acute setting.
The interest in MRI for acute stroke dates from the
development of DWI. The principles of DWI relate to
the reduction in ATPase activity that occurs almost
immediately after onset of severe ischemia, which
International Journal of Stroke, 16(5)
International Journal of Stroke 16(5)
then causes a redistribution of water from the extracel-
lular space to the intracellular space, this leads to
‘‘restricted diffusion’’ and reduction in the ADC,
which correlates with irreversibly damaged tissue. An
early DWI study in a rat model of MCAo used the
comparison of T2-weighted images and DWI for early
detection of ischemia, with the assumption that hyper-
intensity on DWI ¼ irreversible injury (now termed
ischemic core).57 A few years later, it was found that
the comparison of PWI and DWI was a better predictor
of ischemic penumbral tissue than conventional T1 and
T2 images.58 It was reported that PWI within 6 h of
stroke onset had a sensitivity of 95% and a specificity
of 100% in detecting the salvageable tissue and that
intermediate ADC values corresponded to penumbral
tissue.59,60 However, it become clear that the DWI
lesion did not always reflect only ischemic core. DWI
lesions have been shown to be reversible with early
reperfusion, although in a fraction of cases, this early
reversal might be temporary with the tissue ultimately
becoming infarcted.61–65 Early work with PWI sug-
gested that the ischemic penumbra was shown to cor-
respond to the region with a mean increase of 73% in
mean transit time (MTT) of the gadolinium bolus and
with a 29% increase in relative cerebral blood volume
(rCBV),66 although others suggested relative CBF was
more accurate.67
The ‘‘perfusion-diffusion mismatch’’ concept was
coined by Warach et al. and immediately became popu-
lar.58 This concept, derived from PET, dictates that sal-
vageable tissue corresponds to the difference between
the smaller diffusion lesion and the larger perfusion
deficit (Figure 2(b)).68–70 Consistent with previous
animal and human work summarized above, mismatch
incidence decreases with time, from 75% at 6 h to 44%
at 18 h post-stroke onset.71 While these techniques have
been extensively used to detect the ischemic penumbra,
it was later suggested that the PWI/DWI mismatch
region could be much larger than the true penumbra.72
In fact the rim of the perfusion lesion reflected the oli-
gemic tissue seen on PET (due to excellent collateral
blood supply) rather than the penumbra, which
makes the PWI/DWI mismatch less accurate than ori-
ginally described.73–75 Further efforts were made to
make the PWI lesion more specific for penumbra and
core by directly validating PWI against PET studies of
CBF,76,77 but also by improving perfusion algo-
rithms,78,79 as well as by applying stricter and validated
perfusion thresholds.80 Currently, a time to maximum
(Tmax) of > 6 s is most accurate in delineating the pen-
umbra from the core.41,81
More recently, some research groups have focused
on the use of susceptibility-weighted imaging (SWI),
which maps the differences in magnetic susceptibility
of deoxygenated blood, blood products, iron, and
Ermine et al.
calcium. Using this technique, the positive DWI/SWI
mismatch has also been shown to represent severely
hypoxic tissue, consistent with the ischemic penumbra,
although again, this is not widely used due to complex
and lengthy MRI sequences.82,83
Arterial spin labeling (ASL) is another perfusion
MRI technique that can quantify CBF without the
injection of a contrast agent. The accuracy of ASL at
detecting the infarcted regions was shown on a small
subset of patients with acute ischemic stroke, where the
hypoperfused regions obtained from ALS were com-
pared to those obtained from dynamic susceptibility
contrast on PWI and found to be consistent.84
Furthermore, a later study by Bivard et al. determined
the ALS–CBF threshold (set at 40%) that accurately
identified the penumbral tissue through ASL–DWI mis-
match, and was shown to be specific and sensitive in
comparison to PWI–DWI mismatch.85 The advantage
of using ASL for ischemic penumbra identification is
that it allows for rapid and non-invasive quantitative
measurement of CBF but spatial resolution is relatively
poor and there are problems with loss of signal if there
is long delay between labeling of the flowing blood and
arrival to ischemic tissue, due to large vessel occlusion.
While MRI techniques are powerful in detecting
acute ischemia (and hemorrhage), it is relatively time
consuming, not always easily accessed quickly from the
emergency room, and has several contraindications
(e.g. metallic inserts such as pacemakers or claustro-
phobia). Nonetheless, it is used for routine hyperacute
clinical imaging (prior to treatment decisions) in many
centers worldwide, particularly in Europe.
Computed tomography
There are different uses of CT in acute ischemic stroke,
including non-contrast computed tomography
(NCCT), CT angiography, and computed tomography
perfusion (CTP). NCCT can identify recent hemor-
rhages and may distinguish ischemic tissue (so called
early ischemic signs) as well as reveal non-stroke con-
ditions (e.g. brain tumors) and for this reason is widely
used in the acute stroke setting, but it cannot directly
identify the penumbra.86 Overall NCCT was shown to
have poor sensitivity to ischemia, as compared to
DWI.87 NCCT can display two types of ischemic
changes: parenchymal attenuation and focal swelling.
Although NCCT does not differentiate specifically
core and penumbra, a comparison with CTP has
shown that the parenchymal attenuation likely corres-
ponds to the core and the isolated focal swelling, likely
corresponds to the penumbra, as it is a region with
elevated CBV.86,88
The evolution of CT scanners to multidetector
allowed for imaging of the whole brain rapidly and the
503
development of CTP. CTP uses an iodinated contrast
agent and X-ray to measure CBV, CBF, MTT, and is
comparable to PWI. Thanks to the semiquantitative
CBV and CBF maps generated, CTP is very sensitive
in identifying the core; however, it is not as specific for
the differentiation of core and penumbra.89–91 Two CTP
parameters are sensitive to penumbral identification,
Tmax and delay time (DT). Indeed similar to PWI, a
Tmax > 6 s can estimate hypoperfused tissue with
CBF < 20 ml/100 g/min, i.e. the ischemic penumbra.92 A
DT of > 2 s was also shown to accurately represent the
penumbra, and when associated with CBF < 40% was
shown to represent the core, but subsequently DT > 3 s
and core < 30% has been shown to be more specific
(Figure 2(c)).8,9 A caveat is the time-dependence of the
core threshold, which was well known from animal stu-
dies7 but has been documented in man only
recently,10,11,93,94 pointing to the need to adjust the core
threshold to time elapsed since stroke onset if a more
accurate picture of the physiological situation is desired.
To objectively select patients who can benefit from
thrombolysis and fasten the process, automated measure-
ment of MTT, Tmax, and CBF were developed, through
a mathematical processing called deconvolution, with
several variations.95
Xenon-enhanced CT is another CT technique that
was used in the early days of CT imaging, and requires
the inhalation of xenon. The CBF is measured as posi-
tively proportional to the absorption of xenon by the
tissue. This measurement of CBF was proven accurate
in baboons and was further capable of delineating the
ischemic penumbra.96–98 However, this technique has a
huge limitation with the use of xenon, which induces
side effects, notably sedation.
MR and CT perfusion have similar accuracy in iden-
tifying key perfusion thresholds such as Tmax and DT,
although CBF and CBV are less comparable.99
However, MRI has the clear advantage to CT in that
it uses a different modality (DWI) to measure core,
whereas CT relies on perfusion measures such as CBF
or CBV. Nevertheless, due to the wide availability of
CT scanners, CT currently is the typical assessment of
acute stroke for decision-making in most centers
around the world.
Salvaging the ischemic penumbra:
Currently available treatments
The aim of ischemic stroke therapy is to reperfuse the
penumbra and salvage as much brain tissue as possible
to unsure a better clinical outcome. Currently, intraven-
ous injection of tissue plasminogen activator (tPA) is
the gold standard medical treatment for ischemic
stroke. Another highly successful reperfusion treatment
International Journal of Stroke, 16(5)
504
is mechanical thrombectomy for large vessel occlusion.
For both, earlier treatment increases the chance of
benefit (the ‘‘time is brain’’ mantra) but it has become
increasingly apparent that to focus on stroke onset time
to guide decisions is oversimplistic. Some patients have
little to gain from reperfusion treatment early after
stroke onset and others stand to gain many hours
later. This relates to size of core and penumbra, and,
is underpinned by the collateral supply to the
tissue.102,103 The comparison of standard clinical pre-
dictors (i.e. onset-to-treatment time) with CTP imaging
measurements, such as ischaemic core and penumbral
volumes, showed that imaging parameters (especially
infarct core volume) were better predictors of good or
bad clinical outcome following thrombolytic treatment
than time to treatment, and, that CTP improves the
identification of patients who can benefit from tPA
from those who are less likely to106,107.
Several clinical trials have shown the clinical benefits
of salvaging the penumbra in patients suffering from
stroke and further identified imaging parameters that
could predict the outcome of a given patient from
thrombolytic therapies.31,104,105 The comparison of
standard clinical predictors, such as onset-to-treatment
time, with CTP imaging measurements, such as ischemic
core and penumbral volumes, showed that imaging par-
ameters (especially infarct core volume) were better pre-
dictors of good or bad clinical outcome following
thrombolytic treatment than time to treatment, and,
that CTP improves the identification of patients who
benefit from tPA from those who are less likely to.106,107
Clinical trials have used the different imaging men-
tioned above to visualize the core and penumbra and to
extend the time windows for reperfusion treatment.
DEFUSE, an observational study involving 74 patients
and EPITHET, a randomized controlled trial, used
PWI/DWI mismatch to examine the time window for
tPA to 6 h. They suggested (although not definitively
due to too lenient perfusion thresholds) that tPA
improved clinical outcome and salvaged the penumbra
between 3 and 6 h of stroke onset.108,109 Desmoteplase,
a thrombolytic agent derived from bat saliva, was
investigated for its therapeutic potential following
ischemic stroke. However, mostly due to methodo-
logical problems with perfusion CT, the phase 3 trial
(DIAS-2) failed to show a benefit for desmoteplase in
the 3–9 h window.110 The aforementioned trials from
the early 2000s suffered from lack of standardization
of core and penumbral assessments. The development
of automated core and penumbral volumetric software
(including RAPID (iSchemaView, Menlo Park, CA,
USA)) contributed to the success of later trials using
PWI/DWI and/or CTP patient selection. These trials,
including DEFUSE 3, DAWN, EXTEND, EXTEND
IA, and SWIFT PRIME, are directly derived from the
International Journal of Stroke, 16(5)
International Journal of Stroke 16(5)
historical core/penumbra concepts, with perfusion CT
(and some MR) being the dominant selection modality
in these ground-breaking trials. These trials have
proven that perfusion imaging/core mismatch (or a clin-
ical-core mismatch variant seen in DAWN) is efficient at
selecting patient more likely to respond to reperfusion
therapy.111–116 This is particularly so in the late time
window trials (DAWN, DEFUSE 3, and EXTEND)
where the original concept of the ischemic penumbra
to select patients for therapy at late timepoints has
been definitively proven. In the earlier time window stu-
dies (EXTEND IA, SWIFT PRIME), there is still a view
that the use of perfusion imaging to select a more treat-
ment responsive subgroup of patients (which clearly
occurred in these trials) may lead to a proportion of
patients who still may benefit being excluded.114,115
Compared to most of the early window thrombec-
tomy RCTs, the DEFUSE 3 study showed a larger abso-
lute benefit of thrombectomy beyond 6 h (up to 16 h),
which might be due to their better patient selection
(e.g. the presence of penumbra).112 However, it should
also be noted that in this trial, the control group had
quite low rates of good outcome. In a similar vein, the
DAWN trial enrolled patients with large vessel occlusion
who had a mismatch between infarct size and clinical
deficit (an alternative way to look at the penumbra)
and showed a very large absolute benefit of thrombec-
tomy treatment in the 6–24 h window.111
Thrombolysis trials have also used perfusion ima-
ging to accurately identify the penumbra and extend
the treatment time window. The EXTEND trial com-
pared the clinical outcomes of patients who received
alteplase or placebo between 4.5 and 9 h of symptom
onset or with wake-up stroke (< 9 h from the mid-point
in time from going to bed and awakening with symp-
toms). EXTEND predominantly used CTP mismatch
selection (< 20% selected with MRI) and showed a
significant benefit in mismatch patients treated with
alteplase.113 A subsequent pooled analysis of the alte-
plase trials using the perfusion imaging core/penumbra
selection approach (EXTEND, ECASS IV, and
EPITHET) showed that the treatment benefit of alte-
plase compared to placebo was seen exclusively in the
patients who fulfilled target mismatch criteria by auto-
mated volumetric analysis.109,113,117 Notably,
EPITHET and ECASS IV did not use an automated
volumetric approach of core and penumbra. Other
trials have used the core/penumbra selection approach
with CTP to test another thrombolytic, namely tenec-
teplase. Indeed, the first study to use the ‘‘dual target’’
selection approach (large vessel occlusion þ core/pen-
umbra mismatch) was in a phase 2B trial in 2012. This
study showed greater reperfusion and improved clinical
outcomes compared to alteplase.118 A subsequent study
using a similar dual target selection approach
Ermine et al.
(EXTEND IA TNK part 1) showed that tenecteplase
lead to superior early recanalization rates and better
clinical outcomes than did alteplase.116 Notably, other
studies of tenecteplase but not using the dual target
approach (vessel occlusion þ penumbra/core mismatch)
have been less successful in showing superiority of
tenecteplase to alteplase.119,120
The bottom-line from these revolutionary penum-
bral imaging selection studies, is while patients should
be treated as quickly as possible, patients with a favor-
able imaging profile (penumbra/core mismatch) have
good collaterals and slow infarct growth. Such patients
can achieve excellent outcomes from reperfusion ther-
apy up to 24 h after stroke onset.
Conclusion
The ischemic penumbra has been in the center of ische-
mic stroke research for the last 40 years. Acute imaging
of the penumbra is a critical step toward selection of
patients that can best benefit from penumbral-salvaging
reperfusion therapies. While the imaging techniques
have evolved through the years, there is still no imaging
gold standard for core or penumbra. This is because
they are in fact imaging surrogates for the cellular pro-
cesses identified in the original experimental studies.
Currently the choice between CT and MRI is made
based on availability, feasibility, and time pressure.
Routine penumbral imaging is widely used around the
world, although there is still no wide consensus about
its necessity in the early time window. Nonetheless,
core/penumbral imaging has been crucial to extending
the time window for reperfusion therapy. It has become
clear, with translation of the experimental concept of
the penumbra into its routine imaging in clinical prac-
tice, that ‘‘tissue is at least as important as time.’’
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Charlotte M Ermine https://orcid.org/0000-0003-4726-
1120
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