Penumbra, the basis of neuroimaging in acute stroke treatment: Current evidence

Journal of the Neurological Sciences 288 (2010) 13–24

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Review

Penumbra, the basis of neuroimaging in acute stroke treatment: Current evidence

Gyanendra Kumar a,⁎, Munish Kumar Goyal a, Pradeep Kumar Sahota a, Rajan Jain b

a Department of Neurology, University of Missouri-Healthcare Columbia, Columbia, CE 507 Five Hospital Drive, Columbia, Missouri, 65212, USAb Department of Radiology, Division of Neuroradiology, Henry Ford Hospital, Detroit, Michigan, USA

⁎ Corresponding author. Tel.: +1 573 882 4141; fax:E-mail address: [email protected] (G. K

0022-510X/$ – see front matter © 2009 Elsevier B.V. Adoi:10.1016/j.jns.2009.09.027

a b s t r a c t
a r t i c l e i n f o
Article history:Received 12 June 2009Received in revised form 6 August 2009Accepted 23 September 2009Available online 29 October 2009

Keywords:Acute strokeThrombolysisPenumbraNeuroimaging

In modern medicine brain imaging is an essential prerequisite not only to acute stroke triage but also todetermining the specific therapy indicated. This article reviews the need for imaging the brain in acutestroke, penumbral pathophysiology, penumbral imaging techniques, as well as current status of variousimaging modalities that are being employed to select patients for specific therapeutic approaches.

+1 573 884 4249.umar).

ll rights reserved.

© 2009 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141.1. Need for imaging the brain in acute stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2. The penumbra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142.2. Location of penumbra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2.2.1. Gray matter vs. white matter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142.2.2. Anterior vs. posterior circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2.3. Factors that determine the fate of penumbra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142.3.1. Time is brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152.3.2. Hyperglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152.3.3. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162.3.4. Hematocrit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162.3.5. Normobaric oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

3. Role of CT in acute stroke. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163.1. Non-contrast CT (NCCT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163.2. CT angiography (CTA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163.3. Perfusion CT (PCT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

4. Role of MRI in acute stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174.1. Diffusion-weighted imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

4.1.1. False-negative and false-positive DWI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174.1.2. Role of ADC in predicting clinical outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

4.2. Gradient echo (GRE) sequences and susceptibility weighted imaging (SWI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204.3. Magnetic resonance diffusion–perfusion imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5. Candidate selection: CT vs. MR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206. Extending the window of thrombolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

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14 G. Kumar et al. / Journal of the Neurological Sciences 288 (2010) 13–24

1. Introduction

1.1. Need for imaging the brain in acute stroke

Imaging of brain is essential prior to initiation of any specifictherapy to treat acute stroke [1]. The premise of any form of treatmentin acute stroke rests on 1) the existence of the ischemic penumbra, i.e.,the region of hypoperfused — but not yet infarcted — tissue at risk toproceed to infarction, and, 2) the concept that imaging can identifythese patients.

When a cerebral artery is occluded, a core of brain tissue diesrapidly. Surrounding this infarct core is an area of brain that ishypoperfused but not dead, due to collateral blood flow. This area iscalled the ischemic penumbra [2–4].

The fate of the penumbra depends upon reperfusion of theischemic brain [5]. In the case of persistent arterial occlusion, theinfarct core will grow and progressively replace the penumbra. In thecase of early recanalization, either spontaneous or resulting fromthrombolysis, the penumbra may be salvaged from infarction [6].

Imaging in patients with acute stroke should be targeted towardassessment of the four Ps — parenchyma, pipes, perfusion, andpenumbra. This approach enables the detection of intracranialhemorrhage, differentiation of infarcted tissue from salvageabletissue, identification of intravascular thrombi, selection of theappropriate therapy, and prediction of the clinical outcome [7].

Goals of imaging in acute stroke [Rowley][7].

Assessment ofparenchyma

To rule out hemorrhage and detect early signs of acute stroke

Assessment ofpipes

To evaluate extracranial and intracranial circulations for evidenceof intravascular thrombus

Assessment ofperfusion

For cerebral blood volume, cerebral blood flow, and mean transittime

Assessment ofpenumbra

To evaluate tissue at risk of infarcting if ischemia continueswithout recanalization of arterial occlusion

This review guides the reader, through a structured discussion onpenumbra that forms the basis of modern neuroimaging techniques inacute stroke management, and the most recent contributions inneuroimaging in the field of acute stroke, to a better understanding ofthe subject matter.

2. The penumbra

2.1. Definition

Deriving its name from the halo surrounding a total solar eclipse,the term ‘ischemic penumbra’ emerged 28 years ago from basicscience stroke research [4].

Neurophysiologically, it is the tissue that exists between perfusionthresholds of electrical failure and ion-pump failure [4] A PET-based(positron emission tomography) hemodynamic approach character-ized it as tissue that is in a state of severe ‘misery perfusion’, with lowcerebral blood flow (CBF), high oxygen extraction fraction (OEF), andrelatively maintained cerebral metabolic rate of oxygen (CMRO2) [8].

Reference operational criteria have been formulated for identify-ing the ischemic penumbra [8]. These include the following: 1)hypoperfused tissue with physiologic characteristics of cellulardysfunction but not cell death; 2) the tissue contributes to the acuteclinical deficit; 3) the tissue has an undetermined fate; and 4) salvageof this tissue correlates with clinical recovery.

Several techniques have emergedover the years to imagepenumbra.While somehavebecomeavailable to the clinician, being integrated intoeveryday clinical practice, many are still only available to the strokeresearcher (Table 1).

2.2. Location of penumbra

2.2.1. Gray matter vs. white matterMost research on drug development for neuroprotection in acute

stroke was targeted to protect gray matter rather than white matter.This was suggested as a reason for failure of clinical trials designed todemonstrate the benefit of salvaging the penumbra [17].

A PET study using the tracer F-FMISO (F-fluoromisonidazole) hasshown that salvageable viable hypoxic tissue exists in both gray andwhite matter at a median of 16.5 h after onset of stroke. Their studysuggested that white matter is at least as resistant to ischemia as graymatter and may show slower evolution to infarction [18]. MRIdiffusion–perfusion mismatch was used to demonstrate that salvage-able penumbra existed in both compartments [19]. More mismatchexisted in white matter than in gray matter at a median of 3.7 h fromonset, though eventually the proportion of spontaneously salvagedtissue was similar for both [19].

A subsequent study using voxel based methods to study CBFseparately in gray and white matter not only endorsed the existenceof penumbra in white matter but also demonstrated a significantdifference of CBF in the penumbral tissue between the twocompartments, especially in areas that eventually infarcted [20]. Thesame authors later quantitatively demonstrated that gray matter wasat risk of infarction at higher CBF values and at shorter mean transittime (MTT) delays than white matter (20 mL/100 g/min vs. 12.3 mL/100 g/min; and 6.8 s vs. 7.1 s, respectively) [21].

These differences between gray and white matter responses toischemia draw attention to the need for devising separate neuropro-tective strategies for each.

2.2.2. Anterior vs. posterior circulationThe existence of penumbral tissue in acute ischemia affecting the

anterior circulation has been demonstrated across the board, in bothclinical and animal studies [22,23]. The reported benefit of IV rt-PA invertebrobasilar stroke up to 7 h after onset [24] was explainedrecently by a multimodal MR study that demonstrated MR DWI–PWImismatch in 5 patients with acute basilar artery occlusion [25]. Thissuggests a potential significant role of penumbral imaging in posteriorcirculation strokes. Because of limited spatial resolution and artifactsin the posterior fossa, posterior circulation poses a challenge inpenumbral imaging [22]. In the near future, as whole brain coveragebecomes possible with the latest CTP scanners, the risk of missingperfusion deficits in the posterior circulation will be minimized [22].

2.3. Factors that determine the fate of penumbra

Spontaneous or therapeutic recanalization of the occluded vesselmay result in salvage of the penumbra [5]. The MERCI and PENUMBRAdevices received FDA clearance based on their demonstrated ability torecanalize the primary occlusive arterial lesion without considering thestatus of arterial branches distal to the treated vessel [26]. However,recanalization of the primary occlusive arterial lesion does notnecessarily imply capillary reperfusion [27]. Also, lack of recanalizationdoes not necessarily reflect absence of reperfusion [28]. Among 57patients who did not achieve recanalization on the DIAS trial, 24.6%achieved favorable clinical outcome after 90 days [29], suggesting thatreperfusion can occur in the absence of recanalization. One possibleexplanation is retrograde collateralflow. Adequate collateral circulationmay contribute to maintain tissue viability in the absence of completerecanalization. But this is still a hypothesis at best that is yet to bevalidated. To systematically evaluate the complex relationship ofrecanalization, reperfusion, and collateral flow with good and badoutcomes, theneed forprospective studies has beenacknowledged [30].

Several other factors may lead to irreversible inclusion of thepenumbra into the infarct core. Many of these factors that influencethis indefinite outcome of penumbra are a subject of research. The role

Table 1Penumbral imaging techniques.

Whole brain CTperfusion [9]

Dynamic CTperfusion [10]

Xenon CT [11] PET multitracer15O2 [12]

PET 11C-FMZ(+H215O) [13]

18F-FMISO[14]

SPECT 99mTc-HMPAO[12]

MRI (DWI/PWI)[15,16]

Parametersassessed

CBV CBF, CBV, MTT,TTP

CBF CBF, CBV, MTT,CMRO2, OEF

Tracer binding Tracer uptake CBF CBF, CBV, MTT, TTP,ADC

Ischemicpenumbradefined as

Not defined Relative CBFb34%a andCBVN2.5 mL/100 g

CBF 7–20 ml/100 g/min

CBF 7–22ml/100 g/min/andCMRO2N39 mmol/100 g/min andOEFN70%

RelativebindingratioN3.4b andCBFb14 ml/100 g/min

Uptake ratioN1.3a

40–70% reduction oftracer signala

Relativea TTP (orMTT) delayN4 s,relativea CBFb37%,and relativea ADCabove 50%

Benefits 1. Hypoattenuationon CBV mapsrepresents theischemic core

1. Inexpensive 1. Quantitative 1. Quantitativelyaccurateassessment of thepenumbra

1. Based onphysiologicalneuronalintegrity

1. Produces adirect positiveimage ofviable hypoxictissue

1. Can also demonstratecollateral flow andremote phenomenasuch as diaschisis

1. No radiationexposure

2. Provides wholebrain coverage

2. Widelyavailable

2. Definespenumbra

2. Validated 2. Hypoperfusionmeasured with SPECTcan add valuableprognostic informationafter acute stroke.

2. Fast

3. Fast

3. Fast

3. Cheaper than PET

3. Increasingavailability

4. Inexpensive

4. High degreeof sensitivityand specificityfor detectingischemia

4. Greater availabilitythan PET

4. Directvisualization ofischemic core

5. Widely available5. Definespenumbra

5. Penumbra can bedefined6. High degree of

sensitivity andspecificity fordetecting ischemia

Pitfalls 1. Does not providemeasures of CBFand MTT

1. Not useful forposterior fossa

1. Technicallycomplex

1. Expensive 1. Expensive 1. Expensive 1. Semi-quantitative 1. Motion artifacts

2. Penumbracannot be defined

2. No directvisualization ofischemic core

2. Not validated2. Not widelyavailable

2. Not widelyavailable

2. Not widelyavailable

2. Lack of standardizedprotocols

2. Questions onvalidity of mismatch

3. Radiationexposure

3. Limited to 2to 4 brain slices

3. Pharmacologiceffects of Xe




3. Radiation exposure

4. Iodine contrast 4. Iodinecontrast

4. Arterial access 4. Arterialaccess

4. Arterialaccess

5. No informationabout Penumbra 5. Radiation

exposure

5. Time consuming5. Timeconsuming

5. Timeconsuming

6. Only suitablefor gray matter

6. Onlysuitable forgray matter7. Requires

additionalPerfusionimaging

7. RequiresadditionalPerfusionimaging8. Notpractical9. Unvalidated

ADC—apparent diffusion coefficient; CBF—cerebral blood flow; CBV—cerebral blood volume; CMRO2—cerebral metabolic rate of oxygen; DWI—diffusion-weighted imaging; FMISO—fluoromisonidazole; FMZ—flumazenil; HMPAO—hexamethylpropyleneamine oxime; MTT—mean transit time; OEF—oxygen extraction fraction; PET—positron emissiontomography; PWI—perfusion-weighted imaging; SPECT—single photon emission computed tomography; TTP—time to peak; and Xe—xenon.

a Relative to mean contralateral hemisphere value.b Relative to contralateral healthy white matter.

15G. Kumar et al. / Journal of the Neurological Sciences 288 (2010) 13–24

of some of these determinants is being gradually elucidated in recentstudies.

2.3.1. Time is brainThe extent of the ischemic penumbra is time-dependent. It decreases

over time by gradual recruitment into the core, and represents a keytarget for therapeutic intervention, albeitwith a progressively shrinkingtemporal window of opportunity — hence the ‘time is brain’ rule [31].This course of events varies from patient to patient, but up to one-thirdof patients still exhibit large volumes of penumbra 18 h after strokeonset [32].

Thus, penumbra is also patient-dependent. From patient to patient,survival of the penumbra can vary from less than 3 h to well beyond48 h. Duration of penumbra varies from person to person dependingupon a variety of factors such as location of vessel occlusion, efficacy ofcollateral circulation, and the location of ischemic lesion (gray vs. whitematter paradigm and anterior vs. posterior circulation). Ninety to 100%of patients with supratentorial arterial occlusion show ischemicpenumbra in the first 3 h of a stroke, but, interestingly enough, 75–80% of patients still have penumbral tissue at 6 h after stroke onset[6,33,34]. The relatively negative results to date of thrombolysis trialsbetween 3 and 6 h, in spite of the high percentage of patients withpenumbra within this time window, may relate to selection method-

ology as these trialsdidnot consistentlyusepenumbral imaging to selectpatients for therapy [34–36]. Thismayalso explain thebetter outcome inthe group of MRI-selected tPA patients in the pooled data of ATLANTIS,ECASS, and NINDS tPA trials [37]. The varying duration of ischemicpenumbra means that the window for therapeutic intervention isdifferent for each patient andmay be longer than the currently accepted3-hour window for the administration of reperfusion therapies [31].However, for this to occur with improved outcomes, a rapid andaccessible neuroimaging technique able to assess the ischemic penum-bra is required [38]. A recent study demonstrated, using multimodaltranscranial Doppler (TCD)/MRI selection criteria, that tPA treatmentcan be safely and effectively extended to the 3- to 6-hour window [39].

2.3.2. HyperglycemiaA prospective study of 63 patients using MR diffusion-weighted

imaging (DWI)-perfusion weighted imaging (PWI) [40] demonstratedthat acute hyperglycemia independently correlates to reduced tissuesurvival, and higher blood glucose levels correlate with larger finalinfarct sizes and worse functional outcomes. The authors alsodemonstrated that higher acute blood glucose in patients withperfusion–diffusion mismatch was associated with greater lactateproduction, which, in turn, was independently associated with thereduced salvage of the penumbral tissue. In a similar study [41], high


acute blood glucose levels (≥7 mmol/L) were strongly associated withinfarct expansion on serial MRI and with worsening of functionaloutcomes. In 139 tPA-treated patients, an acute hyperglycemic state(N158 mg/dL) was found to be an independent predictor of failure ofrecanalization, delaying reperfusion of ischemic penumbra [42].

2.3.3. AgeAn analysis of 60 patients [43] demonstrated an age-dependent

evolution of acute DWI–PWI mismatch into infarction and calculatedthat a loss of about 0.65% of the mismatched tissue occurs per year ofage. These findings suggest that age may be a potential determinant ofpenumbral salvage. However, the mechanism of this deleterious effectof age is unclear andmay be due to impaired cerebrovascular responses,altered neuronal and glial function, or both.

2.3.4. HematocritA study by Allport et al. [44] on 64 acute stroke patients found that it

was inversely correlated with reperfusion, and that it was significantlyassociated with infarct expansion irrespective of thrombolytic therapy.Moreover, there was a trend toward reduced penumbral salvage withelevated hematocrit. This may be attributable to increase in bloodviscosity and impaired capillaryflow resulting from the rise in hematocrit.

2.3.5. Normobaric oxygenNormobaric oxygen therapy has been recently identified as a factor

positively influencing the fate of penumbra in a recent pilot study [45]that randomized patients with acute stroke (b12 h) and diffusion–perfusionmismatch onMRI to high flowoxygen therapy for 8 h or roomair. Significantly higher penumbral salvagewas observed at 4 h in thoserandomized to oxygen. Moreover, oxygen-treated patients improvedclinically during therapy and at 24 h, and smaller MR diffusion lesionswere seen in this group than in control subjects at 4 h. Currentguidelines do not recommend routine use of oxygen in acute strokepatients [1]. Authors [45] propose that oxygen therapy may promoteselective shunting of blood to ischemic tissue consistentwith a previousobservation that oxygen causes a vasodilatory response instead ofvasoconstriction [46]. Authors acknowledged the need for larger studiesto investigate the usefulness of this modality both in the pre-hospitalsetting and asanadjunct to tPA, and todetermine the optimumdurationof therapy [45].

3. Role of CT in acute stroke

The three key techniques of computed tomography scanning, non-contrast CT, CT angiography, and CT perfusion are discussed individually.

3.1. Non-contrast CT (NCCT)

NCCT is fast, widely and easily available, and does not requireintravenous contrast administration. It not only helps rule outintracranial hemorrhage (a contraindication to thrombolysis), but alsohelps detect acute ischemia to a certain extent. Its sensitivity is limited inthis regard, however, compared to DWI. The following signs can helpidentify acute ischemia: hyperdense MCA sign, insular ribbon sign, andobscuration of lentiform nucleus. The hyperdense appearance of anacute thrombus in an intracranial vessel is a highly specific but poorlysensitive sign (Fig. 1A andB) [47].MCAcalcification andhighhematocritlevel may result in a bilateral hyperattenuation [48–51].

Acute ischemia of the lenticulostriate territory may result inobscuration of the lentiform nucleus, which appears hypoattenuateddue to cytotoxic edema (Fig. 1C). This featuremay be seen on CT imageswithin 2 h after the onset of a stroke [52].

Cytotoxic edema of the insular cortex also causes local hypoattenua-tion,which results in loss of definition of the gray–white interface in thelateral margins of the insula— “loss of the insular ribbon” (Fig. 1D) [53].

Detection of early acute ischemic stroke on unenhanced CT imagesmay be improved by using variable window width and center levelsettings to accentuate the contrast between normal and edematoustissue [54].

Because of a potential increase in the risk of hemorrhageinvolvement of more than one-third of the MCA territory anunenhanced CT was a criterion for the exclusion of patients fromthrombolytic therapy in the ECASS trial [36]. This ‘one-third rule’ hasshownpoor interobserver correlation, primarily because of variability inthe level of axial CT images. [55–58].

The Alberta Stroke Program Early CT Score (ASPECTS) was proposedin 2001 as a means of quantitatively assessing acute ischemia on CTimages by using a 10-point topographic scoring system [59]. Accordingto this system, the MCA territory is divided into 10 regions, each ofwhich accounts for one point in the total score (Fig. 2). The normalMCAterritory is assigned a total score of 10. For each area involved in strokeon the unenhanced CT images, one point is deducted from that score.Hence, a score of 0 translates into a finding of diffuse ischemicinvolvement throughout the MCA territory. It was demonstrated thatthe baselineASPECTS correlated inverselywith theNational Institutes ofHealth Stroke Score (NIHSS), and, as the ASPECTS decreased, theprobability of dependence, death, and symptomatic hemorrhageincreased. In addition, clinical agreement with the ASPECTS wassuperior to that with the one-third MCA rule. The authors concludedthat the ASPECTS system is a systematic, robust, and practical methodthat is applicable to axial images acquired at different levels [59].

3.2. CT angiography (CTA)

CT angiography typically involves a volumetric helical acquisitionthat extends from the aortic arch to the circle ofWillis. The examinationis performed by using a time-optimized bolus of contrast material forvessel enhancement [60].

CT angiographic demonstration of thrombotic occlusion (in intra-cranial and extracranial vasculature) can guide appropriate therapy inthe form of intraarterial thrombolysis or mechanical thrombusextraction. Intraarterial thrombolysis may be more efficacious thanintravenous therapy in patients with acute stroke and a significantthrombus burden [61,62].

Furthermore, the identification of carotid artery disease andvisualization of the aortic arch may provide clues to the cause of thestroke and guide the interventional neurologist.

There is good correlation between CT angiographic arterial occlusionand NIHSS [63,64].

3.3. Perfusion CT (PCT)

This techniqueuses CT scan to track thefirst pass of an intravenouslyadministered contrast bolus [65]. Two types of perfusion techniques areavailable. Whole brain perfusion CT provides a map of cerebral bloodvolume (CBV) and the region of hypoattenuation on these CBV maps isthought to represent the ischemic core. Although it provides wholebrain coverage, it does not measure CBF or MTT. Dynamic perfusion CT,on the other hand, has the potential to generate absolute measures ofCBF, CBV, and MTT. Since this technique involves acquisition ofsequential CT slices to track intravenously injected contrast and iscurrently restricted to two to four brain slices, thus limiting thesensitivity to stroke not caused by proximalmajor artery occlusion [65].

Recent studies on PCT in acute stroke demonstrated that tissuewith CBVb2 ml/100 g represents the core; while a relative MTT above145% of the normal hemisphere best outlines all at-risk tissue [66].The penumbra can thus be estimated as the tissue existing betweenthose two thresholds (Fig. 3). Using this methodology, PCT para-meters correlate very well with MR DWI–PWI and are a goodpredictor of the final infarct volume and clinical recovery [10,67–69].PCT is also potentially useful in decision making when the time of

Fig. 1. (A) Hyperdense Left MCA (arrow); (B) Left internal carotid arteriogram AP view, of the same patient as in (A), showing filling defect thrombus; (C) Obscuration of leftlentiform nucleus outline (arrow) in acute left MCA infarct; and (D) Loss of insular ribbon on the right (arrow). Hypodensity and slight swelling of right insula.


onset is unknown, such as with awakening stroke [70]. In combinationwith CT angiography, PCT has comparable utility with that of MR inselecting patients for thrombolysis [67].

Moreover, a combined NCCT–PCT–CTA protocol (multimodal CT) hasbeen shown tobe fast, reliable, andeffective in improving strokedetectionin the emergency setting [48,71,72], and is now used in some strokecenters to assess potentially thrombolysis-eligible patients. Multi-centercollaborative studies are needed to clarify and validate the role of thesepotentially powerful modalities.

4. Role of MRI in acute stroke

It is not simply important to see whether pathology has occurredat the level of the brain, but also to localize the level of the vascularocclusion that is causing it, be it at the level of the circle of Willis, thecervical carotids or even the aortic arch, since evidence also points to

Fig. 2. ASPECTS.

the advantage of treating the clot itself more directly (mechanicalthrombus extraction). All these advances have thus prompted theneed for improved imaging at all the levels of the brain andneurovascular tree. This benefit is offered by MRI.

4.1. Diffusion-weighted imaging

While CT scan is oblivious to the cytotoxic edema that results inacute stroke from Na+/K+ pump failure, diffusion-weighted (DWI)MRI can not only image the consequent reduction of Brownian motionin extracellular space, but also quantify it in form of the apparentdiffusion coefficient (ADC) [73]. The impaired water motion causes anincreased (bright) signal on DWI sequences. The decrease in diffusioncan be quantitatively measured on the apparent diffusion coefficient(ADC) maps, with darker areas representing decreased diffusion.

CT has been proven to be less sensitive for early brain infarctioncompared to DWI [74].

DWI allows demonstration of acute ischemic changes within minutesafter vessel occlusion with a reduction of the ADC, whereas conventionalMR images take at least 6–8 h after stroke onset to become abnormal [75].

When imaging patients within 6 h, Gonzalez et al. found 100%sensitivity and 86% specificity for diffusion-weighted MR imaging [76].Further expanding this study, they found that, in the diagnosis of strokein the early period (b12 h after presentation), DWI is superior toconventional MR imaging and CT [77]. DWI has been shown to bepositive as early as 39 min after the onset of symptoms [78].

4.1.1. False-negative and false-positive DWIIn clinically defined TIA patients diffusionMRI demonstrates ischemic

abnormalities in almost 50% of the patients [79]. Thesemicroinfarcts, “thefoot prints of ischemia”, are too small to be symptomatic [80].

Lesions in the brainstem or lacunes are most frequently missed onDWI. Theymay be too small to be imaged. Sometimes they are seen aspunctuate lesions on follow-up images or presumed to be present onthe basis of persistent clinical deficits [81,82]. Some patients with

Fig. 3. Non-contrast head CT shows sulcal effacement in the right MCA territory (A). (B) CTP, CBF map showing markedly decreased blood flow in the infarct where as slightlydecreased blood flow in the adjacent ischemic penumbra. (C) CTP, CBV map showing markedly decreased blood volume in the infarct where as increased blood volume in theadjacent ischemic penumbra. (D) CTP, MTT map showing increased MTT in the right MCA territory as compared to the left. (E) DWI showing diffusion restricted infarct in the rightMCA region.


symptoms from large expanses of ischemic brain infarction still havenormal DWI but have abnormal PWI lesions. These patients haveregions with prolonged regional mean transit time (rMTT) anddecreased regional cerebral blood flow (rCBF) but normal regionalcerebral blood volume (rCBV). They are examples of “penumbrawithout core” (Fig. 4) [82].

A few pathologies exist that closely resemble a stroke on DWI,namely infectious diseases and epilepsy. Since DWI is very sensitive toneurophysiologic changes occurring in the cortex, in status epilepticusDWI hyperintensities are accompanied by hyperperfusion and nothypoperfusion as in stroke [83]. This supports the validity of ADCmeasurements in acute stroke. ADC can show the depth and extent ofthe ischemia [84]. This is useful since DWI lesions diminish and ADCvalues revert partially or completely to normal following therapy [84–89]. ADC normalization seems to be time-dependent. It occurspredominantly in the basal ganglia andwhitematter after thrombolysisin distal vascular occlusions, especially MCA branches [90]. Without

therapy, ADC returns to normal or supranormal levels within 7 to10 days from ischemia onset [91].

4.1.2. Role of ADC in predicting clinical outcomeStudies have demonstrated that ADC can also help predict outcome,

i.e., the lower theADC, theworse theoutcome [90,92,93]. In a studyof 68patients who underwent MRI within 6 h of onset of acute ischemicstroke, the rate of complete reperfusion after 24 h was significantlyhigher in patients with ADC normalization compared with patientswithout normalization. All of them had at least partial tissue perfusionon the first day after stroke. Patients with ADC normalization showed atendency toward better clinical outcome. Brainswithmore severe initialdecreases in ADCwere less likely to normalize [90].While the benefit ofdiffusion MRI in providing prognostic information has been repeatedlydemonstrated in anterior circulation ischemia, several small case serieshave shown that lesion volume on diffusion MRI correlates poorly withclinical outcome in posterior circulation as small strategic brainstem

Fig. 4. ‘Penumbra without core’. (A) CTP, CBF map showing decreased blood flow in the right MCA territory compared to the left side. (B) CTP, CBV map showing increased blood volume in the right MCA territory compared to the left side. (C)CTP, MTTmap showing increasedMTT in the right MCA territory compared to left side, suggesting slow flow and ischemia but not infarction yet. (D) DWI, no infarct seen. (E)MR FLAIR, right MCA branches show bright signal with subtle sulcaleffacement. (F) Follow up CT showing no infarction. (G) Right ICA angiogram, oblique view, parenchymal phase showing wedge shaped area of hypoperfusion. 19

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infarcts can lead to devastating outcomes whereas large cerebellarinfarcts may only cause mild symptoms.

4.2. Gradient echo (GRE) sequences and susceptibility weighted imaging(SWI)

Both these sequences detect the paramagnetic effects of deoxyhe-moglobin and methemoglobin, leading to a loss of signal in regions ofboth acute and chronic blood. The characteristic appearance ofhyperacute hemorrhage on these sequences is a hyperintense rimsurrounding a hypointense periphery which in turn encloses anisointense or mixed signal intensity core [94].

Two prospective studies have demonstrated that MRI is as accurateas CT in detecting hyperacute intraparenchymal hemorrhage in patientspresenting with stroke symptoms within 6 h of onset [95,96]. In somecases, GRE/SWI may identify regions of hemorrhagic transformation ofan ischemic infarct not seen on CT (Fig. 5), suggesting that MRI can beemployed as the sole imagingmodality toevaluate acute strokepatients,including candidates for thrombolysis. However, in patients presentingwith symptoms suggestive of subarachnoid hemorrhage, a CT shouldalways be performed as Susceptibility effects from skull base maymakeit difficult for GRE/SWI to detect subarachnoid hemorrhage [97,98].

These sequences also have the ability to detect clinically silent priormicrobleedsnot visualized onCT.MRI evidence ofmicrobleeds is seen in38% to 66% of patients with primary intracerebral hemorrhages, in 21%to 26% of patientswith ischemic stroke, and in 5% to 6% of asymptomaticor healthy elderly individuals [99]. There is growing evidence thatmicrobleeds visualized on GRE sequences portend an increased risk ofhemorrhagic transformation following antiplatelet and thrombolytictherapy [100]. However, the role of microbleeds in thrombolyticdecision making remains uncertain.

SWImaximizes the sensitivity to susceptibility effects by combininga long-TE high-resolution fully flow-compensated 3D GRE sequencewith filtered phase information in each voxel. As a result, SWI has anexquisite sensitivity to the venous vasculature, blood products, andvascularmalformations [101]. SWI has been shown to bemore sensitivethan GRE for detection of acute hemorrhage [102].

4.3. Magnetic resonance diffusion–perfusion imaging

The more commonly used dynamic susceptibility weighted perfu-sion imaging measures magnetic field changes induced by passage ofparamagnetic contrast, like gadolinium, in brain tissue, but with lesseraccuracy than PCT, particularly for CBF. The less available, arterial spinlabeling PWI is a newer technique that avoids the use of a contrast agentand involves tracking the motion of magnetically labeled arterial blood

Fig. 5. (A) Hemorrhagic conversion of right PCA infarct, GRE image showing petechialhemorrhages along gyri (arrow). (B) Hemorrhagic conversion right PCA infarct, T2weighted image showing hyperintense right PCA infarct.

entering the skull [103].MRperfusionweighted imaging is an importanttechnological advancement in stroke imaging which, combined withDWI, provides highly relevant homodynamic information used fortherapeutic decision making in acute stroke [104]. Combined DWI/PWIcan also be a means of monitoring novel neuroprotective approaches.

Schaefer et al. [81] studied 134 acute stroke patients with DWI andPWI within 12.3 h of ischemic onset. The sensitivities of CBV, CBF, andMTT for detection of perfusion abnormalities were 74%, 84%, and 84%respectively. Specificities of CBV, CBF, and MTT were 100%, 96%, and96%, respectively. These results were similar within 12 h.

Diffusion-weighted imaging and CBV are the best predictors of thefinal infarct volume [81]. TheDW–CBVmismatchpredicts lesion growthinto CBV abnormality. It is most commonly seenwith proximal cerebralarterial occlusions. Both CBF andMTT aremore sensitive than CBVmapsbut have less specificity, although they help to identify tissues withaltered perfusion [81]. CBF measurements by MRI cannot differentiatecritically hypoperfused regions from benign oligemic regions [105].Occasionally, large perfusion abnormalities are seen in patients withoutclinical deficits [81]. Lower NIH scores and small MTT abnormalitypredict excellent neurologic outcome [106]. The clinical deficits in acutestrokepatientsmirror abnormal PWIdistributionmore than theymirrorDWI lesions [107]. Hyperacute phase PWI volumes have moreimportant prognostic implications than DWI as they are more closelyassociated with final infarct size and stroke severity [106,108].

5. Candidate selection: CT vs. MR

Data from the largest stroke tissue plasminogen activator (tPA)trials such as Alteplase Thrombolysis for Acute NoninterventionalTherapy in Ischemic Stroke (ATLANTIS), European Cooperative AcuteStroke Study (ECASS), and National Institute of Neurological Disordersand Stroke (NINDS) were recently pooled to assess the predictors ofoutcome and symptomatic bleeding complications of intravenous tPAperformed within the first 6 h of symptom onset in patients withacute middle cerebral artery infarction (174 patients). The rate ofsymptomatic intracerebral hemorrhage was found to be significantlylower in patients selected on the basis of an MRI evaluation comparedwith those recruited only on the basis of a computed tomography (CT)scan [37]. The benefit of MRI assessment over CT in reducing the riskof tPA-related symptomatic bleeding was confirmed in anotherobservational study [109] based on 382 consecutive patients.

Most centers do not perform MR imaging soon enough to screencandidates for IV tPA due to concerns about time consumption andinsensitivity to subarachnoid hemorrhage. The role of MR imagingmay be largely confined to selecting candidates for catheter-basedthrombolysis and in clinical stroke research evaluating extension ofthe time window for next generation of IV thrombolytics (Table 2).

6. Extending the window of thrombolysis

Several studies have sought to determine whether thrombolysismight be beneficial beyond 3 h of onset of stroke. A recent largerandomized, double-blind trial, ECASS III [110], showed benefit ofthrombolysis between 3 and 4.5 h of stroke onset, citing the incidenceof ICH as 2.4%. Going by the definition of symptomatic ICH used inNINDS study the incidence of ICH in ECASS III was 7.9% [110]. ECASS IIIused very stringent exclusion criteria to select patients for random-ization and baselinemedian NIHSS score was only 9 compared to 14 inNINDS. Other previous similar studies that did not use diffusion–perfusion mismatch to select patients had failed to show benefit ofthrombolysis beyond 3 h [35,36,111]. A body of evidence, from clinicalas well as animal studies, is now accruing that the benefit ofthrombolysis extends beyond 3 h but the window of opportunityfast disappears being a function of time since stroke onset, the mostbenefit being shownwithin the first 90 min [34]. Also, the incidence ofICH does not increase with increasing onset-to-treatment time [34].

Table 2Penumbral imaging trials.

Trials DIAS [29] DEFUSE [113] DEDAS [114] DIAS2 [115] EPITHET [116] ROSIE [117] MR RESCUE [118]

Imagingmodality

MRI (PWI+DWI) MRI (PWI+DWI) MRI (PWI+DWI) CT+CTP+CTA or MRI+MRA (PWI+DWI)

MRI+MRA (PWI+DWI) MRI (PWI+DWI) MRI (PWI+DWI)

Window(h)

3–9 3–6 3–9 3–9 3–6 3–24 0–8

Treatment Desmoteplase tPA Desmoteplase Desmoteplase tPA abciximab±reteplase

Mechanicalembolectomy(MERCI)

Exclusion ICH, SAH,diffusionabnormalityN1/3MCA, noperfusion deficit

ICH, infarctN1/3MCA,inability to obtain MRI

ICH, ICA occlusionswithout coexistingseparate occlusionof the MCA

DPMb20% ICH ICH on CT,microbleeds or noperfusion deficit

ICHContrast-enhanced neckMRA suggestsproximal ICAocclusion,proximal carotidstenosis greaterthan 67%, ordissection.

Studydesign

Multicenter,placebo-controlled,randomized,double-blind

Multicenter, open-label

Multicenter,placebo-controlled,randomized,double-blind

Multicenter, placebo-controlled, randomized,double-blind

Multicenter, placebo-controlled, randomized,double-blind

Multicenter,open-label, safetyand proof ofprinciple

Multicenter,randomized,stratified formismatch

Endpoint Primary safetyendpoint, sICHefficacyendpoints—reperfusion andclinical outcome

Primary endpoint —favorable clinicalresponse to earlyreperfusion.

1) Primary safetyend point was therate of sICH.

1) The primary endpointwas good clinical outcomeat 90 days.

1) The primary endpointwas infarct growthbetween baseline DWI andthe day 90 T2 lesion inmismatch patients.

Safety endpoint(sICH), perfusionlesion reduction,and functionaloutcome

Hemorrhagictransformation,clinical outcome

2) Primary efficacyco-end pointswere MRIreperfusion 4 to8 h after treatmentand good clinicaloutcome at90 days.

2) Secondary endpointsincluded change in lesionvolume between baselineand day 30, rates of sICH,and mortality rates.

2) Major secondaryendpoints werereperfusion, goodneurological outcome, andgood functional outcome

Results 1) Low rate ofsICH (2.2%)

1) Early reperfusion isassociated withfavorable clinicalresponse in patientswith DPM, even morefavorable in patientswith ‘TargetMismatch’*

1) No sICH DIAS-2 did not show abenefit of desmoteplase.The high response rate inthe placebo group could beexplained by the mildstrokes recorded (lowbaseline NIHSS scores,small core lesions, andsmall mismatch volumesthat were associated withno vessel occlusions),which possibly reducedthe potential to detect anyeffect of desmoteplase.

Alteplase was non-significantly associatedwith lower infarct growthand significantlyassociated with increasedreperfusion in patientswho had mismatch.Because reperfusion wasassociated with improvedclinical outcomes, phase IIItrials beyond 3 h aftertreatment are warranted.

Ongoing Early data showbenefit fortreatment whenmismatch ispresent.

2) Higher rate ofreperfusion(71.4% comparedto 19.2% withplacebo) andbetter clinicaloutcome with125 μg/kg.

2) Earlyrecanalization onMRA correlatedwith areduction in PWIlesion volume.

2) At a dose of125 μg/kgdesmoteplaseappeared toimprove clinicaloutcome,especially inpatients fulfillingall MRI criteria.3) Resultsgenerally supportthe results ofpredecessor, DIAS

CT—computed tomography; CTP—CT perfusion; CTA—CT angiography; DEFUSE—diffusion and perfusion imaging evaluation for understanding stroke evolution; DEDAS—doseescalation of desmoteplase for acute ischemic stroke; DIAS, DIAS-2— desmoteplase in acute ischemic stroke; DWI—diffusion-weighted imaging; EPITHET—echoplanar imagingthrombolysis evaluation trial; ICA—internal carotid artery; ICH—intracerebral hemorrhage; MERCI—mechanical embolus removal in cerebral ischemia; MRI—magnetic resonanceimaging; MRA—magnetic resonance angiography; MR RESCUE—recanalization of stroke clots using embolectomy; PWI—perfusion weighted imaging; ROSIE—ReoPro retavasereperfusion of stroke safety study:imaging evaluation; SAH—subarachnoid hemorrhage; sICH—symptomatic intracerebral hemorrhage; and tPA— tissue plasminogen activator.⁎ ‘Target mismatch’: the group of patients who did not have the ‘malignant profile’. ‘Malignant profile’was defined as a baseline DWI lesion 100ml ormore and/or a PWI lesion of 100ml or more with 8 seconds or longer of Tmax delay.


Whether thrombolysis should be offered to patients beyond 3 h ofstroke onset will depend upon data from the next generation trialsusing diffusion–perfusion mismatch to select patients (Table 2), andresults of the third international stroke trial [112], the world's largestthrombolysis for stroke trial.

7. Conclusion

Imaging techniques are being utilized as tools to optimize selectionof candidates for acute stroke therapies. Three large trials support animaging-based selection approach. Two of these studies demonstrated apositive dose–response relationship for good clinical outcome andreperfusion employing MRI selection of patients with diffusion–perfusion mismatch for treatment with intravenous desmoteplase 3 to9 h fromonset (DIAS andDEDAS). Third demonstrated favorable clinicaloutcome with early reperfusion utilizing MRI selection of patients for

treatment with intravenous tPA (DEFUSE). Two other large trials failedto show benefit of thrombolysis beyond 3 h utilizing imaging-basedselection criteria (EPITHET andDIAS-2). Results of two largemulticentertrials are awaited (MR RESCUE and ROSIE).

Neuroimaging is the cornerstone of strokemanagement inmodernmedicine, especially in the age of neuroendovascular intervention andneurocritical care. From shaping principles of cerebrovascularischemic pathophysiology and guiding therapeutic modalities basedon these principles, to application of this knowledge to create newtherapeutic approaches, it has become the mainstay of everydayclinical decision making in acute stroke.

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Glossary

The relationship between CBF and CBV is expressed by the equationCBF=CBV/MTT.

Mean transit time (MTT): indicates the time difference between the arterial inflow andvenous outflow.

Cerebral blood volume (CBV): indicates the volume of blood per unit of brain mass(normal range in gray matter, 4–6 mL/100 g).

Cerebral blood flow (CBF): indicates the volume of blood flow per unit of brain mass perminute (normal range in gray matter, 50–60 mL/100 g/min).

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Documents

Penumbra, the basis of neuroimaging in acute stroke treatment: Current evidence