STROKE (C SILA, SECTION EDITOR)

Advanced Neuroimaging to Guide Acute Stroke Therapy

Gurpreet Singh Sandhu & Jeffrey L. Sunshine

Published online: 22 September 2012# Springer Science+Business Media, LLC 2012

Abstract Traditionally non-contrast CT has been consid-ered the first choice imaging modality for acute stroke.Acute ischemic stroke patients presenting to the hospitalwithin 3-hours from symptom onset and without any visiblehemorrhages or large lesions on CT images are consideredoptimum reperfusion therapy candidates. However, non-contrast CT alone has been unable to identify best reperfu-sion therapy candidates outside this window. New advancedimaging techniques are now being used successfully for thispurpose. Non-invasive CT or MR angiography images canbe obtained during initial imaging evaluation for identifica-tion and characterization of vascular lesions, includingocclusions, aneurysms, and malformations. Either CT-based perfusion imaging or MRI-based diffusion and perfu-sion imaging performed immediately upon arrival of a pa-tient to the hospital helps estimate the extent of fixed coreand penumbra in ischemic lesions. Patients having occlusivelesions with small fixed cores and large penumbra are pre-ferred reperfusion therapy candidates.

Keywords Acute stroke imaging . Ischemic stroke imaging .

Hemorrhagic stroke imaging . Brain imaging . Perfusionimaging . Penumbra . Neuroimaging . Stroke

Introduction

With approximately 795,000 new episodes and 160,000deaths every year, acute stroke remains a leading cause ofdisability and mortality in the United States. Approximately

87 % of all acute strokes are brain ischemia, 10 % intra-cerebral hemorrhages, and the remaining 3 % are subarach-noid hemorrhages [1]. Hemorrhagic stroke patients are usu-ally monitored in neuro-intensive care, with surgicaldrainage of the hematoma performed on case-by-case basis.Acute ischemic strokes patients presenting to the hospitalwithin 3 hours of symptom-onset (called 3-hour window)may be given IV recombinant tissue plasminogen activator(r-tPA) after excluding a hemorrhage or a large ischemiclesion, usually by performing a non-contrast computed to-mography (CT) scan of the head [2]. Unfortunately, only asmall fraction (5.9 %–13.2 %) of all acute ischemic strokepatients is eligible for this therapy probably due to timeconstraints of the 3-hour window [3, 4••]. The extensionof this time window to 4.5 hours following results from theECASS-3 and other studies has only been able to improvethe eligibility rate marginally [4••, 5–7].

Advanced CT and magnetic resonance (MR) imagingtechniques are now being used increasingly to triage ische-mic stroke patients falling outside the 3-hour window forreperfusion therapy. For successful triage the imagingshould be able to exclude an intracranial hemorrhage, verifythe presence of a vascular occlusion, and estimate the extentof infarcted brain tissue. Ischemic stroke patients with largeinfract volumes on initial imaging evaluation respond poor-ly to reperfusion therapy [8, 9]. Finally, imaging should beable to estimate the extent of hypo-perfused tissue atimpending risk of infarction without timely restoration ofadequate nutrient supply [2]. We review imaging-basedstrategies commonly employed to achieve these objectives.First, we discuss parenchymal imaging techniques used todetect brain ischemia and intracranial hemorrhages. Subse-quently, we describe vascular imaging techniques employedto identify and characterize obstructive lesions, aneurysms,and vascular malformations. Finally, we describe the con-cept and imaging of ischemic penumbra for estimation of

G. S. Sandhu : J. L. Sunshine (*)Department of Radiology,University Hospitals and Case Western Reserve University,Bolwell B 123, 11100 Euclid Avenue,Cleveland, OH 44106, USAe-mail: Jeffrey.Sunshine@UHhospitals.org

Curr Cardiol Rep (2012) 14:741–753DOI 10.1007/s11886-012-0315-5

the extent of ischemic brain tissue at impending risk ofinfarction.

Detection of Acute Brain Ischemia

Non-contrast CT images most typically obtained upon firstcontact with the stroke patients may be used to identify brainischemia. An acute ischemic lesion appears as a hypo-density on the CT image, potentially following an earlierloss of grey-white differentiation as the first CT sign ofischemia. Common examples of loss of grey-white differ-entiation are disappearance of the insular ribbon and lostdistinction of the lentiform nucleus following proximal mid-dle cerebral artery (MCA) obstruction [10, 11]. Sulcal ef-facement is another sign and its early appearance suggestssevere ischemia [2]. Large ischemic lesions (infarct involv-ing over one-third of the MCA distribution) on CT imagesare considered poor risk for reperfusion therapy due to ahigh hemorrhage risk [12]. The Alberta Stroke ProgramEarly CT Score (ASPECTS) is a semi-quantitative way ofpredicting the response to intravenous thrombolysis fromnon-contrast CT images of patients with anterior circulationstrokes obtained during the 3-hour window [13]. In thisscoring system each MCA territory is sub-divided into 10regions and each region is allotted 1 point, with a total of 3points for subcortical structures, and 7 for MCA cortex. Onepoint is subtracted for a visible ischemic change in eachregion. Therefore the APSECT score of a patient is inverselyproportional to the number of regions involved and helpsestimate the prognosis. In a prospective study, theASPECTS score (cut-off value ≤7 or >7) was able to accu-rately predict the chance of a favorable outcome (sensitivity90 %, specificity 62 %, P<0.001) and symptomatic intra-cranial hemorrhage risk (sensitivity 90 %, specificity 62 %,P<0.001) following reperfusion therapy [13]. Patients withASPECTS score of ≤3 usually have large lesion volumes(>100 cc) on diffusion-weighted MR images (sensitivity77.3 %, specificity 97.7 %), which are considered poor riskfor reperfusion therapy [14].

An ideal imaging technique should be able to accuratelydepict all ischemic lesions. Unfortunately, non-contrast CThas a high false negative rate (33 %) for detecting brainischemia during the 3-hour window, with the rate reducingto 18 % for the first 6 hours (Fig. 1). New CT-basedtechniques such as CT perfusion and CT angiography havefared relatively better in this regard and have 90 % sensitiv-ity for detecting ischemic lesions [15, 16]. Finally, ischemiclesions can be best identified from diffusion-weighted MRimages (or simply, diffusion images). Brain ischemiaappears as a signal hyper-intensity on these images(Fig. 1). In a randomized crossover comparison study, thesensitivity and specificity rate of diffusion images for

ischemic lesions during the first 6 hours was 91 % and95 %, respectively. In comparison, corresponding valuesfor non-contrast CT images were only 61 % and 65 %[17]. In another prospective study (n0356), the clinicianswere able to detect 4.6 times more ischemic lesions fromdiffusion images than from CT images [18]. Diffusion im-aging is particularly superior to CT for small lesions andlesions located in the brain stem and posterior fossa [2, 19,20]. Diffusion imaging-based ASPECTS scoring system hasalso been described to estimate the prognosis [21]. In astudy (n0350) over 80 % of patients with APSECTS≥8 from DWI images had a favorable outcome (mRS 0–2 at3 months) without thrombolytic therapy, whereascorresponding value for patients with APSECTS ≤7 wasonly 28.8 % and all patients with ASPECTS ≤3 fared poorly[22]. Similarly, DWI-based ASPECTS scoring system forposterior circulation (called pc-ASPECTS) has also beendescribed. In a study (n0132), over 80 % of patients withpc-ASPECTS ≥8 had a favorable outcome without anythrombolytic therapy, whereas the corresponding rate forpatients with pc-ASPECTS ≤5 was only 10 % [23].

Identification of Brain Hemorrhages and Micro-Bleeds

A non-contrast CT is usually considered sufficient for identi-fication of acute intracranial hemorrhages (Fig. 2). Bothhyper-acute (within 12 hours from symptom onset) and acute(12 hours to 2 days) intracranial hemorrhages appear as hyper-densities on CT images [24, 25]. While parenchymal hemor-rhages are best identified from T2*-weighted MR images,subarachnoid hemorrhages are best visible from FLAIRimages. The hemoglobin content of a hematoma is in anoxygenated state during the hyper-acute stage and it progres-sively gets de-oxygenated during the acute stage [25]. There-fore, a hyper-acute hemorrhage appears as a signal hyper-intensity and an acute hemorrhage appears as a hypo-intensity on these images. On gradient echo images, a hypo-intense rim is observed first around a hematoma and the hypo-intense rim gradually progresses towards the center duringlater stages [25]. MRI is as effective or better than CT fordetection of hyper-acute hemorrhages and superior to CT foracute hemorrhages [24, 25]. According to the latest AHAguidelines either CT or MRI can be used to diagnose paren-chymal hemorrhages, however, CT is still the traditional im-aging technique for subarachnoid hemorrhages [2, 26, 27].

Cerebral micro-bleeds are best detected as small foci ofperi-vascular hemosiderin deposits in otherwise normalbrain tissue and denote previous episodes of small paren-chymal hemorrhages. Micro-bleeds are not readily visiblefrom CT images and are best identified from T2*-weightedMR images as punctate, homogeneous, rounded, hypo-intense regions smaller than 5–10 mm in diameter within

742 Curr Cardiol Rep (2012) 14:741–753

the parenchyma [25, 28]. The number and visibility ofcerebral micro-bleeds on MR images depend upon variousimaging parameters such as the field strength, pulse se-quence used, and section thickness (Fig. 3). For example,thin-section susceptibility-weighted images depict 3 timesas many as lesions as conventional T2*-w images [29].Micro-bleeds have been observed in T2*-w images of ap-proximately 56 % cases with primary intra-cerebral hemor-rhages, 18 %–68 % with ischemic strokes, 27 % withlacunar infarcts, 24 % of elderly people and 5 %–6 % ofhealthy asymptomatic adults [25, 30–34]. The number ofmicro-bleeds concurrently present in a patient with a hem-orrhagic stroke relates directly to the future risk of intra-cranial hemorrhage [35, 36]. The 3-year cumulative symp-tomatic hemorrhage risk following an episode of hemor-rhagic stroke in a patient with a single micro-bleed isrelatively low at 14 % and this risk increases to 17 % for2, 38 % for 3 to 5, and 51 % for 6 or more hemorrhages [35].Similarly though at clearly lower levels, the risk of a sub-sequent hemorrhagic stroke in a patient with an ischemic

stroke is only 0.6 % with no visible micro-bleed, 1.9 % with1, 4.6 % with 2 to 4, and 7.6 % with 5/more micro-bleeds[36]. The correlation between the number of micro-bleedsand symptomatic hemorrhage risk following thrombolytictherapy in acute ischemic stroke remains uncertain [37, 38].

Vascular Imaging

Imaging of the vessels, particularly of supplying arteries,helps identify, and characterize blood flow disturbances, andobstructions that can cause ischemic strokes [2]. Althoughdiagnostic catheter angiography remains the gold standardtechnique, both CTA as well as MRA have achieved rea-sonable accuracy for screening evaluation of high-gradestenotic or occlusive lesions [2]. CTA has over 80 % sensi-tivity and 90 % specificity for extra cranial carotid stenoses[39]. Its accuracy in detecting intracranial occlusive lesionsapproaches that of angiography (sensitivity 92 %–100 %,specificity 82 %–100 %) [2, 40, 41]. The ability of CTA to

Fig. 1 42-year-old male with unknown onset of a wake-up strokearrived to the hospital after 11 hours delayed since he was last seennormal. He presented with severe neurologic deficit, was triaged usingMRI, and had marked improvement following reperfusion therapy. HisNIHSS at the time of presentation was 17, and (A) non-contrast CTimages obtained immediately after arrival were unremarkable. Subse-quent MR imaging showed some perfusion-diffusion mismatch. Arrowin the diffusion image (B) and perfusion time to peak map (C) denote

the region with diffusion restriction and reduced perfusion, respective-ly. An M1 segment occlusion of the left MCA was identified fromMRA images and confirmed by catheter angiography (arrow) (D).Angiography images (E) obtained after endovascular mechanicalthrombectomy confirmed success of the procedure. His symptomsimproved markedly (48 hours NIHSS02) and he returned back towork 1 month later. A follow-up CT (F) showed a small infarct limitedto the region with most increased diffusion signal only (arrow)

Curr Cardiol Rep (2012) 14:741–753 743

differentiate high-grade stenoses (string sign) from completeocclusions has a significant clinical relevance [42]. While ahigh-grade stenosis is usually amenable to surgical interven-tion, attempting to open a total occlusion even during thehyper-acute stage remains controversial. MRA also has ahigh sensitivity (86 %–97 %) but variable specificity 62 %–91 %) in detecting extracranial occlusive lesions [2]. Thecorresponding values for intracranial lesions are 60 %–85 %and 80 %–90 % [40].

Although not a true vascular imaging technique, non-contrast CT can be used to identify clots in the proximal

MCA. An MCA thrombus can appear as hyper-density onCT images and correlates with a severe neurologic deficit,large infarction, and poor prognosis [43]. Commonly knownas hyper-dense MCA sign (HMCAS), this finding is ob-served in one-third to half of all cases of thrombus provenby angiography [43, 44]. Clots in the proximal part of theMCA do not respond well to intravenous therapy. In aprospective study (n057), intravenous r-tPA had significant-ly lower reperfusion rate in patients with occlusions inproximal part of the MCA (residual proximal M1 length<5 mm) than those with occlusions in distal part of the artery

Fig. 2 42 year-old male withsubarachnoid hemorrhage sec-ondary to rupture of anteriorcommunicating artery aneu-rysm that was treated by coilembolization. A non-contrastCT (A) performed upon arrivalto the emergency room revealeda subarachnoid hemorrhage.Subsequent CTA imaging (B)showed an anterior communi-cating artery aneurysm (arrow).Coil embolization of the aneu-rysm was performed. Panel C isan angiography image demon-strating obliteration of the an-eurysm by a coil (arrow). AFLAIR MR image (D) obtained5 days later demonstrates resid-ual blood in the brain

Fig. 3 GRE (A), T2-w (B), andFLAIR (C) images of a 48-year-old female demonstratinga micro-bleed in the left occip-ital lobe. The micro-bleed canbe identified as a signal hypo-intensity (arrows) in theseimages. Signal hypo-intensityfrom the micro-bleed in GREimage is relatively more pro-nounced than that in T2-w andFLAIR images

744 Curr Cardiol Rep (2012) 14:741–753

(residual proximal M1 length ≥5 mm and M2 segment)(recanalization rate 62.1 % vs 82.8 %, P00.008) [45•].Due to this poor response rate, intra-arterial thrombolysishas fared better than intravenous thrombolysis in cases withpositive HMCAS sign, including those that may presentduring the 3-hour window (favorable outcome rate, 53 %vs 23 %, P00.001 and mortality rate, 7 % vs 23 %, P00.022) [46]. Similarly, proximal MCA clots can also beidentified from structural MR images (called clot sign). Infact, FLAIR and GRE images have higher sensitivity thannon-contrast CT images for such lesions (82 % with GRE vs54 % with CT) [44, 47]. However, the prognostic value ofthe MRI-based clot sign is yet to be established in a pro-spective study.

In primary hemorrhagic strokes vascular imaging helps inidentifying the source of bleeding. Again catheter angiogra-phy remains the gold standard due to its high spatial reso-lution and ability for imaging of selective vessels.Intracranial aneurysms can be detected with over 90 %sensitivity and specificity using CTA (Fig. 2) [48, 49]. Largeaneurysms can be easily identified from MRA also; howev-er, due to its typical lower spatial resolution this techniquehas fared poorly for small lesions (only 38 % sensitivity foraneurysms with diameters <3 mm) [50]. After excludingprimary aneurysms, the search for intracranial vascular mal-formations can be performed using CTA and new time-resolved MRA techniques [49, 51•, 52], which also permitfurther lesion characterization.

Estimation of the Ischemic Core and Penumbra

A cascade of electro-physiologic events happening after thestart of brain ischemia determines the spatial variations inevolution of the ischemic lesion over time. Electrical activ-ity of the neurons cease within seconds of complete arrest ofnutrient supply and their ionic homeostasis deteriorates inthe subsequent few minutes. Tissues with deteriorated ionichomeostasis are collectively called ischemic core and thetissues with no electrical activity but maintained ionic ho-meostasis are called penumbra. Typically, the ischemic coreforms irreversibly damaged (or fixed) tissue at the center ofthe lesion, whereas, the penumbra represents the salvageabletissue surrounding the core. With increase in time delayfrom the start of ischemic episode the penumbra graduallyevolves into the ischemic core [53, 54].

Either CT or MR imaging can be performed to estimatethe extents of penumbra and ischemic core within ischemiclesions. The CT-based protocol typically involves acquisi-tion of 3 data sets in a single setting: a non-contrast CT, CTangiography, and dynamic first-pass CT perfusion. CT an-giography data is obtained after injecting a CT contrastagent (volume ≈ 100 cc). The brain regions with abnormal

blood perfusion are identified from CT angiography-sourceimages. Typically 1 or 2 slabs (2–4 cm thick, through newwhole brain options) of CT perfusion data centered on thebrain region with abnormal blood perfusion are acquiredduring the first pass of a CT contrast agent (volume ≈40 cc/slab). Temporal variations in the attenuation valuesfrom individual pixels of the CT perfusion data are used toconstruct CBV and cerebral blood flow (CBF) maps of thebrain slabs [2, 55]. Regions of an ischemic lesion withreduced CBV value are believed to represent the ischemiccore [2, 9, 56, 57], whereas, the regions with reduced CBFvalue represent both, the ischemic core, as well as thepenumbra [2, 57–59]. Therefore, the regions with a reducedCBF value but normal CBV value are considered to repre-sent penumbra. Although the CT perfusion technique ini-tially supplanted MRI, emerging reports suggest that CTperfusion techniques need further refinement to achievereproducible reliability in clinical settings [60–64]. Variousprocessing tools currently being used to generate CBV andCBF maps from the same raw CT data give different resultsand the most accurate processing tool is yet to be identified[65, 66•, 67–69]. Xenon-enhanced CT is an older techniquefor perfusion imaging, where data is obtained after coldxenon gas inhalation. However, this technique has primarilybeen used for investigational purposes only [2, 70] withonly rare direct clinical penetration.

The MRI-based protocol involves diffusion and perfu-sion imaging of the brain. Diffusion imaging is performedusing a pulse sequence with a pair of strong gradient pulsesof equal strengths and opposing directions. Ischemic corehas a restricted diffusivity of the water molecules andappears as signal hyper-intensity on the diffusion image[71, 72••]. Perfusion imaging is commonly performed usingdynamic susceptibility contrast (DSC) technique, where,T2*-weighted images are consecutively obtained duringthe first pass of a gadolinium contrast agent through thebrain capillary bed. Time delay in arrival of the gadoliniuminto vascular bed of the lesion and associated signal changesare used to the generate perfusion images. Detailed infor-mation about these techniques and statistical methods usedto construct perfusion images by estimating local relativeCBV, CBF, mean transit time, time-to-peak, etc. can befound elsewhere [73, 74]. Absolute quantification of perfu-sion parameters is not possible with DSC perfusion MRIdue to non-linearity of signal response to contrast and thepossible loss of T2* weighting from gadolinium entering theinterstitial space [75]. Dynamic contrast-enhanced (DCE)perfusion MRI technique, in which spatial variations in T1relaxation times are exploited to generate perfusion maps, isimmune to this latter problem [76]. This technique mayallow quantitative MR perfusion data in future [77]. Arterialspin labeling is a technique that does not require gadoliniuminjection, with perfusion images generated from movement

Curr Cardiol Rep (2012) 14:741–753 745

of magnetically-labeled protons of blood through the brain[78, 79]. Currently, DSC MRI remains the typical approachfor stroke imaging however, the other techniques are slowlyfinding more applications for this purpose [2]. The regionswith reduced perfusion values appear as higher values onperfusion parameter maps and consist of both the ischemiccore as well as penumbra. Therefore, regions of an ischemiclesion visible with demonstrable hypo-perfusion and outsidethe signal hyper-intensity on the diffusion images representthe possible penumbra (Fig. 1) [57].

Table 1 shows the complexity of results from the nowmany but varied studies demonstrating the value of penum-bra in improving outcomes from reperfusion therapy. Moreideal reperfusion therapy candidates are those who have alarge penumbra and a small ischemic core. Some penumbratissue is present in virtually all ischemic lesions during the3-hour window and the presence of penumbra declines withincrease in the time from symptom onset [80]. Imaging ofpenumbra has not proven directly beneficial in mixed trialpopulations to date during the 3-hour window though suchimaging applied to patient selection has shown some im-proved outcomes from reperfusion therapy beyond the 3-hour window [81, 82]. Reported favorable outcome ratesfrom IV thrombolysis in patients selected using diffusionand perfusion imaging during the first 6 hours from symp-tom onset is similar to that in patients selected using non-contrast CT during the 3-hour window [81–83].

Too large of an ischemic core may also add the risk ofbleeding to attempted treatments. Ischemic lesions involv-ing >1/3 of the MCA territory on CT images, or CBV ordiffusion lesion volume >100 cc have been defined as largeischemic cores [84, 85]. Current evidence suggests that this100 cc limit for likely successful outcome from reperfusionshould be further reduced to 70 cc [86•]. As diffusionimaging estimates the ischemic core most accurately theincidence of reperfusion-related symptomatic hemorrhagesis lower in patients identified using diffusion-perfusion im-aging than those identified using non-contrast CT, evenduring the 3-hour window [81, 82].

Lesions with small or moderate ischemic cores and largepenumbra are the ideal reperfusion therapy targets. TheDIAS 1 study suggested that early reperfusion of suchlesions achieved using IV desmoteplase during 3–9 hours’time delay from symptom onset would be beneficial (favor-able clinical outcome rate 52.5 % with early reperfusion andonly 24.6 % without it) [87]. However, these results werenot repeated in DIAS-2 with possible explanations includingsmaller lesion size and higher desmoteplase dose thanDIAS-1 [88]. The DEFUSE study demonstrated significant-ly better outcomes from early reperfusion achieved fromintravenous r-tPA treatment during 3–6 hours delay inlesions with small to moderate ischemic core and a signifi-cant penumbra (significant symptomatic improvement rate

at discharge: 67 % with early reperfusion vs 19 % with noearly reperfusion) [85]. Similar trends were observed fromEPITHET study [84]. Early reperfusion of lesions with apenumbra provided significant symptomatic benefit (goodneurologic outcome rate 73 % with early reperfusion vs27 % without it, P<0.0001) and reduced the lesion growth(mean lesion growth with time 0.79 with early reperfusionvs 2.25 without it, P00.001) in this study. A combinedanalysis of DEFUSE and EPITHET studies has demonstrat-ed that early reperfusion of lesions with a small to moderateinfarct core and a significant penumbra improves the chanceof a favorable response 5.6 times (OR, 5.6; 95 % CI, 2.1 to15.3) and attenuates the infarct growth (10 mL with reper-fusion vs 40 mL without reperfusion; P<0.001). In contrast,no benefit from early reperfusion has been observed forlarger infarct lesions, irrespective of presence or absenceof a penumbra, in these and other studies [86•, 89••, 90].Small lesions (lesion volume <10 cc) matched on bothdiffusion and perfusion imaging generally have favorableoutcomes, even without therapy [84, 85, 89••]. Such lesionshave very small ischemic cores and no significant penumbraand hence they do not benefit as clearly from successfulreperfusion.

Patients with large neurologic deficits (National Instituteof Health Stroke Scale, NIHSS≈15) and presenting to thehospital after long delay times (for example 12 hours) aregenerally considered very poor candidates and are often notoffered any reperfusion options, though imaging may permitselection of still favorable candidates for treatment. In 1study, 64 % of patients with large deficits and moderate sizediffusion lesions (<70 cc) responded well after removing alarge vessel blockade in the anterior circulation by endovas-cular therapy. In contrast, none of patients with a diffusionlesion volume >70 cc had a favorable response in this study[86•]. In another study (n030, 27 had anterior circulationstrokes and 3 had posterior circulation strokes), 33 % ofpatients with severe strokes and penumbra identified usingCT perfusion imaging had been able to achieve acceptableoutcomes following endovascular therapy after a 8–24 hoursdelay from symptom onset [91]. Results of recent anecdotalreports and our experience suggest that penumbra estima-tion also helps identification of appropriate reperfusion ther-apy candidates in posterior-circulation strokes in patientswho may tolerate longer ischemic times and benefit fromreperfusion in the posterior territories [92, 93].

Practical Aspects

Currently we perform a non-contrast CT upon first contactwith patients having clinical features suggestive of acuteischemic stroke. Intravenous r-tPA is offered after excludinga large already visible lesion and intracranial hemorrhage to

746 Curr Cardiol Rep (2012) 14:741–753

Tab

le1

Resultsof

variou

sstud

iesshow

ingou

tcom

esfrom

reperfusiontherapyof

acuteischem

icstroke

patientsfollo

wingadvanced

imagingperformed

fordetectingapenu

mbra

Study

Imagingmodality

and

reperfusionregimen

Objectiv

e,numberof

subjects,baselin

eNIH

SS,im

agingselection

criteriaandcomparisonterm

sRelevantoutcom

es

Thomalla

Get

al.

(prospectiv

e)[83]

MRIvs

non-contrastCT

1.Com

parisonof

outcom

esfrom

IVr-tPA

during

0–6hours

window

follo

wingnon-contrastCT(n01085,medianbaselin

eNIH

SS011),diffusion-perfusionMRI(n0174,

medianbaselin

eNIH

SS013)andpooled

placebo(n01081,medianbaselin

eNIH

SS011).

1.Significantly

higher

favorableoutcom

erate

inMRIgroup

(48%)than

correspondingvalues

from

CTgroup(40%)as

wellas

pooled

placebogroup(33%).

IVr-tPA

2.MRIinclusioncriteria:

perfusion-diffusionmismatch

>1.2,

diffusionlesion

involving<50

%of

theMCA

territo

ryandno

visibleintracranial

hemorrhage.

2.SICH

rate

inMRIgroup(2.9

%)similarto

that

inpooled

placebogroup(1.9

%)andlower

than

that

inCTgroup(8.2

%).

Schellin

gerPD

etal.

(pooleddata

analysisfrom

5centers)

[81]

MRIvs

non-contrastCT

1.Com

parisonof

outcom

esfrom

IVr-tPA

inpatientsselected

usingCTin

the3-hour

window

(n0714,

medianNIH

SS012)

andpatientsselected

usingMRIin

the3-hour

window

(n0316,

medianNIH

SS013)and3–

6hoursinterval

(n0180,

median

NIH

SS014).

1.Nodifference

offavorableoutcom

e,SICH

andmortalityrates

betweenthe3groups.

IVr-tPA

2.MRIselectioncriterion:perfusion-diffusionmismatch

>1.2.

2.Overall,patients

selected

usingMRIhadlower

SIC

Hrate

than

thoseselected

usingCT(O

R00.52

,95

%CI:0.27

to0.99

9,P00.05

).

3.The

useof

MRIsignificantly

improved

thefavorableoutcom

erate

during

the3–

6hour

window

(OR01.467;

95%

CT01.017

to2,117,

P00.040).

4.With

inthe3-hour

window,atrendin

favorof

MRIwas

observed

forfavorableoutcom

e(35.5%

vs32.2

%),SICH

(2.8

vs5.3%)as

wellas

mortality(11.7%

vs13.7

%)rates.

Kohrm

annM

etal.

(prospectiv

e)[82]

MRIvs

non-contrastCT

1.Com

parisonof

outcom

esfrom

IVr-tPA

inpatientsselected

usingnon-contrastCTin

the3-hour

window

(n0209)

with

outcom

esfrom

patientsselected

usingMRIin

3-hour

(n0103)

and3–6hours(n070)windows.MedianNIH

SSwas

13for

each

group.

1.Nosignificantdifference

of90-day

favorableoutcom

e(48%,

51%

and56

%),SICH

(9%,1%,6%)andmortality(21%,

13%,11

%)ratesbetweenpatientsselected

usingCTin

the3-

hour

window,MRIin

the3-hour

window

andMRIduring

3to

6hour

window.

IVr-tPA

2.MRIinclusioncriteria:

perfusion-diffusionmismatch

>1.2

anddiffusionlesion

involving<50

%of

theMCA

territo

ry.

2.Overall,patients

selected

usingMRIhadsign

ificantly

lower

SIC

H(3

%vs

9%,P00.013

)andmortality

(12%

vs21

%,P00.02

1)ratesthan

thoseselected

usingCT.

DIA

S1[87]

(placebo-controlled,

double

blind,

random

ized)

MRI

1.Com

parisonof

outcom

esfrom

placeboandvariousdosesof

desm

oteplase

givenduring

3–9hourswindow

inpatients

selected

usingMRI.

1.A0%

SICHratewith

placebo,26.7

%with

desm

oteplase

inpart

1(thisphasewas

term

inated

prem

aturely)

and2.2%

inpart2.

Placebo

andIV

desm

oteplase

(25/

37.5/50

mgin

part1

and62.5/90/125μg

/kgin

part2).

2.Total

47subjectsrecruitedin

part1and57

inpart2.

Total27

patientstreatedwith

placebo(m

edianNIH

SS012)and75

with

desm

oteplase

(medianNIH

SS012).

2.Betterreperfusion(71.4%

vs19.2

%)andFCR(60%

vs22.2

%)rateswith

125μg

/kgdosesthan

with

placebo.

3.Im

aginginclusioncriteria:

perfusionabnorm

ality

>2cm

indiam

eter,anddiffusion/perfusionmismatch

≥20%

(exceptio

ns;

diffusionabnorm

ality

in1/3of

MCA

territo

ry).

3.BetterFCRwith

earlyreperfusionthan

with

noreperfusion

(52.5%

vs24.6

%).

DEDAS(placebo-

controlled,

double

blind)

[99]

MRI

1.Com

parisonof

safety

andefficacy

ofplacebo(n08,

median

NIH

SS012)and90

μg/kg

(n014,medianNIH

SS010)and

125μg

/kg

(n015,medianNIH

SS09)

desm

oteplase

during

3–9hourswindow

inpatientsselected

usingMRI.

1.NoSICH

observed

inanygroup.

Curr Cardiol Rep (2012) 14:741–753 747

Tab

le1

(con

tinued)

Study

Imagingmodality

and

reperfusionregimen

Objectiv

e,numberof

subjects,baselin

eNIH

SS,im

agingselection

criteriaandcomparisonterm

sRelevantoutcom

es

IVdesm

oteplase

(90/

125μg

/kg)

2.MRIinclusioncriteria:

≥20%

perfusion/diffusionmismatch

definedas

aperfusiondeficitover

2cm

indiam

eter,with

orwith

outdiffusionabnorm

ality,involvingthecerebral

cortex.

2.A

significantly

higher

favorableclinical

response

rate

with

higher

dose

ofthedrug

than

with

placebo(25%

with

placebo,

28.6

%with

90μg

/kgand60

%with

125μg

/kgdose).

DIA

S2[88]

(placebo-controlled,

double

blind,

random

ized)

MRIor

CTperfusion

1.Com

parisonof

safety

andefficacy

ofplacebo(n063,median

NIH

SS09)

and90

μg/kg

(n057,medianNIH

SS09)

and

125μg

/kg

(n066,medianNIH

SS09)

desm

oteplase

during

3–9hourswindow

inpatientsselected

usingMRI.

1.Noclinical

benefitfrom

desm

oteplase.

IVdesm

oteplase

(90/

125μg

/kg)

2.Im

aginginclusioncriteria:

A≥2

0%

penumbraas

measured

from

diffusionandperfusionMRIor

perfusionCT(exceptio

ns;

patientswith

core

lesionsinvolving>1/3of

MCA

territo

ryor

all

oftheACA

territo

rywereexcluded).

2.Favorable

clinical

response

rate

of47

%with

90μg

/kg,

36%

with

125μg

/kgdose

and46

%with

placebo.

3.SICH

rate

of3.5%

with

90μg

/kg,

4.5%

with

125μg

/kgdose

and0%

with

placebo.

Overallmortalityrate

of11

%with

90μg

/kg,

21%

with

125μg

/kg

dose

and6%

with

placebo.

DEFUSE(prospectiv

e,multi-central)[85]

MRI

1.Com

parisonof

outcom

esfrom

ivr-tPA

inpatientswith

various

MRIprofilesduring

3–6hourswindow

(n074,medianbaselin

eNIH

SS011).Patientswith

anacutehemorrhageor

ahypo-

density

involving>1/3of

theMCA

territo

ryat

thebaselin

enon-

contrastCTwereexcluded

from

study.

1.A

mismatch

profile

was

observed

in54

%,target

mismatch

in49

%,sm

alllesion

in26%andmalignant

lesion

in8%

subjects.

IVr-tPA

(0.9

mg/kg)

2.A

mismatch

profile:aperfusiondeficit≥1

0cc

and≥1

20%

ofthediffusionabnorm

ality.

2.In

themismatch

group,

thefavorableclinical

response

rate

was

higher

insubjectswith

earlyreperfusionthan

thosewith

outearly

reperfusion(56%

vs16

%;odds

ratio

5.4).Sim

ilartrends

were

observed

inthetarget

mismatch

group(67%

vs19

%;odds

ratio

8.7).

3.A

smalllesion

profile:both,diffusionabnorm

ality

aswellas

perfusiondeficitless

than

10cc

byvolume.

3.In

no-m

ismatch

group,

no(0/4)patient

with

earlyreperfusion

and71

%(5/7)subjectswith

outearlyreperfusionresponded

favorably.

4.A

no-m

ismatch

profile:patientswith

outmismatch

profile

orsm

alllesions.

4.Only1outof

total6subjectswith

amalignant

profile

hada

favorableresponse

and3hadaSICH.In

comparison,

theSICH

rate

inthetarget

mismatch

profile

was

6.5%,with

noeffect

from

reperfusion.

Inthemismatch

profile,theSICH

rate

was

22%

with

earlyreperfusionand6.3%

with

outearly

reperfusion.

5.A

malignant

profile:diffusionlesion

≥100

cc.

6.A

target

mismatch

profile:alesion

falling

into

themismatch

category

butnotthemalignant

category.

EPITHET(a

placebo-

controlled,

random

ized,

multi-central)

[84]

MRI

1.Com

parisonof

outcom

esfrom

placebo(n049)andIV

r-tPA

(n052)during

3–6hourswindow

invariousMRIprofiles.

Medianvalueof

NIH

SS013.Patientswith

anacutehemorrhageor

ahypo-density

involving>1/3of

theMCA

territo

ryat

the

baselin

enon-contrastCTwereexcluded

from

study.

1.A

mismatch

profile

was

observed

in86

%,target

mismatch

in52

%,andmalignant

profile

in34.7

%cases.

IVr-tPA

2.A

mismatch

profile:aperfusiondeficit≥1

20%

ofthediffusion

deficitby

volumeandminim

umdifference

of10

ccbetweenthe

2volumes.

2.Reperfusion

rate

inthetreatm

entgroupwas

higher

than

that

intheplacebogroup(56%

vs26

%,P00.01).

3.A

malignant

profile:diffusionlesion

and/or

perfusionlesion

(tim

edelay≥8

s)≥1

00cc.

3.In

themismatch

group,

patientswith

asuccessful

reperfusion

hadahigher

chance

ofsignificantneurologic

improvem

entafter

748 Curr Cardiol Rep (2012) 14:741–753

Tab

le1

(con

tinued)

Study

Imagingmodality

and

reperfusionregimen

Objectiv

e,numberof

subjects,baselin

eNIH

SS,im

agingselection

criteriaandcomparisonterm

sRelevantoutcom

es

3months(goodneurologic

outcom

erate

73%

with

reperfusion

vs27

%with

outreperfusion,

P<0.0001)andlower

infarct

grow

th(m

eangrow

th0.79

vs2.25,p00.001)

than

thosewith

out

reperfusion.

4.A

target

mismatch:alesion

falling

into

themismatch

category

butnotthemalignant

category.

4.In

thetreatm

entgrouptarget

mismatch

profile

hadbetter

outcom

esthan

malignant

mismatch

profile

(goodneurologic

outcom

erate

65%

vs24

%,P00.007).

Natarajan

SK

etal.

(retrospectiv

e)[91]

CTperfusion

1.Study

ofoutcom

esfrom

endovascular

recanalizationperformed

8–24

hours(m

eantim

e12.8

hours)

aftersymptom

onsetin

patientsselected

usingCTperfusion(n030,medianNIH

SS013).

1.A

completeor

partialrecanalizationrate

was

achieved

in66.7

%of

patients,with

10%

SICH

rate.

endovascular

therapy

2.Im

aginginclusioncriteria:

absenceof

intracranial

hemorrhage,

ahypo-density

involving<1/3of

theMCA

territo

ryandCBV

lesion

volume>130%

oftheCBFlesion

volume.

2.Mean3.5pointim

provem

entin

NIH

SSat

dischargefrom

baselin

e,a33

%acceptable

functio

naloutcom

erate

and23.3

%mortalityrate

was

observed.

SandhuGSet

al.

(retrospectiv

e)[90]

MRI

1.Study

ofoutcom

esfrom

endovascular

therapy3–6hoursafter

symptom

-onset

inpatientswith

comparativ

elysevere

strokes

(n08,

meanbaselin

eNIH

SS016.5)andwith

outmismatch

(ie,

perfusionlesion

volume<120%

ofthediffusionlesion

volume).

1.Study

subjectshadrelativ

elylargeischem

iccores(m

ean

diffusionlesion

volume0119.5mL)andno

significant

penumbra(m

eanperfusionlesion

volume:

118mL).

Endovasculartherapy

2.Only1patient

hadafavorableresponse,4hadaSICH,and5

died.

Yoo

AJet

al.

(retrospectiv

e)[86•]

MRIor

CTperfusion

1.Com

parisonof

outcom

esfrom

intra-arterial

therapyin

patients

having

asignificantpenumbraand2differentischem

iccore

sizes(smallischem

iccore

0diffusionlesion

volume<70

cc,

largeischem

iccore

0diffusionlesion

volume>70

cc).

1.Noneof

6patientswith

largeischem

iccoreshadafavorable

response

despite

50%

recanalizationrate.

endovascular

therapy

2.Six

patientshadalargeischem

iccore

and26

hadsm

all

ischem

iccore.

2.Amongstpatientswith

smallischem

iccores,patientswith

early

recanalizationhadasignificantly

higher

favorableresponse

rate

(64%)than

thosewith

late

orno

recanalization(12%).

3.Meanbaselin

eNIH

SSwas

18.Allsubjectshadan

occlusionin

internal

carotid

orproxim

almiddlecerebral

artery

andfixed

lesionsinvolving<1/3of

middlecerebral

artery

territo

ryand

perfusion-diffusionmismatch

>20

%.

CBFCCerebralbloo

dflow

,CBVcerebral

bloo

dvo

lume,NIH

SSNationalInstitu

teof

Health

Strok

eScale,ICH

intracranial

hemorrhage,SICH

symptom

atic

intracranial

hemorrhage

Curr Cardiol Rep (2012) 14:741–753 749

all patients presenting within the 3-hour window, and toselected patients (age <80 years and no prior history ofstroke or diabetes mellitus) presenting within 4.5 hours ofsymptom onset. For patients with a large neurologic deficitand presenting outside this window, we provide furtherimaging using either CT or MRI principally to exclude largeinfarct cores and also to estimate penumbra. We applyadvanced imaging to patients with fluctuating neurologicdeficits and no visible ischemic lesions on CT as well. Inaddition, as wake-up strokes presenting in the morning withnew neurologic deficits form approximately one-fourth ofall incidences [94, 95] a detectable fraction of these patientsmay harbor still salvageable brain tissue. So we also mayapply advanced imaging in these settings to identify patientswith conditions favorable to treatment (Fig. 1).

The start of reperfusion therapy following imaging triagewith the shortest possible time delay permits salvage of thegreatest potential volume of tissue in acute ischemic strokepatients. Using modern technology the necessary imagingdata can be obtained and a decision about possible reperfu-sion therapy can be made in 15–25 minutes [96, 97•, 98]. Avast majority of the advanced stroke care centers in theWestern world are equipped for image acquisition and in-terpretation within 1 hour of arrival to the emergency room[96]. Different centers prefer CT or MRI-based protocolsdepending most often upon the available facilities, institu-tional practices, and technical expertise. Non-contrast CT,CTA, and CT perfusion data required for evaluation of apossible ischemic stroke can be obtained in ≈ 10 minutes.The MR-based protocol usually consists of T2*-w gradientecho, FLAIR, time-of-flight MRA, diffusion and perfusionimaging, and the necessary data can be performed in ≈15 minutes [96], and may be reduced further, for example,to just diffusion images if CT and CTA have been obtainedalready. Rapid image evaluation into perfusion or otherparameters can be performed using automated softwareprograms now widely available [89••].

Conclusions

Although a non-contrast CT still remains a first choiceimaging technique for acute stroke for many sites, theemerging evidence strongly argues toward a vital role ofnewer imaging techniques. Advanced imaging of acute is-chemic stroke patients may well help identify at-risk braintissue, any vascular pathology, and exclude stroke mimics ina single step. Brain hemorrhages and ischemia can be accu-rately identified with the available techniques. The advent ofnew CT and MR angiography protocols has reduced thereliance on conventional angiography for initial vascularevaluation. An accurate identification of penumbra and atleast exclusion of large fixed lesions helps us maximize the

chance of symptomatic improvement and minimize therisks, for example, of hemorrhage from reperfusion therapy.Future clinical trials will help further refine this concept andenable achievement of the best possible risk-benefit ratiofrom reperfusion therapy in acute ischemic stroke patients.Comprehensive imaging may be particularly beneficial forthose presenting after longer delay, or with uncertain historyand risks.

Disclosure Conflicts of interest: G.S. Sandhu: has received researchgrant support in development of MRI from Siemens Medical Solu-tions; J.L. Sunshine: has received research grant support in develop-ment of MRI from Siemens Medical Solutions.

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