The Interface Between Technology and Acute Ischemic Therapy

Development

MARC FISHER

Department of Neurology, University of Massachusetts Medical School, 119 Belmont Street, Worcester, MA 01545, USA

(Received 11 January 2013; accepted 19 February 2013)

Associate Editor Matthew Gounis and Baruch Lieber oversaw the review of this article.

Abstract—The evaluation and treatment of acute ischemicstroke patients is a rapidly evolving area in contemporarymedical practice that has experienced many recent advances.The interface between physicians and scientists/engineers hasbecome a major driver for these advances. This special issuebrings together contributions from physicians andresearchers from a broad spectrum of disciplines who worktogether to solve the challenges in the management of strokepatients.

Keywords—Acute ischemic stroke, Imaging, Clinical trials,

Thrombolysis.

The evaluation and treatment of acute ischemicstroke (AIS) patients is a rapidly evolving area incontemporary medical practice that has experiencedmany recent advances. The interface between physi-cians and scientists/engineers has become a majordriver for these advances. One area of mutual interestand interaction among these stakeholders is imagingwhich has provided a real time window into the pre-viously terra incognito of patient’s brains with an acutecerebrovascular event.22 From the initial use of com-puterized tomography in the 1970s to rapidly delineatethe presence of intracerebral hemorrhage, the devel-opment of CT angiography to evaluate the patency orlack thereof in AIS patients and the demonstrationthat standard and advanced MRI techniques could notonly acutely distinguish between hemorrhagic andischemic stroke but also provide information about theexistence of potentially salvageable ischemic tissue, i.e.,the ischemic penumbra, imaging technology has beena key element in improving stroke diagnosis and a

beacon for the development/implementation of noveltherapies.9,15 Another important area of interactionbetween physicians and scientists/engineers is the devel-opment of nonpharmacological therapies to recanalizeoccluded vessels within the brain or to enhance thenatural process of recovery after AIS.

The target of AIS therapy is ischemic tissue that canbe salvaged with timely therapy to reduce infarct sizeand to mediate a better functional outcome.4 Theexistence of potentially salvageable ischemic tissue orthe ischemic penumbra was initially observed in animalstroke models and hypothesized in humans.5 If theischemic penumbra is the target of AIS therapy, thenthe ability to identify its existence and extent wouldprovide a mechanism to treat more patients effectivelyand potentially at later time points after onset. MRIappears to afford this opportunity because diffusion-weighted MRI (DWI) demonstrates severely ischemicbrain tissue quickly after AIS onset and it wasobserved in both animals and humans that this ische-mic region expands over time.12 The DWI lesionin most situations represents the ischemic core or irre-versibly damaged, ischemic region, although it must beacknowledged that DWI lesions can to a minor extentbe reversed with early therapeutic intervention.8

Another MRI technique that contributes to the evalu-ation of the ischemic lesion and can help to identify theischemic penumbra is perfusion-weighted MRI (PWI).PWI in AIS patients is typically acquired by the injec-tion of a contrast agent that has paramagnetic prop-erties, so as it transits the brain vasculature the contrastagent attenuates T2* signal acquisition.23 With rapidsequential imaging at 1 s intervals, a signal washoutcurve is acquired. In ischemic brain tissue the decline inT2* signal intensity is attenuated because delivery ofthe contrast agent is impeded by the vascular occlusionor stenosis underlying the event. By comparing the

Address correspondence to Marc Fisher, Department of Neu-

rology, University of Massachusetts Medical School, 119 Belmont

Street, Worcester, MA 01545, USA. Electronic mail: fisherm@

ummhc.org

Cardiovascular Engineering and Technology (� 2013)

DOI: 10.1007/s13239-013-0138-6

� 2013 Biomedical Engineering Society

normal hemisphere to the ischemic one, maps of meantransit time and time to peak of the signal intensitycurve can be derived, leading to a semi-quantitativedepiction of cerebral blood flow. Ischemic tissue can bedefined and its volume quantified. It was suggested thatthe brain region that is abnormal on PWI but normalon DWI provides an approximation of the ischemicpenumbra.20 Identifying the DWI lesion is straight-forward because it is easily identifiable as a region ofhyperintensity. Defining the PWI lesion is problematicbecause it requires accurate thresholding to provide aprecise delineation of which brain tissue has a sufficientdegree of blood flow reduction that places this tissue atrisk of infarction without early reperfusion.6 Currently,so-called Tmax mapping is recommended for the mostaccurate identification of the PWI lesion and a Tmax

delay of 5–6 s as compared to the normal hemisphereappears to be an appropriate threshold for PWI lesionidentification.14

Evidence has accumulated that the use of DWI/PWIMRI to approximate the ischemic penumbra providesuseful information. In the DEFUSE study AISpatients with a PWI lesion >20% larger than the DWIlesion, DWI/PWI mismatch who received intravenoustissue plasminogen activator (tPA)in the 3–6 h timewindow and who successfully recanalized an arterythat was occluded prior to treatment had a morefavorable clinical outcome than those patients who didnot recanalize.1 In the DEFUSE study, it was alsoobserved that a malignant mismatch pattern identifieda group of patients more likely to have hemorrhagiccomplications and a poor outcome. The malignantpattern identified in DEFUSE was either a very largebaseline DWI lesion, more than 100 cm3 or a largePWI lesion that was quite severe. In the DEFUSE-2study, the same imaging approach was used but all ofthe AIS patients were treated with an endovasculardevice therapy up to 8 h from stroke onset.11 Again itwas observed that patients with a >20% DWI/PWImismatch who were successfully recanalized with theendovascular therapy had a substantially better clinicaloutcome. Patients who did not have a DWI/PWImismatch were not benefitted by recanalization andactually tended to have a more unfavorable outcomethan patients who were not recanalized. A third study,the EPITHET trial, randomized patients to intrave-nous tPA or placebo between 3–6 h after AIS onset,after DWI and PWI were performed.2 Patients treatedwith tPA who had a DWI/PWI mismatch tended tohave less ischemic lesion growth and a better clinicaloutcome. Several clinical case series also demonstratedthat patients with a DWI/PWI mismatch treated in the3–6 h time window with intravenous tPA had favor-able clinical outcomes, comparable to patients treatedin the <3 h time window.17,19 In aggregate the current

data suggests that DWI/PWI mismatch imaging can-not only identify patients more likely to respond tointravenous tPA or endovascular device therapy butthat this imaging approach can also potentially iden-tify patients who are not likely to respond and may beat increased risk for adverse effects.3 Further studiesare needed to conclusively prove that penumbralimaging with MRI can indeed identify AIS patientsmore or less likely to respond to treatment, especiallyat prolonged time windows after stroke onset.

The second AIS area of interaction between scien-tists/engineers and the medical community is in thedevelopment of nonpharmacological therapies, i.e.,devices. The AIS device therapy approach furthestalong the clinical development pathway is devicesemployed to recanalize occluded arteries. Two earlydevices that demonstrated promise for a reasonabledegree of intracranial vascular opening were theMERCI and PENUMBRA devices.16,21 Both deviceswere evaluated in studies that did not have a contem-porary, nontreated control group, but when comparedto historical untreated controls in a prior intra-arterialthrombolysis trial demonstrated a significantly higherrate of recanalization. Both of these studies includedpatients out to 8 h after stroke onset but did not selectpatients based upon the identification of a persistentischemic penumbra. Importantly, neither of thesedevices demonstrated any evidence of improved clini-cal outcome when compared to the aforementionedhistorical control group. Both the MERCI and PEN-UMBRA devices were cleared for use by the devicebranch of the FDA and were subsequently widely usedby the neurointerventional community. More recently,data concerning two new devices that are stent-retrievers emerged. Both of these two devices, SOLI-TAIRE and TREVO were compared in randomizedtrials to the older MERCI device in AIS patients whowere quite severely affected at baseline and treatmentwas initiated up to 8 h after stroke onset. The SOLI-TAIRE and TREVO devices achieved significantlygreater rates of recanalization of the occluded intra-cranial vessel when compared to the predicate MERCIdevice and in both of these trials the rate of day-90favorable clinical outcome was significantly better withthe stent-retriever.13,18 In the SOLITAIRE trial 58%of the SOLITAIRE patients had a favorable outcomevs. 33% of the MERCI patients and in the TREVOtrial 40% of the patients treated with that device had afavorable outcome vs. 21% of the MERCI treatedpatients. The rates of favorable outcome with these 2stent-retrievers is quite remarkable when consideringthe late time point of treatment initiation and the quitesevere level of pretreatment stroke induced deficit.Neither the SOLITAIRE nor TREVO trials employedMRI-based penumbral imaging for patient selection.

M. FISHER

Based upon the results of DEFUSE-2 discussed pre-viously, a study that employed either the older MERCIor PENUMBRA devices, it can be hypothesized thatMRI-based penumbral identification when combinedwith the powerful ability of both the SOLITAIRE andTREVO devices to safely and effectively induce arterialrecanalization should provide a very effective meansfor maximizing beneficial treatment outcomes in AISpatients with large and medium size vessel occlusionwho present for medical evaluation up to 8 h afteronset. Trials are being organized in which these twodevices and other newer devices will be compared tostandard medical therapy in patients who also haveimaging confirmed ischemic penumbra. It can beanticipated that these trials will provide conclusiveevidence that device induced recanalization can sig-nificantly improve clinical outcome with a modestsample of patients included in the trials and that pen-umbral imaging will enhance the selection of patientsmore likely to benefit from such treatment.

A second area of device therapy development forAIS is devices primarily targeted to improve upon thenatural tendency of AIS patients who survive torecover function to some extent. The first device cur-rently in phase III clinical development in this area isone that delivers external laser light energy to both theischemic and nonischemic sides of the brain. Twopreliminary human studies of this laser light deviceemployed up to 24 h after stroke onset demonstratedencouraging trends of improved outcome.10,24 Unfor-tunately, a phase III trial was recently stopped forfutility. A second device currently in phase III trials isone that stimulates the sphenopalatine ganglion,leading to an enhancement of blood flow. Preliminarystudies of this device initiated up to 24 h after strokeonset also have shown benefits on clinical outcome.7

The result of the current trial should also be availablein the not too distant future. Because of the relativelylate time window for deployment of these two devicesit is unlikely that they affect the evolution of theischemic lesion and it is much more likely that anybenefits observed with them relate to effects on brainrecovery/reorganization.

The increasingly encouraging endeavor to improvediagnostic and treatment capabilities for AIS requiresinput and expertise from a wide variety of talented anddedicated contributors. Physicians have advancedknowledge and insights about the clinical and patho-physiological components of AIS and are also eager toimprove and expand treatment capabilities. Scientistsand engineers bring much important and wide rangingknowledge to these areas and have already providedmany important advances to stroke diagnosis andtreatment paradigms. Future collaborations basedupon taking advantage of the knowledge of all

contributors to multidisciplinary teams will maximizethe important and ongoing efforts to enhance ourability to better care for AIS patients.

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M. FISHER