Identifying the Ischemic Penumbra

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As discussed above, although irreversible cell death begins within minutes after stroke onset within regions of maximally reduced blood flow (the infarct "core"), for several hours there exists a surrounding "penumbra" of ischemic but noninfarcted tissue that is potentially salvageable [134-137]. The concept of an "ischemic penumbra" provides a rationale for the use of neuroprotective drugs and reperfusion techniques to improve outcome after acute ischemic stroke. However, the extent of penumbral tissue is thought to diminish rapidly with time, hence the therapeutic time window is narrow. With intravenous t-PA [the only stroke therapy approved by the Food and Drug Administration (FDA)] the window is 3 h, which severely limits its use [138]; delayed therapy increases the risk of hemorrhage [115]. Similarly, administering therapy outside of the therapeutic window is considered one of the most important factors leading to the failure of neuroprotective drug trials. Developing methods to rapidly and accurately identify the ischemic penumbra is therefore an important area of current stroke research.

Imaging studies have validated the concept that tissue viability is heterogeneous distal to an occluded brain blood vessel. In animal models, the ischemic penumbra can be visualized by autoradiographic techniques that compare regions of reduced blood flow to regions of actively metabolizing tissue (2-de-oxyglucose), or larger regions of suppressed protein synthesis to core areas with complete loss of ATP. In humans, imaging and biochemical studies similarly suggest that the window for efficacy may be prolonged in select individuals. Positron emission tomography (PET) [139,140] can detect oxygen-utilizing tissue (oxygen extraction fraction) within regions oflow blood flow,as well as locate "C-flumaze-nil recognition sites on viable neurons within under-perfused brain areas. While PET is arguably the most accurate method, the greatest promise and experience appear to lie with multimodal magnetic resonance imaging (MRI) and multimodal CT because of their widespread availability, lower cost, technical ease, and shorter imaging times. With MRI, there is often a volume mismatch between tissue showing reduced water molecule diffusion (a signature for cell swelling and ischemic tissue) and a larger area of compromised tissue perfusion early after stroke onset - the so-called diffusion-perfusion mismatch. The difference, at least for all practical purposes, is believed to reflect the ischemic penumbra [129, 141-144]. Perfusion MRI currently affords arelative, rather than absolute, quantitative measure of cerebral tissue perfusion. Recent studies indicate that perfusion-CT can also be used to identify regions of ischemic, noninfarcted tissue after stroke, and that perfusion-CT may be comparable to MRI for this purpose [145-147]. The main advantage of perfu-sion-CT is that it allows rapid data acquisition and postprocessing, and can be performed in conjunction with CT angiography to complete the initial evaluation of stroke [148]. Xenon-enhanced CT is a more accurate technique than perfusion-CT and provides quantitative measurements of cerebral blood flow within 10-15 min; however, it requires the use of specialized equipment and at present its use is restricted to only a few centers [149]. Imaging methods such as these can optimize the selection of candidates for thrombolytic therapy or for adjunctive therapy many hours after stroke onset. Importantly, imaging may also provide quantitative surrogate endpoints for clinical trials. Several clinical trials employing imaging to select patients who might benefit from delayed therapy are now in progress. The Desmo-teplase in Acute Ischemic Stroke Trial (DIAS) is the first published acute stroke thrombolysis trial using MRI both for patient selection and as a primary efficacy endpoint [150].In this trial,patients were selected on the basis of perfusion-diffusion mismatch on the admission MRI and treated as late as 3-9 h after stroke symptom onset with intravenous (i.v.) desmo-teplase, a newer plasminogen activator with high fibrin specificity. Desmoteplase-treated patients had significantly higher rates of reperfusion, as defined by MR-perfusion, and improved 90-day clinical outcome. These results support the utility of MRI in improving patient selection and as a surrogate outcome measure.

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