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Science to Practice |
Department of Neuroradiology,
Beth Israel Deaconess Medical Center,
Shapiro 4th Floor, 330 Brookline Ave,
Boston, MA 02215,
e-mail: dhackney@bidmc.harvard.edu
SUMMARY
On the basis of these data, it appears that MR imaging can assist in measuring the effect of thrombolytic therapy. This has immediate application to laboratory and clinical trials of experimental treatment. The application of this imaging approach to routine patient care will depend on the still unknown value of predicting the infarct size and the ischemic penumbra in choosing therapy for patients with this difficult problem.
THE SETTING
There have been important advances in treatment of acute brain ischemia during the past decade due to both established protocols of intravenous thrombolytic therapy leading to substantial improvements in outcome and to numerous other approaches in various stages, from preliminary trials to clinical practice (1). Unfortunately, intravenous thrombolysis is reserved for patients who are seen for treatment within a few hours after onset of symptoms. Intraarterial thrombolysis can be instituted at longer delays, but this may be available only at specialized centers. Most patients with strokes arrive at the emergency department too late for intravenous therapy. These restraints on who is eligible for thrombolysis, and when, are due to the rapidly increasing risk of hemorrhage with increasing time after the ictus, and, to a lesser extent, the decreasing efficacy in reversing deficits. In most laboratory studies of thrombolysis, the size of the infarction is not confirmed before the treatment is instituted, which limits the precision of estimates of the effects of therapy. In this issue of Radiology, Chen et al (2) report a study that addresses these problems; their results imply that better selection of patients and newer treatments may substantially improve outcomes.
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Chen et al (2) induced ischemia in rats by using a standard model and then performed magnetic resonance (MR) imaging to estimate the volumes of brain that were ischemic or that displayed abnormal diffusion. In clinical studies, the difference between ischemic and abnormal diffusion (ie, the penumbra) is a useful, but not perfect, marker of irreversible injury (3). Chen et al were able to measure the effect of microplasmin at two dose levels and standard tissue plasminogen activator (tPA) on eventual infarct size. They found that the volume of brain with abnormal diffusion and with infarction, which was assessed with triphenyltetrazolium chloride staining, was reduced in each treatment group compared with that of the control group. They also found that bleeding rates were similar to or less than those of the control group for the microplasmin groups but were significantly above those of the control group for the tPA group (P < .05). Thus, their results demonstrate the ability to identify the ischemic and putatively infarcted regions before therapy, to institute therapy in a model that compares thrombolytic agents, and to document the response and complication rates. These findings serve as a model for future laboratory investigations of treatment of acute stroke and unify the approaches developed for clinical studies.
THE PRACTICE
Clinical use:
Clinical care, clinical trials, and experimental studies of stroke rely on predictions of the expected infarction volume in the absence of therapy. These predictions are necessary to estimate the likely benefit of intervention and to assess efficacy after treatment. Historically, these predictions were based on the severity and duration of symptoms. Unfortunately, this results in rather crude estimates, because these factors do not account for wide ranges of ischemia within the symptomatic brain.
Imaging has made a major contribution by permitting far more accurate predictions of infarct volume. However, results of MR and computed tomography (CT) still present only snapshots of a dynamic process. Current clinical imaging protocols for patients with stroke include assessment of hemorrhage and the region of ischemia and attempts to identify irreversibly injured brain tissue (3). Investigators have established the "ischemic penumbra" as a critical concept in stroke. This is postulated to be tissue that is ischemic but not yet irreversibly injured and destined for infarction. With MR imaging, the difference between brain tissue with low perfusion (usually defined as that with elevated transit time or prolonged time to peak) and abnormal slow diffusion has been considered a good estimate of the ischemic penumbra. This region is often taken to represent brain tissue that may be protected from infarction with prompt thrombolytic therapy. Results of animal and human studies have shown that the region of abnormal slow diffusion does not always represent brain tissue destined for infarction. There are as yet no standardized definitions of the ischemic penumbra, and studies have varied criteria (4). Thus, the assumption that a small penumbra argues against institution of therapy may be inappropriately conservative.
CT perfusion is a more recent addition to stroke imaging. It appears to produce information comparable to that produced by MR imaging for perfusion estimates. Although there is no CT version of diffusion imaging, it appears that CT perfusion may display regions of irreversible ischemia as having low cerebral blood volume (5). It is too soon to know whether the cerebral blood volume criterion for prediction of irreversible injury is as confounded as is the slow diffusion criterion. Outside of clinical trials, the current treatment recommendation remains administration of intravenous tPA for patients seen within 3 hours of symptom onset who meet inclusion criteria, and perhaps intraarterial thrombolysis for those seen within 3–6 hours of symptom onset. There is a small but finite risk of catastrophic hemorrhage among patients who fit these indications. There is also a suspicion that many patients with longer duration of symptoms would respond well to therapy, if those at low risk of hemorrhage could be identified.
Future opportunities and challenges:
The severity of brain injury, and presumably the bleeding risk, depend not only on the duration but also on the depth of ischemia, a factor that is not captured by simply counting the hours since onset. Imagers hope that the size of the infarct core will help predict bleeding risk and that the size of the ischemic penumbra will help predict potential response to therapy. Neurologists hope that, whatever the predictive value of imaging, they will be able to offer patients treatments that are safer and more effective.
FOOTNOTES
See also the article by Chen et al in this issue.
References
Related Article
This article has been cited by other articles:
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  S. Siemonsen, T. Fitting, G. Thomalla, P. Horn, J. Finsterbusch, P. Summers, C. Saager, T. Kucinski, and J. Fiehler T2' Imaging Predicts Infarct Growth beyond the Acute Diffusion-weighted Imaging Lesion in Acute Stroke Radiology, September 1, 2008; 248(3): 979 - 986. [Abstract] [Full Text] [PDF]
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