World Stroke Congress 2008: Advances in Stroke Imaging: An Expert Interview With Marc Fisher, MD

Laurie Barclay, MD

Disclosures

December 19, 2008

The World Stroke Congress (WSC) highlighted advances in neuroimaging techniques as they apply to diagnosis, assessment, and prognosis of acute stroke.

At the WSC held in Vienna, Austria, from September 24 through 27, 2008, advances in neuroimaging techniques were presented as they apply to diagnosis, assessment, treatment monitoring, and prognosis of acute stroke, and integration into clinical practice.

Several studies highlighted the concept of ischemic penumbra, or the area of ischemic but still viable cerebral tissue surrounding the infracted area of nonviable tissue. Using magnetic resonance imaging (MRI) or computed tomography (CT) to define the penumbra may help identify those patients most likely to respond to thrombolytic therapy, whether with tissue plasminogen activator (tPA) alteplase or newly developed drugs such as desmoteplace.

Particularly noteworthy were recently published findings from the European Cooperative Acute Stroke Study (ECASS) suggesting that in selected patients, it may be safe and beneficial to treat acute stroke with intravenous alteplase beyond the usual therapeutic window of 3 hours after the onset of symptoms up to 4.5 hours.

To gain clinical perspective on these findings and their likely effects on diagnosis and management of acute stroke, Medscape interviewed Marc Fisher, MD, a professor of neurology at the University of Massachusetts Medical School. Dr. Fisher, who is widely published in stroke research, was co-author of 2 abstracts presented at WSC and will be writing an editorial for Stroke regarding the recent ECASS findings.

Medscape: What specific algorithms do you currently recommend for diagnosis and management of acute stroke?

Dr. Fisher: The typical paradigm for us when a patient with stroke first comes in: a plain CT to rule out hemorrhage, followed by a CT angiogram to look for the site of vascular occlusion. For many patients, we then go on to do CT perfusion to look for evidence of an ischemic penumbra. In the less-than-3-hour patients, we don't feel compelled to do the CT perfusion. For those who are beyond 3 hours, we do the CT perfusion to make a decision about whether we're going to do intra-arterial therapy. If we don't have evidence of a penumbral pattern on the CT perfusion, then we don't do intra-arterial therapy.

Medscape: How does this algorithm improve management?

Dr. Fisher: All this is unproven, but the basic hypothesis would be that if you're going to do intra-arterial treatment, you need a clot for the interventionalist to get at. We use evidence of a penumbral pattern on the CT perfusion to tell us that there is salvageable tissue that can be affected by opening the artery. We're making go-no go decisions; if there is no CT angiogram occlusion in the patient who is beyond 3 hours, then we stop there. The next step is to look for evidence of an ischemic penumbra.

Medscape: Do other institutions use other algorithms?

Dr. Fisher: An alternative option is to follow a similar protocol using MRI, but at our institution, it's harder to get patients into the MRI urgently, and time is really important. With either the CT or the MRI, the purpose of the first scanning procedure is to rule out brain hemorrhage, followed by accessible occlusion, then diffusion-perfusion mismatch. If access to the MR machine in our institution was similar to that of CT, I'd use MR. All the information can be obtained in one go. The data acquisition methods and processing are really pretty similar for both methods.

Medscape: Have studies been done with either the CT or the MR protocol to see how sensitive or specific they are?

Dr. Fisher: Neither of them has been validated, but with MR there have been an increasing number of studies. Depending on the patient population, there has been some suggestion that the diffusion-perfusion mismatch helps to identify patients who are more likely to respond to treatment. Most of these studies have used MRI, and some studies presented at the WSC support this suggestion.

Medscape: What is the role of imaging in determining prognosis of acute stroke, in assisting development of a treatment plan, and in monitoring response to treatment?

Dr. Fisher: We have done animal studies using MRI. These and clinical studies suggest that in ischemic stroke, the target is the penumbra, although there is no validated proof of this hypothesis. Therefore, penumbral imaging, with CT perfusion, for example, is useful in identifying patients who can benefit from thrombolytic therapy. The better the imaging technology is to identify the penumbra, the more useful it is for clinicians to make treatment decisions.

The concept of treating patients beyond the 3-hour window with thrombolytic therapy is based on the ischemic penumbra. If, in a clinical trial, you treat patients who won't respond to therapy because they don't have salvageable tissue, those patients are not informative and will affect the power of the trial.

There have been some phase 2 trials, and now we really need phase 3 trials to see whether imaging studies, whether CT or MRI, will help identify patients who won't respond to treatment such as tPA. I'm involved in a trial of neuroprotective therapy, and we're using MRI to select suitable patients who have evidence of penumbra for entry into the trial.

Medscape: At the WSC, what imaging studies were presented that you believe are especially noteworthy?

Dr. Fisher: At the Vienna meeting, a combined analysis of 3 trials was presented in which patients with diffusion-perfusion mismatch on MRI were selected for a trial of desmoteplace vs placebo.[1] If there was no diffusion-perfusion mismatch, these patients had no difference in 90-day outcomes with thrombolytic therapy vs placebo. The more mismatch, and therefore penumbra, they could identify pre-treatment, the more likely the patients were to respond to treatment. Penumbral selection is therefore important for patient selection for thrombolytic therapy.

Medscape: What other recent studies in acute stroke management do you feel are most important?

Dr. Fisher: The big news is findings from the ECASS trial published in the September issue of the New England Journal of Medicine.[2] This is the most important news in acute stroke therapy in 13 years.

ECASS looked at about 800 patients in whom alteplase (tPA) thrombolytic therapy could be started within 3 to 4.5 hours of acute stroke onset. The imaging they used in this trial was very primitive, just a head CT to exclude brain hemorrhage. Patients were also excluded if they had extensive evidence of ischemia.

The authors found that in the tPA group, more patients had a favorable outcome than in the placebo group, but mortality was similar in both groups. The risk for symptomatic hemorrhage was significantly higher with alteplase than with placebo, but it was still very small; 2.4% vs 0.2%, even though the incidence of any intracranial hemorrhage was 27.0% vs 17.6%.

At a superficial, simplistic level, it's a home run, because the findings show that in patients meeting inclusion and exclusion criteria used in the trial, we can extend the window to use intravenous tPA up to 4.5 hours, which will lead to a dramatic increase in the percentage of patients with ischemic stroke who will be treated, maybe from about 3% using the 3-hour window up to about 10%.

When you think about this with a little more depth, the problem I see with the trial is that it used very simplistic imaging. It doesn't really address questions of which patients are most likely to benefit from alteplase therapy because they didn't analyze subgroups of patients with stroke, using the National Institutes of Health ischemia severity scale, for example. In the data analysis, they didn't analyze strokes of different severity separately, so it may be that the treatment effect was restricted to very mild patients. For example, very severely impaired patients were excluded from the trial.

It's difficult to discern which patients responded to alteplase therapy and which patients are not likely to respond, which is a very big problem in day-to-day practice. I'll be writing an editorial for Stroke regarding this study, and I'll be asking whether there are more data.

Medscape: What future directions do you feel are important for stroke imaging research?

Dr. Fisher: The basic idea is to have more high quality imaging to better guide diagnosis and therapy. Other lytic drugs are being developed, such as desmoteplace.

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