Jordana Bieze Foster

It's been a long, frustrating 12 years since an acute stroke drug last won over the FDA, a time in which the percentage of eligible patients actually helped by the drug has remained stuck in the single digits. All signs indicate, however, that the next acute stroke therapy to win approval will do so on the strength of a very different type of clinical trial, one that uses advanced imaging techniques to demonstrate the potential for doubling or even tripling the number of patients who may benefit.

Using penumbral imaging to identify salvageable regions of brain, new clinical trials are demonstrating that thrombolytic therapies can be effective well beyond the 3-hour window established with the 1996 approval of recombinant tissue plasminogen activator. Research even suggests that tPA itself can be effective up to 6 hours from stroke symptom onset in patients with an identifiable penumbra.

"Imaging could allow for a huge extension of the time window or even eliminate the time window," said Chelsea S. Kidwell, MD, an associate professor of neurology at Georgetown University and medical director of the Georgetown and Washington Hospital Center stroke centers.

Time is still brain. The sooner a stroke patient receives treatment-no matter what type of treatment-the better the odds it will be effective. Many clinicians feel, however, that the 3-hour time limit is the primary reason why as few as 3% of all stroke patients receive tPA.1 With ongoing trials suggesting that window could be extended to 9 hours, if not longer, many more patients stand to benefit.

"We will never treat more than 10% of patients if we're always constrained to 3 hours," said Anthony J. Furlan, MD, director of the Vascular Neurology Program and associate director of the Cerebrovascular Center at The Cleveland Clinic.

He estimated that an additional 10% to 15% of patients could receive therapy for every 3 hours added to the treatment window.

Expanding the time window alone does not appear to be enough, however. Several multicenter randomized placebo-controlled trials1-4 have tested the effectiveness of intravenous tPA beyond 3 hours using the same eligibility criteria as the pivotal 1995 clinical trial on which the drug's approval was based5 and failed to demonstrate efficacy. A pooled analysis of the same trials did suggest a benefit beyond 3 hours, but not extending to 6 hours.6

In a paper published in March 2006, however,7 German researchers studied 174 stroke patients who were selected for intravenous tPA treatment up to 6 hours from symptom onset. Patient selection was based on the presence of an ischemic penumbra, or mismatch, shown on MR diffusion- and perfusion-weighted imaging (DWI-PWI), meaning the MR perfusion volume of their brains delineating treatable stroke damage was at least 20% larger than the volume's diffusion core correlating with dead or irretrievably damaged tissue.

They then compared the results with those of the pooled treatment (n = 1085 patients) and placebo (n = 1081 patients) groups from the earlier analysis. Patients in the MRI-treated group were more likely than patients in either pooled group to have favorable 90-day outcomes based on the modified Rankin Scale (mRS), and they were significantly less likely than those in the pooled treatment group to have experienced symptomatic intracranial hemorrhage (sICH).

Even more convincing than the German retrospective assessment were the findings from the Diffusion-weighted imaging Evaluation For Understanding Stroke Evolution (DEFUSE) prospective multicenter study published 6 months later.8 DWI-PWI was not used for selection but was performed on 74 consecutive stroke patients given tPA within 3 to 6 hours of symptom onset. The presence or absence of early reperfusion, assessed using PWI immediately following therapy in 45 patients, was not associated with 30-day clinical outcome, measured using the National Institutes of Health Stroke Scale (NIHSS) and the mRS, in the overall group; however, those with early reperfusion and DWI-PWI mismatch were significantly more likely to have a favorable clinical response than patients with a DWI-PWI mismatch without early reperfusion (56% versus 19%). By comparison, none of the 4 patients with early reperfusion and no mismatch had favorable clinical outcomes.

The DEFUSE findings also suggest that not all mismatches are created equal. Of those patients with mismatch and early reperfusion, a pattern of large DWI lesions and/or large PWI lesions with long delays on a Tmax perfusion map was seen in 3 patients who died following sICH. When the patients with this "malignant mismatch" profile were excluded from the mismatch/early reperfusion analysis, the rate of favorable clinical response in the remaining "target mismatch" patients improved from 56% to 67%.

"The DEFUSE study seems to support what most of us thought, which is that you can extend the tPA window if you have the appropriate mismatch," said Marc Fisher, MD, a professor of neurology at the University of Massachusetts Medical School.

For further confirmation, clinicians and researchers are looking to the results of the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) conducted at 14 centers in Australia, New Zealand, and Europe.9 The study had enrolled 101 patients as of February. All had undergone DWI-PWI before being randomly selected to receive either intravenous tPA or a placebo 3 to 6 hours after symptom onset. Researchers hope to show that tPA in patients with DWI-PWI mismatch is associated with lower rates of DWI lesion expansion (from baseline to 90 days) and increased reperfusion. The study was completed in June.

Meanwhile, the most highly anticipated stroke imaging trial of the year left radiologists scratching their heads about the disappointing results. No more than 47% of acute stroke patients administered the clot-dissolving protein desmoteplase 3 to 9 hours after the onset of symptoms showed improvement. The positive outcome rate was about the same among patients given a placebo.

Desmoteplase (desmodus rodundus salivary plasminogen activator) is a thrombolytic agent derived from vampire bat saliva that many expect to be the next stroke drug to win FDA approval. It has been granted fast-track status. Potential advantages of desmoteplase include a longer half-life than tPA, which allows it to be administered in a single bolus injection rather than a continuous drip, and a high specificity for fibrin, which theoretically lowers the associated risk of hemorrhage. Clinical trials of desmoteplase from phase II onward have specified DWI-PWI mismatch as an inclusion criterion.

Researchers used functional MRI or perfusion CT in the Desmoteplase In Acute Ischemic Stroke study (DIAS II) to identify candidates for treatment. Promising candidates exhibited a positive diffusion-perfusion mismatch. CT perfusion used different parameters to generate the same results.

In total, 186 patients received either placebo or 1 or 2 doses of desmoteplase within 3 to 9 hours of symptom onset.

Compared with placebo, the clot-dissolving protein desmoteplase did not change clinical outcomes for acute ischemic stroke patients in the phase III clinical trial. Results were presented at the European Stroke Conference on May 31 in Glasgow by Dr. Werner Hacke, director of neurology at the University of Heidelberg in Germany.

Early desmoteplase studies suggested that the tPA treatment window could be expanded, particularly in patients with perfusion-diffusion mismatch. In the current study, however, clinical outcome did not differ among the 3 groups.

"This study should not be misinterpreted as proving that desmoteplase after 3 hours does not work or that patient selection after 3 hours with mismatch imaging is not reliable," said Dr. Anthony Furlan, coprincipal investigator and section head of stroke and neurologic intensive care at The Cleveland Clinic. "Rather, this study further emphasizes the complexity of treating acute stroke after 3 hours and the need for larger, more sophisticated clinical trials, the design of which will be informed by the results of trials like this one and other acute imaging-based studies."

Intravenous desmoteplase treatment appears safe, but clinical benefits remain uncertain, according to Furlan.

"We were disappointed in the results but not entirely surprised, since we were trying to answer many new questions with a small sample size," he said. "The hope was that by using new imaging technology to select patients for treatment, we could optimize patient selection. However, DIAS II indicates that the problem of reperfusion therapy after 3 hours is more complex than we anticipated."

Furlan suggests that a study with at least 600 participants would yield more information.

Researchers also are investigating whether MRI can help improve outcomes associated with the second acute stroke therapy to receive FDA approval, the Merci Retriever (Concentric Medical), a mechanical embolectomy device. Previous trials of the device12,13 demonstrated its effectiveness when used within 8 hours of symptom onset in patients with severe stroke (NIHSS score of 8 or more) who were either ineligible for tPA or in whom tPA did not achieve recanalization. The pooled results of those trials were presented in February at the annual International Stroke Conference in San Francisco.

The latest assessment of the Merci Retriever device, the MR and Recanalization of Stroke Clots Using Embolectomy (MR-RESCUE) study,14 will differ from previous trials in several ways. The most obvious, as the acronym suggests, is that one of the study's objectives is to use MRI to identify which patients will benefit from mechanical embolectomy. All 120 patients slated to be enrolled in the study will undergo MR-based penumbral imaging. After outcomes have been determined, researchers will analyze whether imaging patterns were predictive of success or failure.

In this case, however, ischemic penumbra is not being defined by DWI-PWI mismatch. Cognizant of the limitations of mismatch-based penumbral estimates, the MR-RESCUE researchers instead are using computer software modeled on quantitative diffusion and perfusion data from patients in whom recanalization was previously successful to more precisely quantify the extent of potentially salvageable tissue (Figure 1).

"We've set up all the sites so there's a computer attached to the scanner that calculates penumbra within minutes of the scan," said Kidwell, principal investigator for the study. "If we can demonstrate that this is useful, it's simply a matter of connecting a computer to the scanner, or it may be that a lot of imaging scanners can process this type of algorithm into their scanning protocols."

As in the earlier trials, outcome measures will include angiographically verified recanalization and 90-day clinical outcomes based on mRS score. MR-RESCUE patients will also undergo follow-up MRI at 7 days to confirm reperfusion, something not addressed by previous investigations. The MR-RESCUE trial will randomly select patients to receive either mechanical embolectomy or standard medical treatment, in an effort to address a common criticism of the earlier trials, in which all enrolled patients received treatment with the Merci Retriever.

"While we believe and hope the device works, it's imperative to have a control arm so that we can be sure," Kidwell said. "Probably, this will be the first and only randomized trial of mechanical embolectomy."

Because of the heterogeneous nature of stroke, many experts believe that the future of stroke therapy will depend not on any single form of treatment but rather some combination. DWI-PWI is being used for patient selection in a phase II trial of one such combination of the platelet aggregation inhibitor abciximab (ReoPro) and the recombinant plasminogen activator reteplase (Retavase). Inclusion criteria for the Reperfusion of Stroke Safety Study-Imaging Evaluation (ROSIE) trial include evidence of a perfusion defect on PWI and DWI lesions involving no more than one third of the middle cerebral artery territory, along with an NIHSS score of 16 or less and a time from symptom onset of 3 to 24 hours. Follow-up MRI is performed at 24 hours from the start of treatment to assess reperfusion.

Preliminary results in the first 34 patients, presented at the 2006 International Stroke Conference in Kissimmee, FL,15 suggest that acceptable reperfusion rates could be achieved with abciximab in combination with any of the tested doses of reteplase but not with abciximab alone. The study, which is scheduled to enroll 72 patients, is ongoing.

Imaging is playing a different role in another ongoing combination therapy trial, the third installment of the Interventional Management of Stroke studies, which is investigating the combined effects of intravenous and intra-arterial thrombolysis. All 900 projected enrollees in the IMS III trial will receive intravenous tPA. Those with angiographically detected occlusions will then receive 1 of 3 intra-arterial therapies: mechanical embolectomy using the Merci Retriever, conventional intra-arterial tPA, or sonothrombolysis, in which low-energy ultrasound is used along with tPA to accelerate clot lysis.

In the IMS II trial, sonothrombolysis delivered using the Neurowave microinfusion catheter (Ekos) achieved recanalization in 69% of 30 patients, compared with 50.5% of 18 patients given intra-arterial tPA using a standard microcatheter. Those results were also presented at the 2006 International Stroke Conference.16

One obvious question raised by the concept of using penumbral imaging to expand the therapeutic window is just how far the window can open. Research from Johns Hopkins University School of Medicine suggests the cutoff need not be 8 hours, or even 24 hours. After recognizing that a small but not insignificant number of stroke patients who arrived as transfers from other hospitals days after symptom onset still demonstrated persistent DWI-PWI mismatch, the Johns Hopkins researchers have had success treating these patients with induced hypertension.

In a study of 42 patients in whom MRI was performed more than 48 hours after symptom onset,17 15 patients had a mismatch pattern. Nine of the 42 patients (6 with mismatch) were treated with induced hypertension, with 8 demonstrating early improvement in neurological deficits. All 6 patients with mismatch improved, and follow-up PWI confirmed reperfusion in those patients (Figure 2).

Because clinicians and researchers are not routinely looking for mismatch in patients more than 48 hours after symptom onset, it's difficult to say how many patients may fall into this category or what the best form of treatment might be, said Robert J. Wityk, MD, an associate professor of neurology and medicine and codirector of the Cerebrovascular Division at Johns Hopkins.

"The disbelievers would say, here it is 3 to 4 days out and they're still seeing mismatch; it can't possibly mean anything," Wityk said. "We just want to know if there's something we can do to make them better."

Jordana Bieze Foster is a freelance writer based in Masschusetts and a frequent contributor to Applied Neurology.

1. Clark WM, Albers GW, Madden KP, Hamilton S. The rtpa (alteplase) 0-to 6-hour acute stroke trial, part a (a0276g): results of a double-blind, placebo-controlled, multicenter study. Thrombolytic therapy in acute ischemic stroke study investigators. Stroke 2000;31:811-816.

2. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS study: a randomized controlled trial. Alteplase thrombolysis for acute noninterventional therapy in ischemic stroke. J Am Med Assoc 1999;282:2019-2026.

3. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). J Am Med Assoc 1995;274:1017-1025.

4. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second Europen-Australasian Acute Stroke Study investigators. Lancet 1998;352:1245-1251.

5. NINDS Group. Tissue plasminogen activator for acute ischemic stroke. NEJM 1995;333:1581-1587.

6. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA Stroke Trials. Lancet 2004;363:768-774.

7. Thomalla G, Schwark C, Sobesky J, et al. Outcome and symptomatic bleeding complications of intravenous thrombolysis within 6 hours in MRI-selected stroke patients: Comparison of a German multicenter study with the pooled data of ATLANTIS, ECASS, and NINDS tPA trials. Stroke 2006;37:852-858.

8. Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging profiles predict clinical responses to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508-517.

9. Davis SM, Donnan GA. Echoplanar imaging thrombolysis evaluation trial: EPITHET. Presented at the American Stroke Association International Stroke Conference, Feb. 16, 2006, Kissimmee, FL.

10. Hacke W, Albers G, Al-Rawi Y, et al. The desmoteplase in acute ischemic stroke trial (DIAS): A phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005;36:66-73.

11. Furlan AJ, Eyding E, Albers GW, et al. Dose escalation of desmoteplase for acute ischemic stroke (DEDAS): Evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006;37:1227-1231.

12. Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: Results of the MERCI trial. Stroke 2005;36:1432-1440.

13. Smith WS. Safety of mechanical thrombectomy and intravenous tissue plasminogen activator in acute stroke. Results of the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, part I. AJNR 2006;27:1177-1182.

14. Kidwell CS, Jahan R, Starkman S, et al. MR and recanalization of stroke clots using embolectomy (MR-RESCUE). Presented at the American Stroke Association International Stroke Conference, Feb. 16, 2006, Kissimmee, FL.

15. Warach S, Butman J, Davis L, et al; the ROSIE Investigators. ReoPro Retavase Reperfusion of Stroke Safety Study-Imaging Evaluation (ROSIE): interim safety and efficacy results. Presented at the American Stroke Association International Stroke Conference late-breaking science oral abstracts, Feb. 18, 2006, Kissimmee, FL.

16. Tomsick T. Preliminary results of the IMS II trial. Presented at the American Stroke Association International Stroke Conference, Feb. 17, 2006, Kissimmee, FL.

17. Perez A, Restrepo L, Kleinman J, et al. Patients with diffusion-perfusion mismatch on magnetic resonance imaging 48 hours or more after stroke symptom onset: Clinical and imaging features. J Neuroimaging 2006;16:329-333.

Articles

More than a decade after the last FDA approval for a stroke drug, vampire bat saliva navigates process using updated techniques

Penumbral Imaging Propels Trials Toward Wider Therapeutic Window

It's one thing for acute stroke imaging to predict final infarct volume or a patient's risk of 90-day mortality. It's quite another for imaging to predict whether a patient will recover upper extremity dexterity or language skills, or to what extent the patient will be able to function independently.

Researchers are only beginning to explore MRI's potential for making these types of functional outcome predictions, and although some studies have in fact found lesion volume on MRI to be predictive of function, these have been plagued by methodological flaws.1 In April 2006, an 82-patient study conducted by researchers from the University of Edinburgh concluded that imaging variables were not independent 3-month outcome predictors for a heterogeneous group of patients but suggested that MR diffusion-weighted imaging might have predictive value in patients with severe stroke.2

Because the National Institutes of Health Stroke Scale is such a strong predictor of outcome, any added value from imaging may be inconsequential in patients with less severe stroke, in whom small NIHSS changes have large effects on outcome. In those with more severe stroke, small NIHSS changes have less of an effect on outcome, opening the door for MRI's additional predictive information to carry more weight.

"It might be worth using MR lesion volume as a predictor in patients with severe strokes only, but not in all strokes," said Joanna M. Wardlaw, MD, a professor of neuroradiology at Edinburgh.

Increasingly, researchers are examining the predictive value of MRI in the shorter term, looking for associations between lesion volume and acute functional recovery. Investigators from Dusseldorf reported that MRI-based penumbral imaging was predictive of recovery of grip force and movement rate during repetitive finger-thumb pinching movements between day 1 and day 8 after acute hemiparetic stroke in 36 patients.3 Researchers from Johns Hopkins University found that a diffusion-clinical mismatch, which uses clinical language tests instead of imaging to approximate perfusion abnormality, was predictive of language improvement within 1 week in 81 patients with acute left hemispheric stroke.4

Still largely unknown is the extent to which individual impairments, such as lack of grip strength, translate to functional impairment in a patient population known for its ability to compensate both neurologically and functionally. Such compensation mechanisms may render imaging better able to predict impairment than function, but this too may vary depending on stroke severity or other factors.

"What matters to patients and healthcare providers in general is whether the patient can return to independent existence, and if not, then how much help do they need," Wardlaw said.

1. Schiemanck SK, Kwakkel G, Post MW, Prevo AJ. Predictive value of ischemic lesion volume assessed with magnetic resonance imaging for neurological deficits and functional outcome poststroke: A critical review of the literature. Neurorehabil Neural Repair 2006;20:492-502.

2. Hand PJ, Wardlaw JM, Rivers CS, et al. MR diffusion-weighted imaging and outcome prediction after ischemic stroke. Neurology 2006;66:1159-1163.

3. Weller P, Wittsack HJ, Siebler M, et al. Motor recovery as assessed with isometric finger movements and perfusion magnetic resonance imaging after acute ischemic stroke. Neurorehabil Neural Repair 2006;20:390-397.

4. Reineck L, Agarwal S, Hillis AE. "Diffusion-clinical mismatch" is associated with potential for early recovery of aphasia. Neurology 2005;64:828-833.

Severe stroke patients could see greatest benefit from additional imaging information

MRI's predictive value may depend on patient selection

A growing body of research indicates that MR diffusion-weighted imaging (DWI) can help predict risk of recurrent stroke in patients presenting with transient ischemic attack. But a lack of proven therapeutic options-underscored by recent setbacks in trials of neuroprotective agents-will limit opportunities for imaging to play a preventive role in this frustrating patient population.

Recent evidence of MRI's predictive value in patients who have had a TIA came from researchers at the University of Pennsylvania, who found that patients with acute (within 48 hours) infarction on DWI were significantly more likely than patients with negative DWI findings to experience stroke, death, or other high-risk outcome within 90 days.1

In 61 patients who underwent MRI, 15 had 90-day outcomes categorized as high risk, which also included greater than 50% arterial stenosis related to symptoms or a cardioembolic source that warranted anticoagulation. In contrast, a scoring system based on age, blood pressure, clinical features, and duration of symptoms was not predictive of risk.

"It's kind of humbling, actually," said Brett L. Cucchiara, MD, an assistant professor of neurology at Penn and corresponding author of the study. "Patients with vague symptoms end up having diffusion abnormalities. Patients in whom I would have bet money that there was no diffusion abnormality ended up having an infarct."

The Penn findings, published in July 2006, were consistent with those of researchers from the University of Calgary in Alberta, Canada, published a year earlier.2 In 69 patients with TIA and 51 patients with minor stroke, the Calgary researchers found that the adjusted 90-day risk of new stroke was 32.6% in patients with an acute (within 24 hours of symptom onset) DWI lesion and vessel occlusion, 10.8% in those with a DWI lesion but no vessel occlusion, and 4.3% in those with negative DWIs. DWI findings also were predictive of functional dependence at 90 days.

As tempting as it may be to envision MRI becoming the type of screening tool for TIA that cardiac enzyme tests are for patients with chest pain, experts say that type of scenario is nowhere close to becoming reality.

"We may be able to identify patients who are vulnerable, but we don't necessarily have treatments that are proven," said Andrew M. Demchuk, MD, an associate professor of neurology and director of the Calgary stroke program.

Researchers and clinicians had hoped that neuroprotective agents might be just the type of therapy that could be used preventively in such a population. But optimism about neuroprotective agents, which surged after a successful trial of NXY-059 was published in February 2006,3 has waned since the second clinical trial of the same drug was discontinued in October because of lack of efficacy.

Whereas previous trials of NXY-059 and other potential neuroprotective agents have delivered the drugs in the hours following stroke onset, it's still possible that neuroprotective drugs might be more effective if administered preventively in the TIA population, according to Demchuk.

"In animals, some of the greatest benefit is that you can pretreat," he said. "But that's just a hypothesis. We've been so burned by neuroprotective approaches that the question is how much enthusiasm will there be to pursue this line of therapy."

1. Cucchiara BL, Messe SR, Taylor RA, et al. Is the ABCD score useful for risk stratification of patients with acute transient ischemic attack? Stroke 2006;37:1710-1714.

2. Coutts SB, Simon JE, Eliasziw M, et al. Triaging transient ischemic attack and minor stroke patients using acute magnetic resonance imaging. Ann Neurol 2005;57:848-854.

3. Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischemic stroke. NEJM 2006;354:588-600.

Screening tool may be ahead of its time, as results of recent trials fail to keep up with imaging advances

MRI of TIA faces barrier of therapeutic limitations

In the weeks leading up to the 2007 International Stroke Conference, stroke imaging experts could have been preparing to debate such cutting-edge topics as whether MRI or CT is best suited for the ischemic mismatch imaging techniques that one day will routinely be used to select patients for thrombolytic therapy. But 2 weeks before the February conference, the stroke imaging community instead was buzzing about a Jan. 27 Lancet study1 that was decidedly free of bells and whistles: a 356-patient single-site prospective comparison in which conventional gradient-echo and diffusion-weighted MRI outperformed unenhanced CT for the diagnosis of patients with suspected acute stroke.

Since noncontrast CT-based acute stroke diagnosis has become the norm in all but the most progressive centers, the financial and logistical barriers to augmenting or replacing frontline CT with MRI are formidable. Even so, the results of one clinical trial after another suggest the next generation of stroke therapies will almost certainly depend on penumbral imaging, for which researchers have for the most part favored perfusion-diffusion MRI techniques over CT perfusion. For physicians wary of making that philosophical leap, the results of the Lancet study, funded by the National Institute of Neurological Disorders and Stroke, may represent an important intermediate step.

Much of the attention given that study focused on what it did not do. It did not address the issue of penumbral imaging. It acknowledged but did not attempt to solve the issues of hospital logistics that often limit acute stroke patients' access to MRI in even the most elite academic institutions. Because patients who were too medically unstable to undergo MRI were excluded from the study, it did not fully address the issue of patients with severe stroke, in whom rapid diagnosis and triage is most critical. All of these factors must be considered in determining the most effective role for each imaging modality in stroke diagnosis and management.

But what the Lancet study did do was address the issue of MRI for acute stroke at its most basic level. The only stroke therapies currently approved by the FDA-intravenous tissue plasminogen activator within 3 hours of symptom onset and the Merci Retreiver mechanical embolectomy device in patients who are ineligible for intravenous tPA-won their approvals based on clinical trials in which the only imaging technique used in patient selection was unenhanced CT to rule out intracranial hemorrhage.2,3

Other research4-8 has suggested that diffusion-weighted MRI is not only equally capable of identifying hemorrhage but also more accurate for diagnosing acute ischemic stroke, particularly small lesions that are easily missed on CT. But no study had done so in a prospective manner, in a large sample of patients representative of populations seen in clinical practice, and with MRI performed prior to CT in the majority of patients (which theoretically biases the results in favor of CT, because infarcts are more easily detected over time).

Although the pivotal trial of tPA2 was published more than a decade ago, before diffusion-weighted and gradient-echo MR imaging were common practice, it essentially established unenhanced CT as the sole imaging prerequisite for intravenous tPA therapy.

By showing that MRI can rule out intracranial hemorrhage as effectively as unenhanced CT, within the same 3-hour window, the Lancet study challenged this premise. In addition, MRI identified acute ischemic stroke in 46% of 356 patients with suspected acute stroke, compared with 10% identified using unenhanced CT; in 90 patients scanned within 3 hours of symptom onset, acute ischemic stroke was detected in 46% using MRI and only 7% using CT.

"We have a method that for ischemic stroke is five times more effective than the so-called gold standard," said Steven Warach, MD, PhD, senior investigator and chief of stroke diagnostics and therapeutics at the NINDS and an author of the Lancet study. "MRI is more expensive, and hospitals have not made it as accessible as CT. But those are solvable problems. The obstacles are not technical or medical, they're more logistical."

The logistical obstacles, to be sure, are not trivial. Emergency departments in most community hospitals and even many academic centers do not have easy access to an MR scanner, because the scanner is on another floor, it is too often in use by other patients who cannot be rescheduled, or round-the-clock staffing is not available in the event that a patient arrives at 2 a.m. CT also has advantages for patients with contraindications to MRI or those who are medically unstable. About 75% of stroke patients at Massachusetts General Hospital present with minor strokes, according to unpublished data from the hospital. These respond well to intravenous tPA and may not require more sophisticated imaging.

Still, the remaining 25% of patients with severe stroke account for the majority of deaths, morbidity, and costs-up to 10 times more than minor strokes in hospital costs alone, said R. Gilberto Gonzalez, MD, PhD, a professor of radiology at Harvard Medical School and chief of neuroradiology at Massachusetts General Hospital.

Anticipating that those high-risk patients will benefit most from therapies that require MRI-based selection makes investing in MRI seem like a good idea at places like the University of California, San Diego, where radiology department chair William G. Bradley Jr., MD, boasts that two 3-Tesla scanners are being installed adjacent to emergency departments specifically for use on stroke patients.

"The future really is with MR," Bradley said. "CT is going to be the workhorse, but I think we'll learn a lot more with MRI."

MRI-based diagnosis of acute intracranial hemorrhage is based on the so-called deoxyhemoglobin border sign,9,10 a hypointense rim around an area of hyperintensity (well visualized on gradient-echo images), typically surrounded by edema (Figure 1). The Lancet study found no significant difference between CT and MRI for detecting acute intracranial hemorrhage, with 25 positive diagnoses made using CT (along with 3 false negatives) and 23 positive diagnoses made with MRI (4 false negatives).

These results are consistent with those of the Hemorrhage and Early MR Imaging Evaluation (HEME study) published by NINDS and University of California, Los Angeles, researchers in 2004,11 in which MR and CT were found to be equivalent for the diagnosis of acute intracerebral hemorrhage; in 4 cases, acute hemorrhagic transformation was seen on MRI but not on CT. That same year, using CT as the gold standard for comparison, researchers from the University of Heidelberg reported that MRI was 100% sensitive and accurate for intracerebral hemorrhage in the hands of experienced readers and 95% sensitive when read by medical students.12

The relative sensitivity of MRI and CT for intracranial hemorrhage is something that radiologists at UCSD have been tracking since MRI became accessible to the emergency department in the summer of 2003. But despite finding in favor of MRI in that regard, Bradley acknowledges that the circumstances under which intravenous tPA was approved present a potential liability issue for anyone who uses MRI alone to screen patients before administering the therapy.

"You pretty much have to do CT today," he said. "We've shown we can exclude hemorrhage very well with MR, but you run some risk if there's a problem."

Even research demonstrating the diagnostic equivalence of MRI and CT for ruling out hemorrhage may not fully address this issue, in the absence of a revised clinical trial of intravenous tPA using diffusion-weighted MRI alone instead of unenhanced CT alone. Such a revisiting of the original clinical trial protocol is unlikely, primarily because the emergence of perfusion-based penumbral imaging has convinced clinicians and researchers that the existence of salvageable tissue-not the number of hours from symptom onset, which was a key inclusion criterion in the 1995 tPA trial-should determine whether a patient receives thrombolytic therapy. And although both modalities can be used to generate the perfusion maps on which penumbral estimates are based, MR-based perfusion techniques have thus far spent the most time in the research spotlight.

The concept of the ischemic penumbra, initially studied in monkeys and confirmed using PET in humans,13 is based on the pattern of cerebral blood flow reduction that results from the ischemic event. Severely diminished levels of cerebral blood flow characterize the irreversibly infarcted core and differentiate it from the ischemic penumbra, or region of potentially salvageable tissue, which also experiences reduced blood flow but can be sustained for a number of hours by collateral circulation. During this time, thrombolytic therapy is most likely to be effective.

MRI-based penumbral imaging, which has emerged as a surrogate for the clinically impractical PET, uses diffusion-weighted imaging (DWI) techniques to define the ischemic core and perfusion-weighted imaging (PWI) techniques to define the extent of cerebral blood flow reduction (Figure 2). The mismatch between the 2, or the region between the perimeter of the core and the perimeter of the hypoperfused area, represents the ischemic penumbra.

Because penumbral imaging has shown that mismatch persists for many hours after the 3-hour window for intravenous tPA has closed, multiple clinical trials of new therapeutic options14-17 and expansion of the tPA window18,19 are testing the concept of treatment based on MRI-determined penumbra rather than time from symptom onset (see accompanying article). If these physiology-based trials lead to FDA approvals, a much higher percentage of stroke patients would be eligible for treatment than the 3% to 8.5% who currently receive intravenous tPA.20 And if selection criteria for the approved therapies require diffusion and perfusion imaging, that would almost certainly mean a much bigger role for MRI in acute stroke management.

"It'll change the whole imaging paradigm," said Anthony J. Furlan, MD, director of the vascular neurology program and associate director of the cerebrovascular center at The Cleveland Clinic.

To be sure, MRI-based penumbral imaging isn't perfect. Unlike PET, MRI provides an estimate rather than a true measure of blood flow. Coupled with the heterogeneous distribution of ischemia, this means that diffusion MRI may in fact overestimate the amount of irreversibly infarcted tissue and perfusion MRI may overestimate the extent of hypoperfusion.

"Mismatch is a very simplistic view of acute cerebral ischemia," said David Liebeskind, MD, neurology director of stroke imaging and associate neurology director of the UCLA Stroke Center. "It's only representative of the moment in time when you happen to be injecting the contrast media. So doing a diffusion-perfusion study at 1 point is not necessarily going to tell you what's going to happen 3 hours later. When you add that no 2 patients are identical, it becomes difficult to classify or stratify based on exact thresholds of mismatch."

Perhaps not surprisingly, questions abound as to which of the many perfusion-weighted imaging parameters provide the best estimate and what degree of mismatch should define penumbra. In a review of 11 papers describing DWI-PWI findings in patients with acute stroke, researchers from the University of Edinburgh identified 5 different definitions of mismatch and 7 different methods for measuring perfusion.21 In their own 46-patient study, the same researchers also found that approximately half of patients without DWI-PWI mismatch experienced lesion growth (11 of 21 when cerebral blood flow was used as the perfusion parameter, and 5 of 13 when mean transit time was used), suggesting that MRI-based penumbral imaging does not identify all patients who might benefit from stroke therapy.22

"Most studies of thrombolysis and mismatch did not include patients without mismatch, so we do not know whether they will benefit from thrombolysis or not," said Joanna M. Wardlaw, MD, a professor of neuroradiology at the University of Edinburgh and coauthor of both studies.

Researchers are continuing to refine the techniques used to define DWI-PWI mismatch. A multivariate voxel-based model developed at UCLA, which achieved 81% accuracy in initial reports,23 is currently being incorporated into the MR-RESCUE (MR and recanalization of stroke clots using embolectomy) study.17 Marc Fisher, MD, a professor of neurology at the University of Massachusetts Medical School, is among those leading efforts to assess the feasibility in animal models of using arterial spin labeling perfusion to develop probability density maps.

Despite the limitations of DWI-PWI mismatch and the lack of consensus as to how precisely it should be used, however, stroke physicians do agree that therapy based on a penumbral estimate-even an imperfect estimate-is still preferable to the current time-dependent paradigm.

"We're trying to get information that helps us decide whether to treat somebody," Gonzalez said. "We just need to know that there's a major penumbra. To be practical, it has to be easy to evaluate. Is it going to be scientifically perfect? No. But you don't need that."

Studies have shown perfusion CT to be comparable to diffusion-perfusion MRI for defining ischemic penumbra24,25 (Figure 3). Perfusion CT is being included as a selection tool in the second installment of the phase III Desmoteplase in acute ischemic stroke (DIAS-2) trial.

Like its MRI counterpart, CT perfusion provides only an estimate of ischemic penumbra. Interpretation of CT perfusion maps is generally thought to be more technically difficult than that of diffusion- and perfusion weighted images. A 2004 study from the Barrow Neurological Institute found postprocessing of CT perfusion data by 3 experienced technologists resulted in less reproducibility than the authors felt would be necessary for clinical practice.26

"CT perfusion is not as easy as one would think," said Furlan, who has been an investigator with multiple clinical trials, including DIAS-2. "We see some variability between centers."

Still, the fact that CT is far more accessible than MRI in most emergency rooms means that the future of stroke imaging will likely include penumbral imaging using both modalities.

"What I envision is that smaller hospitals will do CT perfusion, and bigger hospitals will do MRI," Fisher said.

He noted that telemedicine may also come to play an important role when the CT perfusion images obtained at smaller centers that have limited stroke expertise need to be interpreted.

That scenario is essentially an extension of the "drip and ship" model used in many areas, where CT is done and intravenous tPA initiated within the 3-hour window at a small hospital, while ineligible patients and severe cases-which represent approximately 25% of stroke patients, in whom intravenous tPA is unlikely to be effective-are transported to a major stroke center for MR and angiographic imaging and intra-arterial thrombolysis or mechanical embolectomy.

But if the current evolution in ambulance triage protocols unfolds in such a way that patients with severe strokes are taken directly to major stroke centers, the potential for utilization of penumbral imaging-and improved patient outcomes-will be that much greater.

"To me, this is the key to the future of stroke care," Fisher said. "We need to increase the number of patients we treat, which means we need to treat them later after onset, and it doesn't do any good to treat them after the tissue is gone."

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Prospective single-site study sets stroke community buzzing about performance of MR imaging versus unenhanced CT for triage of stroke type and severity

Jordana Bieze Foster

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