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September 1, 2001

New imaging strategies for patient selection for thrombolytic and neuroprotective therapies

September 1, 2001 issue
57 (suppl_2) S48-S52


Ischemic stroke trials have traditionally sought to limit the range of disease studied according to several dimensions based on clinical examination and CT scan results. It has been proposed that the optimal sample for stroke trials would include a positive imaging diagnosis of a pathology rationally linked to the drug’s mechanisms of action and that this would improve the likelihood of positive results.
This principle has been supported by the results of the Prolyse in Acute Cerebral Thromoembolism II (PROACT II) study. Whereas trials of iv thrombolysis between 3 and 6 hours after symptom onset in a general sample of patients were not positive, selection of a subgroup by angiography was an effective strategy in this time period for PROACT II. This study contradicted the hypothesis that treatment of stroke beyond 3 hours would not be successful.
MRI with diffusion and perfusion has been an appealing imaging modality because it provides pretreatment angiography, perfusion, and lesion volume information during a brief, non-invasive assessment. Current literature supports the validity of MRI as a marker for clinical severity and clinical improvement. The diffusion–perfusion mismatch, the MRI marker for the ischemic penumbra, is a very strong predictor of lesion volume growth. Several acute trials in progress use a positive imaging diagnosis for the basis of selection. As the field of stroke clinical trials examines opportunities for improving trial design, positive imaging diagnoses in patient selection are likely to assume an increasingly useful role.

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The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med . 1995; 333: 1581–1587.
Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism [in process citation]. JAMA . 1999; 282: 2003–2011.
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 European-Australasian Acute Stroke Study Investigators. Lancet . 1998; 352: 1245–1251.
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). JAMA . 1995; 274: 1017–1025.
Moseley ME, Cohen Y, Mintorovitch J, et al. Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and spectroscopy. Magn Reson Med . 1990; 14: 330–346.
Lovblad KO, Laubach HJ, Baird AE, et al. Clinical experience with diffusion-weighted MR in patients with acute stroke. AJNR . 1998; 19: 1061–1066.
Warach S, Chien D, Li W, Ronthal M, Edelman RR. Fast magnetic resonance diffusion-weighted imaging of acute human stroke [published erratum appears in Neurology 1992;42: 2192]. Neurology . 1992; 42: 1717–1723.
Warach S, Gaa J, Siewert B, Wielopolski P, Edelman RR. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol . 1995; 37: 231–241.
Baird AE, Warach S. Magnetic resonance imaging of acute stroke [published erratum appears in J Cereb Blood Flow Metab 1998;18: preceding 1047]. J Cereb Blood Flow Metab . 1998; 18: 583–609.
Lovblad KO, Baird AE, Schlaug G, et al. Ischemic lesion volumes in acute stroke by diffusion-weighted magnetic resonance imaging correlate with clinical outcome. Ann Neurol . 1997; 42: 164–170.
Warach S, Dashe JF, Edelman RR. Clinical outcome in ischemic stroke predicted by early diffusion-weighted and perfusion magnetic resonance imaging: a preliminary analysis. J Cereb Blood Flow Metab . 1996; 16: 53–59.
Barber PA, Darby DG, Desmond PM, et al. Prediction of stroke outcome with echoplanar perfusion- and diffusion-weighted MRI. Neurology . 1998; 51: 418–426.
Barber PA, Davis SM, Darby DG, et al. Absent middle cerebral artery flow predicts the presence and evolution of the ischemic penumbra. Neurology . 1999; 52: 1125–1132.
Beaulieu C, de Crespigny A, Tong DC, Moseley ME, Albers GW, Marks MP. Longitudinal magnetic resonance imaging study of perfusion and diffusion in stroke: evolution of lesion volume and correlation with clinical outcome. Ann Neurol . 1999; 46: 568–578.
Darby DG, Barber PA, Gerraty RP, et al. Pathophysiological topography of acute ischemia by combined diffusion-weighted and perfusion MRI. Stroke . 1999; 30: 2043–2052.
Marks MP, Tong DC, Beaulieu C, Albers GW, de Crespigny A, Moseley ME. Evaluation of early reperfusion and i.v. tPA therapy using diffusion- and perfusion-weighted MRI. Neurology . 1999; 52: 1792–1798.
Warach S, Li W, Ronthal M, Edelman RR. Acute cerebral ischemia: evaluation with dynamic contrast-enhanced MR imaging and MR angiography. Radiology . 1992; 182: 41–47.
Schlaug G, Benfield A, Baird AE, et al. The ischemic penumbra: operationally defined by diffusion and perfusion MRI. Neurology . 1999; 53: 1528–1537.
Baird AE, Benfield A, Schlaug G, et al. Enlargement of human cerebral ischemic lesion volumes measured by diffusion-weighted magnetic resonance imaging. Ann Neurol . 1997; 41: 581–589.
Tong DC, Yenari MA, Albers GW, O’Brien M, Marks MP, Moseley ME. Correlation of perfusion- and diffusion-weighted MRI with NIHSS score in acute (6.5 hour) ischemic stroke. Neurology . 1998; 50: 864–870.
Linfante I, Llinas RH, Caplan LR, Warach S. MRI features of intracerebral hemorrhage within 2 hours from symptom onset. Stroke . 1999; 30: 2263–2267.
Schellinger PD, Jansen O, Fiebach JB, Hacke W, Sartor K. A standardized MRI stroke protocol: comparison with CT in hyperacute intracerebral hemorrhage. Stroke . 1999; 30: 765–768.
Patel MR, Edelman RR, Warach S. Detection of hyperacute primary intraparenchymal hemorrhage by magnetic resonance imaging. Stroke . 1996; 27: 2321–2324.
Laubach HJ, Jakob PM, Lovblad KO, et al. A phantom for diffusion-weighted imaging of acute stroke. J Magn Reson Imaging . 1998; 8: 1349–1354.
Warach S, Pettigrew LC, Dashe JD, et al. The effect of citicoline on ischemic lesions as measured by diffusion-weighted magnetic resonance imaging. Ann Neurol . 2000; 48: 713–722.
Prescription Drug User Fee Reauthorization and Drug Regulatory Modernization Act of 1997. House of Representatives Report, 105th Congress, 1st session, Report 105-310, Section 4, 1997:54–56.

Information & Authors


Published In

Volume 57Number suppl_2September 1, 2001
Pages: S48-S52
PubMed: 11552055

Publication History

Published online: September 1, 2001
Published in print: September 1, 2001


Affiliations & Disclosures

Steven Warach, MD, PhD
From the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.


Address correspondence and reprint requests to Dr. Steven Warach, National Institute of Neurological Disorders and Stroke, Section on Stroke Diagnostics and Therapeutics, 36 Convent Drive, MSC 4129, Room 4A03, Bethesda, MD, 20892-4129.

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