Published online before print July 22, 2004, doi: 10.1161/01.STR.0000138450.15078.b5
(Stroke. 2004;35:2099.)
© 2004 American Heart Association, Inc.
Original Contributions |
Are There Time-Dependent Differences in Diffusion and Perfusion Within the First 6 Hours After Stroke Onset?
From the Departments of Neuroradiology (J.F., T.K., K.K., H.Z.) and Neurology (M.R., G.T., C.W., J.R.), University Hospital Eppendorf, University of Hamburg, Germany.
Correspondence to Dr Jens Fiehler, Department of Neuroradiology, Universitätsklinikum Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail fiehler{at}uke.uni-hamburg.de
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionConclusionReferences |
|---|
Background and Purpose— Stroke heterogeneity in computed tomography-based studies has been attributed as main cause for missing efficacy of intravenous tissue plasminogen activator (tPA) therapy within 3 to 6 hours. We investigated early time-dependent differences in acute stroke pathophysiology by multiparametric magnetic resonance imaging (MRI).
Methods— Stroke MRI of 112 acute ischemic stroke patients within <6 hours were dichotomized into a <3-hour group (n=52) and a 3- to 6-hour group (n=60). Infarct volume was determined on days 5 to 8. Lesion volumes were determined for apparent diffusion coefficient (ADC_man) and the subregion with ADC values <550x10–9 mm/s2 (ADC <550), and for the time-to-peak (TTP) delay of 2 to 4 seconds, 4 to 6 seconds, 6 to 8 seconds, and >8 seconds. A subsample analysis was performed for occlusions of the middle carotid artery (MCA) trunk (n=36) and MCA branches (n=30), and for all patients treated by intravenous tPA (n=70).
Results— ADC and TTP lesion volumes were not different within <3 hours compared with volumes at 3 to 6 hours. In patients receiving intravenous tPA (n=70), there were no significant differences in ADC_man, TTP >2 seconds, and infarct volume (days 5 to 8) between the 2 groups. There was a greater proportion of ADC <550/ADC_man, which was most pronounced in patients with MCA trunk occlusions after 3 to 6 hours and a larger mismatch in the <3-hour group compared with that of the 3- to 6-hour group. In MCA branch occlusions, there was a less severe TTP delay after 3 to 6 hours. However, all differences missed the significance level (P=0.05) after correction for multiple testing.
Conclusions— We observed no significant time-dependent differences within 6 hours after stroke onset in degree and volume of diffusion and perfusion impairment. An exclusion from intravenous tPA solely based on a rigid 3-hour time window seems unjustified in MRI-confirmed ischemic stroke.
Key Words: ischemia • magnetic resonance imaging • magnetic resonance imaging, diffusion-weighted • stroke, acute • thrombolysis
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferences |
|---|
Intravenous therapy with tissue plasminogen activator (tPA) is effective if initiated within 3 hours after stroke onset.1 The extension within a 3- to 6-hour time window did not prove effective in the European Cooperative Acute Stroke Study II study2 or in several other trials.3–5 A number of factors may have contributed to this failure, but stroke heterogeneity has been cited as the main cause.6 Apparently, this heterogeneity does not nullify the efficacy of intravenous tPA treatment within the time period of <3 hours but does not allow effective treatment without patient selection within 3 to 6 hours.
The success of the Prolyse in Acute Cerebral Thromboembolism Trial II study7 within the 6-hour time window might be attributed at least in part to the design focused on the angiographically proven middle cerebral artery (MCA) occlusion. It was argued that an appropriate selection of stroke patients might extend the window also for intravenous thrombolysis toward 6 hours after stroke onset.8,9 Noncontrast computed tomography alone appears to have little predictive value on lesion growth.10–12 Multiparametric MRI, however, can delineate large volumes of tissue at risk for infarction13,14 even beyond the 3-hour time window.15
We investigated early time-dependent differences in perfusion and diffusion parameters in acute stroke by multimodal MRI with the hypothesis of a shrinking "tissue at risk." Several perfusion and diffusion parameters were compared between patients examined in the <3-hour time window versus those examined after 3 to 6 hours. We sought to characterize the "tissue at risk" by analyzing the degree and the volume of ADC decrease16,17 and perfusion delay.18
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferences |
|---|
Imaging
One-hundred twelve consecutive patients with an ischemic stroke caused by a vessel occlusion in the anterior circulation within 6 hours after stroke onset and a completed follow-up imaging on days 5 to 8 were identified in a retrospective analysis of our prospective stroke database from February 2000 to August 2003. An additional MRI was performed in most of the cases (n=89) after 24 hours. There were no limitations caused by other MR findings, age, or severity of symptoms. Multiparametric MRI was performed immediately after clinical evaluation and before possible thrombolysis with tPA. The lesion volume was determined on computed tomography of days 5 to 8 if MRI was not feasible because of extensive monitoring devices from intensive care. A stroke neurologist assessed the National Institutes of Health Stroke Scale (NIHSS) score at each imaging time point. Informed consent was obtained from all patients. The local ethics committee approved the study. Forty patients15 and 68 patients,17 respectively, were subjects of previous studies with different focus.
MRI studies were performed on a 1.5-T clinical whole-body scanner (Magnetom Symphony/Sonata, Siemens) using a standard head coil. The measurements included an axial diffusion-weighted imaging (DWI) sequence, a perfusion-weighted imaging (PWI) sequence, a magnetic resonance angiography (MRA), and in most of the cases a fluid-attenuated inversion recovery (FLAIR) sequence. The table time was <20 minutes in most of cases. Sequence parameters have been detailed recently.19
Determination of Occlusion Type, Postprocessing, and Statistical Analysis
The localization of vessel occlusion was determined from the initial MRA study. Occlusion type was categorized as follows:20 (1) occlusion of the internal carotid artery (ICA) in the neck with accompanying MCA embolism (ICA/MCA); (2) occlusion of the intracranial bifurcation of the ICA (carotid "T" occlusion [CTO]); (3) MCA and anterior cerebral artery occlusion without CTO (ACA/MCA); (4) proximal MCA trunk occlusion (MCA trunk); (5) MCA trifurcation lateral to the medial lenticulostriate arteries (MCA trif); and (6) single or multiple MCA branch occlusion with free trifurcation (MCA branch).
Recanalization was analyzed from the follow-up MRI study after 24 hours on the basis of the PWI and MRA studies. Reperfusion within <20% volume of the initial TTP abnormality was classified as "failed reperfusion;" other incomplete and complete recanalization/reperfusion were classified as "successful reperfusion."
Postprocessing of the DWI and PWI image data was performed offline using SCAN from the University of California Stroke Attack Team. The ADC was determined on a pixel-by-pixel base using the Stejskal–Tanner equation and the b values of 0 and 1000 of the trace images. After manual delineation of ADC lesion volumes (ADC_man),the lesion volumes with severe ADC decreases (ADC <550) were determined using a threshold function (550x10–9 mm/s2). Remaining volumes in ADC_man with ADC values of >550x 10–9 mm/s2 are indicated by ADC >550 (Figure 1). Additionally, the ratio of ADC <550/ADC_man was determined. For PWI, the changes in T2* were expressed as change in relaxation rate (DeltaR2*, where R2*=1/T2*) and calculated as DeltaR2*(t)=–ln[Si (t)/S0]/TE, where Si (t) is the signal intensity at the time point t after injection of the contrast agent, S0 is the signal intensity without contrast agent, and TE is the echo time. Principles of the indicator dilution theory for nondiffusible tracers were applied to the analyzed concentration time curves. Time-to-peak (TTP) delay maps were calculated as time delay from the peak of the arterial input function to the maximum of SI changes within the affected hemisphere. The arterial input function was determined from pixels at the location of the MCA contralateral to the side of infarct, where the bolus shape was high and steep and the full width at half-maximum was small.21
|
The brain volume with a perfusion deficit was manually delineated in comparison to the contralateral hemisphere. Using a threshold function within this region, TTP delay volumes in steps of 2 to 4 seconds, 4 to 6 seconds, 6 to 8 seconds, and >8 seconds were classified, following previous reports.18 The entire lesion volume with a delay of >2 seconds was summarized as TTP >2 seconds. The mismatch volume was defined as TTP >2 seconds – ADC_man (VOL_mism). The b=0 images of the DWI scan of days 5 to 8 were used as T2-weighted images for manual delineation of final lesion volumes (infarct). If MRI was not feasible on days 5 to 8 because of extensive monitoring devices from intensive care, outcome lesion volume was determined by manual delineation on a computed tomography scan (n=6).
Statistical analysis was performed using SPSS 11.02. Data were dichotomized into a <3-hour group and a 3- to 6-hour group. A Mann–Whitney U test for independent samples was used to evaluate significant differences (P<0.05) between groups of lesion volumes (ADC <550, ADC_man, TTP >2 seconds, the TTP delay volumes, and VOL_mism) and also the ratio of ADC <550/ADC_man. Infarct volume was determined in patients treated with intravenous tPA therapy. Significant differences were primarily reported without correction for multiple testing to avoid a type 2 error (false acceptance of the null hypothesis). Bonferroni correction for multiple tests has been performed in a second step. Pearson correlation coefficient and results of a linear regression analysis with time as a independent variable are reported for the parameters ADC_man, TTP >2 seconds, and VOL_mism.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferences |
|---|
One-hundred twelve patients (41 women and 71 men, age 62±13 years [mean±SD]) with MRI within 6 hours (3.0±1.0 [mean±SD] hours) after stroke onset and on days 5 to 8 were analyzed. Initial NIHSS score was 13.6±4.7. Patients were treated conservatively (acetyl salicylic acid and low-molecular-weight heparin; n=24), with early hemicraniectomy (n=2), by intravenous tPA (n=70), or with intra-arterial tPA (n=8). Eight patients were treated within a randomized, placebo-controlled, double-blinded acute stroke trial. Patients were categorized in 2 groups: (1) patients with MRI <3 hours (<3-hour group, n=52) and (2) patients with MRI 3 to 6 hours after stroke onset (3- to 6-hour group, n=60). The following occlusion types were observed (<3-hour group/3- to 6-hour group): proximal ICA/MCA (n=5/13), CTO (n=5/10), combined ACA/MCA (n=2/2), MCA trif (8/1), MCA trunk (n=17/19), and MCA branch (n=15/15). There were more patients treated with intravenous tPA therapy in the <3-hour group than in the 3- to 6-hour group, and more patients were treated with intra-arterial tPA therapy in the 3- to 6-hour group (Table).
|
There were no significant differences between the <3-hour group and the 3- to 6-hour group in the following parameters (Table): entire ADC lesion volume (ADC_man),ADC <550, TTP >2 seconds lesion volume (Figure 1), mismatch volume, TTP delay volumes, and the NIHSS score evaluated on day 0 and on days 5 to 8. Correlation analysis revealed no significant correlation of the parameters ADC_man (R=0.009, P=0.925), TTP >2 seconds (R=0.052, P=0.596), and VOL_mism (R=0.059, P=0.545) with time (Figure 2). Only the ratio of severe ADC decreases (ADC <550/ADC_man) was larger in the 3- to 6-hour group than in the <3-hour group (0.39 versus 0.32; P=0.049). This difference missed the significance level of P=0.05 after correction for multiple testing, as did all further differences reported.
|
To correct for the considerable heterogeneity of occlusion types between the <3-hour group and the 3- to 6-hour group, an analysis of the largest subsamples [patients presenting with occlusion of the MCA trunk (n=36) and MCA branches (n=30)] was performed. Patients with occlusion of the MCA trunk showed a larger mismatch volume (200 versus 139 mL, P=0.047) in the <3-hour group compared with the 3- to 6-hour group. The TTP >2 seconds volume was not significantly different between both groups (P=0.051). Patients in the 3- to 6-hour group showed a considerably larger ratio of severe ADC decreases (ADC <550/ADC_man; 0.32 versus 0.49, P=0.017) within the entire ADC lesion. There were no significant differences in other lesion volumes (Figure 3). In patients with occlusion of MCA branches, there was a smaller volume with a TTP delay of >8 seconds and a larger volume with a TTP delay of 2 to 4 seconds, and a significantly larger volume in the 3- to 6-hour group (Figure 3). Other lesion volumes and the ratio of severe ADC decreases were not different between both groups.
|
Because of the heterogeneity in therapy regimens of the entire groups imaged at <3 hours and at 3 to 6 hours, the comparison of infarct volumes of days 5 to 8 (Figure 4a) and the analysis of recanalization data (Figure 4b) were performed only in patients receiving intravenous tPA. In these patients, the ADC_man and TTP >2 seconds lesion volumes and final lesion volumes on days 5 to 8 were not significantly different in the <3-hour group (n=38) as compared with the 3- to 6-hour group (n=32) (Figure 4).
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferences |
|---|
The novel aspect of our study is the comparison of the degree and the volume of the diffusion and perfusion abnormality in a <3-hour group and a 3- to 6-hour group after onset of ischemic stroke; we tested the hypothesis that the "tissue at risk" is shrinking. In our study of 112 stroke patients, there were no significant differences between the entire <3-hour group and the entire 3- to 6-hour group after stroke onset in both lesion volumes of perfusion or diffusion abnormality and of mismatch volume (Table, Figure 1b through 1d). In the subsample of patients receiving intravenous tPA (n=70), there were no differences in initial DWI and PWI lesion volumes or in final infarct volume between patients treated <3 hours and after 3 to 6 hours. Thus, we observed no inferior effect of intravenous tPA beyond the 3-hour time window concerning the infarct volumes in our sample. The missing differences in lesion volumes between the time windows were in line with the study of Rother et al.15
Small differences in initial MRI parameters became apparent foremost after categorization into occlusion types. The subgroup of patients with occlusion of the MCA trunk (n=36) showed a smaller mismatch volume 3 to 6 hours after stroke onset. Without change of the total ADC lesion volume, there was a larger volume with severe ADC decreases (ADC <550) within 3 to 6 hours after stroke onset, reflecting the more severe metabolic impairment. Patients with occlusion of MCA branches (n=30) did not show differences in lesion volumes of perfusion or diffusion abnormality and mismatch volume but showed a less severe TTP delay (Figure 3). However, it has to be acknowledged explicitly that after correction for multiple tests, none of these significant differences was seen anymore.
These observations suggest that there are very small differences in diffusion and perfusion indicating a marginally decreasing volume of salvageable tissue. Neither these small differences nor the lower recanalization rate after 3 to 6 hours showed a measurable effect on final infarct volume after tPA (Figure 4). Thus, our data give no explanation for the diminishing benefit from intravenous tPA after 3 to 6 hours. The increasing likelihood of hemorrhage over time has been considered as an obvious reason for this effect.22 However, a recent analysis of pooled computed tomography-based stroke trials found no association between the time from symptom onset to start of treatment and the occurrence of substantial hematoma.23
In line with several authors, we considered ADC decreases <550x10–9 mm/s2 as severe.24–28 We observed no ADC lesion growth over time but a greater volume of severe ADC decreases (ADC <550) within the entire ADC lesion (0.39 versus 0.32). There was a lower proportion of severe ADC decreases (ADC <550/ADC_man) within <3 hours, especially in occlusions of the MCA trunk (0.32 versus 0.49).
Both the volume13,14 and the severity18,29 of the initial perfusion deficit are associated with the growth of the initial DWI lesion at follow-up imaging. After categorization into occlusion types, we observed a larger mismatch volume in MCA trunk occlusion at <3 hours. In patients with MCA branch occlusions, the TTP delay of >8 seconds was larger and the tissue volume with a TTP delay of 2 to 4 seconds was smaller at <3 hours than at 3 to 6 hours (Figure 3). Given that a TTP delay >4 seconds correlates with functional deficit and that the hypoperfused tissue and TTP delay >6 seconds correlate with infarct volume,18 our observations may indicate toward a higher risk of lesion growth at <3 hours or marginally more salvageable tissue.
One of the drawbacks of the study is that most of the patients were examined near the 3-hour cutoff within 2 to 4 hours after symptom onset (Figure 2a). Problems caused by a somewhat inaccurate determination of the time point from symptom onset cannot completely be ruled out. This possible stochastic error might obscure further time-dependent differences. However, these data reflect the clinical reality of acute stroke management, and the 3-hour cutoff derived from the available clinical information is important for therapy decisions in many centers. Inherent limitations of the perfusion MRI methodology should also be considered. Especially in patients with steno-occlusive disease, the usage of the AIF from the contralateral MCA21 might result in an overestimation of the region with abnormal flow.30
|
Conclusion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferences |
|---|
Based on our MRI data, the "tissue at risk" and thus the salvageable tissue are not significantly shrinking within 6 hours after stroke onset. An exclusion from intravenous tPA solely based on a rigid 3-hour time window seems not justified in MRI-confirmed ischemic stroke.
|
Acknowledgments |
|---|
We acknowledge the Boehringer Ingelheim Foundation for supporting a research cooperation of Dr Fiehler with University of California at Los Angeles. Dr Weiller is supported by EU/QLK 6-CT-1999-02140. Furthermore, we acknowledge helpful discussions with our partners within the Kompetenznetzwerk Schlaganfall sponsored by the Bundesministerium für Bildung und Forschung (B5; No. 01GI9902/4).
Received February 19, 2004; revision received May 20, 2004; accepted June 21, 2004.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferences |
|---|
- Tissue plasminogen activator for acute ischemic stroke. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995; 333: 1581–1587.
[Abstract/Free Full Text] - Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. 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.[CrossRef][Medline] [Order article via Infotrieve]
- Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, Rosen D, Stewart-Wynne EG, Tuck RR. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian StreptoKinase (ASK) Trial Study Group. JAMA. 1996; 276: 961–966.[Abstract]
- Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial–Italy (MAST-I) Group. Lancet. 1995; 346: 1509–1514.[CrossRef][Medline] [Order article via Infotrieve]
- Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. 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. JAMA. 1999; 282: 2019–2026.
[Abstract/Free Full Text] - Muir KW, Grosset DG. Neuroprotection for acute stroke: making clinical trials work. Stroke. 1999; 30: 180–182.
[Abstract/Free Full Text] - Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II Study: a randomized controlled trial. PROlyse in Acute Cerebral Thromboembolism. JAMA. 1999; 282: 2003–2011.
[Abstract/Free Full Text] - Hacke W, Warach S. Diffusion-weighted MRI as an evolving standard of care in acute stroke. Neurology. 2000; 54: 1548–1549.
[Free Full Text] - Albers GW. Expanding the window for thrombolytic therapy in acute stroke. The potential role of acute MRI for patient selection. Stroke. 1999; 30: 2230–2237.
[Abstract/Free Full Text] - Patel SC, Levine SR, Tilley BC, Grotta JC, Lu M, Frankel M, Haley EC Jr, Brott TG, Broderick JP, Horowitz S, Lyden PD, Lewandowski CA, Marler JR, Welch KM. Lack of clinical significance of early ischemic changes on computed tomography in acute stroke. JAMA. 2001; 286: 2830–2838.
[Abstract/Free Full Text] - Roberts HC, Dillon WP, Furlan AJ, Wechsler LR, Rowley HA, Fischbein NJ, Higashida RT, Kase C, Schulz GA, Lu Y, Firszt CM. Computed tomographic findings in patients undergoing intra-arterial thrombolysis for acute ischemic stroke due to middle cerebral artery occlusion: results from the PROACT II Trial. Stroke. 2002; 33: 1557–1565.
[Abstract/Free Full Text] - Kucinski T, Koch C, Eckert B, Becker V, Kromer H, Heesen C, Grzyska U, Freitag HJ, Rother J, Zeumer H. Collateral circulation is an independent radiological predictor of outcome after thrombolysis in acute ischaemic stroke. Neuroradiology. 2003; 45: 11–18.[Medline] [Order article via Infotrieve]
- Baird AE, Benfield A, Schlaug G, Siewert B, Lovblad KO, Edelman RR, Warach S. Enlargement of human cerebral ischemic lesion volumes measured by diffusion-weighted magnetic resonance imaging. Ann Neurol. 1997; 41: 581–589.[CrossRef][Medline] [Order article via Infotrieve]
- Sorensen AG, Copen WA, Ostergaard L, Buonanno FS, Gonzalez RG, Rordorf G, Rosen BR, Schwamm LH, Weisskoff RM, Koroshetz WJ. Hyperacute stroke: simultaneous measurement of relative cerebral blood volume, relative cerebral blood flow, and mean tissue transit time. Radiology. 1999; 210: 519–527.
[Abstract/Free Full Text] - Rother J, Schellinger PD, Gass A, Siebler M, Villringer A, Fiebach JB, Fiehler J, Jansen O, Kucinski T, Schoder V, Szabo K, Junge-Hulsing GJ, Hennerici M, Zeumer H, Sartor K, Weiller C, Hacke W. Effect of intravenous thrombolysis on MRI parameters and functional outcome in acute stroke <6 hours. Stroke. 2002; 33: 2438–2445.
[Abstract/Free Full Text] - Oppenheim C, Grandin C, Samson Y, Smith A, Duprez T, Marsault C, Cosnard G. Is there an apparent diffusion coefficient threshold in predicting tissue viability in hyperacute stroke? Stroke. 2001; 32: 2486–2491.
[Abstract/Free Full Text] - Fiehler J, Knudsen K, Kucinski T, Kidwell CS, Alger JR, Thomalla G, Eckert B, Wittkugel O, Weiller C, Zeumer H, Rother J. Predictors of apparent diffusion coefficient normalization in stroke patients. Stroke. 2004; 35: 514–519.
[Abstract/Free Full Text] - Neumann-Haefelin T, Wittsack HJ, Wenserski F, Siebler M, Seitz RJ, Modder U, Freund HJ. Diffusion- and perfusion-weighted MRI. The DWI/PWI mismatch region in acute stroke. Stroke. 1999; 30: 1591–1597.
[Abstract/Free Full Text] - Fiehler J, Foth M, Kucinski T, Knab R, von Bezold M, Weiller C, Zeumer H, Rother J. Predictors of apparent diffusion coefficient normalization in stroke patients. Stroke. 2002; 33: 79–81.
[Abstract/Free Full Text] - Kucinski T, Koch C, Grzyska U, Freitag HJ, Kromer H, Zeumer H. The predictive value of early CT and angiography for fatal hemispheric swelling in acute stroke. Am J Neuroradiol. 1998; 19: 839–846.[Abstract]
- Ostergaard L, Weisskoff RM, Chesler DA, Gyldensted C, Rosen BR. High resolution measurement of cerebral blood flow using intravascular tracer bolus passages. I. Mathematical approach and statistical analysis. Magn Reson Med. 1996; 36: 715–725.[Medline] [Order article via Infotrieve]
- Marler J, Tilley B, Lu M, Brott T, Lyden P, Grotta J, Broderick J, Levine S, Frankel M, Horowitz S, Haley E, Lewandowski C, Kwiatkowski TP. Early stroke treatment associated with better outcome: the NINDS rt-PA Stroke Study. Neurology. 2000; 55: 1649–1655.
[Abstract/Free Full Text] - Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick J, Brott T, Frankel M, Grotta J, Haley E, Kwiatkowski T, Levine S, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley B, Albers G, Bluhmki E, Wilhelm M, Hamilton S; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of Atlantis, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 6: 768–774.
- Pierpaoli C, Alger JR, Righini A, Mattiello J, Dickerson R, Des Pres D, Barnett A, Di Chiro G. High temporal resolution diffusion MRI of global cerebral ischemia and reperfusion. J Cereb Blood Flow Metab. 1996; 16: 892–905.[CrossRef][Medline] [Order article via Infotrieve]
- Kidwell C, Saver J, Mattiello J, Starkman S, Vinuela F, Duckwiler, Gobin Y, Jahan R, Vespa P, Kalafut M, Alger J. Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann Neurol. 2000; 47: 462–469.[CrossRef][Medline] [Order article via Infotrieve]
- Tong D, Adami A, Moseley M, Marks M. Relationship between apparent diffusion coefficient and subsequent hemorrhagic transformation following acute ischemic stroke. Stroke. 2000; 31: 2378–2384.
[Abstract/Free Full Text] - Adami A, Thijs V, Tong DC, Beaulieu C, Moseley ME, Yenari MA. Use of diffusion weighted MRI to predict the occurrence and severity of hemorrhagic transformation in a rabbit model of embolic stroke. Brain Res. 2002; 944: 32–39.[CrossRef][Medline] [Order article via Infotrieve]
- Selim M, Fink JN, Kumar S, Caplan LR, Horkan C, Chen Y, Linfante I, Schlaug G. Predictors of hemorrhagic transformation after intravenous recombinant tissue plasminogen activator: prognostic value of the initial apparent diffusion coefficient and diffusion-weighted lesion volume. Stroke. 2002; 33: 2047–2052.
[Abstract/Free Full Text] - Schlaug G, Benfield A, Baird A, Siewert B, Lovblad K, Parker R, Edelman R, Warach S. The ischemic penumbra: operationally defined by diffusion and perfusion MRI. Neurology. 1999; 53: 1528–1537.
[Abstract/Free Full Text] - Yamada K, Wu O, Gonzalez RG, Bakker D, Ostergaard L, Copen WA, Weisskoff RM, Rosen BR, Yagi K, Nishimura T, Sorensen AG. Magnetic resonance perfusion-weighted imaging of acute cerebral infarction: effect of the calculation methods and underlying vasculopathy. Stroke. 2002; 33: 87–94.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  G. Thomalla, A. Kruetzelmann, S. Siemonsen, C. Gerloff, M. Rosenkranz, J. Rother, and J. Fiehler Clinical and Tissue Response to Intravenous Thrombolysis in Tandem Internal Carotid Artery/Middle Cerebral Artery Occlusion: An MRI Study Stroke, May 1, 2008; 39(5): 1616 - 1618. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Oppenheim, C. Lamy, E. Touze, D. Calvet, M. Hamon, J.-L. Mas, and J.-F. Meder Do transient ischemic attacks with diffusion-weighted imaging abnormalities correspond to brain infarctions? AJNR Am. J. Neuroradiol., September 1, 2006; 27(8): 1782 - 1787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Wu, S. Christensen, N. Hjort, R. M. Dijkhuizen, T. Kucinski, J. Fiehler, G. Thomalla, J. Rother, and L. Ostergaard Characterizing physiological heterogeneity of infarction risk in acute human ischaemic stroke using MRI Brain, September 1, 2006; 129(9): 2384 - 2393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Thomalla, C. Schwark, J. Sobesky, E. Bluhmki, J. B. Fiebach, J. Fiehler, O. Zaro Weber, T. Kucinski, E. Juettler, P. A. Ringleb, 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, March 1, 2006; 37(3): 852 - 858. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-W. Kang, J. A. Chalela, W. Dunn, S. Warach, and NIH-Suburban Stroke Center Investigators MRI Screening Before Standard Tissue Plasminogen Activator Therapy Is Feasible and Safe Stroke, September 1, 2005; 36(9): 1939 - 1943. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||