Evolution of Lesion Volume in Acute Stroke Treated by Intravenous t-pa

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1 JOURNAL OF MAGNETIC RESONANCE IMAGING 22:23 28 (2005) Original Research Evolution of Lesion Volume in Acute Stroke Treated by Intravenous t-pa Jean-Baptiste Pialat, MD, 1 * Marlene Wiart, PhD, 1 Norbert Nighoghossian, MD, PhD, 1 Patrice Adeleine, PhD, 2 Laurent Derex, MD, PhD, 1 Marc Hermier, MD, PhD, 1 Jean-Claude Froment, MD, 1 and Yves Berthezene, MD, PhD 1 Purpose: To determine the evolution of the ischemic lesion volumes in a population treated with tissue plasminogen activator (t-pa), MRIs were performed before treatment and 24 hours later; final infarct size was evaluated 60 days later. Materials and Methods: A total of 42 patients with hemispheric stroke were recruited for a thrombolytic study. Intravenous t-pa was given after MRI within the first seven hours after stroke onset. Volumes were evaluated on day 0 and day 1 with diffusion-weighted imaging (DWI), on day 60 with T2-weighted imaging (T2WI), and recanalization was assessed based on day 1 MR angiography (MRA). Results: Lesion volume increased between day 0 and day 1, and decreased between day 1 and day 60. It was lower in the group of patients with recanalization on day 1 MRA. Conclusion: Volume analysis emphasizes the effectiveness of recanalization as a predictive factor for better outcome, based on final infarct size. The decrease in lesion volumes between day 1 and day 60 suggests that other factors leads to overestimation of day 1 abnormal diffusion volume. This could explain the delayed partial reversibility of the DWI abnormality. Key Words: brain; infarction; magnetic resonance; thrombolysis; stroke J. Magn. Reson. Imaging 2005;22: Wiley-Liss, Inc. 1 Laboratoire CREATIS, Unité Médicale de Recherche CNRS 5515 Unité 630 INSERM, Lyon, France. 2 Service de Biostatistiques, Hospices Civils de Lyon, Lyon, France. *Address reprint requests to: J.B.P., Service de Radiologie, Hôpital de la Croix Rousse, 103 grande rue de la Croix Rousse Lyon cedex 04, France. jean-baptiste.pialat@chu-lyon.fr Received August 9, 2004; Accepted April 4, DOI /jmri Published online in Wiley InterScience ( MRI DIFFUSION-WEIGHTED IMAGING (DWI) represents a useful tool for detecting early ischemia (1,2). The combination of DWI with perfusion weighted imaging (PWI) allows the assessment of mismatch areas. The mismatch concept is helpful to explain the growth potential of the ischemic lesion and the clinical outcome (3 5). However, animal and human studies are consistent with a partial reversibility of DWI lesions (6 10); accordingly, we aimed to assess the course of volume growth through a sequential study. MATERIALS AND METHODS Patient Protocol Consecutive patients who presented to our stroke unit with symptoms of acute hemispheric stroke were recruited for this prospective study. Inclusion criteria included the following: 1) acute internal carotid artery (ICA) territory stroke, regardless of severity; 2) stroke symptom duration of less than seven hours; 3) absence of hemorrhage on baseline brain computed tomography (CT) scan; and 4) no contraindication to MRI or thrombolysis (e.g., recent serious head trauma, recent major surgery, recent history of urinary or gastrointestinal bleeding, and known coagulopathies). Exclusion criteria were: 1) prior intracranial hemorrhage; 2) preexisting neurological, psychiatric, or other illness that would confound the neurological evaluation; and 3) lack of informed consent obtained from the patient or his/her authorized representative. Intravenous thrombolysis with a recombinant tissue plasminogen activator (t-pa), alteplase (Actilyse; Boehringer Ingelheim, Biberach, Germany), was given after MRI completion within the first seven hours after stroke onset according to a previously published protocol (11). MRI Protocols Stroke MRI was performed at presentation, on day 1 after symptom onset, and a follow-up MRI was performed on day 60. All MRIs were obtained using a 1.5-T whole body MR imager (Magnetom Vision; Siemens AG, Medical Group, Erlangen, Germany) equipped with enhanced gradient hardware for echo-planar imaging (EPI). The present study included the following sequences: At day 0 and day 1: 1. Time-of-flight turbo magnetic resonance angiography (three-dimensional TOF Turbo MRA) with a TR of 35 msec, TE of 6.4 msec, flip angle of 20, matrix 2005 Wiley-Liss, Inc. 23

2 24 Pialat et al. Figure 1. MRI of a stroke lesion. Axial DWI at day 0 (D0) and day 1 (D1), and axial T2WI at day 60 (D60). ROIs representing the lesions are drawn on each image. size of , field of view of 240 mm, one excitation, and an acquisition time of six minutes and 14 seconds, with three axial slabs (thickness: 31.9 mm; partitions: 24; distance factor: 0.38) focused on the circle of Willis. 2. EPI isotropic DWI sequence with a TR of 5000 msec, TE of 137 msec, with 3 b-values (b 50, b 500, and b 1000), one excitation. 19 axial slices, slice thickness of 5 mm, interslice gap of 0.5 mm, matrix size of , and field of view of 240 mm. At day 60: 1. Three-dimensional TOF Turbo MRA sequence with the same parameters as on day 0 and day T2-weighted imaging (T2WI) using a dual fastspin-echo sequence with a TR of 3000 msec, TE of msec, 19 axial slices, slice thickness of 5 mm, distance factor of 0.5 mm, matrix size of , and field of view of 230 mm. Volume Measurement Baseline diffusion lesion volumes were determined on a dedicated personal computer station, with homemade software, by a trained radiologist, unaware of the clinical data. DWI parameters were measured by manually placing regions of interest (ROIs) within the lesion on DWI and in the symmetrical contralateral areas. ROIs correlated with the abnormal area edges. Minimal ROI value at day 0 was 1 cm 3. To define DWI lesion volume, we used the trace images obtained at the highest b value (b 1000 sec/ mm 2 ). The global lesion volume was determined by multiplying the area of diffusion hyperintensity by the sum of the slice thickness and the interslice gap. The interslice gap area was calculated as the mean area between the two consecutive slices. The same methods were used on day 60 T2WI images with areas of residual hyperintensity. An example of ROIs on DWI and T2WI images is shown in Fig. 1. Recanalization Vessel occlusion was determined from the MRA study as follows: internal carotid artery (ICA) occlusion); middle cerebral artery (MCA) M1 segment occlusion; MCA M2 segment occlusion; MCA distal branch occlusion,; anterior cerebral artery (ACA) occlusion; or no vessel occlusion. Patients were classified into two groups according to the arterial recanalization observed on day 1 MRA in comparison with day 0 MRA: no recanalization (No Recanal) vs. partial or full recanalization (Recanal). Reproducibility Measurements Two experienced observers, blinded to the severity of clinical deficit, measured the lesion on two occasions and the mean value was used. The inter and intraobserver variation in measurements was assessed by comparing the differences in measurements for the 42 cases. The intra- and interobserver reliability in measured DWI lesion volumes was r 0.9, with a mean deviation of less than 5% for intraobserver reproducibility. Statistical Methods Mean volumes with SD were calculated at day 0, day 1, and day 60. Logarithmic transformation was applied on DWI and T2WI volumes in order to obtain a normal distribution, and then analysis of variance (ANOVA) of repeated measures was performed. Differences between the volumes at each time point between the Recanal and the No Recanal groups were explored with the Mann-Whitney U-test. To compare time from stroke onset to treatment between these two groups, the Student s t-test and the Spearman s correlation coefficient were calculated. All tests were performed with SPSS V 11.5 software. All P values were two-tailed, and P values of 0.05 or less were considered to indicate statistical significance. RESULTS Between March 2001 and November 2002, early MRI was performed in 94 consecutive patients admitted to our stroke unit for suspected acute ischemic stroke. This sample size represents 19% of patients hospitalized during the same period. Among these 94 patients, 48 consecutive patients underwent MRI before intrave-

3 Evolution of Infarct Volumes After t-pa 25 nous recombinant t-pa. A total of 42 patients completed the entire protocol (23 men and 19 women). The mean SD age was years. The mean SD time from stroke onset to brain MRI was three hours and 18 minutes one hour and 37 minutes. The mean SD time from stroke onset to t-pa was four hours and 21 minutes one hour and 24 minutes. Occlusion types were ICA occlusion (N 11), M1 segment of MCA occlusion (N 13), M2 segment of MCA occlusion (N 6), distal branches of MCA occlusion (N 4), and anterior cerebral artery (MCA) (N 2). Six patients presented no vessel occlusion but three of them had severe ICA stenosis. According to day 1 MRA, two groups of patients were defined: Patients with partial or full recanalization: Recanal (N 27), and patients with persistent occlusion: No Recanal (N 15). Diffusion volumes at day 0 and day 1 and T2- weighted volumes at day 60 were calculated for each patient of both groups (Table 1). Mean volumes were cm 3 at day 0, cm 3 at day 1, and cm 3 at day 60. Mean volumes for patients with arterial recanalization were cm 3,51 61 cm 3, and cm 3, respectively. Those for patients without arterial recanalization were cm 3, cm 3, and cm 3 at day 60. The time course of lesion volumes is presented in Fig. 2. ANOVA performed with the logarithmic-transformed volumes found a significant increase between day 0 and day1(p 0.001), and a decrease between day 1 and day 60 (P 0.001) in both the Recanal and No Recanal groups. A significant increase between day 0 and day 60 was observed in the Recanal group (P 0.015). In contrast, the difference between day 0 and day 60 was not significant (P 0.501) for the No Recanal group. At day 0, no statistical difference was observed with the Mann-Whitney U-test between the two groups (P 0.276); the difference appeared near significance at day 1(P 0.057) and was significant at day 60 (P 0.037). Time from stroke onset was briefer in the Recanal group than in the No Recanal group ( minutes vs minutes), based on the Student s t-test (P 0.002) and Spearman s nonparametric correlation (r 0.470; P 0.002). DISCUSSION DWI is a very important tool for acute stroke evaluation. Both animal (1,12) and human studies (2,13,14) have highlighted its ability to detect early the ischemic lesion with better sensitivity than other conventional MRI techniques (15,16). Even without a complete understanding of the biophysical background, it is certain that an acute increase of DWI signal intensity during ischemia is due to a failure of ion pumps and anoxic cell membrane depolarization with a subsequent water shift from the extracellular to the intracellular space, which, in turn, causes cell swelling (17). This so-called cytotoxic edema, with containment in the intracellular space, induces a translational movement of water particles that decrease, with a reduced apparent diffusion coefficient (ADC) (18,19). Physiological studies in Table 1 DWI and T2 Volumes of Recanalized and Nonrecanalized Patients Patient ID Day 0 diffusion lesion volume Day 1 diffusion lesion volume Day 60 T2 lesion volume NONRECANALIZED PATIENTS RECANALIZED PATIENTS animals have illustrated the severity of hypoperfusion, which induces membrane depolarization (20) and irreversible evolution to cell death. A DWI lesion was considered indicative of the ischemic core. When perfusion imaging was developed in stroke MRI, abnormality was shown most often larger than the diffusion abnormality in the acute phase after onset (21). A PWI-DWI mismatch region was defined as the outer rim of the visualized perfusion abnormality with no diffusion lesion. This concept was in line with the model of ischemic penumbra developed by Astrup et al (22) and defined as a ring around the more densely ischemic center, with such moderate energy imbalance that it would not lead to neuronal damage. How-

4 26 Pialat et al. Figure 2. Time course of lesion volumes. Plots represent logarithmic-transformed volumes of diffusion lesions at day 0 (Log_volume_D0) and day 1 (Log_volume_D1); T2WI lesions at day 60 follow-up; and (Log_volume_D60) of recanalized (Recanal) and nonrecanalized (No Recanal) patients on day 1 MRA. Graph shows an up and down kinetic in both groups with loss of parallelism between day 1 to day 60 and more important decrease for the recanalized group than nonrecanalized one. ever, the ischemic penumbra is a time-dependent dynamic concept, with lesion growth from the center to the periphery and recruitment of tissue at risk into the infarct (21,23). Thus, the mismatch (and thus, inversely, the DWI growth) became the target of stroke therapeutics to evaluate the salvageable tissue (3,24,25). The mismatch model assumes that the initial diffusion lesion represents irreversibly infarcted core tissue. However, human and experimental studies have demonstrated that diffusion lesions may be reversible when reperfusion occurs rapidly (1,8,26). The aim of our study was to analyze the course of the lesion volumes in order to provide relevant information about the evolution of the diffusion process. The interpretation of DWI changes, especially beyond the first 24 hours, may involve a mixture of pathological events, including the evolution of hyperacute cell injury, development of vasogenic edema, and ischemic cell lysis (27). The increase in lesion growth is possibly due to a persistent active ischemic process, but opinions about the time of lesion extent are discordant. Some animal experiments reported a limited ischemic evolution in the first hours after stroke onset (28), but other studies that reported a persistence of mismatch after 24 hours suggest a longer extent of the growing time process (29,30). Because both ADC and T2 influence signal intensity on DWI, this increase in DWI signal intensity was also possibly due to an increase in the T2 contribution induced by vasogenic edema (31). This assumption is supported by previous studies, which show that in humans the maximum evolution of vasogenic edema culminates at 24 to 48 hours (28). On the contrary, the vasogenic edema contribution in the first seven hours was found to be negligible in rats (20). The spread of ADC would thus stop at approximately seven hours and any further increase in volume would mainly be due to edematous swelling (28). These results in animals need to be clarified in human experiments, but measures of the DWI volume clearly must take into account the expansion of vasogenic edema, especially during the first 24 hours. Most of the normalization previously reported concerned ADC values (7,9,10); many studies have focused on the ADC time course with quantitative values of diffusion modifications and pixel-by-pixel analyses were developed. Shen et al (32) found a bimodal distribution of ADC values, which seemed to indicate some viability threshold in the acute stage. Recently, Bykowski et al (33) used cerebrospinal fluid (CSF)-suppressed DWI to determine ADC in order to suppress the partial volume averaging of CSF), which could improve the accuracy of differentiating reversible from irreversible ischemic injury. However, at a later time evolution, the heterogeneity of the lesion demonstrates addition of microbleeding, with hyposignal induced by paramagnetic hematic degradation products and brain blood barrier breakdown leading to modification of water repartition. In contrast to other studies (8,9), very little normalization was observed at day 1 in this population, which received thrombolytics. Globally, a significant increase of DWI lesion volumes appears from day 0 to day 1. Only three of the 42 patients had lower volumes at day 1. These three patients had small lesions from 4 to 7 cm 3 at day 0, and the decrease was from 0.5 to 2 cm 3. All three presented day 1 arterial recanalization. The first time point follow-up after t-pa was realized at day 1 in our study. The early changes in diffusion intensity incoming in the cerebral hypoperfused territory as early normalization reported in some studies (7,34,35) could not be revealed. Concerning late evolution of the lesion volume, stability between day 0 and day 60 volumes in the Recanal group is consistent with an early pathologic process

5 Evolution of Infarct Volumes After t-pa 27 with no subsequent evolution, except the rise and fall of the vasogenic component. In contrast, the increase in lesion volumes from day 0 to day 60 in the No Recanal group may support an ongoing pathologic process after 24 hours. This could indicate that recanalization is a predictor of favorable outcome, as previously reported (36). However, we could not differentiate early from late recanalization due to the lack of follow-up MRI before day 1. The significant decrease from day 1 to follow-up study at day 60 is in line with previous human studies (37,38). The decrease primarily consists of regression of the vasogenic component, but cell lysis, necrosis, and retraction of the late infarcted core may also play a role. Comparison between day 1 DWI and day 60 T2WI is a limitation, but T2WI is more appropriate than diffusion to evaluate late infarct size (16,21), although DWI is more pertinent than T2 for stroke imaging at day 0 and day 1 (16,37). Using T2WI could overestimate the late infarct size because of the hypersignal of sulcus enlargement next to the lesions; however, volumes decreased significantly in both groups between day 1 and day 60. In conclusion, normalization of DWI lesions in acute stroke is difficult to assess because of the occurrence of multiple confounding factors after the initial hours, especially vasogenic edema, which causes a rise and fall in the time evolution of the lesion volume. The ischemic lesion is thus overestimated to a greater degree when initial imaging is performed later in stroke evolution. Recanalization observed at day 1 seems to decrease the growth potential of the lesion, but it is highly correlated with time from stroke onset to the thrombolytic treatment. REFERENCES 1. Minematsu K, Li L, Fisher M, Sotak CH, Davis MA, Fiandaca MS. Diffusion-weighted magnetic resonance imaging: rapid and quantitative detection of focal brain ischemia. Neurology 1992;42: Yoneda Y, Tokui K, Hanihara T, Kitagaki H, Tabuchi M, Mori E. Diffusion-weighted magnetic resonance imaging: detection of ischemic injury 39 minutes after onset in a stroke patient. Ann Neurol 1999;45: Barber PA, Darby DG, Desmond PM, et al. Prediction of stroke outcome with echoplanar perfusion- and diffusion-weighted MRI. Neurology 1998;51: 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: 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: Minematsu K, Li L, Sotak CH, Davis MA, Fisher M. Reversible focal ischemic injury demonstrated by diffusion-weighted magnetic resonance imaging in rats. Stroke 1992;23: ; discussion Li F, Han SS, Tatlisumak T, et al. Reversal of acute apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats. Ann Neurol 1999; 46: Kidwell CS, Saver JL, Mattiello J, et al. Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann Neurol 2000;47: Fiehler J, Knudsen K, Kucinski T, et al. Predictors of apparent diffusion coefficient normalization in stroke patients. Stroke 2004; 35: Grant PE, He J, Halpern EF, et al. Frequency and clinical context of decreased apparent diffusion coefficient reversal in the human brain. Radiology 2001;221: Trouillas P, Nighoghossian N, Derex L, et al. Thrombolysis with intravenous rtpa in a series of 100 cases of acute carotid territory stroke: determination of etiological, topographic, and radiological outcome factors. Stroke 1998;29: 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: Warach S, Gaa J, Siewert B, Wielopolski P, Edelman RR. Acute human stroke studied by whole brain echo planar diffusionweighted magnetic resonance imaging. Ann Neurol 1995;37: Marsault C, Oppenheim C, Le Bihan D. Does diffusion and perfusion MRI modify the diagnosis and management of cerebral ischemic accidents? Bull Acad Natl Med 2000;184: ; discussion [Fre] 15. Noguchi K, Ogawa T, Inugami A, et al. MRI of acute cerebral infarction: a comparison of FLAIR and T2-weighted fast spin-echo imaging. Neuroradiology 1997;39: Lutsep HL, Albers GW, DeCrespigny A, Kamat GN, Marks MP, Moseley ME. Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke. Ann Neurol 1997;41: Mintorovitch J, Yang GY, Shimizu H, Kucharczyk J, Chan PH, Weinstein PR. Diffusion-weighted magnetic resonance imaging of acute focal cerebral ischemia: comparison of signal intensity with changes in brain water and Na,K( )-ATPase activity. J Cereb Blood Flow Metab 1994;14: Le Bihan D, Breton E, Lallemand D, Grenier P, Cabanis E, Laval- Jeantet M. MR imaging of intravoxel incoherent motions: application to diffusion and perfusion in neurologic disorders. Radiology 1986;161: Benveniste H, Hedlund LW, Johnson GA. Mechanism of detection of acute cerebral ischemia in rats by diffusion-weighted magnetic resonance microscopy. Stroke 1992;23: Hoehn-Berlage M, Norris DG, Kohno K, Mies G, Leibfritz D, Hossmann KA. Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: the relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances. J Cereb Blood Flow Metab 1995; 15: 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: Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia the ischemic penumbra. Stroke 1981;12: 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: Fisher M. Characterizing the target of acute stroke therapy. Stroke 1997;28: Grandin CB, Duprez TP, Smith AM, et al. Usefulness of magnetic resonance-derived quantitative measurements of cerebral blood flow and volume in prediction of infarct growth in hyperacute stroke. Stroke 2001;32: Rother J, de Crespigny AJ, D Arceuil H, Iwai K, Moseley ME. Recovery of apparent diffusion coefficient after ischemia-induced spreading depression relates to cerebral perfusion gradient. Stroke 1996;27: ; discussion Baird AE, Warach S. Magnetic resonance imaging of acute stroke. J Cereb Blood Flow Metab 1998;18: Loubinoux I, Volk A, Borredon J, et al. Spreading of vasogenic edema and cytotoxic edema assessed by quantitative diffusion and T2 magnetic resonance imaging. Stroke 1997;28: ; discussion Heiss WD, Graf R, Wienhard K, et al. Dynamic penumbra demonstrated by sequential multitracer PET after middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 1994;14: Marchal G, Beaudouin V, Rioux P, et al. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based data analysis. Stroke 1996;27:

6 28 Pialat et al. 31. Neumann-Haefelin T, Kastrup A, de Crespigny A, et al. Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue injury, blood-brain barrier damage, and edema formation. Stroke 2000;31: ; discussion Shen Q, Meng X, Fisher M, Sotak CH, Duong TQ. Pixel-by-pixel spatiotemporal progression of focal ischemia derived using quantitative perfusion and diffusion imaging. J Cereb Blood Flow Metab 2003;23: Bykowski JL, Latour LL, Warach S. More accurate identification of reversible ischemic injury in human stroke by cerebrospinal fluid suppressed diffusion-weighted imaging. Stroke 2004;35: Ringer TM, Neumann-Haefelin T, Sobel RA, Moseley ME, Yenari MA. Reversal of early diffusion-weighted magnetic resonance imaging abnormalities does not necessarily reflect tissue salvage in experimental cerebral ischemia. Stroke 2001;32: Tanaka Y, Kuroiwa T, Miyasaka N, Tanabe F, Nagaoka T, Ohno K. Recovery of apparent diffusion coefficient after embolic stroke does not signify complete salvage of post-ischemic neuronal tissue. Acta Neurochir Suppl 2003;86: Hermier M, Nighoghossian N, Adeleine P, et al. Early magnetic resonance imaging prediction of arterial recanalization and late infarct volume in acute carotid artery stroke. J Cereb Blood Flow Metab 2003;23: Lansberg MG, Thijs VN, O Brien MW, et al. Evolution of apparent diffusion coefficient, diffusion-weighted, and T2-weighted signal intensity of acute stroke. AJNR Am J Neuroradiol 2001;22: Eastwood JD, Engelter ST, MacFall JF, Delong DM, Provenzale JM. Quantitative assessment of the time course of infarct signal intensity on diffusion-weighted images. AJNR Am J Neuroradiol 2003; 24: