(Stroke. 1997;28:419-427.)
© 1997 American Heart Association, Inc.
Articles |
Spreading of Vasogenic Edema and Cytotoxic Edema Assessed by Quantitative Diffusion and T2 Magnetic Resonance Imaging
the Laboratoire de Recherches Cerebrovasculaires, Centre National de la Recherche Scientifique, Unite de Recherche Associee 641, Universite Paris VII (I.L., J.B., S.G., J.S., P.M.), and Laboratoire de Biophysique Moleculaire, Institut National de la Sante et de la Recherche Medicale U350, Institut Curie, Orsay (A.V., B.T.) (France).
Correspondence to Isabelle Loubinoux, Laboratoire de Recherches Cerebrovasculaires, Centre Universitaire Villemin, 10, avenue de Verdun, 75010 Paris, France. E-mail meric@idf.ext.jussieu.fr.
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Background and Purpose The apparent diffusion coefficient (ADC) of water should be sensitive to the cytotoxic edema triggered by energy failure during ischemia. Elevated values of T2, the nuclear MR transverse relaxation time of water, seen on T2 nuclear MR images detect vasogenic edema and infarcted areas. The temporal and spatial changes in ADC and T2 abnormalities after occlusion of the middle cerebral artery (MCAO) were therefore estimated by these two quantitative techniques.
Methods Permanent MCAO was performed on rats. Quantitative ADC and T2 maps of brain water were obtained, from which the ischemic volumes were calculated at various times up to 48 hours after MCAO.
Results The areas of decreased ADC represented 36±7% of the final infarct volume (24 hours) at 0.5 hours and 64±4% at 5 hours after MCAO, suggesting that there is recruitment of peripheral areas with disturbed energy metabolism and cytotoxic edema. The ADC and T2 contours closely matched at 3.5, 24, and 48 hours after MCAO.
Conclusions T2 imaging can assess ischemic insults as well as ADC imaging, but only 3.5 hours after the onset of ischemia. Assessment of edematous swelling (
24.5% of total infarcted volume) demonstrates that ADC and therefore T2 imaging detect all the tissue that will become infarcted approximately 7 hours after occlusion. The spread of ADC and T2 abnormalities would therefore stop at approximately 7 hours, and any further increase in volume observed on the images would be mainly due to edematous swelling.
Key Words: brain edema • cerebral ischemia, focal • magnetic resonance imaging • middle cerebral artery occlusion • rats
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It has been widely reported that the extent of cerebral infarction induced by MCAO can be accurately and reproducibly estimated by in vivo conventional T2 MRI.1 2 3 4 VT2, the area with elevated T2, matches the infarcted areas determined by established histological and enzymatic techniques, such as staining with cresyl violet, hematoxylin-eosin, and 2,3,5-triphenyltetrazolium chloride1 2 3 4 at times from 1 day to 3 months after occlusion. It has been demonstrated that the size of the infarct does not increase between 24 and 72 hours,3 so that VT2(24h) can be considered the final lesion size.
The elevated water T2 values obtained on T2 NMR images detect vasogenic edema.5 6 7 Quantitative T2 imaging could therefore be a suitable atraumatic method of evaluating the extent and the degree of vasogenic edema that develops during ischemia. However, T2 imaging does not detect any abnormality earlier than 2 to 3 hours after MCAO8 and therefore cannot be used to assess the severity of the earliest ischemic events, which determines the outcome of ischemic tissue.9
Diffusion MRI has recently been suggested as a way of investigating the earliest ischemic events, since diffusion images can detect ischemic insults as early as 2.7±1.5 minutes after MCAO.10 The MRI sequences used in diffusion imaging are designed to enhance the sensitivity of the MR signal to the incoherent microscopic motion of water protons in tissue.11 Thus, diffusion imaging should detect any abnormal tissue water diffusion due to ischemic injury. Areas of abnormal intensity on diffusion-weighted images after MCAO have been found to match areas with perfusion deficits,3 8 9 12 13 14 15 disturbance of energy metabolism (loss of tissue ATP, imbalance of transmembrane ionic gradients),8 12 16 and cytotoxic edema.17 The extracellular shrinkage due to cytotoxic edema can be detected by measuring the electrical impedance of the cortex18 or by iontophoresis.19 Cellular swelling produces a redistribution of extracellular water into the more diffusion-restricted intracellular compartments and thus a decrease in the mean diffusion of water in the tissue.8 11 14 20 Therefore, this type of edema corresponds to a cellular swelling and not a tissular swelling. Diffusion in the intracellular space is thought to be restricted by obstacles to diffusion (eg, cell walls, membranes, or macromolecules).21 The mean diffusion of water can be reduced still further because the extracellular shrinkage also induces an increase in extracellular tortuosity and thus a decrease in the diffusion of ionic extracellular markers measured by iontophoresis.19 Since diffusion imaging is closely linked to the tissue energy state, it has been proposed as a tool for assessing the extent and degree of ischemic insult. It is not possible to quantify diffusion events with diffusion-weighted imaging because the signal intensity is also T1- and T2-weighted, and these NMR parameters are altered in ischemic tissue.22 Even in the first few hours of ischemia, when T2 was first thought to be unaltered, slight hypointensity has been observed on T2 images.22 However, quantitative maps of the ADC can be prepared from serial diffusion-weighted images.11
We therefore investigated the capacity of this quantitative method of MRI by comparing it with the well-established T2 MRI method for monitoring focal ischemic insults in the rat. The dynamics of the spreading of ADC and T2 abnormalities were also determined within all the structures insulted. To our knowledge, no study has yet described the spreading of ADC and T2 abnormalities through the ischemic tissue using these two quantitative techniques in parallel. As previously reported by others,2 3 the volumes assessed by diffusion imaging at 24 hours after MCAO were similar to the volumes assessed by T2 imaging at the same time, so that both diffusion imaging and T2 imaging give the final infarct size 24 hours after occlusion. However, ADC returns to control values after 24 to 48 hours of ischemia.23 We therefore determined the extent to which ADC imaging is a reliable technique for measuring infarct size as late as 48 hours after MCAO. Also, since ischemic tissue showed great edematous swelling that was visible after 24 hours of ischemia, this tissue swelling was estimated on NMR images. Swelling due to the formation of vasogenic edema was therefore differentiated from cytotoxic edema.
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Animals and Surgical Procedure
Experiments were performed under permit No. 727 from the French Ministere de l'Agriculture. The model of MCAO used was derived from that of Zea Longa et al.24 Briefly, male Sprague-Dawley rats (n=8) weighing 280 to 370 g were anesthetized with a mixture of 1.5% halothane, 40% oxygen, and 58.5% nitrous oxide for 30 minutes during the surgery. The right CCA and the ICA were temporarily clamped with microvascular clips, and the ECA and its branches were coagulated. A silk suture was placed around the ECA close to the CCA bifurcation. The ECA was cut off 2 to 3 mm distal to the CCA bifurcation, and a 21-mm-long 4-0 nylon thread (Ethnor) terminating in a resin cylinder (diameter, 0.32 mm; length, 2.8 mm) was introduced through the ECA into the ICA. The silk suture was tightened around the ECA stump to prevent bleeding, the clips on the CCA and ICA were removed, and the nylon thread was carefully and totally inserted. The embolus obstructed the origin of the right MCA, whereas blood flow visibly continued through the ICA at the site of surgery. The midline incision of the neck was sutured and covered with lidocaine gel for local anesthesia. The rectal temperature was maintained at approximately 37.5°C with a heating lamp throughout surgery. Halothane was then reduced to 0.5%, and the animals were placed in the magnet. All NMR experiments were performed under such anesthesia. We previously ensured that arterial blood gases, arterial pH, and mean arterial blood pressure did not change during these conditions during the experiment. The body temperature was monitored by a rectal probe and maintained close to 37.5±0.1°C with a heating pad during the NMR experiments.
MRI
MRI was performed at 4.7 T on a Bruker Biospec 47/30 spectrometer equipped with a 30-cm-bore horizontal magnet and a custom-designed gradient system (diameter, 15 cm; maximal gradient strength, 60 mT/m). Immediately after surgery, the animals were installed in a nonmagnetic ear-bar device to prevent any movement during imaging, and this device was then placed into a custom-designed probe equipped with a slotted cylindrical resonator (diameter, 44 mm). NMR experiments were run for 5 hours and at 24 and 48 hours after MCAO.
Coronal (TR, 150 ms; TE, 38 ms) and transversal (TR, 250 ms; TE, 60 ms) localizer images were acquired for accurate positioning of subsequent slices. The first coronal diffusion-weighted images were then acquired at 30 to 60 minutes after occlusion. The first slice of the set of diffusion-weighted images was positioned 2 mm distal to the rhinal fissure and corresponded to approximately 3.2 mm from the bregma according to the coordinates of Paxinos and Watson.25 The volume of ischemic tissue at a given time can be accurately quantified provided that a suitable number of MRI "slices" covering the whole ischemic area are acquired.1 Six noncontiguous coronal diffusion-weighted images were collected with the use of a multislice water-proton selective spin-echo sequence26 (TR, 2000 ms; TE, 99 ms) modified by the Stejskal-Tanner technique as described by Le Bihan et al.11 The interslice gap was set to 1 mm, which is a suitable distance for avoiding overlaps of slice-selection gradients. Diffusion images were acquired on a 128x128 matrix, with a field of view of 6 cm, two scans, slice thickness of 1 mm, a diffusion gradient pulse duration (
) of 30 ms in the readout direction X (ie, left-right within the image plane), and a gradient separation time (
) of 43.7 ms, resulting in a diffusion time of -/3=33.7 ms. The in-plane spatial resolution was 0.47x0.47 mm2, providing a voxel size of 0.22 µL. Seven sets of coronal images were recorded for quantitative determination of ADC, with several equidistant diffusion gradient b values of 0, 438, . . ., 2290, and 3580 s/mm2 (acquisition time, 8 minutes per set of images; total acquisition time, 80 minutes). The first b gradient was set at 438 s/mm2 to avoid the contribution of perfusion to the ADC.11 27
Signals S(b=0) and S(b
0) of raw images were used to compute pixel-by-pixel ADC images according to the relation given by the intravoxel incoherent motion model11 :
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The ADC image was obtained by plotting the natural logarithm of the ratio of signals S(b)/S(b0) as a function of the gradient b. It was analyzed with the use of a least squares fit to a straight line.
ADC values were first calculated from six b values (438, 890, 1288, 1753, 2290, and 3580 s/mm2) in pilot experiments. Because recording the entire series of diffusion-weighted images took 80 minutes, we investigated the extent to which the temporal resolution could be improved by reducing the number of b values. The very linear regression for the six b values (correlation coefficient: r.95; SE of the slope [ADC value] <5%), also shown by others,28 allowed sets of images with only three b values of 0, 438, and 2290 s/mm2 to be used, reducing the recording time to 30 minutes with no significant difference in ADC determination. Images with b=2290 s/mm2 rather than b=3580 s/mm2 were chosen for their optimal contrast and signal-to-noise ratio. The acquisition time was further improved (20 minutes) by using only one b factor weighting set of images (2290) in addition to the standard spin-echo images (b=0) to determine an ADC image with two regression points. This could be done provided that a series of six b-weighting images was recorded later to give an image of the intercept log(1-f). The ADC values obtained with two or three b values were not statistically different from the ADC values calculated from a 6-point regression (Student's t test upon 100 measurements). We were thus able to accumulate accurate ADC images during the 2 hours after MCAO, when the pattern of ADC changed rapidly with time. Thus, ADC images were obtained at 0.5, 1, 2, 3, 4, 5, 24, and 48 hours after MCAO.
T2 images were obtained at 3.5, 24, and 48 hours after MCAO with the use of a multislice/multiecho sequence (TR, 2232 ms; TE range, 36 to 108 ms; slice thickness, 1 mm; interslice gap, 1 mm; acquisition time, 20 minutes). The T2 measurement obtained with our imaging protocol has been validated on a phantom, and the field of view was set at 12 cm to avoid artifacts coming from eddy currents. The matrix was 256x256, so that the same spatial resolution was obtained for both diffusion and T2 images. The echo-signal amplitude S(nTE) of the nth echo (TE) is given by:
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.98; SE of the inverse of the slope [T2 value] <10%). Quantitative and qualitative ROI image analysis was performed with the use of Optimas 4.02 (Bioscan) for both ADC and T2 images. The global ROIs delimiting areas with abnormal ADC values (AADC) and T2 values (AT2) were drawn on each slice, on ADC and T2 images.
A single threshold separating healthy and ischemically affected tissue could not be determined because the ADC and T2 values differed from one structure to another. ADC values were 56.9±2.6x10-5 mm2/s for the cortex, 50.3±1.4x10-5 mm2/s for the striatum, 52.3±1.3x10-5 mm2/s for the hypothalamus, and 51.4±2.0x10-5 mm2/s for the thalamus. T2 values were 65.9±1.1 ms for the cortex, 63.7±1.4 ms for the striatum, 66.0±0.9 ms for the hypothalamus, and 55.8±2.2 ms for the thalamus. ROIs were thus determined by manual drawing after visual inspection of the parameter alterations.
For each slice, the ADC and T2 contours of the ROIs were compared by superimposing them. This allowed assessment of the anatomic locations of similarities and discrepancies between both ADC and T2 ROIs.
The swelling due to vasogenic edema was estimated 24 hours after occlusion on ADC or T2 images. This swelling was estimated taking into account that edematous tissue compressed healthy tissue (Fig 1
). The volume of the contralateral hemisphere (VH) was reduced to a compressed volume (VC). We postulated that the compressions in this contralateral hemisphere (VH) and in the entire healthy tissue (VT-VI) were similar (Fig 1). VT was the total brain volume (2·VH), and VI was the ischemic volume with ADC or T2 disturbances that was measured on the images. Therefore, the compression factor (F) is equal to:
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Statistical Analysis
The MRI data were analyzed on every slice (maximum, six). The global volumes VADC and VT2 were estimated from the sum of the overall abnormal area values AADC and AT2 (multiplied by the slice thickness) delimited on the six noncontiguous slices for both ADC and T2 images. VADC was measured at 0.5, 1, 2, 3, 4, 5, 24, and 48 hours after MCAO, and VT2 was measured at 3.5, 24, and 48 hours after MCAO. White matter and tissue swelling were included in the volumes VADC and VT2.
For each rat, the global volume VADC value at each time was normalized by the final infarct size (the value VADC obtained at 24 hours after MCAO) and expressed as a percentage. Mean values were then calculated among rats, and the time course of VADC was determined. The volumes VADC and VT2 at a given time were compared by calculating the ratio VT2/VADC for each slice. Mean values were then calculated and expressed as a percentage for each rat. A mean value was calculated among rats. Statistical differences between two times were calculated with the paired Student's t test. Differences at P<.05 were considered significant.
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Twenty-five percent of the rats displayed a postischemic seizure. The mortality rate was limited to 12% (one of eight rats) at 24 and 48 hours after MCAO. This rate was similar to that found by others with this model of ischemia.24 29 The rat that died did not suffer a seizure. Thus, although postischemic seizures are considered to be aggravating factors, mortality does not seem to be linked to the occurrence of seizures.
Volumes of Ischemic Insults Estimated by ADC Imaging
The ADC images showed that the structures affected by ischemia were the striatum in all cases and the frontoparietal cortex and thalamic and hypothalamic areas in some cases, as previously reported24 30 (Fig 2). More precisely, 50% of the rats had a cortical insult, 62% had a hypothalamic insult, and 50% had a thalamic insult. The interindividual variability of the insults may originate from the interindividual variability of the anatomy of the cerebral rat vasculature.31 The ADC and T2 images indicated that four rats had no cortical insult, whereas the entire MCA territory was affected in the other four rats.
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The VADC in the rats with cortical and subcortical insults was significantly larger than the VADC in rats with only subcortical insults. Two types of insult were therefore identified: subcortical insults and so-called cortical insults, in which case the animals had both cortical and subcortical insults. The mean value of VADC at 24 hours after MCAO [VADC(24h)] was 88±11 mm3 for subcortical insults and 234±2 mm3 for cortical insults. Whatever the type of insult considered, the VADC(24h) was not statistically different from the mean VADC(48h). The two groups of rats were then pooled, and the overall mean VADC(24h) was 96.9±17.1% of the mean VADC(48h). This is in agreement with a previous study that found that the volumes measured on diffusion-weighted images at 24 and 72 hours after MCAO were not statistically different.3 It follows that the VADC(24h) can be considered the final lesion size.
As the final ischemic volume in the rats varied, the VADC values at each time were normalized by the VADC(24h) for each rat. The mean VADC values were 36±7% (0.5 hour), 44±2% (1 hour), and 64±4% (5 hours) of the VADC(24h) (Fig 3). Hence, ADC disturbances occurred rapidly and then spread at a rate of 5%/h of the final volume in the first hours after MCAO. This spreading was similar, whether the insults were cortical and subcortical or only subcortical. Therefore, the spreading of the ADC disturbance seemed independent of the structure insulted.
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The ADC changes in ADC ROIs were calculated in each structure with the contralateral structure used as a reference. ADC was decreased by approximately 18% (0.5 hour) and 35% (2, 24, and 48 hours after occlusion) in all structures.
Volumes of Ischemic Insults Estimated by T2 Imaging
T2 maps were compared with ADC maps on each slice of each rat (Fig 4). This comparison pointed out that the brain seen on ADC images was approximately 17% smaller than the brain seen on T2 images (Fig 4). This difference appeared when a diffusion gradient was applied. The use of a diffusion gradient decreased the signal at the brain surface and made the upper layers of the cortex disappear. This might be due to rapidly diffusing protons present in the pial circulation or in the cerebrospinal fluid. VADC and VT2 were compared only for tissue visible by both techniques, and therefore the external cortical drawing of T2 ROIs was delimited according to the external cortical drawing defined on ADC images.
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Under these conditions, the global VADC and VT2 volumes did not differ significantly at all the times when T2 images were acquired. The VT2 values were 95.3±1.9% of the VADC at 3.5 hours, 100.3±1.9% at 24 hours, and 103.0±4.7% at 48 hours after MCAO. At 3.5 hours after MCAO, T2 hyperintensities had not yet affected the borders of the ischemic ROIs assessed by ADC imaging (striatal borders and also cortical, thalamic, and hypothalamic borders when these structures were ischemic), but these discrepancies did not lead to a significant difference in volume values. In particular, T2 values were not increased in the dorsal part of the cortex where the ADC values were decreased by 10% to 20% (Fig 4
, arrow), whereas ADC values were decreased by approximately 35% in the core of the ischemic territory. Increased T2 values only in areas of severely decreased ADC values have also been observed 2.5 to 4 hours after occlusion.32 Thereafter, T2 ROIs and ADC ROIs were very similar at 24 and 48 hours after occlusion.
The T2 increases in T2 ROIs were calculated in each structure with the contralateral structure used as a reference. T2 values were increased by approximately 17% at 3.5 hours and by 60% at 24 and 48 hours after occlusion in all structures. T2 imaging can therefore assess ischemic insults as well as ADC imaging, but only 3.5 hours after the onset of ischemia.
Assessment of Edematous Swelling
Since the midline between the two hemispheres was found to be shifted at 24 and 48 hours (see Fig 4), a large part of VADC and VT2 corresponded to tissue swelling due to vasogenic edema. We estimated this swelling by the volume parameter Vtissue dilation. This value was 53.3±0.6 mm3 and represented 24.2±0.8% of VADC(24h) for cortical insults and was 18.5±4.4 mm3 and represented a similar percentage (24.7±0.9%) for subcortical insults. This suggests that dilation volume is proportional to infarct size. These results also indicate that the edematous swelling is particularly large.
VS, the total infarcted volume without the edema contribution, represented approximately 75% of the volume measured at 24 hours after occlusion. Since VADC(5h) was 64% of VADC(24h) and ADC disturbances spread at a rate of approximately 5%/h, we deduced that the 75% were already affected by the ADC decrease after approximately 7 hours after MCAO (Fig 3). This assumed that the dilation of the ischemic tissue was negligible before this time. This assumption was supported by previous studies which show that the vasogenic edema contribution in the first 7 hours after MCAO is negligible.32 Therefore, all of the tissue destined to become necrotic would have decreased ADC values at 7 hours after MCAO, and the final infarct limits would be reached after 7 hours of ischemia, well before 24 hours after occlusion. Any further increase in volume (25%) would then be attributable to edematous swelling.
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This study documents the changes in the volumes of ADC and T2 ROIs defined by quantitative diffusion and T2 imaging on six noncontiguous slices covering the entire ischemic area from 30 minutes to 48 hours after the onset of ischemia. Because the size of the ischemic insults varies with time, NMR imaging was a particularly appropriate noninvasive method for monitoring the spread of the insult by measuring changes in the ischemic area.
Spreading of ADC ROIs and Cytotoxic Edema
It has been suggested that ADC imaging could be used in the early diagnosis of stroke to predict the final infarct size revealed by histological examination at 1 or 3 days.29 However, there is growing evidence from multislice studies that diffusion imaging detects only a fraction of the ultimate infarct in the first hours after occlusion.2 3 Our results clearly show that the spatial extent of the decreased ADC area (VADC) varies from 0.5 hour to 24 hours after the onset of ischemia (Fig 3). The infarct size is maximal at 24 hours after MCAO.2 This is confirmed by our results showing that there is no further spatial increase in ADC ROIs between 24 and 48 hours after the onset of ischemia. This also suggests that the earliest diffusion images do not detect the large area, often called the penumbra, that is progressively included in the infarct area between 0 and 24 hours after MCAO.2 3 The spatial progression determined in this study is similar to that found by others33 between 2.5 and 7.5 hours after MCAO. We have also shown that this spatial extent does not depend on the size of the insult or on the structure affected.
Spreading of T2 ROIs and of Vasogenic Edema
No abnormalities were detectable on T2 images earlier than 3 hours after MCAO. When T2 abnormalities were clearly visible (3.5 hours after the onset of ischemia), the T2 ROIs were significantly smaller than the T2 ROIs determined at 24 hours. Our results on the changes in volumes are thus in agreement with a previous study performed on four slices.4
Matching of ADC and T2 ROIs
As previously reported by others,2 3 the volumes assessed by diffusion-weighted imaging at 24 hours after MCAO are similar to the volumes assessed by T2 imaging at the same time. Our results also show that the ADC and T2 ROIs match 48 hours after MCAO. The ROIs assessed by ADC imaging and by T2 imaging at 3.5 hours are also anatomically similar except that the dorsal part of the cortex, which undergoes a slight decrease in ADC (-15%), is not detected by T2 imaging. Moseley et al8 observed a close anatomic correspondence between diffusion-weighted and T2-weighted ROIs at 5, 9, and 12 hours, suggesting that the two methods of imaging detect similar areas of ischemic insult in this period. These data were not fully convincing, since it is known that the changes in the intensity in diffusion-weighted images are the consequence of changes in both ADC and T2. However, the results obtained in the present study by quantitative ADC mapping and T2 mapping performed separately also indicate that there is an anatomic correspondence between the images provided by the two methods during the period from 3.5 to 48 hours.
VT2 assessed at 3 hours after MCAO was reported to be smaller than VADC.29 32 However, our data indicate that VT2 is not significantly different from VADC at 3.5 hours after MCAO and thereafter. Increases in T2 are hardly significant at 3.5 hours after MCAO. Therefore, this quantitative study suggests that the VT2 volume should not be measured before 3.5 hours. ADC abnormalities thus appear in a limited area at 0.5 hour after MCAO, while T2 abnormalities appear later, at 3.5 hours after MCAO. They spread into the MCA territory with time. These abnormalities mainly spread in the cortex, where the anastomoses preserve some residual blood flow.
ADC Decrease and Cytotoxic Edema
The diffusion abnormalities and thus the ADC changes in ischemic tissues are attributed mainly to cellular swelling and the associated extracellular shrinkage induced by ischemia.17 The cellular swelling induced by ischemia is due to the disturbance in ionic gradients caused by the perturbed energy metabolism in the cerebral ischemic areas. This explanation of the changes in ADC is supported by the close anatomic correspondence between areas of low ADC and maps of acidosis, lactate accumulation,13 and ATP depletion after MCAO.34 It has recently been shown that the region of altered ADC is larger than that of total ATP depletion in the early stages of ischemic development.13 34 VADC thus includes the core of the ischemic territory with total ATP depletion plus areas where energy metabolism is not totally impaired and where a minimal cerebral blood flow is presumed to persist.13
The correspondence between areas of decreased ADC and areas of perfusion deficit has been assessed by 14C-iodoantipyrine quantitative autoradiography,13 15 hydrogen clearance polarography,12 or MRI perfusion imaging.3 8 9 14 Significant reductions in ADC were found to be directly linked to severe hypoperfusion.3 9 12 13 14 15 Changes in ADC appear in rats at a cerebral blood flow threshold of approximately 35 mL/100 g per minute in the first hours of ischemia,13 15 and thus only severe but not mild hypoperfusion induces significant changes in ADC.3 9 13 14 15
Processes Involved in the Recruitment of the Penumbra
It has been demonstrated that the blood flow gradually decreases in the penumbra areas, which are not included in the VADC in the early ADC images after MCAO, but which are gradually incorporated into VADC up to 24 hours after MCAO.13 35 36 Therefore, the decrease in blood flow in the penumbra areas could be a major cause of the appearance of ADC abnormalities. However, Roberts et al9 used partial stenosis of the MCA to demonstrate that mild hypoperfusion can induce slight decreases in ADC (-10% to -20%), which did not deteriorate during the 6 hours of the experiment, whereas in our study ADC values decrease up to 35% in ischemic tissue. This suggests that additional processes to a mild decrease in blood flow are necessary to explain the recruitment of the penumbra. Since radical scavengers and excitatory amino acid antagonists have been shown to protect penumbral tissue from ischemic insult and from cytotoxic and vasogenic edema,4 29 the production of free radicals and the release of excitatory amino acids by severely ischemic tissues are probably involved in penumbral recruitment. It is likely that cytotoxic edema and extracellular shrinkage may increase the extracellular concentration of excitatory amino acids and enhance their deleterious effects.19 37 Peripheral depolarization waves that increase the metabolic rate in energetically challenged areas like the penumbra would likely also be involved.34 38 39 Transient waves of decreased ADC induced by transient extracellular shrinkage attributed to depolarization waves40 were observed during ischemia by fast diffusion imaging.41
Whatever the processes involved, our results suggest that brain tissue cannot undergo more than a few hours of mild ischemia before deteriorating when the tissue is close to severely ischemic areas. Multiparametric studies in which ADC imaging performed with an improved temporal resolution and quantitative multiregional blood flow measurements are used in parallel are necessary to determine more precisely the processes involved in the development of the penumbra and particularly whether peripheral areas with slight decreases in ADC correspond to areas of partial ischemia.
Vasogenic Edema and Swelling
Brain tissue swelling has been estimated with great caution on histological slices42 but has never been estimated on NMR images, although NMR imaging is clearly a more suitable and easy means of estimating edematous swelling than histological samples.1 Swelling was not observable on our ADC and T2 images in the first hours of ischemia when increases in T2 were moderate (
17%). In contrast, swelling was highly visible after 24 hours of ischemia when T2 increases were large (60%). The estimated brain tissue swelling at 24 hours (24.5% of total infarcted volume) was close to the estimation obtained from histological slices (22%).42 The study of Brint et al42 and the present findings demonstrate that this swelling is proportional to infarct size and increased tissue water content.43 A histological study (triphenyltetrazolium chloride and hematoxylin-eosin stains) in which edema was taken into account indicates that all the ischemic tissue detected after 6 hours of ischemia is destined to become necrotic.44 The present study shows that both ADC and T2 imaging detect all the tissue that will later become necrotic approximately 7 hours after occlusion. The spread of ADC and T2 abnormalities would thus stop at approximately 7 hours, and any further increase in volume would mainly be due to edematous swelling. Consequently, when reductions of the spatial extent of ischemic insults are evidenced by pharmacological studies in which putative protective treatments are administered more than 7 hours after MCAO, these reductions might not correspond to an actual reduction of the spatial extent of the cellular damage but only to a reduction of edematous swelling.
In conclusion, the significant changes in T2 that occur after 2 to 3 hours of ischemia indicate more severe insults than those associated with the significant changes in ADC that appear in the first few minutes. Therefore, ADC imaging is a more sensitive method than T2 imaging for monitoring the extent of ischemic insults in the early period after the onset of a focal ischemia. However, it detects only severe metabolic disturbance and not perifocal and less ischemic areas. There is evidence that the penumbra is recruited within the first 7 hours of ischemia. Finally, after 7 hours of ischemia these ADC and T2 images reveal ischemic tissue that is irreversibly damaged30 and destined to become necrotic.32 Additional extension of putative ischemic insult observed on NMR images can be mainly attributed to the swelling induced by edema. These experimental results in rats cannot be directly extrapolated to predict the evolution of focal ischemia in humans. However, they must be taken into account in studies in progress concerning applications of diffusion imaging in diagnosis of the extent of ischemic insults45 and evaluation of the therapeutic effects of treatments.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by Centre National de la Recherche Scientifique, Unite de Recherche Associee 641, Universite Paris VII, "IFR Circulation Lariboisiere," and Direction de la Recherche et de la Technologie (952515A). Isabelle Loubinoux was supported by a fellowship from Institut de Formation Superieure Biomedicale, Paris, France. We thank Jean-Loup Correze for skillful technical assistance.
Received July 16, 1996; revision received October 4, 1996; accepted November 6, 1996.
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References |
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Editorial Comment
Department of NeurologyUniversity of New Mexico School of MedicineAlbuquerque, NM
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Brain edema is an important part of the ischemic process but has been difficult to study because of the need to either measure water content or to estimate edematous regions in tissue.1R The present report describes a unique method to monitor brain edema in experimental rats with the use of the noninvasive methods of MRI. The authors took advantage of the unique characteristics of diffusion-weighted imaging and T2-weighted imaging (T2 MRI) to identify edematous regions in an infarct.
In rats with permanent MCAO by the intraluminal suture method, they found that 24% of the ROI with T2 abnormalities seen at 24 hours was from brain edema. They were able to make this calculation because diffusion-weighted imaging is presumably derived from changes in cellular volume in an injured area, indicating ischemic cells. The T2 MRI signal, on the other hand, comes from both increased intracellular and extracellular water. While the biological data are not new,2R the ability to obtain such data noninvasively represents a significant step in the rapidly advancing array of NMR methods available to study tissue damage.
Most investigators agree that the initial changes in an ischemic lesion are due to swelling of the cells from influx of calcium and failure of the ATPase pump.3R 4R Vasogenic edema, which is due to leakage of the cerebral blood vessel secondary to the primary insult, occurs later in ischemia. The distinction between vasogenic and cytotoxic edema has been difficult to apply to ischemic lesions because of the simultaneous presence of both types in the lesions.5R 6R The authors make a critical assumption that the diffusion-weighted signal is from cytotoxic changes, while T2 MRI shows both the cytotoxic and vasogenic components. If one accepts this operational definition, making vasogenic edema the driving force for the tissue compression, their equations allow for the calculation of an infarcted volume (VS). When VS is subtracted from the imaged volume, a value is obtained for the tissue swelling or what they define as the vasogenic component. This is the amount of compression exerted on the opposite hemisphere by the excess fluid in the ischemic region.
One drawback of the study, which may also be an important strength, is that only eight rats were studied. Half of the rats had small subcortical lesions, while the others had both cortical and subcortical insults. This suggests that there were two populations with little overlap. By normalizing the data to the final volume in each rat, data from both groups were able to contribute to the analysis. Thus, calculation of vasogenic edema can be done with fewer animals.
Noninvasive measurements in experimental stroke have confirmed older findings and yielded important new insights into the pathophysiology of stroke.7R 8R If the present results are confirmed, many interesting applications can be anticipated. The ability to measure brain edema noninvasively will enhance studies of drugs to reduce secondary damage.
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Selected Abbreviations and Acronyms |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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1R. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1992.
2R.
Hatashita S, Hoff JT. Brain edema and cerebrovascular permeability during cerebral ischemia in rats. Stroke.. 1990;21:582-588.
3R. Siesjo BK, Bengtsson F. Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis. J Cereb Blood Flow Metab.. 1989;9:127-140.[Medline] [Order article via Infotrieve]
4R. Ginsberg MD, Pulsinelli WA. The ischemic penumbra, injury thresholds, and the therapeutic window for acute stroke. Ann Neurol.. 1994;36:553-554.[Medline] [Order article via Infotrieve]
5R. Klatzo I. Presidential address: neuropathological aspects of brain edema. J Neuropathol Exp Neurol.. 1967;26:1-14.[Medline] [Order article via Infotrieve]
6R.
Katzman R, Clasen R, Klatzo I, Meyer JS, Pappius HM, Waltz AG. Report of Joint Committee for Stroke Resources, IV: brain edema in stroke. Stroke.. 1977;8:512-540.
7R. Moseley ME, Cohen Y, Mintorovitch J, Chileuitt L, Shimizu H, Kucharczyk J, Wendland MF, Weinstein PR. Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and spectroscopy. Magn Reson Med.. 1990;14:330-346.[Medline] [Order article via Infotrieve]
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Warach S, Chien D, Li W, Ronthal M, Edelman RR. Fast magnetic resonance diffusion-weighted imaging of acute human stroke. Neurology.. 1992;42:1717-1723.
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