(Stroke. 2000;31:2901.)
© 2000 American Heart Association, Inc.
Original Contribution |
Failure to Demonstrate Peri-Infarct Depolarizations by Repetitive MR Diffusion Imaging in Acute Human Stroke
From the Department of Neurology, Klinikum Mannheim, Ruprecht Karls University Heidelberg, and Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians University Munich (Germany).
Correspondence and reprint requests to Dr Tobias Back, Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians-University Munich, Marchioninistrasse 15, D-81377 Munich, Germany. E-mail Tobias.Back{at}lrz.uni-muenchen.de
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Abstract |
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Background and Purpose—Peri-infarct depolarizations (PIDs) have been demonstrated with diffusion-weighted MRI (DWI) in experimental stroke and are regarded as an important mechanism of ischemic injury. We tested the hypothesis that PIDs are of relevance for the early enlargement of human brain infarcts.
Methods—Ten stroke patients were investigated by repetitive imaging of the apparent diffusion coefficient (ADC) in the acute phase (7 patients) or subacute phase (3 patients) of developing cortical infarction. In each patient, 20 ADC maps were obtained from serially measured echo-planar DWI (interval of 45 seconds). Data analysis focused on the potential spatial and temporal ADC changes, including structured qualitative analysis, calculation of subtraction images, serial analysis of regions of interest positioned in the infarct core and border, and calculation of hemispheric lesion areas, depending on various ADC thresholds ranging between 0 and 800 µm2/s.
Results—Data analysis was unable to disclose any time-dependent changes in ADC that would resemble PID. In ischemic regions, the ADC reduction significantly progressed from the infarct border (555±96 µm2/s) to the infarct core (431±104 µm2/s, P<0.01).
Conclusions—By using an MRI protocol with high temporal resolution and elaborated postprocessing, we were unable to demonstrate a pattern of diffusion changes that would be indicative of PID in human stroke. Experimental infarction and human stroke may differ in the detectability of PID.
Key Words: magnetic resonance imaging, diffusion-weighted • spreading cortical depression • stroke
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The development of diffusion- and perfusion-weighted MRI has provided new insights into the evolution of focal cerebral ischemia in humans and in animal models of stroke.1 2 3 4 Serial diffusion-weighted imaging (DWI) has repeatedly demonstrated the enlargement of human cerebral ischemic lesions during the initial days after symptom onset.5 6 7 8 Several mechanisms may contribute to this phenomenon: vasogenic swelling of the initial lesion is usually observed, but recruitment of new tissue may also be involved in infarct growth. It has been suggested that subsequent infarct enlargement can be predicted by the initial mismatch between the perfusion deficit (larger) and the lesion size in DWI (smaller).5 7 9
In experimental stroke, Gyngell et al4 have shown by
repeated DWI that regions with disturbed diffusion increased during the
first 6 hours after middle cerebral artery (MCA) occlusion. The
simultaneous measurements of 1H spectra and
electrophysiological monitoring disclosed
that infarct growth is promoted by spreading depression–like events
known as peri-infarct depolarizations (PIDs), which lead to transient
increases in the lactate signal (1H spectra),10
negativation of the direct current potential, and stepwise enlargement
of the diffusion lesion.4 11 The propagation pattern of
PID was studied by repetitive MR diffusion
mapping,12 which demonstrated that depolarizations can be
visualized by the transient reduction of the apparent diffusion
coefficient (ADC), evolving from the infarct border and traveling with
a speed of 
3.5 mm/min over the ipsilateral cortex—a pattern
that exactly resembles the
electrophysiological changes seen in
cortical spreading depression.13 The stimulation of the
ischemic infarct border by local application of potassium,
thereby inducing waves of depolarizations, has been shown to
substantially increase subsequent ischemic
injury.14 15 There is strong experimental evidence that
PID contribute to infarct growth by means of their high
metabolic impact14 (for review, see Back et
al16 ).
At present, there is uncertainty whether this important mechanism of ischemic injury can be detected in stroke patients and should be a target of pharmacological intervention. To document diffusion changes that might follow a pattern known from spreading depression, we monitored early infarct evolution with a dedicated MRI protocol, using rapid repetitive diffusion MRI, in patients presenting with acute hemispheric stroke. Data analysis focused on potential signal changes in the infarct border or the diffusion-perfusion mismatch regions, which are prone to further lesion enlargement over time.
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Subjects and Methods |
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Patients and Controls
Three healthy volunteers and 10 patients in the acute or subacute phase of stroke evolution were investigated prospectively. In all patients, there was cortical involvement in the MCA or anterior cerebral artery (ACA) territories (Table 1
). Hemorrhage had been excluded
by a cranial CT scan. The suspected clinical diagnosis of MCA and/or
ACA occlusion was confirmed by ultrasound and MRI. The severity of the
clinical deficit was assessed by the NIH Stroke Scale17
and Scandinavian Stroke Scale18 scores at the time of MRI.
Informed consent was obtained from all patients in writing before MRI.
The study was approved by the local ethics committee. For clinical
data, see Table 1.
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MRI Techniques
MRI was performed on a 1.5-T MR System (Magnetom Vision,
Siemens) with resonant echo-planar hardware. A standardized
protocol was used: (1) Transverse, coronal, and sagittal localizing
sequences followed by transverse oblique contiguous images (slice
thickness 5 mm) aligned with the inferior borders of
the corpus callosum (sequences 2 to 5). (2) Proton density– and
T2-weighted images (turbo spin echo, repetition time/echo times 1 and
2 [TR/TE1/TE2] 2620 ms/14 ms/85 ms; field of view [FOV]
180x240 mm2; matrix 192x256). (3)
T1-weighted images (spin-echo, TR/TE 530 ms/12 ms). (4) MR angiography
(fast, low-angle shot [FLASH]-3D: TR/TE/
, 35 ms/7.2 ms/20°;
matrix 200x512; performed in 4 of 10 patients). (5) Similar to the
methods applied in experimental MRI studies of spreading
depression,10 19 20 repetitive measurements of the ADC
were performed. Twenty consecutive ADC maps were measured with a
diffusion-weighted (DW) spin-echo echo-planar sequence (TR 2200 ms/TE
100 ms, b=0/160/360/640/1000 s/mm2; FOV
240x240 mm2; matrix 96x128) and the
sequential application of 3 separate diffusion-sensitizing gradients in
perpendicular directions. Three transverse slices of 4-mm thickness
(distance gap 1.2 mm to reduce slice cross talk) were positioned
in the infarct center. The acquisition time was 30.8 seconds per
measurement; the measurements were repeated each 45 seconds. Isotropic
ADC maps were calculated on a pixel-by-pixel basis by a linear
least-squares fit after logarithmic averaging of the
direction-dependent DW images.6 Perfusion maps were
measured by using a free induction decay echo-planar sequence
after the first pass of a contrast bolus through the brain (TR/TE/,
2000 ms/65 ms/90°; 13 slices; 40 acquisitions; 1:20 minutes; FOV
240 mm2; matrix size 128x128). Contrast
agent (30 mL gadodiamide) was injected manually through a large-gauge
venous cannula at the antecubital vein (performed in 6 of 10
patients).
Data Processing and Analysis
Data analysis focused on the spatial and temporal
changes of brain regions showing a disturbance of diffusion
properties. Postprocessing included a computerized 2D matching
procedure compensating for in-plane motion artifacts and eddy current
distortions21 after all DW images were inspected for
spiking and noncorrectable motion artifact. ADC maps were calculated on
a pixel-to-pixel basis by a linear least-squares fit after averaging of
the direction-dependent DW images. ADC subtraction images were
calculated by subtracting the actual image (2 to 20) from the first
image. Twenty repetitive ADC maps and 19 subtraction ADC images were
used per patient for a structural visual analysis that was
performed by 3 readers independently (T.B., J.G.H., and A.G.). A serial
analysis was performed of regions of interest (ROIs; 3x4
pixel) positioned in the infarct core, the infarct border, and
contralateral brain regions, and calculation of hemispheric lesion
areas (HLAs), depending on various ADC thresholds ranging between 0 and
400, 500, 600, 700, or 800 µm2/s. To
assess the hemodynamic alterations and confirm the ROI
position, parameter maps of the contrast bolus passage were
used (time-to-peak map; ie, the intensity of each pixel is related to
the relative position of the peak of the bolus-passage curve).
For statistical analysis of repetitive ADC or HLA
measurements, respectively, the paired Wilcoxon test for
repeated measures was used. Significant changes in ADC or HLA,
respectively, were assumed if the Wilcoxon test revealed
significant alterations of ADC or HLA in at least 3 consecutive
measurements (because the duration of peri-infarct depolarizations was
determined as 
2.5 minutes in animal studies19 22 ). The
different ROIs (cortex, striatum, infarct core, etc) were tested by the
Student t test. The variance of ADC values determined in
different ROIs was tested by the F test. P<0.01 was
accepted as significant if not stated otherwise.
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Results |
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The median latency between onset of stroke and the MR investigation amounted to 9.7 hours. Repetitive measurements of ADC in normal control subjects showed very stable measurement conditions, with a range of ADC values <10% (Table 2
).
Computer simulations revealed that ADC changes in the 10% range would
be identified by the data postprocessing strategies described. Visual
qualitative analysis of repetitive, strongly DW images measured
in 10 stroke patients as well as the entire postprocessing strategies
did not disclose any time-dependent changes in local ADC (Figures 1 and 2).
Patient 4 was excluded from data analysis because of severe
motion artifacts. We were not able to detect alterations in ADC, which
would resemble spreading depression, as known from animal studies. The
ADC values determined in various ROIs are presented in Table 2. As an example, the positioning of ROIs is shown in Figure 3. ROIs were placed in the infarct
center, the inner and outer infarct borderzones, the contralateral
cortex, striatum, and white matter (Figure 3). The distribution
of ADC in the infarcted hemisphere showed that there was a gradient of
ADC reduction from the infarct periphery toward the infarct core
regions, where ADC was lowest and amounted to 57% of contralateral
cortex (Table 2). The same pattern became obvious when various
ADC thresholds were applied depicting only pixels within a certain
range of ADC (Figure 4). The time course
of ADC values as determined in ROIs positioned in the infarct region,
the diffusion-perfusion mismatch area, or the contralateral hemisphere
did not disclose any significant changes during the measurement period
(Figure 5). Also, the 20 consecutive
measurements of HLAs depicting certain ADC ranges of the
ischemic lesions, as stated above, did not reveal significant
changes over time (Figure 6). However,
the serial ADC values measured within the ischemic regions
(infarct core and inner and outer borderzones) varied over time in a
significantly greater range compared with the contralateral
nonischemic brain regions (F test, P<0.01).
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In 6 of 10 patients, the perfusion deficit was visualized by bolus-tracking images. The area with increased time-to-peak matched well the region with disturbed diffusion (n=3) or contained a larger territory (n=3) as an indication of the hemodynamic compromise beyond the diffusion lesions. In the latter 3 patients, the area with reduced ADC encompassed 1815 mm2 and the perfusion deficit 2648 mm2, respectively (mean values, determined at midinfarct level). ADC as measured in those mismatch regions amounted to 798±37 µm2/s and did not differ from contralateral values (807±33 µm2/s). MR angiography was able to demonstrate proximal MCA occlusion (M1 segment) in 2 of 5 cases with extended large MCA territory infarction. MCA branch occlusion lead to a rarefaction of MCA branching or, alternatively, could not be visualized due to the limited spatial resolution.
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Discussion |
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In animal models of focal cerebral ischemia, repetitive imaging of DW or ADC images has been able to demonstrate a typical pattern of spreading alterations in tissue diffusion which paralleled electrophysiological measurements confirming the occurrence of spreading depression of electrical activity.4 10 19 20 Those spreading depression–like peri-infarct depolarizations have been observed in cat cortex up to 16 hours after MCA occlusion (ie, the end point of experiments).23 24 We have chosen a very similar MRI protocol to investigate patients presenting with acute supratentorial stroke. Attention was paid (1) to minimize the latency between symptom onset and MRI measurements (which was a median of 9.7 hours in our series) and (2) to apply a MR technique that would be sufficient with regard to the stability of measurements and the spatial/temporal resolution to detect such reversible changes in ADC traveling over the cortical surface. However, we were unable to demonstrate ADC alterations which, in their spatial and temporal patterns, would resemble PIDs. By using control studies and computer simulations, we ensured that ADC changes in the 10% range would be detectable by the postprocessing strategies used. Thus, technical limitations are unlikely to explain the negative results.
The ADC values obtained in the ischemic regions under
investigation are in good agreement with the
literature.25 26 27 The ROI analysis clearly showed
a gradient of ADC reduction, with progressively lower ADC values moving
from the infarct periphery toward the infarct core (Table 2
,
Figure 4). This observation supports the view that the
ischemia-induced early change in ADC is a blood flow–dependent
event which reflects the severity (and duration) of the perfusion
deficit,28 29 but partial volume effects at the edges of
the lesions may partly account for this finding. It has been shown that
the mismatch between the perfusion deficit (larger) and the diffusion
lesion (smaller) may indicate the tissue at risk of undergoing
infarction and potential infarct enlargement.5 6 7 27 In
our series, half of the patients examined by bolus-tracking perfusion
images showed this mismatch pattern and, therefore, could be expected
to experience infarct growth over time. Even patients with a mismatch
did not show evidence of significant ADC changes over the 15-minute
observation period. ADC values within the mismatch regions remained
normal. The fact that ADC values within ischemic regions
varied in a significantly greater range over time than those observed
on the contralateral side indicates an increased temporal (and spatial)
heterogeneity within the diffusion lesion. Whether this
is due to partial tissue depolarization without a spread into the
adjacent cortex (as observed in a recent animal study30 )
or may reflect the different pathophysiological
state of the tissue under investigation currently remains
unanswered.
We interpret our negative findings with caution. There are 3 potential explanations for the observations:
(1) PIDs were not detected because they do not occur in human stroke. Certainly, we cannot exclude this possibility, but the fact that spreading depression–like depolarizations have been observed in primates,31 in cat brain,23 24 32 and in rats22 33 34 clearly speaks in favor of this phenomenon as a uniform response of rodent and mammalian cortex to various stimuli. Recently, in neurotrauma patients the occurrence of spreading depression has been observed by using a multiparametric approach.35 Not only stroke and brain trauma evolution but also the aura in migraine is thought to be modulated and/or induced by spreading depression,16 36 37 38 which underlines that there is little reason why the human brain should differ in this respect from other mammalians.
(2) PIDs do occur in human stroke and, despite being detectable by means of diffusion MRI, were not displayed. First, it may well be that we have missed transient depolarizations which last 2 to 5 minutes, because the time period covered by repetitive ADC imaging amounted to 15 minutes per patient. Given the assumption that 1 depolarization would occur per 2 hours, the statistical probability to detect this phenomenon is just 1 per 8 patients. Our cohort consisted of 10 patients, but only 7 of them had been investigated within 24 hours after onset of symptoms. Therefore, an extended study that includes a higher number of patients is clearly desirable to substantiate our findings. Second, the cortical architecture is much more complex in humans, which also may affect the propagation pattern of tissue depolarization. We performed ADC measurements in 3 transverse planes through the infarct center so that depolarizations traveling distant from the planes under investigation would have been missed. Yet, it appears that peri-infarct depolarizations are much rarer in human stroke (if they occur at all) compared with animal studies.
(3) PIDs do occur in human stroke, but they cannot be detected by
diffusion MRI. We do not know whether tissue depolarization in the
human cortex would alter ADC in the magnitude known from animal
studies. Recent findings made by Moskowitz and coworkers37
in the cortex of a migraine patient when using blood oxygen
level–dependent (BOLD) MRI are also interesting in this respect.
During the migraine aura, they observed a spreading suppression of
functional (visual) activation traveling over the occipital cortex
at 3.5 mm/min, ie, a depression of the normal
hemodynamic response after cortical
activation.37 Simultaneous measurements of the
ADC did not show significant alterations (oral
communication, M.A. Moskowitz, MD, Charlestown, Mass, 1999).
This finding is in line with a recent study that used perfusion- and
diffusion-weighted MRI in migraine patients demonstrating cortical
"spreading hypoperfusion" without accompanying changes in tissue
diffusion during the aura.38
We favor the view that the lack of ADC changes possibly indicates a lower level of spreading depression–associated electrical and/or hemodynamic compromise in human brain. Alternatively, the blood flow threshold for altering tissue water diffusion may be lower in humans compared with that in animal studies of ischemia (ie, 0.41 mL · g-1 · min-139 ). This may also explain why we were unable to detect PID with ADC imaging but BOLD MRI may be appropriate to detect an equivalent of the spreading depression observed in experimental studies. It has been shown that the pharmacological inhibition of ischemic depolarizations reduces infarct volumes in animal models of stroke.34 40 41 42 It appears, therefore, of high importance to extend MRI investigations of the occurrence and characteristics of peri-infarct depolarizations in human stroke.
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Acknowledgments |
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We gratefully acknowledge the European Neurological Society ENS for providing a research grant to Dr Back. We are grateful to Prof Dr Th. Brandt, director of the Department of Neurology, Klinikum Grosshadern, Munich, who generously exempted Dr Back from the clinical duties during the fellowship period, and we wish to cordially thank Prof Dr M.G. Hennerici, director of the Department of Neurology, Klinikum Mannheim, for his support of the study and the fruitful review of the manuscript.
Received April 20, 2000; revision received August 7, 2000; accepted August 14, 2000.
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