Imaging in acute stroke: the case of magnetic resonance tomography and positron emission tomography

Wolf-Dieter Heiss, MD

Max Planck Institute for Neurological Research, Department of Neurology and
University of Cologne, Germany

Introduction

Therapy in acute ischaemic stroke can only be effective as long as potentially salvageable tissue is present within the brain area affected by the perfusional disturbance. Therefore, the identification of the penumbra - tissue perfused at a level which impairs function but preserves morphology [1-3] – and the distinction of this potentially reversible condition from irreversibly damaged tissue is of utmost importance for the initiation of treatment strategies targeted at reperfusion and protection of ischaemically compromised but viable brain areas. Whereas the model of regional ischaemic damage with a core of fast developing necrosis and a surrounding area with delayed damage and a potential for recovery, i.e. the penumbra, was developed from animal experiments, the transfer of this concept into clinical application in patients with acute ischaemic stroke is limited by the inaccuracy in differentiating functional impairment from morphological destruction in early stroke. Various imaging modalities have been applied for this task: positron emission tomography of regional cerebral blood flow and energy metabolism was the first imaging technique employed for penumbra detection, which was defined as the region with increased oxygen extraction fraction and termed “misery perfusion” for this purpose[4]. PET is still considered the gold standard for detection of penumbra and irreversibly damaged tissue [5,6], but its availability is limited to a few centres and restricted by the complex logistics involved. Diffusion- and perfusion weighted magnetic resonance imaging (DW- and PW-MRI) is widely available and has become the routine method for the acute evaluation of stroke patients. The area of perfusion / diffusion mismatch has been used as a surrogate marker of the penumbra and promising results were achieved in identifying patients with a chance to respond to therapy [7-9]. Recently also determination of perfusion by x-ray computed tomography was successfully applied to detection of potentially salvageable ischaemically compromised tissue [10].

Limitations of PW-/DW-MRI

Without doubt PW-/DW-MRI is the most widely available and most utilised method to detect tissue amenable for therapy in patients with acute stroke and it is therefore the preferred method for selection of patients and for evaluation of treatment effects in stroke trials [11-13]. However, the assumption that the perfusion / diffusion mismatch represents the penumbra as challenged by several limitations of PW-/DW-MRI [14]:

1.     True penumbra cannot be clearly differentiated from tissue experiencing oligemia; the perfusion-weighted imaging abnormality often overestimates the final infarct volume and thereby the amount of tissue at risk [15].

2.     The initial diffusion lesion does not o­nly consist of irreversibly infracted tissue; diffusion lesions may be reversed if blood flow is restored at an early time point [7-9].
These facts are further accentuated by methodological limitations, especially perfusion techniques and data evaluation are not truly quantitative and vary among centres [16]. In order to account for these inaccuracies Kidwell et al [14] proposed a modified model of ischaemic compromised tissue as observed by PW-/DW-MRI in which the penumbra includes the perfusion-diffusion mismatch region, minus the region of benign oligaemia as well as a portion of the initial diffusion abnormality itself. The definition of this tissue compartment, however, remains to be controversial and several attempts have been made to identify perfusion or apparent diffusion coefficient thresholds for better differentiation of these regions [15,17-21], but a consensus o­n the best method is still hampered by the lack of standardisation of methodological approaches to image post processing and analysis which restricts pooling of data and cross-comparison of results across studies. More sophisticated analytical procedures may help to improve accuracy in distinguishing core from penumbral tissue [22].

Comparison of MRI and PET

Absolute or relative thresholds derived from PW- and DW-MRI are still not reliable in predicting the fate of ischaemic tissue [22]. Therefore, a validation of MR signatures o­n results from PET measurements might help in the interpretation of the respective finding and in the assessment of the accuracy of the various measures for predicting tissue outcome. Comparative studies with PET and MRI were performed in 3 groups of patients with respect to assessment of cortical damage, measurement of perfusion and delineation of penumbra tissue.

Irreversible cortical damage

For the prediction of irreversible cortical damage results from DWI (median 6.5 h after symptoms o­nset) and 11C-flumazenil (FMZ) PET (median 85 min between DWI and PET were compared with infarct extension 24 to 48 h later o­n T2-weighted MRI in 12 acute stroke patients [23]. Cortical areas were categorised as infarction or normal according to their appearance o­n follow-up MRI and volumes of interest (VOIs) of 6-mm diameter were fitted into the cortical rim of the coregistered DWI, ADC, and FMZ images. Across all patients’ volumes of interest, the threshold probability integrals of final infarction or noninfarction were interactively computed, and positive prediction curves were obtained o­n which 95 % prediction limits could be defined [24]. These values – FMZ binding 3.2 times the mean of the contralateral white matter, DWI intensity 1.18 times the contralateral area, ADC 0.83 times the contralateral region – represent the 95 % probability threshold of final infarction. When the volumes of tissue beyond these thresholds were compared, close correlations between volumes with FMZ and DWI beyond threshold as well as between predicted and final infarct volumes were obtained, but the volumes did not completely overlap. Overall, 83.5 % of the final infarct (median, 14.9 cm3) was predicted by decreased FMZ binding, 84.7 % by increased DWI signal, and 70.9 % by reduced ADC value. However, because of the incongruities, o­nly a small part of the final infarct was not predicted by FMZ or DWI value beyond the critical limit (median, 1.1 cm3). The false-positive rates showed significant differences: o­nly a small part (median, 0; mean, 0.9 cm3) of the finally noninfarcted tissue had initially decreased FMZ binding, whereas 5.1 cm3 of finally normal tissue showed an increased DWI signal (25.9 % of the total volume of DWI increase) and 3.6 cm3 showed a decreased ADC value (22.3 % of total volume). These differences were significant (P<0.01, Wilcoxon test). The volumes of infarcted tissue not predicted by decreased FMZ or changed DWI signal were comparable. In single cases, areas with markedly increased DWI signal did not show either impaired FMZ binding or a lesion o­n late MRI, as reported previously [25], but in most cases the differences with respect to FMZ binding and DWI signals were at the borderline of the ischaemic territory.

Perfusion in and around the ischaemic territory

For the assessment of perfusion within the oligaemic and ischaemic territory results from PWI (median 8 h after symptoms o­nset) were compared with cerebral blood flow measurements obtained with 15O-H2O-PET (interval 60 min between PWI and PET) in 11 acute stroke patients [26]. After coregistration of the MR and PET images, an individual brain atlas was created for each patient. Then the volume of hypoperfusion of <20 mL/100 g per minute (PET CBF) was created with the use of a voxel-based threshold function. Within the same brain atlas, the TTP images were analyzed with stepwise increasing thresholds, i.e. with increasing relative TTP delays (2, 4, 6, 8, 10 seconds with respect to the unaffected hemisphere). The volume of CBF hypoperfusion ranged from 1.2 to 362 cm3 (median, 34.5 cm3). The voxel-based 3-dimensional fusion of each patient’s hypoperfusion volume (CBF) and the respective set of TTP volumes were used to create subcompartments to calculate sensitivity and specificity values for each TTP threshold. The TTP threshold of 4 seconds reliably identified hypoperfused tissue (sensitivity, 0.827) and excluded normoperfused tissue (specificity, 0.768). Increasing the TTP threshold to 6 seconds impaired the ability to detect hypoperfusion (sensitivity, 0.765) but improved the rate of correctly identified normoperfused tissue (specificity, 0.875). From this small sample size, it can be concluded that a TTP delay between 4 and 6 seconds is useful to differentiate cerebral hypoperfusion of <20mL/100 g/ min.

Delineation of penumbra tissue

For the demarcation of the volume of tissue at risk (penumbra) the areas of mismatch from PWI / DWI were compared to those of increased oxygen extraction fraction (OEF) as determined from PET of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in 5 patients with acute and 5 patients with subacute state after stroke due to vascular stenosis [27]. As surrogate markers of the penumbra, PWI / SWI revealed a mismatch between the volumes of TTP prolonged beyond 4 sec and the volume of increased DWI signal, and volumes of increased OEF (>150 %) were calculated from CBF and CMRO2 maps measured by PET. The comparison of the volumes identified by these modalities demonstrated a high variability: all 10 patients showed areas of TTP prolongation o­n PW images (median volume, 162 cm3; range, 8 to 450 cm3). However, in o­nly 6 of 10 patients was an elevated OEF identified o­n PET images (median volume, 65 cm3; range, 12 to 240 cm3). The areas of OEF elevation were always located within the areas of TTP prolongation but were significantly smaller and covered only 8 % to 58 % (median, 33 %) of the TTP area. These preliminary data demonstrate a high sensitivity but a low specificity of the chosen threshold to identify penumbral tissue as defined by PET: in 40 % of the patients with TTP > 4, no OEF elevation was found. In the remaining 60 % with OEF elevation and TTP > 4, o­nly a third of the TTP volume corresponded to elevated OEF. These findings may explain the poor relation between increased OEF and TTP values in a correlation analysis based o­n volumes of interest. The results of our small patient sample indicate that TTP threshold > 4 seconds does not sufficiently discriminate between normal and increased OEF in ischaemic tissue.

Conclusion

These preliminary data o­n the comparison of PET and DWI/PWI for assessment of perfusion, identification of irreversible tissue damage, and distinction of penumbra indicate that imaging with these different modalities yields complementary information o­n the dynamics of pathophysiological events in ischaemic brain tissue. The findings of DWI/ADC imaging correlate well with those of FMZ PET and predict the final infarct extension 20,28. However, the increased DWI signal carries a considerable false-positive rate, a clinically important restriction of DWI that was demonstrated in previous studies of patients with transient ischaemic attack and those treated with thrombolysis 7,8,29. PWI-derived TTP maps are only indirect surrogates of CBF because they are based o­n a different pathophysiological approach [30]. Hence, a TTP prolongation of > 4 seconds allows o­nly a fair estimate of hypoperfusion 20mL/100 g/ min [31]. Because of this indirect assessment of perfusion from TTP prolongation, which therefore inconsistently corresponds to elevated OEF [32], the mismatch volume in PWI/DWI does not reliably reflect misery perfusion as defined by PET. Despite the importance of MRI in clinical practice for the selection of patients who might benefit from revascularization procedures, the differences between the imaging methods and their specific methodological restrictions should be taken into account when results are compared and definitions of various tissue conditions are transferred between the modalities.

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