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- MATERIALS AND METHODS
Summary: Purpose: To elucidate uncoupling of perfusion and metabolism and its significance in epilepsy, 15O water and 18F fluorodeoxyglucose (FDG) positron emission tomography (PET) and Tc-99m hexamethyl-propyleneamine-oxime (HMPAO) single-photon emission computed tomography (SPECT) were examined by SPM (statistical parametric mapping) and quantitation by using SPAM (statistical probabilistic anatomic map).
Methods: [15O]water and [18F]FDG-PET, and [99mTc]-HMPAO SPECT were performed in 25 patients (SPECT in 17 of 25) with medial temporal lobe epilepsy. For volume of interest (VOI) count analysis, the normalized counts using VOI based on SPAM templates of PET and SPECT were compared with those of the normal controls. Perfusion or metabolism was found abnormal if the Z score was >2 for each VOI. For SPM analysis, the differences between each patient's image and a group of normal control images (t statistic for p < 0.01) on a voxel-by-voxel basis were examined to find significant decreases in perfusion or metabolism.
Results: With SPAM VOI count analysis, areas of hypoperfusion were found in 13 patients in the epileptogenic temporal lobes by [15O]water PET and areas of hypometabolism in 21 patients by [18F]FDG-PET. With voxel-based SPM analysis, the epileptogenic zones were localized in 15 by [15O]water PET and in 23 patients by [18F]FDG-PET. The localization by [15O]water PET was concordant with that of [18F]FDG-PET. The areas of hypoperfusion on [15O]water PET were absent or smaller than the areas of hypometabolism on [18F]FDG-PET. Interictal [99mTc]-HMPAO SPECT revealed the hypoperfused zones in seven of 17 patients on visual assessment.
Conclusions: SPAM VOI count and SPM analysis of [15O]water and [18F]FDG-PET and [99mTc]-HMPAO SPECT revealed that in the same patients, the areas of hypoperfusion were concordant with but smaller than the areas of hypometabolism. Discordance of perfusion and metabolic abnormalities represents an uncoupling of perfusion and metabolism in the epileptogenic zones, and this might explain the lower diagnostic accuracy of perfusion imaging in temporal lobe epilepsy.
During physiologic stimulation, blood flow is not tightly coupled to the oxidative metabolism in an activated cortex (1). In several pathologic conditions including epilepsy, there is evidence of an altered relation between blood flow and metabolism (2). In the epileptogenic zones, blood flow is uncoupled from the glucose metabolism on 15O water and on 18F fluorodeoxyglucose (FDG) positron emission tomography (PET) (3–6). In these studies, the regional cerebral glucose metabolic rates were lower than the regional cerebral blood flow in epileptogenic zones. This uncoupling was suggested to be the cause of the lower diagnostic value of interictal perfusion single-photon emission computed tomography (SPECT), which uses the uptake of [99mTc] agents to represent the regional cerebral blood flow.
Interictal perfusion SPECT was previously found to be useful for localizing the epileptogenic zones (7). However, recent meta-analysis revealed that the sensitivity of interictal perfusion SPECT was less than desirable (8). In a [15O]water PET study (6) and a [99mTc]- hexamethyl-propyleneamine-oxime (HMPAO) SPECT study by the authors on the interictal blood flow (9), a sensitivity as low as 35% was revealed. In contrast, the sensitivity of [18F]FDG-PET was reported to be higher (7,9,10). Further understanding of the impact of the regional uncoupling between blood flow and metabolism on the localization of the epileptogenic zones is necessary.
Recently, statistical parametric mapping (SPM) (11–13) made it possible to display objectively the significantly hypoperfused or hypometabolic areas on a voxel-basis for both [15O]water and [18F]FDG-PET, and [99mTc]-HMPAO SPECT. Before this approach, a visual assessment and calculation were used of the counts in the regions of interest manually drawn on the individual images or templates (6), which required a high level of expertise and resulted in lower reproducibility because of variable partial volume effects. SPM with its user independence and objectivity were found to concord well with expert interpretation (14,15). Recently another objective VOI-drawing method was developed with statistical probabilistic anatomic maps (SPAM) based on the population magnetic resonance imaging (MRI) images of Evans et al. (16) and was successfully applied to interpret [18F]FDG-PET images (17).
In this study, the differences of hypoperfusion and hypometabolism between [15O]water, [18F]FDG, and the [99mTc]-HMPAO images in the epileptogenic zones were investigated by voxel-based analysis by using SPM and automatic VOI count analysis with SPAM templates. A decrease in blood flow and glucose metabolism was measured in the temporal lobes ipsilateral and contralateral to the epileptogenic zones in patients with medial temporal lobe epilepsy. We tried to unravel the uncoupling of blood flow and metabolism in the epileptogenic zones and its clinical implication on [15O]water and [18F]FDG-PET, and [99mTc]-HMPAO SPECT.
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- MATERIALS AND METHODS
Gaillard et al. (3) performed simultaneous imaging of [15O]water PET and [18F]FDG-PET. They found that ratio of the local cerebral glucose metabolic rate to the regional cerebral blood flow was lower in the inferior lateral temporal cortex with the template region of interest (ROI) method. Template ROI was superior to ROI manually drawn on individual images. In our study, the subjectivity of drawing an ROI was overcome by a SPAM-based VOI template. As the VOI is derived from a population-based MRI template, the counts of the seven VOIs of each temporal lobe could be calculated reproducibly. Rather than comparing asymmetric indices, the counts of the VOI of each temporal lobe was compared with those of normal controls. After defining the normal range of normalized counts, the hypoperfused or hypometabolic areas were determined by using Z values on the [15O]water or [18F]FDG-PET by SPAM VOI count analysis.
SPM, which had been used for brain activation studies, also can be used for locating areas with significant hypometabolism or hypoperfusion compared with normal controls. Compared with the [18F]FDG images of the age-matched normal controls, the hypometabolic areas recognized by visual assessment was detected by SPM analysis on the [18F]FDG-PET (14,15). Assessment of the hypoperfused areas was difficult visually on the [15O]water PET. However, by using SPM, a voxel-based quantification of the regional blood flow was possible on [15O]water PET. The area of decreased perfusion was determined by using [99mTc]-HMPAO SPECT in the same way.
This voxel-based SPM analysis supported the earlier SPAM VOI analysis results. In contrast to the SPAM VOI analysis, in SPM, the variation of counts was calculated on a voxel basis. Although SPM analysis yielded areas of hypoperfusion or hypometabolism similar to those of SPAM VOI analysis, not only were the areas of hypometabolism wider than the areas of hypoperfusion, but also the epileptogenic zones were found more often by [18F]FDG-PET than by [15O]water PET. Both reproducible and objective SPAM VOI and voxel-based SPM methods corroborated our visual observations and the previous reports (3,5,6,18). Zubal et al. (19) recently described a method for using interictal SPECT/PET ratio images to demonstrate epileptogenic foci. Because spatial normalization between two different imaging methods can be readily performed, this ratio image might be another good approach to demonstrate uncoupling on a voxel basis.
The sensitivity of interictal-perfusion SPECT was recently questioned (9,20); however, it was not evident that this was due to the properties of [99mTc] agents or rather the lower resolution of SPECT. In our study with statistical quantitative methods, [15O]water PET could not yield sensitivity equivalent to that of [18F]FDG-PET. Interictal perfusion SPECT and PET could not compete with [18F]FDG-PET in finding epileptogenic zones.
Several investigators reported uncoupling of the blood flow and glucose metabolism in the epileptogenic zones in intractable epilepsy (3,5,6,18). Our study is the confirmation of these findings by new operator-independent methods: automatic SPAM VOI count analysis and voxel-based SPM analysis. Quantitation of hypoperfused or hypometabolic voxels in the ipsilateral epileptogenic temporal lobes with an arbitrary cutoff value of uncorrected p = 0.01 on SPM analysis revealed even an absence or much smaller extent of hypoperfused areas than of hypometabolic areas. Because of the uncoupling of blood flow and glucose metabolism in the epileptogenic cortex, interictal [15O]water PET or [99mTc]-HMPAO SPECT is not useful and might be sometimes misleading.
Three possible mechanisms were proposed for this uncoupling. First, [18F]FDG-PET represents a relatively long-term state in intractable epilepsy patients, but [15O]water PET represents a short-term state. Because the interictal spike discharge is not infrequently accompanied by increased metabolism and perfusion (21), the increased perfusion might be observed on interictal perfusion studies. Second, as the ictal episodes are followed by an increased perfusion of variable duration in the epileptogenic zones, even tens of minutes (22) or hours (23) after ictus, an interictal [15O]water PET or [99mTc]-HMPAO SPECT might represent the “aftereffect” of the previous ictus without subclinical ictal discharges. The decreased metabolism in the interictal period can be concealed by the overlying hyperperfusion at the epileptogenic zones. However, the postictal aftereffect on glucose metabolism also was reported (24). Third, the glucose metabolism might be further downregulated to prevent ictal propagation in the areas near the epileptogenic zones. This explains why the hypometabolic areas are wider than the hypoperfused areas. Possibly the lower brain glucose concentration associated with the downregulated glucose transport in the cerebral capillary membrane might be involved in the wider area of hypometabolism (25).
There has been a possibility and a recent suggestion that the decreased uptake of [18F]FDG on the [18F]FDG-PET does not represent decreased glucose metabolism. [18F]FDG decrease, not glucose metabolism, might be characteristic of the epileptogenic zones (26). If the lumped constant was estimated by using dynamic [18F]FDG-PET data, the lumped constants should be lower if this were the case. This interpretation awaits further evidence.
In conclusion, [15O]water PET and [99mTc]-HMPAO SPECT showed an uncoupling of perfusion from glucose metabolism on [18F]FDG-PET in the epileptogenic zones in temporal lobe epilepsy. When the user-independent SPAM VOI counts were compared on [15O]water PET and [18F]FDG-PET, the epileptogenic zones with an abnormal metabolism or perfusion could be located best by [18F]FDG-PET. Voxel-based analysis using the SPM method yielded areas of decreased perfusion and metabolism and their uncoupling on [15O]water PET, [18F]FDG-PET, and [99mTc]-HMPAO SPECT in epileptogenic zones. Both the quantitative VOI-based and voxel-based methods corroborated the uncoupling in the epileptogenic zones in medial temporal lobe epilepsy.