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Summary: Purpose: The goal of neuroimaging in epilepsy is to localize the region of seizure onset. Single-photon emission computed tomography with tracer injection during seizures (ictal SPECT) is a promising tool for localizing seizures. However, much uncertainty exists about how to interpret late injections, or injections done after seizure end (postictal SPECT). A widely available and objective method is needed to interpret ambiguous ictal and postictal scans, with changes in multiple brain regions.
Methods: Ictal or postictal SPECT scans were performed by using [99mTc]-labeled hexamethyl-propylene-amine-oxime (HMPAO), and images were analyzed by comparison with interictal scans for each patient. Forty-seven cases of localized epilepsy were studied. We used methods that can be implemented anywhere, based on freely downloadable software and normal SPECT databases (http://spect.yale.edu). Statistical parametric mapping (SPM) was used to localize a single region of seizure onset based on ictal (or postictal) versus interictal difference images for each patient. We refer to this method as ictal–interictal SPECT analyzed by SPM (ISAS).
Results: With this approach, ictal SPECT identified a single unambiguous region of seizure onset in 71% of mesial temporal and 83% of neocortical epilepsy cases, even with late injections, and the localization was correct in all (100%) cases. Postictal SPECT, conversely, with injections performed soon after seizures, was very poor at localizing a single region based on either perfusion increases or decreases, often because changes were similar in multiple brain regions. However, measuring which hemisphere overall had more decreased perfusion with postictal SPECT, lateralized seizure onset to the correct side in ∼80% of cases.
Conclusions: ISAS provides a validated and readily available method for epilepsy SPECT analysis and interpretation. The results also emphasize the need to obtain SPECT injections during seizures to achieve unambiguous localization.
Epilepsy is a devastating illness with a major economic and psychosocial impact (1). Although medications are often beneficial, millions have epileptic seizures that are refractory to medical therapy (2,3). Hope for a cure can be offered to these patients through selective surgery to remove the region of seizure onset. However, for this surgery to be performed, the region of seizure onset must be identified with a high level of certainty. The gold standard for seizure localization has been invasive intracranial EEG recording (4,5). However, this procedure carries some operative risk (6,7) and has limited spatial sampling because of the finite number of electrodes that can be inserted safely. Recent advances in neuroimaging methods offer the possibility of localizing seizures safely, noninvasively, and in a manner that maps seizure activity throughout the entire brain (8,9).
Although functional brain abnormalities in the interictal state (between seizures) can provide clues about the region of seizure onset, it is crucial to map brain activity in the ictal state (during seizures) to know the site of seizure initiation (10–12). Most neuroimaging methods such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) are impractical here because images would have been acquired during seizures while patients are actively moving and medically unstable. Single-photon emission computed tomography (SPECT) has the unique advantage of mapping brain activity at the time of radiotracer injection (during seizures), whereas the actual imaging can be done 60 to 90 min later when the patient is fully stable. Thus after injection, the SPECT agent is rapidly taken up by the brain, based on cerebral blood flow (CBF) and does not redistribute (13,14). Because CBF is closely linked to neuronal activity (15), the SPECT injection provides a “snapshot” of brain activity at the time of injection, which can be viewed later by neuroimaging.
Ictal SPECT imaging has shown great promise in localizing seizure onset (12,13,16,17). Recent advances in quantitative analysis have further improved the diagnostic yield of ictal SPECT, including digital registration and subtraction of baseline (interictal) images taken from the same patient at a time when seizures are quiescent (12,16,18,19). However, the lack of a validated and widely available method for analyzing and interpreting ictal and interictal SPECT images has limited the use of this diagnostic tool (20). Interpretation of ictal SPECT can be ambiguous and subjective because multiple areas are often activated and may be considered positive, depending on analysis threshold (21). Preliminary studies using statistical parametric mapping (SPM) offer the possibility of objective interpretation (18,20,22,23); however, validation and threshold determination are needed, and freely available normal SPECT databases are necessary for this method to be widely applied. In addition, although prior studies suggest that early SPECT injection timing is critical for improving diagnostic yield (10,24–26), this has not been rigorously studied. The lack of this information has made it difficult for most centers to justify the considerable investment in personnel and technical resources needed to attain consistent early SPECT injections. Finally, it has long been known that focal CBF decreases occur in the postictal period (immediately after seizures) (27–30); and regional CBF decreases have also been reported during seizures both at the epileptic focus (31) and in surrounding regions (18,32–35). Prior work has not thoroughly investigated the possible role of these CBF decreases in seizure localization.
The goal of our present study is to provide a reliable method that can be used at any center to analyze and interpret epilepsy SPECT images. To accomplish this, we have studied [99mTc]-labeled hexamethyl-propylene-amine-oxime (HMPAO) SPECT in a group of patients with surgically confirmed seizure localization. We have included patients with both mesial temporal lobe epilepsy and neocortical epilepsy, because pathophysiology and surgical outcome may differ in these two groups (36). We then used ictal–interictal SPECT analyzed by SPM (ISAS). ISAS is similar to difference imaging (19), or SISCOM (16), in using differences between ictal and interictal images for each patient. However, ISAS has the added benefits of using a standard normal reference to determine statistical significance of any changes and providing more objective methods of interpretation. We determined appropriate statistical thresholds to optimize sensitivity and specificity of the method. We then analyzed the localizing value of CBF increases and decreases in the ictal and postictal periods in this population. Finally, we provide all details of the methods along with downloadable scans from our healthy normal SPECT database, so that this approach will be readily available to others.
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The goal of SPECT studies in epilepsy patients is to localize a single region of seizure onset objectively and unambiguously for epilepsy surgery. The results reported here emphasize the importance of true-ictal SPECT for achieving this goal. In addition, whereas we found that postictal SPECT does not unambiguously localize the lobe of seizure onset, postictal perfusion decreases can be useful for lateralizing the correct hemisphere. These results were obtained by using ISAS, an objective analysis method based on SPM, which we have validated and made available for public use along with our healthy normal SPECT database (http://spect.yale.edu/).
Our results demonstrate that ictal SPECT is far superior to postictal SPECT for seizure localization. These results are in agreement with prior work suggesting that ictal SPECT is superior (10,17,24–26), but our results are more conclusive and statistically rigorous. We report that CBF increases on ictal SPECT provided correct unambiguous localization in 70–80% of cases, whereas this was true in <10% of postictal injections. The clear superiority of ictal over postictal scans also was supported by ROC analysis in both mesial temporal and extratemporal epilepsy. We found that some clinically useful information can be salvaged from postictal SPECT scans, because postictal CBF decreases can at least lateralize seizure onset to the correct hemisphere in ∼80% of postictal scans. This hypoperfusion in the hemisphere of seizure onset, particularly in the postictal period, was in agreement with prior studies (18,32–35). Thus whereas hypoperfusion was not good for unambiguously localizing the lobe of seizure onset, it was quite successful at lateralizing the afflicted hemisphere by using the hypoperfusion asymmetry index. Postictal scans may be helpful in cases in which other localizing information is scarce and can help tailor the placement of intracranial EEG electrodes to a more limited region, but they do not meet the goal of localizing seizures sufficiently to prevent the need for intracranial monitoring. These results demonstrate the critical need for true ictal SPECT injections to localize seizure onset. Ictal SPECT scans can be attained anywhere—it is simply a matter of personnel and logistics to inject patients immediately on seizure onset and then to acquire SPECT images in a timely manner. We hope that these results will help justify the investment of crucial resources needed at all medical centers performing SPECT imaging, so that patients can receive studies that are diagnostically useful.
This study also demonstrates that ISAS is a relatively easy, quick, and objective method for analyzing ictal–interical SPECT differences. In a recent review by Knowlton et al. (20), the advantages of SPM analysis for providing objective interpretation of epilepsy SPECT results were discussed, and the authors identified the need for these methods to be widely available, not just in specialized centers. We hope that this work will begin to fill that need by providing a freely available method that can be implemented anywhere. All that is required is a computer running MATLAB and an operator with sufficient imaging experience to download and implement the SPM analysis (see http://spect.yale.edu/). As in difference imaging (19) or SISCOM (16), ISAS is based on calculating the difference between ictal and interictal SPECT for each patient. Added advantages of ISAS are (a) the statistical significance of these differences is calculated by comparison with the normal variation from one scan to the next in healthy normal subjects, and (b) more-objective methods are used for interpretation of the results. We have validated ISAS by using our population of mesial temporal and neocortical epilepsy patients and our database of healthy normal SPECT pairs. Ideally, each center would establish its own database of normal SPECT pairs acquired under the same conditions used for their clinical scans, although in many cases, this may not be feasible because of the cost involved. Similarly, although the database of 14 scan pairs is a reasonable sample size for SPM (41,45), it is possible that an even larger database would improve our results. At least as a starting point, we have made our database of normal SPECT pairs available, so that other centers can independently test and validate the method with their own patient populations. Because the purpose of the database is mainly to provide an estimate of the variance in SPECT signal for each voxel in the brain between pairs of scans done on different days, it may be possible to use the database at other centers as long as the scan-to-scan variability is similar to ours. It should be noted that our SPECT scans were performed with [99mTc]-HPMAO (Ceratech, Medi-Physics, Amersham Healthcare), which has slightly different gray matter distribution from [99mTc]-ECD (Neurolite; Bristol-Myers Squibb Medical Imaging, N. Billerica, MA, U.S.A.) (46). We have not tested this method by using [99mTc]-ECD SPECT scans.
In the past, most epilepsy SPECT images were simply analyzed by visual comparison of ictal and interictal images. This method has many drawbacks, including the lack of intensity normalization, the difficulties in making comparisons between corresponding slices, and the lack of quantitative assessment (19). Subsequent improvements over simple visual interpretation have included ROI analysis (47) and ictal–interictal subtraction images coregistered to MRI (16,19). Recently, voxel-based statistical analysis using SPM has become a widely used method in analyzing functional neuroimaging studies. This method of analysis for SPECT data has been shown to be a useful diagnostic tool in localizing partial epilepsy (18,20,23).
In our investigation, we attempted to discern the appropriate parameters for analyzing ictal–interical SPECT images with SPM. We found that, although this method provides objective data on the statistical significance of SPECT changes, the interpretation of results may not be completely straightforward. One reason is that often in a single analysis, multiple clusters may be significant at the cluster level, even when using significance values that are corrected for multiple comparisons. Thus it was necessary to establish “reading rules” for determining which clusters to consider positive and how to determine the localization of positive clusters. The goal of noninvasive epilepsy localization is to identify a single region for surgical resection. Therefore criteria for interpreting SPM SPECT results were established here, aimed at identifying a single positive region whenever possible. The interpretation consisted of first identifying the most significant cluster of contiguous voxels, referred to as a “positive cluster.” Next, the region (lobe) identified by this cluster was identified and referred to as a “positive region.” This approach allowed us to use the statistically robust approach of SPM to identify significant clusters of voxels, correcting for multiple comparisons. We then determined the location of the cluster based on the lobe in which majority of the voxels in the cluster were located. Of note, we did not base the location on the most significant voxel. This was because we often found that the single most significant voxel was in the surgically incorrect lobe, whereas the majority of the voxels from the most significant cluster were in the correct lobe. These finding support the concept of an epileptogenic region, rather than a single epileptogenic focus (4,48).
Our analysis method differs from that of Lee et al. (23) in that we used the difference between an ictal and interictal scan for each patient, whereas they compared a single ictal scan with a database. Prior work has shown that omission of the interictal SPECT can lead to false localization (12,19). For example, increased CBF in the epileptogenic region may not show up in the face of baseline decreased CBF in this region. This can lead to pseudonormalization of CBF during seizures, which may not be detected without the interictal scan. Although omission of the interictal SPECT may still allow CBF increases to be seen in more obvious cases, we suspect that more subtle cases, especially with neocortical onset, may be difficult to localize correctly without the interictal comparison. Nevertheless, because omission of the interictal SPECT would lead to a considerable reduction in cost and time, a direct comparison of ISAS and the method of Lee et al. (23) should be pursued further. Additional direct comparisons of ISAS with difference imaging, as performed by Chang et al. (18), also would be worthwhile.
Some technical limitations and potential pitfalls of ISAS will require further studies in ongoing work. We excluded patients in the current study with significant anatomic abnormalities, prior resection, or intracranial hardware, because SPECT images are spatially warped to a template for analysis. However, it is feasible by using SPM to remove selective abnormal brain regions during spatial warping (49), so it is possible to analyze patients with anatomic abnormalities by ISAS as well (see http://spect.yale.edu for details). Although ISAS provides a straightforward and objective method for analysis, appropriate caution is required not to use a “black box” approach. It is essential to view the images at each stage of analysis and to assess image quality and registration visually and whether the results “make sense.” We have, therefore, automated the most straightforward processing steps (see http://spect.yale.edu/) to speed analysis time but have so far avoided further automation to encourage viewing results at intermediate stages of analysis and to allow greater user flexibility. For example, because anatomic warping is necessary for SPM analysis compared with a normal database, data should be visually inspected during processing for potential artifacts. In addition, results should be confirmed independently by methods that do not require spatial warping (16,19), which can also be achieved by using simple SPM tools (ImCalc), or other freeware (http://www.colin-studholme.net/software/software.html; see also http://spect.yale.edu). Although these other methods (without warping) do not allow objective statistical comparison with a standard database, they can be useful as a second check of results. Another enhancement that can be implemented in a relatively straightforward manner is unwarping of ISAS results back onto individual patient MRI scans rather than onto the MRI template (deformations toolbox in SPM2, http://www.fil.ion.ucl.ac.uk/spm/ see also http://spect.yale.edu). In this study, we also excluded patients with secondarily generalized seizures. A preliminary analysis demonstrated poor localization by SPECT in patients with secondarily generalized seizures (38); however, further investigation of this population is warranted.
One of the limitations of the current study is sample size. After applying our inclusion/exclusion criteria designed to study a population of patients with clear and definite localizations, only 47 image pairs were included, although our center has a relatively large volume of epilepsy patients. Further breaking down this group by localization, seizure duration, and injection time will result in small numbers within each subgroup. Important additional information may be gained by more detailed analysis of the time course of SPECT imaging changes. For example, from our data, we can speculate that temporal lobe seizures may propagate in the late ictal period, making localization of a single focus more difficult (e.g., patients 6 and 7 in Table 1). Previous studies also support this possibility (50), but a much larger sample size would be needed to investigate this phenomenon in detail. It also is known that the radiotracer can take between 30 and 60 s to be completely taken up in the brain (13,14); thus the injections done during the late ictal period may actually reflect postictal brain activity. On the other hand, the known delay between changes in neuronal activity and changes in CBF during seizures (51) may, at least in part, counteract this timing discrepancy. It is clear that to study fully the time course of CBF changes during and after seizures, a multicenter collaboration will be necessary.
In summary, ictal SPECT is a powerful noninvasive tool for presurgical localization. Our hope is to make a valid method of analysis and interpretation widely available, so that ictal SPECT will not be limited to a few specialized centers. Based on our results, obtaining true ictal injections remains a high priority. Although it is clear that ictal SPECT is far superior to postictal SPECT for presurgical localization, obtaining true ictal injections remains a challenge at most medical centers, mainly for logistic and financial reasons. A coordinated effort will most likely be needed among medical centers to guarantee that consistent ictal injections can be achieved and justified as medically necessary.