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Summary: Purpose: The aim of this study was to evaluate the usefulness of multislice magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation for the identification of the epileptogenic focus in neocortical epilepsy (NE).
Methods: Twenty patients with NE (10 with MRI-visible malformations, 10 with normal MRI) and 19 controls were studied. In controls, N-acetylaspartate NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter, and thresholds were determined by calculating the 95% prediction intervals (PIs) for NAA/Cr and NAA/Cho. Voxels with NAA/Cr or NAA/Cho values less than the 95% PI were defined as “pathological.” Z-scores were calculated. Depending on the magnitude of those z-scores, we used two different methods (score-localization or forced-localization) to identify in a given subject the lobe with the highest percentage of pathological voxels, which was supposed to represent the epileptogenic lobe.
Results: MRSI correctly identified the lobe containing the epileptogenic focus as defined by EEG in 65% of the NE patients. MRSI localization of the focus was correct in 70% of the patients with an MRI-visible malformation and in 60% of the patients with normal MRI. Of the patients, 15% had metabolically abnormal brain regions outside the epileptogenic lobe, and 35% of the patients had evidence for secondary hippocampal damage.
Conclusions: MRSI may be helpful for the identification of the epileptogenic focus in NE patients, even in NE with normal MRI.
In 20 to 40% of all patients with partial epilepsy, seizures arise from neocortical structures (1). In >30% of patients with neocortical epilepsy (NE), the seizures are refractory to medical treatment, and these patients may benefit from epilepsy surgery. However, compared with the good results of surgery in patients with medial-temporal lobe epilepsy [mTLE; outcome Engel class I–II in 80–90% (2,3)], surgery in NE is often less successful [(outcome Engel class I–II in 45–60% (4–6)]. This may be because the accurate identification of the epileptogenic focus is more challenging in NE than in mTLE, particularly in NE without a magnetic resonance imaging (MRI)-visible structural abnormality. In addition to initial ictal signs, ictal and interictal electroencephalography (EEG) recordings, often with intracranial electrodes, are traditionally used to localize the epileptogenic focus. However, initial clinical signs may be very subtle and may be overshadowed by more impressive manifestations of seizure spread. Scalp EEG is often not well localized (7,8), which makes the decision where to place intracranial electrodes difficult. Furthermore, results from intracranial recordings may be misleading because of limited spatial sampling. Therefore noninvasive techniques that can assist in localizing the seizure focus take on a greater role in NE. High-resolution MRI, for example, identifies the epileptogenic lobe in NE in ∼55% (9,10), interictal single-photon emission computed tomography (SPECT) in ∼30–50% (9–11), ictal SPECT in ∼56–80% (9,11–13), and positron emission tomography (PET) in ∼33% of the patients with normal MRI but in ≤100% of the patients with acquired structural lesions or tumors (4,9,11,14–17). Compared with these other techniques, few studies used magnetic resonance spectroscopy (MRS) in NE patients (18–21). Furthermore, in all these previous studies, the measurements were restricted to the lobe suspected to contain the epileptogenic focus, as determined by other techniques, and none of them actually tested the ability of MRS to identify the lobe with the epileptogenic focus by measurements in all lobes. In this study, we used a multislice spectroscopic imaging technique (MRSI) covering ∼50–70% of the whole brain in combination with tissue segmentation in NE patients with and without MRI-visible malformations with the following aims: (a) to evaluate the usefulness of MRS for the correct identification of the lobe or lobes containing the epileptogenic focus as determined by EEG; (b) to determine the frequency of metabolically abnormal brain regions outside the epileptogenic lobe; and (c) to seek evidence for secondary damage to the hippocampus in NE. As most patients did not undergo surgery, ictal surface EEG recordings were used as the “gold standard” for comparison with focus localization by MRSI.
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The first major finding of this study was that, based on the assumptions that the epileptogenic focus is characterized by NAAratio and that these metabolic abnormalities are more widespread in the focus than in remote brain regions, MRSI identified the lobe containing the epileptogenic focus correctly (i.e., in concordance with the localization by ictal EEG) in 65% of the NE patients. This is considerably higher than the ability of this method to identify correctly the lobe containing the epileptogenic focus by chance, which would be 10%. The analysis of the seven patients with incorrect identification of the epileptogenic focus by MRSI showed that only two had no spectroscopic abnormality in the lobe with the epileptogenic focus. Therefore our first assumption that NAAratio characterizes the epileptogenic focus in NE seems to be correct. The other five patients with false focus localization by MRSI had additional regions with NAAratio concordant with the EEG localization of the epileptogenic focus. These regions had been rejected as representing the epileptogenic focus because other regions with NAAratio had a higher percentage of pathological voxels. Therefore despite leading to the correct identification of the epileptogenic lobe in 13 patients, our second assumption of more widespread metabolic abnormalities in the epileptogenic focus was not always correct. In this context, it also is of interest to note that only 25% of the patients had brain regions with NAAratio large enough to qualify for “score-localization” (i.e., in most cases, focus identification was based on “forced localization”). By definition, “forced localization” will identify a brain region as an epileptogenic focus in a subject as long as just one voxel has a “pathological” NAAratio in the whole data set. Thus “forced localization” should theoretically lead to false localization in a considerably higher percentage of patients than does “score-lateralization.” However, identification of the epileptogenic lobe by “score-localization” and “forced localization” had about the same accuracy in this study. This unexpected finding might be explained by two shortcomings of “score localization.” First, even if the three-slice MRSI technique used in this study covered a relatively large part of the brain, no lobe was fully covered. Additionally, some brain regions (e.g., temporal lobes) were more affected by B0 inhomogeneities, resulting in loss of information from these regions. An epileptogenic focus either partly covered by an MRSI slice or in a region with bad spectral quality may eventually have a lower z-score than a fully covered remote area in a region with good spectral quality and thus not be recognized as a focus by MRSI. A second reason for the epileptogenic focus not to be characterized by the highest z-score is that the focus is not necessarily restricted to one lobe but may include two or even more lobes. Because z-scores are calculated for lobes, such a region would be expressed by two or more smaller z-scores and thus eventually not be identified as epileptogenic focus by MRSI, as demonstrated in patient 17. Therefore although z-scores were useful for focus identification in NE, their limitations must be kept in mind, particularly when “forced localization” is used for focus identification. Additional factors, like positioning of the MRSI slices, spectral quality, and distribution of the pathological voxels on the reference images must be taken into account for their interpretation.
Of the NE patients, 15% had metabolic abnormalities in remote regions found ipsi- and contralateral to the primary epileptogenic region. These results are consistent with PET studies, which found metabolic abnormalities in remote brain areas in ≤80% of the NE patients (4,16).
Several possible mechanisms may explain remote abnormalities. First, some of the remote areas with NAAratio might represent brain regions secondarily involved in seizure spread (23). This hypothesis is supported by the findings in patient 7, in whom ECoG localized the epileptogenic focus in the posterior superior temporal gyrus (cf., Fig. 3A). Because of the anatomic connections of this region, a secondary involvement of the hippocampal formation and the medial frontal lobes is very likely. Second, they might indicate cortical malformations too subtle to be detected by MRI but still associated with neuronal dysfunction. Finally, remote abnormalities also may represent projection areas with functional disturbances due to loss of neuronal input from the epileptogenic focus. Any of these three mechanisms could be associated with intrinsic epileptogenicity and may predict continuing seizures after surgical removal of the focus.
Of the NE patients, 35% (57% with normal MRI) had areas with NAAratio in the ipsilateral hippocampus, indicating a secondary involvement of the hippocampus in NE. This finding contrasts with a previous study from this laboratory that found no evidence for secondary hippocampal damage in NE patients with normal MRIs (31). Because the previous study used hippocampal MRSI, which is more suited to detect hippocampal damage than is the multislice MRSI used in this study, this divergent finding must be explained by differences between the two patient populations.
Secondary hippocampal damage in NE might be of clinical importance. In ∼30% of the patients with medically refractory epilepsy, evidence exists for “dual pathology” (i.e., an extrahippocampal lesion, usually a cortical malformation, associated with radiologic evidence for hippocampal sclerosis) (32). The percentage of NE patients with “dual pathology” might be even higher, because in some patients with extrahippocampal lesions, spectroscopic evidence for hippocampal damage also has been detected in absence of MRI signs for hippocampal sclerosis (33). The fact that surgical outcome in patients with “dual pathology” is best when hippocampus and extrahippocampal lesion can be removed has been interpreted as evidence for both being involved in the generation of epileptogenic seizures (34,35). In this study, two patients had purely extrahippocampal cortical malformations (i.e., fulfilled the criteria for “dual pathology”). The other three patients had normal MRIs. However, this does not exclude the presence of subtle or microscopic malformations. Histopathologic examination revealed a cortical dysplasia in one of them (patient 7), who underwent successful temporal lobe resection without resection of the hippocampus. However, further studies in a larger patient group are needed to determine whether hippocampal abnormalities in NE patients with normal MRIs indicate a hidden malformation or otherwise independent hippocampal epileptogenic activity.
This study has limitations: (a) The focus localization was based on ictal scalp EEG recordings The gold standard for focus identification in NE is a good outcome after epilepsy surgery, but only four patients had surgery. In contrast to ictal scalp EEG, which allows focus identification on a lobar scale only, MRSI allows a precise localization of brain regions with NAAratio. However, if for NE, the same is true as for TLE [i.e., that brain regions with NAA reductions correlate well with brain regions with ictal and interictal SEEG abnormalities (36)], then MRSI abnormalities might be helpful for the planning of intracranial EEG exploration in NE. (b) Although using multislice MRSI allows coverage of a large part of the brain, epileptogenic foci only partially covered or outside the MRSI slices may be missed. In such patients, focus localization by MRSI will be wrong. Furthermore, the ability of MRSI to detect foci in the orbitofrontal and temporal regions is limited because of the B0 inhomogeneities in these regions. Using a 3D MRSI sequence could solve the problem of the limited brain coverage; however, the problem of data loss in the basal regions of the brain due to B0 inhomogeneities would persist.
In conclusion, multislice MRSI appears to be a useful tool for the focus localization in NE (i.e., a group of patients in whom the identification of the epileptogenic zone is challenging). In ∼15% of the patients, spectroscopic abnormalities also could be found in remote areas. These remote, metabolically abnormal brain regions might be of clinical importance, because they could potentially represent additional epileptogenic foci.