Temporal lobe epilepsy (TLE) is the most common form of medically refractory epilepsy, and surgical treatment is adopted in such cases (Semah et al., 1998; Choi et al., 2008). Therefore, presurgical examinations are important in locating a seizure focus and its laterality. In TLE, fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to achieve high detectability regarding the lateralization of a seizure focus, as decreased glucose uptake in the epileptogenic temporal lobe (Hammers, 2012) and better surgical prognosis has been reported in cases with FDG-PET hypometabolism (LoPinto-Khoury et al., 2012). Relative to FDG-PET, magnetic resonance imaging (MRI) has been less reliable in detecting abnormalities related to seizure foci (King et al., 1998; Engel et al., 2008; Takaya et al., 2012), although it can provide detailed anatomic information that is indispensable for clinical practice.
Double inversion-recovery (DIR) is a relatively new MR sequence that nullifies signals from both the cerebrospinal fluid and white matter (WM) and improves lesion detection (Turetschek et al., 1998); a recent development is three-dimensional (3D) acquisition (Busse et al., 2006). DIR is considered helpful for increased detectability of hippocampal sclerosis (HS; Zhang et al., 2011) and other abnormal signal changes in epilepsy (Rugg-Gunn et al., 2006; Salmenpera et al., 2007; Morimoto et al., 2013). Recently, by visually evaluating the presence or lateralization of the anterior temporal lobe white matter abnormal signal (ATLAS), better diagnostic capability of DIR at 3T was reported in determining seizure focus laterality of TLE in higher agreement with clinically diagnosed seizure focus laterality than that of T2-weighted imaging (T2WI) or fluid-attenuated inversion recovery (FLAIR). (Morimoto et al., 2013). In patients with TLE, ATLAS is observed as an increased signal area or a loss of gray–white matter demarcation in the anterior temporal lobe (ATL) WM ipsilateral to the seizure focus on T2WI (Coste et al., 2002). This finding has been considered as an indicator of focus laterality (Kuzniecky et al., 1987; Choi et al., 1999; Meiners et al., 1999; Mitchell et al., 1999; Coste et al., 2002; Adachi et al., 2006; Morimoto et al., 2013), and it is not observed in healthy controls (Briellmann et al., 2004; Morimoto et al., 2013). High detectability of seizure focus laterality on DIR gives us an expectation that MRI would play a more important role, comparable to PET for TLE patients without radiation exposure. However, objective and quantitative comparison of these modalities has not yet been carried out.
The purposes of this study were the following: (1) to evaluate diagnostic capability of DIR in quantitatively determining seizure focus laterality of patients with TLE, and (2) to compare the capability of DIR with that of FDG-PET.
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This is the first study that has compared the detectability of DIR and FDG-PET regarding seizure focus laterality using a VBA in TLE patients. FDG-PET is widely used to define epileptogenic cortical areas, and also to guide the placement of intracranial electrodes, because of its high detection levels of seizure focus (Juhasz et al., 2000). On the other hand, MR imaging has been reported to have a lower detectability (King et al., 1998; Engel et al., 2008; Takaya et al., 2012). However, this study has successfully shown that the increased signal intensity areas on DIR-WM corresponded well to the hypometabolic areas on FDG-PET, especially in the anterior temporal lobe, and detection of seizure focus laterality was almost equivalent between DIR-WM and FDG-PET. In addition, visual analysis of ATLAS on DIR showed almost same detectability as that attained by VBA analysis of DIR-WM and FDG-PET, which objectively confirmed the high reliability of visual estimation ATLAS. It is simple and convenient for routine clinical practice, and gives MRI a more important role in image evaluation of TLE. There have been only a few reports regarding DIR images in epilepsy (Rugg-Gunn et al., 2006; Salmenpera et al., 2007; Morimoto et al., 2013). A previous study revealed that DIR achieved higher detectability of seizure focus laterality in TLE than conventional MR sequences by visual evaluation of ATLAS laterality (Morimoto et al., 2013). By a quantitative analysis, Salmenpera et al. (2007) demonstrated that 3D-DIR at 1.5T revealed signal abnormality (ipsilateral, 14%; bilateral, 7%; contralateral, 5%) in TLE patients using voxel-based whole brain analysis inclusive of both the GM and WM. In this study higher detectability was observed, which is considered attributable to an improved signal-to-noise ratio at higher magnetic strength (Wattjes et al., 2007) and the analysis focused only on the WM. Extremely high signal intensity of the GM obscures faint signal changes in the WM on quantitative analysis, because DIR nullifies signals from both the cerebrospinal fluid and WM (Turetschek et al., 1998).
Chassoux et al. (2004) reported that hypometabolic areas on FDG-PET in the patients with TLE were frequently detected in the mesial ATL and tended to spread to the lateral and dorsal parts of the TL, which is similar to what was observed in our study. They also noted that hypometabolic areas were more extended when ATLAS was detected (Chassoux et al., 2004). We found the same tendency with the observation that increased intensity areas in the WM on DIR were located in areas that corresponded to hypometabolic GM on FDG-PET, especially in the ATL (Figs. 1, 2 and S1). These results may mean that increased intensity areas in the DIR-WM show secondary changes caused by corresponding cortical abnormality; this is also suggested by the high κ values of agreement. In addition, they provide supportive evidence that evaluators should focus on the ATLAS, abnormal signal in the ATL-WM, when they want to visually determine the seizure focus laterality in the MR images of TLE patients (Kuzniecky et al., 1987; Choi et al., 1999; Meiners et al., 1999; Mitchell et al., 1999; Coste et al., 2002; Adachi et al., 2006; Morimoto et al., 2013). On the other hand, abnormal areas were less correlated in the dorsal part of the TL. Uncorrelated WM lesions would be degenerative changes like Wallerian degeneration, isolated areas vulnerable to the epileptic discharge, or incidental lesions unrelated to epilepsy.
Contralateral changes on DIR-WM and PET imaging were detected in some cases in our study as in former studies (Chassoux et al., 2004; Salmenpera et al., 2007). It might be induced in patients with TLE because of anatomic connections between bilateral TLs (Cavazos & Sutula, 1990). A patient in this study had contralateral changes and was found to have opposite laterality by both FDG-PET and DIR-WM. Two TLE patients having PET or MRI abnormal findings opposite to the depth EEG were reported (Benbadis et al., 1995). They had poor prognosis when resection was conducted on the side of image abnormality. However, such cases are relatively rare, and no reasoning was provided for causality (Benbadis et al., 1995).
Increased intensity areas on DIR-WM and hypometabolic areas on FDG-PET were larger in the LTLE group than that of RTLE, although no significant difference in the characteristics was found between them. Chassoux et al. (2004) found that VBA analysis of patient groups showed larger hypometabolic areas on FDG-PET, when RTLE images were reversed to the left than when LTLE images were flipped to the right in order to get epilepsy focus sides aligned to one side. One of the probable reasons is that the normal brain has metabolic laterality. If FDG uptake of the healthy volunteers was higher on the left side than on the right side, larger hypometabolic areas would be detected when images of the patients are analyzed by pooling the epileptogenic hemispheres on the left side. In fact, higher metabolism on the left TL than right TL was observed in the healthy brain using FDG-PET (Fujimoto et al., 2008). In addition, patients of LTLE had more prominent findings than those of RTLE for hypometabolism on FDG-PET (Kerr et al., 2013), GM volume reduction (Bonilha et al., 2007; Li et al., 2012), and abnormality of white matter fiber tracts (Kemmotsu et al., 2011). Some possible reasons have been presented. Temporal lobes are more susceptible to epileptic insults on the left (Bonilha et al., 2007; Kemmotsu et al., 2011; Li et al., 2012), and the dominant hemisphere possibly have more intensely connected to the rest of the brain and hippocampal damage may cause neuronal loss from deafferentation in a larger number of remote sites (Bonilha et al., 2007; Kerr et al., 2013). However, the precise mechanism of the asymmetrical and different intracranial damages in the LTLE and the RTLE remains unclear (Li et al., 2012).
Ipsilateral TL was affected on both FDG-PET and DIR-WM only at dorsolateral areas in a patient with lateral TLE, without significant involvement of the ATL. This result is consistent with a previous report (Bercovici et al., 2012) and may indicate difference between medial and lateral TLE patients. However, in our study, there was only this patient who had lateral TLE, and this result cannot be generalized.
In the ATL, hypometabolic areas and increased signal intensity areas were frequently observed in the MTG and PPo, which is in good agreement with a former finding that anterior parts of the STG and the MTG were usually involved in TLE patients, when measured using stereo-EEG with depth electrodes (Bartolomei et al., 1999). We also detected increased intensity areas in the IFOF in some patients. McDonald et al. (2008) reported that patients with TLE exhibited changes in fractional anisotropy and mean diffusivity in the IFOF, which were related to deteriorated verbal memory and naming performances, and predicted cognitive performances. DIR-WM not only has higher detectability of HS, cortical malformation, and other macrostructural changes than conventional MR sequences (Cotton et al., 2006; Rugg-Gunn et al., 2006; Zhang et al., 2011), but also is considered to have a potential to evaluate function in patients with TLE.
Other than DIR, diffusion-tensor imaging has advantage in detecting microstructural changes, and was used to evaluate white matter changes on the ipsilateral side to seizure foci (Kemmotsu et al., 2011). DIR reflects changes in T1 and T2 values and gives another contrast that will help to detect laterality of the seizure focus. Comparison of these two methods is out of focus of this study, but combined usage of these methods is expected to increase detectability and reliability.
Our study has some limitations. No histologic confirmation was obtained for the increased signal changes of DIR-WM. This was because some patients in this study were less severe TLE cases, so that they did not require surgical treatment in the end. The pathologic changes that correspond to ATLAS have yet to be clearly identified. Many possible causes of ATLAS have been discussed including lower myelin density (Meiners et al., 1999), gliosis (Mitchell et al., 1999; Adachi et al., 2006), corpora amylacea (Choi et al., 1999; Mitchell et al., 1999), dilated perivascular spaces (Mitchell et al., 1999), minor inflammatory changes (Mitchell et al., 1999), oligodendroglial cell clusters (Choi et al., 1999; Meiners et al., 1999; Mitchell et al., 1999), heterotopic neurons (Choi et al., 1999), and microdysgenesis (Adachi et al., 2006). However, they may not be specific for ATLAS because these findings were observed also in control specimens (Meiners et al., 1999; Mitchell et al., 1999). In addition, all patients who underwent surgical treatment had a good outcome of seizure control, which suggests a certain reliability of the clinical diagnosis in this study. Secondly, the present study included seven patients with conventional MRI-visible HS. However, in HS-negative eight patients, detection of seizure focus laterality on DIR-WM was comparable to that of FDG-PET, even though the detectability was lower. It suggests that DIR-WM and FDG-PET can provide additional information even for MR-negative patients. Although the number of patients is relatively small, this is the first study that investigated capability of DIR and found it equivalent to those of the FDG-PET. A large-scale patient study would reveal more advantages of DIR.
In conclusion, DIR is shown to have high-detection ability for seizure focus laterality in TLE using VBA. An important finding was that the laterality of increased signal intensity areas in the WM on DIR located concordantly with the hypometabolic areas on FDG-PET, especially when focused on the ATL. DIR would play an indispensable role to avoid radiation exposure, especially in children, and when FDG-PET examination is not available.