Metabolic profiles and correlation with surgical outcomes in mesial versus neocortical temporal lobe epilepsy

Abstract Aims Differentiating mesial temporal lobe epilepsy (MTLE) and neocortical temporal lobe epilepsy (NTLE) remains challenging. Our study characterized the metabolic profiles between MTLE and NTLE and their correlation with surgical prognosis using 18F‐FDG‐PET. Methods A total of 137 patients with intractable temporal lobe epilepsy (TLE) and 40 age‐matched healthy controls were recruited. Patients were divided into the MTLE group (N = 91) and the NTLE group (N = 46). 18F‐FDG‐PET was used to measure the metabolism of regional cerebra, which was analyzed using statistical parametric mapping. The volume of abnormal metabolism in cerebral regions and their relationship with surgical prognosis were calculated for each surgical patient. Results The cerebral hypometabolism of MTLE was limited to the ipsilateral temporal and insular lobes (p < 0.001, uncorrected). The NTLE patients showed hypometabolism in the ipsilateral temporal, frontal, and parietal lobes (p < 0.001, uncorrected). The MTLE patients showed extensive hypermetabolism in cerebral regions (p < 0.001, uncorrected). Hypermetabolism in NTLE was limited to the contralateral temporal lobe and cerebellum, ipsilateral frontal lobe, occipital lobe, and bilateral thalamus (p < 0.001, uncorrected). Among patients who underwent resection of epileptic lesions, 51 (67.1%) patients in the MTLE group and 10 (43.5%) in the NTLE group achieved Engel class IA outcome (p = 0.041). The volumes of metabolic increase for the frontal lobe or thalamus in the MTLE group were larger in non‐Engel class IA patients than Engel class IA patients (p < 0.05). Conclusions The spatial metabolic profile discriminated NTLE from MTLE. Hypermetabolism of the thalamus and frontal lobe in MTLE may facilitate preoperative counseling and surgical planning.


| INTRODUC TI ON
Approximately 40% of patients with temporal lobe epilepsy (TLE) develop drug-resistant epilepsy that may require surgical treatment. 1 Classified by the epileptogenic area, two main syndromes have been described in TLE, mesial temporal lobe epilepsy (MTLE) and neocortical temporal lobe epilepsy (NTLE). 2 A standardized anterior temporal lobectomy is the most targeted and efficient procedure for the treatment of MTLE, 3 and tailored resection of the lateral temporal neocortex is often chosen for NTLE. 4 However, the postoperative seizure outcome is not as favorable in NTLE as MTLE. 5 Further improvements, such as precise identification of TLE subtypes and localization of the epileptogenic zone (EZ), should allow the elaboration of tailored surgical strategies for each patient to achieve better seizure outcomes.
Classification of the TLE subtype is based on seizure symptomatology, ictal and interictal scalp electroencephalography (EEG), and structural magnetic resonance imaging (MRI). However, most patients with MTLE or NTLE share similar clinical pictures, including viscerosensory aura, behavioral arrest, automatism, impaired consciousness, or secondary bilateral tonic-clonic seizures. 6 They also exhibit similar patterns of EEG recordings that show episodic spikes and/or slow waves interictally localized over the unilateral temporal region. 4,7 For TLE with MRI-invisible lesions, it would be much more difficult to differentiate NTLE from MTLE on the basis of structural brain imaging. 5 The use of preoperative high-resolution morphometric MRI or molecular imaging may help discriminate the subtypes of TLE patients and localize the region of seizure origination to improve surgical results via optimized presurgical planning.
Fluorine-18 fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET) is well accepted as an irreplaceable noninvasive presurgical molecular imaging method for patients with TLE. 8 18 F-FDG is a sensitive in vivo imaging tracer that has been widely used to reveal focal hypometabolic regions concordant with seizure onset. 9 PET hypometabolism may be a promising indicator for presurgical evaluation of postoperative outcomes in drug-resistant TLE patients. 10 Indepth evaluation combined with semiology, EEG findings, structural MRI, and PET would further improve EZ localization accuracy and postsurgical prediction in refractory epilepsy. 9,11-13 18 F-FDG-PET in neurodegenerative diseases with dementia reveals lobar-specific patterns of hypometabolism related to particular types of dementia.
For example, 18 F-FDG-PET/computed tomography (CT) shows that hypometabolism in Alzheimer's disease first appears in the precuneus and posterior cingulate cortex and then in the temporoparietal lobes, 14 and hypometabolism in the frontal and anterior temporal lobes with later involvement of the parietal lobes is more suggestive of frontotemporal dementia. 15 We infer that MTLE and NTLE may also have different glucose metabolic features, which would assist in the classification of TLE subtypes and surgical evaluation of outcomes.
Our study retrospectively analyzed patients with TLE and reviewed their clinical, neuroelectrophysiological, neuroimaging, surgical, and follow-up data. The patients were then categorized into MTLE and NTLE subgroups to screen interictal whole-brain voxel-based metabolic profiles using 18 16,17 Clinical data of all patients were complete, and the number of episodes was greater than two times per year. The lateralization and localization of the EZ and therapy were determined using a multidisciplinary team (MDT) consisting of two experienced epileptologists, a neuroelectrophysiologist, a neuroradiologist, a neuropsychologist, and two neurosurgeons. According to these comprehensive data and the current categories proposed in previous studies, 18

Conclusions:
The spatial metabolic profile discriminated NTLE from MTLE.
Hypermetabolism of the thalamus and frontal lobe in MTLE may facilitate preoperative counseling and surgical planning.

K E Y W O R D S
18 F-FDG-PET, metabolic profile, MTLE, NTLE, surgical prognosis abnormality in the unilateral neocortical temporal lobe on MRI and a compatible ictal onset was identified during continuous scalp video EEG monitoring or (b) the structural MRI was normal, but SEEG confirmed neocortical ictal onset. Patients with a history of severe systemic or psychiatric illness, drug abuse, and substance use disorder were excluded. The prognostication of the outcome was graded according to the Engel Surgical Outcome scale. 20 Forty healthy controls (HCs), matched for age and sex, were recruited randomly in our study. 18 F-FDG-PET was used to measure regional cerebral metabolism in all participants. The Institutional Review Committee of Xiangya Hospital approved the protocol before patient recruitment commenced. All participants provided informed consent in writing before participation. For participants under the age of 16 years, consent was obtained from their legal guardians. Metabolic alterations were obtained at an uncorrected height threshold (significance of voxel level) of p < 0.001, with cluster size (K E ) above 20 contiguous voxels. After SPM12 preprocessing, xjView toolkits (http://www.alive learn.net/xjview) were used to visualize, report, and label the significant clusters anatomically. Data on metabolic pattern information about the clusters were obtained, including the number of voxels, peak intensity of each cluster, and anatomical location, which used automated anatomical labeling (AAL) to approximate Brodmann areas. The volume of metabolism changes in the temporal lobe, frontal lobe, parietal lobe, occipital lobe, insula lobe, limbic system, basal ganglia thalamus, brainstem, and cerebellum for each surgical patient was calculated separately using the xjView toolkit.

| Statistical analyses
Statistical analyses were performed using SPSS software for For PET image analysis, analysis of covariance (ANCOVA) was used to compare baseline glucose uptake values of each epilepsy group (left and right MTLE, then left and right NTLE) and HCs, with the group as the between-subject factor and age and sex as confounding covariates. A two-sample t-test was used to compare the different groups. Metabolic changes in the whole brain and cerebellum were calculated, and the MTLE and NTLE groups were compared to HCs separately. The volumes of metabolic changes, including hypermetabolism and hypometabolism, in temporal and extratemporal areas and their relationship with surgical prognosis for each surgical patient were also calculated. The Mann-Whitney U test was used for the comparison of the volumes between different groups.  Figure 1. Table S1 lists the peaks of the most significant voxels and shows the location of the voxels within each cluster.

| Metabolic abnormalities in patients with NTLE
The epileptogenic regions of the NTLE group were also well lateralized to the left NTLE (n = 28) and right NTLE (n = 18  Figure 2. Notably, unlike MTLE, hypermetabolism was observed only in the contralateral cerebellum.

| The volume of hypermetabolism in temporal and extratemporal regions
Significant differences were found in the metabolic patterns of MTLE and NTLE, especially in the hypermetabolic regions. Figure 3 demonstrates the involved volume of metabolic abnormalities in pa-

TA B L E 2
Surgical data of patients who underwent surgery.

| DISCUSS ION
Our study used whole-brain voxel-based 18  to focal metabolic impairment in the insula or lead to insular atrophy. 24,25 The hypometabolic region in NTLE is primarily located in the temporal neocortex associated with the EZ. Notably, we also found some restricted extratemporal cortical regions in the frontal and parietal lobes showing decreased glucose metabolism in NTLE patients, which suggested more extensive brain regions and connected propagated networks affected in NTLE. Therefore, it is plausible that patients with NTLE generally demonstrate behavioral arrest with awareness impairment at the early stage 26,27 followed by motor signs as the seizure activity spreads to the frontoparietal convexity. 28,29 Notably, increasing evidence suggests that epilepsy is a network disorder, and mixed cerebral metabolic patterns were found recently. 30  Although cortical and subcortical hypermetabolism areas beyond the EZs are also present in patients with NTLE, it is much more restricted in the range of glucose metabolism. Notably, the key hypermetabolic region of NTLE is typically the bilateral thalamus, which suggests an underlying propagation pathway from the lateral neocortex of the temporal lobe through the basal ganglia to the contralateral hemisphere that contributes to bilateral tonic-clonic seizures. 40 Considering the extent of involvement, we speculate that in addition to the trans-thalamic circuits, other propagating pathways may exist in NTLE. 41 We also observed significant hypermetabolism in the cerebellum, which is consistent with previous functional MRI and SPECT studies. 42,43 Sufficient data indicate that the cerebellum is engaged during seizures, which manifests as reduced gray matter volumes, 44 increased cerebellar blood flow, and neuronal activities. 45,46 Increased interictal metabolic activities in the cerebellum have also been reported in animal models of epilepsy. 47 The cerebellar metabolic changes in TLE patients in our study suggest a functional significance of temporal-cerebellar connections and the potential ability for cerebellar activation to inhibit seizures. 48 Another possibility is that abnormal glucose metabolism in the cerebellum may be compensatory as one of the downstream targets via divergent output pathways from the temporal lobe. 46 Notably, the bilateral cerebellum is likely affected in MTLE, and abnormal metabolism is only found in the contralateral cerebellar hemisphere in the NTLE group, which highlights the potential importance of the cerebellum in the differentiation of epilepsy phenotypes in TLE.
We further assessed metabolic features and surgical outcomes in patients with two subtypes of TLE. We found that patients with MTLE had a worse surgical prognosis when thalamic or frontal hy-  and surgical prognosis assessment. Although ASMs were discontinued for at least 24 h before the PET scan, they may still have residual effects on brain metabolism. However, most PET studies in epilepsy shared this limitation, which is hard to overcome.

| CON CLUS ION
Distinctive characteristic features of 18

ACK N OWLED G M ENTS
We would like to express gratitude to all the patients with temporal lobe epilepsy for their cooperation in our study. We would also like to thank the researchers for their contributions to collecting and following up with the patients.