==== Front PLoS One PLoS One plos PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0288054 PONE-D-23-07317 Research Article Medicine and Health Sciences Surgical and Invasive Medical Procedures Medicine and Health Sciences Neurology Epilepsy Medicine and Health Sciences Diagnostic Medicine Diagnostic Radiology Magnetic Resonance Imaging Research and Analysis Methods Imaging Techniques Diagnostic Radiology Magnetic Resonance Imaging Medicine and Health Sciences Radiology and Imaging Diagnostic Radiology Magnetic Resonance Imaging Research and Analysis Methods Bioassays and Physiological Analysis Electrophysiological Techniques Brain Electrophysiology Electroencephalography Biology and Life Sciences Physiology Electrophysiology Neurophysiology Brain Electrophysiology Electroencephalography Biology and Life Sciences Neuroscience Neurophysiology Brain Electrophysiology Electroencephalography Biology and Life Sciences Neuroscience Brain Mapping Electroencephalography Medicine and Health Sciences Clinical Medicine Clinical Neurophysiology Electroencephalography Research and Analysis Methods Imaging Techniques Neuroimaging Electroencephalography Biology and Life Sciences Neuroscience Neuroimaging Electroencephalography Medicine and Health Sciences Surgical and Invasive Medical Procedures Surgical Resection Medicine and Health Sciences Clinical Medicine Signs and Symptoms Lesions Medicine and Health Sciences Pathology and Laboratory Medicine Anatomical Pathology Histopathology Medicine and Health Sciences Neurology Epilepsy Epileptic Seizures Tonic-Clonic Seizures Identifying important factors for successful surgery in patients with lateral temporal lobe epilepsy Identifying factors for surgery in patients with lateral temporal lobe epilepsy https://orcid.org/0000-0002-3404-199X Kim Jae Rim Conceptualization Data curation Formal analysis Investigation Methodology Writing – original draft Writing – review & editing 1 Jo Hyunjin Formal analysis Investigation Writing – review & editing 1 ¤ https://orcid.org/0000-0003-2683-8795 Park Boram Data curation Formal analysis Methodology Visualization Writing – original draft 2 Park Yu Hyun Data curation Formal analysis Methodology Software Validation Visualization Writing – original draft 1 3 4 Chung Yeon Hak Data curation Formal analysis Writing – original draft 1 Shon Young-Min Data curation Resources Supervision 1 3 Seo Dae-Won Data curation Resources Supervision 1 Hong Seung Bong Data curation Resources Supervision 1 Hong Seung-Chyul Data curation Resources Supervision 5 Seo Sang Won Conceptualization Formal analysis Methodology Supervision Writing – review & editing 1 2 3 4 * https://orcid.org/0000-0003-1233-959X Joo Eun Yeon Conceptualization Data curation Resources Supervision Writing – review & editing 1 * 1 Department of Neurology, Neuroscience Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea 2 Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea 3 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea 4 Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, South Korea 5 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea Martino Tommaso Editor Policlinico Riuniti of Foggia: Neuroscience Department, S.C. Ospedaliera of Neurology-Stroke Unit, ITALY Competing Interests: There are no restrictions on sharing of data and/or materials of our manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. ¤ Current address: Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America * E-mail: sangwonseo@empal.com (SWS); ejoo@skku.edu (EYJ) 29 6 2023 2023 18 6 e028805416 3 2023 18 6 2023 © 2023 Kim et al 2023 Kim et al https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective Lateral temporal lobe epilepsy (LTLE) has been diagnosed in only a small number of patients; therefore, its surgical outcome is not as well-known as that of mesial temporal lobe epilepsy. We aimed to evaluate the long-term (5 years) and short-term (2 years) surgical outcomes and identify possible prognostic factors in patients with LTLE. Methods This retrospective cohort study was conducted between January 1995 and December 2018 among patients who underwent resective surgery in a university-affiliated hospital. Patients were classified as LTLE if ictal onset zone was in lateral temporal area. Surgical outcomes were evaluated at 2 and 5 years. We subdivided based on outcomes and compared clinical and neuroimaging data including cortical thickness between two groups. Results Sixty-four patients were included in the study. The mean follow-up duration after the surgery was 8.4 years. Five years after surgery, 45 of the 63 (71.4%) patients achieved seizure freedom. Clinically and statistically significant prognostic factors for postsurgical outcomes were the duration of epilepsy before surgery and focal cortical dysplasia on postoperative histopathology at the 5-year follow-up. Optimal cut-off point for epilepsy duration was eight years after the seizure onset (odds ratio 4.375, p-value = 0.0214). Furthermore, we propose a model for predicting seizure outcomes 5 years after surgery using the receiver operating characteristic curve and nomogram (area under the curve = 0.733; 95% confidence interval, 0.588–0.879). Cortical thinning was observed in ipsilateral cingulate gyrus and contralateral parietal lobe in poor surgical group compared to good surgical group (p-value < 0.01, uncorrected). Conclusions The identified predictors of unfavorable surgical outcomes may help in selecting optimal candidates and identifying the optimal timing for surgery among patients with LTLE. Additionally, cortical thinning was more extensive in the poor surgical group. Samsung Medical Center OTC1190671 https://orcid.org/0000-0003-1233-959X Joo Eun Yeon This study was granted by Samsung Medical Center Grant (OTC1190671). We state that the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper and its Supporting Information files. Data Availability All relevant data are within the paper and its Supporting Information files. ==== Body pmcIntroduction Epilepsy surgery is an effective therapeutic option for patients with drug-resistant epilepsy [1]. Temporal lobe epilepsy (TLE) is the most frequent type of epilepsy that is treated surgically [2]. Approximately 10% of patients with TLE have seizures arising from the lateral temporal area; this condition is defined as lateral TLE (LTLE) [3]. As LTLE is diagnosed in a small number of patients, its characteristics and surgical outcomes are less well known compared to those of mesial TLE (MTLE). LTLE is reported to have less favorable surgical outcomes than MTLE [3–6]. The chances of being seizure-free after surgery are lower in patients with LTLE than in those with MTLE. Hence, it is important to appropriately identify individuals who need to undergo epilepsy surgery. The etiological findings on magnetic resonance imaging (MRI) or histopathology can be used to predict surgical outcomes in patients with LTLE [7, 8]. Lateralized or localized ictal scalp electroencephalography (EEG) patterns have also been reported as factors that predict good surgical outcomes [8]. However, the abovementioned studies had limitations, such as a short-term follow-up (21.9±14 months) or small numbers of patients (29 patients). Presurgical neuroimaging studies have provided prognostic implication of epilepsy surgery [9–12]. Recently, cortical thickness analysis has been adopted in epilepsy field [13–17]. The degree and location of cortical thinning differed depending on the type of epilepsy. For example, in TLE, the parahippocampal gyrus was thinned and in frontal lobe epilepsy (FLE) it was thinner in a relatively wider range of cortex. In neocortical epilepsy with normal MRI findings, frontal and hemispheric cortical thickness asymmetries indicated prognostic implications with a high positive value [18]. These findings suggest that the cortical thinning patten may become a prognostic factor for surgical outcomes. In this retrospective cohort study, we aimed to identify the long- and short-term surgical outcomes in patients with LTLE. We investigated the prognostic implications of relatively objective clinical, electroencephalographic, and neuroimaging factors on surgical outcomes. We also developed a model to predict the probability of poor postoperative outcomes in LTLE. Materials and methods We retrospectively reviewed the records of 1,172 patients with refractory epilepsy who underwent epilepsy surgery between January 1995 and December 2018 at Samsung Medical Center in South Korea. Patients with drug-resistant epilepsy underwent a comprehensive presurgical evaluation comprising neurological examination, video electroencephalography (VEEG), and temporal lobe MRI. When possible, 18F fluorodeoxyglucose- proton emission tomography (FDG-PET) and ictal and interictal single-photon emission computed tomography (SPECT) scans were conducted to localize epileptic foci. After scalp VEEG monitoring, invasive VEEG monitoring was performed in patients suspected of having LTLE based on presurgical diagnostics. Patients were diagnosed with LTLE if the seizure onset zone was in the lateral temporal area, not in mesial temporal structures or basal temporal area based on an invasive study. The seizure onset zone was defined as any paroxysmal ictal pattern that was distinct from background activity with clinical symptoms. Patients who were followed-up for less than two years were excluded (Fig 1). Informed written consent was obtained from all participants when they admitted to epilepsy monitoring units (EMU), and it was obtained from the next of kin, caretakers, or guardians on behalf of the minors/children participants involved in this study. The Institutional Review Board of Samsung Medical Center approved the study protocol (IRB number 2021-03-068). We had not access to information that could identify individual participants during study. 10.1371/journal.pone.0288054.g001 Fig 1 Flow chart describing the selection process according to presurgical evaluation. Demographic and clinical data Clinical characteristics registered for each patient were recorded, including age at seizure onset, age at surgery, history of febrile seizures, major brain trauma, central nervous system infection or other medical diseases, and existence of auras or focal to bilateral tonic-clonic seizures. Scalp EEG During scalp VEEG in EMU, the 10–10 system for scalp electrodes was used. Both interictal epileptiform discharges (INIEDs) and ictal epileptiform discharges (IEDs) were classified as localized (ipsilateral temporal) and non-localized (extratemporal or bilateral or none). Neuroimaging MRI was performed using a GE Signa 1.5-Tesla scanner (GE Medical Systems, Inc., Milwaukee, WI, USA) or a 3.0-Tesla scanner (Philips, Best, The Netherlands). All studies included spoiled gradient echo, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) imaging. The MRI results were classified into three subtypes: lateral temporal lesions, such as focal cortical dysplasia (FCD) or tumorous lesion; mesial temporal lesion but normal lateral cortex, such as hippocampal sclerosis (HS); and normal. Additionally, we analyzed cortical thickness from some available MRI data. The cortical thickness was measured by the same measurement procedures has been described in the author’s previous study [19]. FDG-PET was performed (GE Advance PET scanner, GE Medical Systems, Inc.) 4 or more hours after an intravenous injection of 7–10 mCi (259–370 MBq) of FDG. Hypometabolism was determined by visual assessment. FDG-PET results were classified as localized (ipsilateral temporal) and non-localized (extratemporal or bilateral or none). Brain SPECT scans were performed 30–60 min after injection of 25 mCi 99mTc-ethyl cysteinate dimer using a three-headed Triad XLT system (Trionix Research Laboratory, Inc., Twinsburg, OH, USA). Subtraction Ictal SPECT Co-registered to MRI (SISCOM) was analyzed on an offline workstation using the Analyze 7.5 software (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN, USA). SISCOM results were classified as localized (ipsilateral temporal) and non-localized (extratemporal or bilateral or none). Intracranial VEEG and surgery All participants who were suspected LTLE underwent the invasive monitoring using a combination of subdural grids/strips with or without depth electrodes to confirm the ictal onset zone and determine the extent of resection. Once the ictal onset zone was confirmed using sufficient data, the extent of resection was determined. Resection included lesionectomy or corticectomy, which were done alongside the removal of intracranial electrodes. In some cases, anterior temporal lobectomy (ATL) or amygdalohippocampectomy (AH) was necessary. Surgical specimens were reviewed for histopathological and immunohistochemical analysis. The classification of pathology was based on the International League Against Epilepsy guidelines for FCD [20] and HS [21]. Surgical outcome Postoperative seizure outcomes were classified based on Engel’s classification [22]. Patients were divided into two outcome groups: good (corresponding to Engel’s class I) and poor (corresponding to Engel’s class II–IV) outcomes. Statistical analyses The demographic and clinical characteristics of the patients are summarized as number (percentile) for categorical variables and mean ± standard deviation for continuous variables. To compare two groups, we applied the Chi-square or Fisher’s exact test for categorical variables. Student’s t-test or Mann-Whitney U test was performed for continuous variables. Logistic regression analysis was used to identify the independent risk factors for poor surgical outcomes. Variables with a p-value < 0.1 in the univariable model were included in a multivariable logistic regression analysis. The receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) was used to measure how well the model discriminated between seizure-free and recurrent seizure patients. A nomogram was created based on multivariable logistic regression models to provide a visual representation of the model. The optimal cut-off value for the duration of epilepsy prior to surgery was determined using a logistic regression model that gives the maximum difference between good and poor surgical outcomes at five years. Statistical analyses were performed using Statistical Package for the Social Sciences version 27.0 (IBM Corp., Armonk, NY, USA). Statistical significance was set at p-value < 0.05. For cortical thickness analysis of the MRI data, we used a MATLAB-based toolbox (freely available online at the University of Chicago website: http://galton.uchi cago.edu/faculty/InMemoriam/worsley/research/surfstat/). To identify the cortical thinning pattern in the groups, we analysed localized differences in cortical thickness between the good surgical outcome and poor surgical outcome groups using a general linear model after controlling for age, sex, and ICV. To illustrate trends, significances were displayed at an uncorrected threshold of p-value < 0.01. Inclusivity in global research Additional information regarding the ethical, cultural, and scientific considerations specific to inclusivity in global research is included in the Supporting Information (S1 File). Results Patients’ characteristics Sixty-four patients with LTLE were enrolled, and their demographic and clinical data were analyzed (Table 1). Among the participants, 62.5% were male, and the mean age at seizure onset was 18.5 years (standard deviation [SD]: 8.9 [range: 1–34]). The mean age at surgery was 29.0 years (SD, 11.5 [range, 9.0–61.0]), and the mean duration of epilepsy prior to surgery was 10.5 years (SD, 7.4 [range, 1.0–31.0]). 49 (76.6%) patients experienced focal to bilateral tonic-clonic seizures before surgery, and 26 (40.6%) patients experienced more than one seizure per week. There was no difference between the groups, except for the preoperative disease duration and follow up periods after surgery. 10.1371/journal.pone.0288054.t001 Table 1 Participants’ demographics and clinical characteristics. Good (I) Poor (II-IV) p-value (n = 39) (n = 25) Gender     Male, n (%) 24 (61.5) 16 (64.0) 0.843     Female, n (%) 15 (38.5) 9 (36.0) Age at Seizure onset, year 18.3±9.4 18.8±8.1 0.839 Age at Surgery, year 27.2±12.8 31.8±8.6 0.057 Duration of epilepsy prior to surgery, year 8.9±7.0 13.0±7.6 0.034* Follow up after surgery, year 6.9±6.2 10.7±5.9 0.005* Side of surgery     Left, n (%) 22 (56.4) 20 (80) 0.053     Right, n (%) 17 (43.6) 5 (20) Seizure frequency (≥1/week) 18 (46.2) 8 (32.0) 0.261 FBTCS before surgery 28 (71.8) 21 (84) 0.261 Continuous variables are presented as mean ± standard deviation. Categorical variables are presented as N (%). FBTCS, Focal to bilateral tonic-clonic seizure. *p-value < 0.05. Presurgical diagnostics Table 2 details the pre-surgical evaluation results of the participants. Interictal EEG showed concordant with the resected lobe in 52 patients (81.3%). All patients had seizures recorded during scalp VEEG monitoring, and in 48 (75.0%) patients, ictal EEG showed concordance. There was no difference according to surgical outcomes. Temporal lobe MRI was performed in all patients, and 47 (73.4%) patients showed lesions in the lateral temporal areas. Changes in the hippocampus or amygdala were observed in seven (10.9%) patients, but no abnormalities in the lateral temporal cortex were observed. While 10 patients (15.6%) had normal MRI findings. In 55 (85.9%), FDG-PET was performed, and 25 (39.1%) patients showed hypometabolism involved extratemporal areas. SISCOM with interictal and ictal SPECT was performed in 40 patients (62.5%), and five (6.3%) patients showed hyperperfusion areas beyond the temporal areas. There was a difference in structural imaging findings between two groups, but no difference in the functional imaging findings. 10.1371/journal.pone.0288054.t002 Table 2 Participants’ presurgical diagnostics. Good (I) Poor (II-IV) p-value (n = 39) (n = 25) Interictal EEG pattern     Localized, n (%) 31 (79.5) 21 (84.0) 0.751     Non-localized, n (%) 8 (20.5) 4 (16.0)     Total 39 25 Ictal EEG pattern     Localized, n (%) 27 (69.2) 21 (84.0) 0.183     Non-localized, n (%) 12 (30.8) 4 (16.0)     Total 39 25 MRI findings     Lateral lesion 33 (84.6) 14 (56.0) 0.044*     Mesial lesion 2 (5.1) 5 (20.0)     Normal 4 (10.3) 6 (24.0)     Total 39 25 PET pattern     Localized, n (%) 20 (51.3) 10 (40.0) 0.198     Non-localized, n (%) 12 (30.8) 13 (52.0)     Total 32 23 SISCOM pattern     Localized, n (%) 24 (61.5) 12 (48.0) 0.539     Non-localized, n (%) 2 (5.1) 2 (8.0)     Total 26 14 Pathology of lateral temporal area     Focal cortical dysplasia, n (%) 12 (30.8) 14 (56) 0.092     Glioneuronal tumor, n (%) 17 (43.6) 6 (24.0)     Vascular malformation, n (%) 9 (23.1) 0 (0)     Other, n (%) 1 (2.6) 5 (20)     Total 39 25 Categorical variables are presented as N (%). *p-value < 0.05. Surgery, surgical outcome, and histopathology All patients underwent resective surgery according to their respective invasive VEEG monitoring results. The mean follow-up duration after surgery was 8.4 years (SD, 6.3 [range, 2.0–26.0] years). All patients, except one, were followed up for more than 5 years. Out of the 64 patients, 39 (60.9%) patients became seizure-free two years after surgery. 45 of the 63 (71.4%) patients had become seizure-free five years after surgery. The study also found that FCD was the most common underlying pathology, present in 26 (40.6%) of the patients. Glioneuronal tumor was the second most common pathology, present in 23 (35.9%) patients. Vascular malformation was present in 9 (14.1%) patients, and unspecific gliosis was present in 6 (9.4%) patients. Factors that predict seizure outcomes at 2 and 5 years after surgery Table 3 shows the variables associated with seizure outcomes at the 2-year follow-up using the logistic regression analysis. Significant prognostic factors were duration of epilepsy prior to surgery, potentially epileptogenic lesions in the mesial but normal lateral temporal structures on preoperative MRI, and FCD on histopathology in the univariable analysis. However, no independent prognostic factors were identified in multivariable analysis. 10.1371/journal.pone.0288054.t003 Table 3 Univariable and multivariable logistic regression for postsurgical outcome two years after surgery. Univariable OR p-value Multivariable OR p-value OR (95% CI) OR (95% CI) Duration of epilepsy prior to surgery, year 1.080 (1.004–1.161) 0.038* 1.057 (0.98–1.141) 0.150 Interictal EEG (non-localized) 0.738 (0.197–2.768) 0.653 Ictal EEG (non-localized) 0.429 (0.121–1.522) 0.190 MRI findings     Lateral lesion (ref) 1 1     vs Mesial lesion 5.893 (1.019–34.079) 0.048* 3.959 (0.623–25.182) 0.162     vs Normal 3.536 (0.862–14.499) 0.079 2.277 (0.45–11.523) 0.316 PET pattern (non-localized) 2.167 (0.727–6.455) 0.165 Histopathology (FCD) 2.864 (1.01–8.119) 0.048* 1.514 (0.421–5.441) 0.585 OR, odds ratio; CI, confidence interval; EEG, electroencephalography; MRI, magnetic resonance imaging; PET, positron emission tomography; FCD, focal cortical dysplasia. *p-value < 0.05. Table 4 shows the variables associated with seizure outcomes at the 5-year follow-up. Scalp EEG or imaging factors did not affect seizure outcomes, as determined by univariable analysis. However, FCD on postoperative histopathology was found to be the only significant risk factor for seizure outcome (odds ratio [OR], 4.92; 95% confidence interval [CI], 1.52–15.91) in both univariable and multivariable analysis. The duration of epilepsy before surgery was found to affect seizure outcomes, but the difference was not statistically significant. To increase statistical significance, we attempted to find the optimal cut-off point for preoperative epilepsy duration. The cut-off value was determined to be eight years after the onset (OR 4.375, p-value = 0.0214). However, the analysis of the duration of epilepsy as a categorical variable was only a significant prognostic factor in the univariable analysis and not in the multivariable analysis (Table 4(B)). 10.1371/journal.pone.0288054.t004 Table 4 Univariable and multivariable logistic regression for postsurgical outcome five years after surgery. (A) Duration of epilepsy prior to surgery included as a continuous variable Univariable OR p-value Multivariable OR p-value OR (95% CI) OR (95% CI) Duration of epilepsy prior to surgery, year 1.07 (1.00–1.16) 0.064 1.06 (0.97–1.15) 0.194 Interictal EEG (non-localized) 0.80 (0.19–3.37) 0.761 Ictal EEG (non-localized) 0.31 (0.06–1.53) 0.150 MRI findings     Lateral lesion (ref) 1     vs Mesial lesion 2.39 (0.46–12.34) 0.299     vs Normal 2.12 (0.51–8.91) 0.304 PET pattern (non-localized) 1.24 (0.38–3.98) 0.723 Histopathology (FCD) 4.92 (1.52–15.91) 0.007* 4.20 (1.26–13.94) 0.019* (B) Duration of epilepsy prior to surgery included as a categorical variable Univariable OR p-value Multivariable OR p-value OR (95% CI) OR (95% CI) Duration of epilepsy prior to surgery (>8 year) 4.38 (1.24–15.38) 0.021* 3.23 (0.87–12.06) 0.081 Interictal EEG (non-localized) 0.80 (0.19–3.37) 0.761 Ictal EEG (non-localized) 0.31 (0.06–1.53) 0.150 MRI findings     Lateral lesion (ref) 1     vs Mesial lesion 2.39 (0.46–12.34) 0.299     vs Normal 2.12 (0.51–8.91) 0.304 PET pattern (non-localized) 1.24 (0.38–3.98) 0.723 Histopathology (FCD) 4.92 (1.52–15.91) 0.007* 3.83 (1.13–12.95) 0.031* OR, odds ratio; CI, confidence interval; EEG, electroencephalography; MRI, magnetic resonance imaging; PET, positron emission tomography; FCD, focal cortical dysplasia. *p-value < 0.05. Furthermore, we suggested a model for predicting outcomes at 5 years after surgery using a ROC curve and nomogram. The duration of epilepsy prior to surgery showed a clear trend towards association with poorer outcomes, although this was not statistically significant due to the small group size. We included the duration of epilepsy in our model, despite its insignificant p-value, because we believed that with a larger sample size, the variable may become statistically significant and provide useful information for predicting seizure outcomes after surgery. According to the ROC curve analysis, the duration of epilepsy prior to surgery and histopathological results could be used as predictors of seizure outcomes at 5 years after surgery (AUC = 0.733; 95% CI, 0.588–0.879). Similar results were obtained when the duration of epilepsy was used as a categorical variable (AUC = 0.736; 95% CI, 0.595–0.878). The nomogram for the model is shown in Fig 2. 10.1371/journal.pone.0288054.g002 Fig 2 Prognostic nomogram to predict the surgical outcome 5 years after surgery. To use the nomogram, locate the patient’s position on the scale associated with each predictor. The top axis displays prognostic points. Connect the position on each variable axis to the Points (top) axis to determine the number of points corresponding to the appropriate variable position. Calculate the total points for all variables, and then determine the appropriate position on the total points axis and connect it with the associated position on the probability of poor outcome (bottom) to determine the patient’s individual risk. This nomogram is presented in two forms: (A) Duration of epilepsy prior to surgery included as a continuous variable, and (B) Duration of epilepsy prior to surgery included as a categorical variable. Cortical thickness analysis predicting seizure outcomes at 5 years after surgery Cortical thickness analysis was conducted on 46 patients, and data from LTLE were combined and analyzed relative to the epileptogenic lobe to increase statistical power. In this analysis, the left hemisphere means ipsilateral and the right hemisphere means contralateral. The results are displayed in Fig 3. A comparison between the poor and good outcome groups showed that there was thinning in the ipsilateral midcingulate gyrus and contralateral superior parietal lobule (p < 0.01, uncorrected). 10.1371/journal.pone.0288054.g003 Fig 3 Predictors of postsurgical outcome five years after surgery. This shows the areas of cortical thinning in patients who experienced residual seizures (Engel’s Class II–IV) compared to those who were seizure-free (Engel’s Class I) after surgery. The areas of significant cortical thinning are displayed with uncorrected p-value less than 0.01. Subgroup analysis in mesial temporal lesion Seven patients in the study did not have any lesions in the lateral temporal cortex but had changes in the mesial temporal region. Among these patients, six showed hippocampal signal change or atrophy, while one patient had amygdalar signal change. Two patients had a history of encephalitis, and one patient had a history of head trauma. Six patients underwent AH. Three patients had total AH, while three had partial AH. Histological examination showed HS in three patients and normal in three others of six mesial temporal specimens. FCD was found in five of seven lateral temporal specimens. Microdysgenesis was found in another, and subpial gliosis was found in the other specimen. Two out of seven patients were seizure-free at the 2-years follow-up, while four were seizure-free at the 5-years follow-up. Two patients who were seizure-free at 2-year follow-up remained seizure-free at the 5-year follow-up. All the seizure-free patients underwent total AH, while all patients who underwent partial AH had poor surgical outcomes. Discussion In this study, we determined postsurgical outcomes and verified possible prognostic factors in patients with LTLE during the long-term follow-up period. We found that 60.9% of patients became seizure-free during the short-term follow-up period. In the long-term follow-up period, the rate of achieving seizure freedom improved to 71.4%. Our findings highlighted that FCD on histopathology and the duration of epilepsy prior to surgery are important prognostic factors for long-term surgical outcomes in patients with LTLE. The optimal cut-off value was 8 years after seizure onset. The nomogram we developed can help clinicians provide individualized predictions of surgical outcomes for their patients. The cortical thickness analysis we conducted also provides insights into more marked atrophy with poor surgical outcomes. Several previous studies have selectively investigated surgical prognostic factors of LTLE, but they have some limitations. For example, one study included a short follow-up period of only one month of follow-up [7], while other studies had a small number of participants [8, 23]. However, our study has the advantage of a relatively long follow-up period of 8.2 years on average and a relatively large number of participants. Our findings of surgical outcomes are consistent with previous studies that reported rate of 60–79% [7, 8, 23]. Interestingly, our study showed surgical outcome improved over time. This may be related to study population. As reported by Tellez-Zenteno [24], long-term seizure freedom was highest in patients with tumor, but patients older than 50 years at time of surgery was lowest compared to short-term seizure freedom in temporal lobe surgery. We included patients with tumorous lesions and the average age of surgery was 29.0 years. There are also results that surgical outcomes improved patients with FCD [25], and it is agreement with our results. Our study also showed that FCD was associated with poor surgical outcomes, consistent with other studies [8], while tumors on MRI or histopathology were associated with good surgical outcomes [7, 8]. We found that lesions on MRI showed a trend toward better surgical outcomes in univariable analysis. In contrast to some previous studies [8], our study did not identify a prognostic implication for the ictal EEG pattern. FCD is a common cause of intractable epilepsy, characterized by a spectrum of regional cortical malformations [20]. According to our study, FCD identified through histopathology was the most reliable predictor of poor surgical outcomes in patients with LTLE. A previous study of patients with FCD conducted in the same epilepsy center reported that 61.7% and 39.5% of patients were seizure-free at 2 and 5 years after surgery, respectively [26]. The long-term surgical outcome for patients with FCD was worse than that of patients with LTLE. Although there were the differences between groups, including various epileptogenic foci, this finding supports the notion that FCD is a prognostic factor for worse outcomes. However, the predictive value of FCD has been controversial, which could be attributed to differences in the study population [8, 27]. Some studies have suggested that complete resection, including dysplasia, is more predictable than FCD itself [28, 29]. This may be one of the reasons why FCD attributes to worse prognosis in our study. In patients with non-lesional MRI, resection margin was determined only by ictal onset zone. It might lead to incomplete resection and seizure recurrence. All of them were confirmed FCD on histopathology. This study showed that the duration of epilepsy prior to surgery may have an impact on surgical outcomes, especially for patients with LTLE. Previous studies, including meta-analyses, has suggested that patients with shorter epilepsy duration have better surgical outcomes, regardless of the type of epilepsy [28, 30, 31]. A systematic review has also suggested that patients who are appropriate candidates for surgery should be referred earlier. However, the evidence for this recommendation has been weak due to group heterogeneity. Our results support the idea that early referral to an epilepsy surgery center is beneficial for patients with LTLE. Remarkably, there was a significant difference in surgical outcomes 8 years after the onset of epilepsy, with the probability of worse outcome being 4.4 times higher in the longer duration group than in the shorter duration group. Therefore, it is recommended that patients with LTLE are referral to an epilepsy surgery center within 8 years of onset. However, other studies have shown that the duration of epilepsy is not always associated with surgical outcomes [4, 32, 33], indicating that this recommendation should be applied to a specific population. To predict surgical outcomes for patients with epilepsy, several studies have developed models that utilize various factors such as seizure frequency, history of generalized tonic-clonic seizures, MRI, and epilepsy duration [34]. Nomograms, which are graphical tools to predict outcomes, have also been used to predict surgical outcome based on various factors such as sex, seizure frequency, secondary seizure generalization, type of surgery, pathologic cause, age at epilepsy onset, age at surgery, epilepsy duration at the time of surgery, and surgical side [35]. However, many of these studies have included heterogeneous epilepsy groups, which has led to uncertainty about the accuracy of these models. A consecutive study disputed that these models are not superior to clinical judgment and have stressed the need for better tools [36]. Thus, our study proposes a new nomogram for predicting surgical outcomes in patients with LTLE based on epilepsy duration and histopathology. However, external validation of this nomogram in other patient cohorts is necessary to assess its accuracy and generalizability. Cortical thickness has been studied in relation to surgical outcomes, with distinct patterns of cortical thinning associated with different epilepsy syndromes [17]. In TLE, the poor surgical outcome group exhibited more pronounced ipsilateral temporal, contralateral parietal and occipital, and bilateral insular thinning compared to the good surgical outcome group [13]. Meanwhile, neocortical epilepsy is associated with cortical thinning in the ipsilateral hemisphere, particularly in the frontal lobe, which leads to poor surgical outcomes [18]. For FLE, cortical volume loss in frontal and extrafrontal regions is a predictor of seizure outcomes [10]. In other words, if there are structural alterations outside of the resected lobe, regardless of the epilepsy types, the surgical prognosis is unfavorable. This study found that the poor surgical outcome group had more pronounced ipsilateral midcingulate and contralateral parietal thinning than the good surgical outcome group, indicating epileptic networks are wider in patients with residual seizures. Other modalities, such as FDG-PET and stereo EEG, have also shown similar results in worse outcome group, with similar extratemporal hypometabolism [11, 37] and early extratemporal propagation in stereo EEG [38]. In addition, we conducted a review of seven patients who had lesions in the mesial temporal area, with six of them undergoing resection surgery that included AH. The results showed that the patients who underwent partial resection of the hippocampus experienced seizure recurrence, while those who had total resection were seizure-free during long-term follow-up. Given that our findings are based on a limited number, the results from them suggest that partial resection of the hippocampus may lead to poor surgical outcomes. Previous studies have indicated that the large extent of hippocampus resection is associated with better surgical outcomes [33, 39]. However, other studies have shown that the extent of resection is not linked to seizure outcomes [40, 41], and a larger resection may lead to a higher risk of memory decline [39, 40] As a result, the resection of the mesial temporal structure should be individualized for each patient with LTLE to minimize the risk of postoperative seizures and memory impairment. Although the subgroup of patients who had no lesion in the lateral temporal cortex based on MRI, pathologic results showed FCD in all patients, except for two. The patients who did not have FCD underwent surgery before 2000, when the FCD classification was not yet been proposed [42]. If the specimens were reviewed now, it is likely that they would be classified as FCD. As confirmed by invasive monitoring, ictal onset zones were in the lateral temporal area in all patients including the subgroup. As a result, signal changes observed in the mesial temporal area could be attributed to other mechanisms. First, seizures can induce signal changes in MRI, which are transient abnormalities that occur after seizure activity in the epileptogenic zone or distinct regions connected by an epileptic network [43]. In some cases, MRI scans were performed after clustering seizures on the last day of EMU monitoring, which could impact the observed signal changes on MRI. Second, the kindling model might be related to these alterations. Kindling refers to a change in seizure characteristics and behaviors resulting from recurrent seizures due to focal electrical stimulation [44]. Limbic circuits, including the hippocampus and amygdala, are highly vulnerable to kindling, which can eventually lead to epileptogenicity in affected regions. One study showed changes observed in the mesial temporal area may be due to the kindling process [45]. A previous study conducted at the same hospital on patients with MTLE found that 85.5% and 83.5% of patients were seizure free in 2 and 5 years after surgery, respectively [33]. This suggests that patients with MTLE have better surgical outcomes compared to those with LTLE, which is consistent with the findings of other studies [3–6]. Dolezalova et al. reported that 69% of patients with MTLE were seizure-free after one year, whereas only 42% of patients with LTLE were seizure-free after surgery [5]. Similarly, Lee et al. found that 70% of patients with MTLE were seizure-free, while only 33% of patients with LTLE achieved seizure-freedom [6]. However, one study showed no significant difference in seizure-free outcomes between the MTLE and LTLE groups [46]. In patients with MTLE, bitemporal INIED, MRI findings, and bitemporal hypometabolism on FDG-PET were associated with poorer surgical outcomes [33]. However, the predictive value of EEG, MRI, and PET in postsurgical outcomes was not identified in patients with LTLE. This study has several limitations that should be considered when interpreting the results. Firstly, as a retrospective study, there is a potential for incomplete data and bias due to unmeasured confounders. However, to minimized this, the study used a standardized set of pre-surgical evaluations for all patients. Secondly, the study included a small number of patients from a single epilepsy center, which limits the generalizability of the findings to all patients with LTLE. Future studies with larger sample sizes and multiple centers are needed to confirm the results. Thirdly, the nomogram developed in this study needs to be applied to an external validation cohort and calibration before its clinical utility can be established. Fourthly, the absence of healthy controls in the cortical thickness analysis is another limitation. Additionally, factors such as the side of TLE and duration of epilepsy may influence cortical thickness but were not analyzed separately due to small sizes. Therefore, further investigations are needed to address these limitations and confirm the findings. In conclusion, this study indicates that nearly 70% of the patients with LTLE may achieve long-term seizure freedom through resective surgery. However, FCD identified on histopathology was found to be a predictor of poor surgical outcomes. The study suggests that resective surgery should be considered within 8 years of epilepsy onset. We also developed a nomogram based on FCD and duration of epilepsy before surgery, which could help select suitable candidates. If confirmed prospectively, these factors can help select optimal candidates and identify the optimal timing for surgery in patients with LTLE. Additionally, the study found that cortical thinning was more extensive in the group with poor surgical outcomes. Supporting information S1 File Questionnaire on inclusivity in global research. (DOCX) Click here for additional data file. S2 File Data set. (XLSX) Click here for additional data file. 10.1371/journal.pone.0288054.r001 Decision Letter 0 Martino Tommaso Academic Editor © 2023 Tommaso Martino 2023 Tommaso Martino https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version0 12 Apr 2023 PONE-D-23-07317Identifying Important Factors for Successful Surgery in Patients with Lateral Temporal Lobe EpilepsyPLOS ONE Dear Dr. Joo, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. 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Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Partly Reviewer #4: Partly ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No Reviewer #4: I Don't Know ********** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: No Reviewer #3: Yes Reviewer #4: Yes ********** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No Reviewer #4: No ********** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: It’s a retrospective clinical study that needs a major revision. 1) Among all 1167 epilepsy surgery patients, 675 patients underwent one-step resection without invasive EEG studies. These 675 patients necessarily included patients with lateral temporal lobe epilepsy. While these 675 patients were excluded from the investigation target, i.e. the 63 lateral temporal lobe epilepsy, which means the conclusion ratio of 71.4% (45/63) seizure free could be inaccurate. 2) The author didn’t mention the exclusion criteria of the study. Since some lateral temporal lobe epilepsy with specific etiologies like tumor and AVM underwent invasive 2-step invasive EEG studies, what kinds of patients should undergo 1-step non-invasive study resection? 3) Since the solitary seizure-free rate of 71.4% (45/63) is not accurate, the author may compare the seizure-free rates between the lateral temporal lobe epilepsy and the mesial temporal lobe epilepsy among all invasive study temporal lobe epilepsy cases (131). 4) The author didn’t clarify the detail of the invasive EEG investigation. Did he implant deep electrodes into the hippocampus in all lateral temporal lobe epilepsy patients? Is it reasonable to do so in epilepsy with a clear lesion? 5) The author mentioned that he did anterior temporal lobectomy (ATL) and amygdalohippocampectomy (AH) in some lateral temporal lobe epilepsy patients. So how could he compare LTLE with MTLE since he did the same surgeries for them? The author should revise the manuscript according to these questions before being considered for publication. Reviewer #2: This is an interesting retrospective cohort study carried out between 1995 and 2018, among patients with lateral temporal lobe epilepsy (LTLE) who underwent resective surgery in a university-affiliated hospital of South Korea. Sixty-four patients were included in the study. The main results were: 1) statistically significant prognostic factors for postsurgical outcomes were the duration of epilepsy before surgery and focal cortical dysplasia on postoperative histopathology at the 5-year follow-up; 2) cortical thinning was found in ipsilateral cingulate gyrus and contralateral parietal lobe in poor surgical group compared to good surgical group. The Authors also propose a model for predicting seizure outcomes 5 years after surgery using a nomogram. As a minor observation (at page IX, lines 200-201) the Authors state that "there was no difference between the groups, except for the preoperative disease duration" Anyway, reading Table 1, also follow-up after surgery resulted statistically different in the two groups. So, the Authors should correct this sentence. There are several typos in the text. For example at page XVIII, line 378, "...better tools are need..." should be changed in " ...better tools are needed..."; at the same page, line 384, "...the ppor surgical..." should be written "...the poor surgical...". The Authors should read agian their manuscript in order to correct typos. Reviewer #3: This research aimed to evaluate the long-term surgical outcomes and identify possible prognostic factors in patients with lateral temporal lobe epilepsy. Retrospective analysis of sixty-four patients showed FCD was the ignificant prognostic factors for postsurgical outcomes at the 5-year follow-up. Cortical thinning was observed in ipsilateral cingulate gyrus and contralateral parietal lobe in poor surgical group compared to good surgical group. This study lacked of innovation and interesting. It seems that meaningful conclusions cannot be drawn from the results of this study I have the following opinions： 1. In the part of abstract, the author should provide a more detailed method such as MRI analysis and clarify conclusions from the results. 2. In the part of cortical thickness, the author may add to MRI-negative image with same age as another control group. 3. Based on this study, I think the researchers used voxel based morphology to analyze cortical thickness. If so, voxel-wise FWE correction and threshold with FDR corrected should be used. 4. A significant English editing is necessary. Reviewer #4: This is a retrospective, single center cohort study aiming to evaluate the short-term and long-term seizure outcomes following resective surgery in patients with lateral temporal lobe epilepsy. This study focused on interesting and important issue in resective epilepsy surgery. However, several limitations unfortunately dampen the enthusiasm for this study. 1. The definition of lateral temporal lobe epilepsy is unclear. It is based on electro-clinical findings? Imaging findings? The authors should clarify. 2. How many parents were underwent invasive EEG diagnostic with subdural or depth electrodes? Were these findings supported by clinical or imaging diagnosis? 3. It is remarkable, that in this study, the long-term seizure outcome is improved compared to the short-term outcome. What is the reason for this observation? The authors should discuss it more extensively. 4. Since the authors found FCD is significant factor for unfavorable outcome, it is important to know what kind of FCD (classification) was predominantly detected in this cohort. 5. What is the reason for worse outcome in patients with FCD in this cohort? The authors should explain this noteworthy observation 6. The subgroup analysis indicates patients with mesial abnormalities and co-existing FCD. This observation is presuming for including of patients with dual pathologies in this study. This could bias both, the findings and the conclusion made by the authors. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Reviewer #3: No Reviewer #4: No ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0288054.r002 Author response to Decision Letter 0 Submission Version1 15 May 2023 PONE-D-23-07317 Identifying Important Factors for Successful Surgery in Patients with Lateral Temporal Lobe Epilepsy PLOS ONE Author list: Jae Rim Kim, Hyunjin Jo, Boram Park, Yu Hyun Park, Yeon Hak Chung, Young-Min Shon, Dae-Won Seo, Seung Bong Hong, Seung-Chyul Hong, Sang Won Seo*, Eun Yeon Joo May 2023 Dear editorial staff at the PLOS ONE On behalf of the authors, I wish to express our appreciation of the reviewers' careful and helpful review of our manuscript. We revised the manuscript according to the reviewers’ suggestions, and we believe that these changes improved our manuscript. Please find enclosed response file addressing each of the reviewer's comments and the revised manuscript. The page and line references for the changes provided are based on the revised manuscript version. We hope that you and the reviewers now find the revised paper suitable for publication. Thank you for considering our manuscript for publication in PLOS one. We look forward to hearing from you soon. Best Regards, Jae Rim Kim Journal requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Response) According to PLOS ONE’s style requirements, we checked them over and revised. 2. 1)Please include a complete copy of PLOS’ questionnaire on inclusivity in global research in your revised manuscript. Our policy for research in this area aims to improve transparency in the reporting of research performed outside of researchers’ own country or community. The policy applies to researchers who have travelled to a different country to conduct research, research with Indigenous populations or their lands, and research on cultural artefacts. The questionnaire can also be requested at the journal’s discretion for any other submissions, even if these conditions are not met. Please find more information on the policy and a link to download a blank copy of the questionnaire here: https://journals.plos.org/plosone/s/best-practices-in-research-reporting. Please upload a completed version of your questionnaire as Supporting Information when you resubmit your manuscript. Response) According to PLOS ONE’s policy, we completed a questionnaire and uploaded as a S1 checklist. 2) We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed: - https://doi.org/10.1016/j.nicl.2021.102685 In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed. Response) The same author in that previous publication was participated our study for cortical thickness measurement. We deleted that sub-section and moved to other sub-section. And we mentioned that the same method was used for analysis. 3) You indicated that you had ethical approval for your study. Please clarify whether minors (participants under the age of 18 years) were included in this study. If yes, in your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent." Response) We revised our methods section. (page iv, line 71-74) Informed written consent was obtained from all participants when they admitted to epilepsy monitoring units (EMU), and it was obtained from the next of kin, caretakers, or guardians on behalf of the minors/children participants involved in this study. The Institutional Review Board of Samsung Medical Center approved the study protocol (IRB number 2021-03-068). 4) In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. Response) According to your recommendations, we added some sentences. (page iv, line 74-75) We had not access to information that could identify individual participants during study. 3. Thank you for stating the following financial disclosure: "This study was granted by Samsung Medical Center Grant (OTC1190671)." Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. Response) We state that the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 4. Thank you for stating the following in the Competing Interests section: "The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest." Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. Response) There are no restrictions on sharing of data and/or materials of our manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. 5. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. "Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. Response) According to your comment, we uploaded out study’s supplementary data. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Partly Reviewer #4: Partly ________________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No Reviewer #4: I Don't Know ________________________________________ 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: No Reviewer #3: Yes Reviewer #4: Yes ________________________________________ 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No Reviewer #4: No ________________________________________ 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: It’s a retrospective clinical study that needs a major revision. 1) Among all 1167 epilepsy surgery patients, 675 patients underwent one-step resection without invasive EEG studies. These 675 patients necessarily included patients with lateral temporal lobe epilepsy. While these 675 patients were excluded from the investigation target, i.e. the 63 lateral temporal lobe epilepsy, which means the conclusion ratio of 71.4% (45/63) seizure free could be inaccurate. 2) The author didn’t mention the exclusion criteria of the study. Since some lateral temporal lobe epilepsy with specific etiologies like tumor and AVM underwent invasive 2-step invasive EEG studies, what kinds of patients should undergo 1-step non-invasive study resection? 3) Since the solitary seizure-free rate of 71.4% (45/63) is not accurate, the author may compare the seizure-free rates between the lateral temporal lobe epilepsy and the mesial temporal lobe epilepsy among all invasive study temporal lobe epilepsy cases (131). Response for 1-3) Thank you for your comments. We routinely conduct two-step invasive studies except typical patients with mesial temporal lobe epilepsy. Although there are specific lesions in lateral temporal area on MRI, we performed invasive monitoring to find ictal onset zone for tailored resection and minimize risk of surgical failures. We understand your concern, but we are sure include all LTLE patients with inclusion criteria. We excluded patients visited outpatient clinics less than 2 years. 4) The author didn’t clarify the detail of the invasive EEG investigation. Did he implant deep electrodes into the hippocampus in all lateral temporal lobe epilepsy patients? Is it reasonable to do so in epilepsy with a clear lesion? Response) Thank you for your comment. We did not implant depth electrodes into hippocampus in all participants. We did it, if other presurgical studies such as functional imaging suggested impairments or alterations in mesial temporal structure. In those cases, we implanted depth to exclude mesio-lateral or mesial TLE and confirmed resection extent. We revised our method section according to your comment. (page vi, line 134-136) All participants who were suspected LTLE underwent the invasive monitoring using a combination of subdural grids/strips with or without depth electrodes to confirm the ictal onset zone and determine the extent of resection. 5) The author mentioned that he did anterior temporal lobectomy (ATL) and amygdalohippocampectomy (AH) in some lateral temporal lobe epilepsy patients. So how could he compare LTLE with MTLE since he did the same surgeries for them? The author should revise the manuscript according to these questions before being considered for publication. Response) Thank you for your comment. We did tailored resection of lateral temporal area in all patients and additional ATL and AH in some cases such as combined alterations in imaging. In other words, patients with MTLE underwent standard ATL and AH, but all patients with LTLE underwent tailored corticectomy or lesionectomy. But patients in the subgroup underwent AH simultaneously. So, surgical procedures were not same in LTLE compared to MTLE. Reviewer #2: This is an interesting retrospective cohort study carried out between 1995 and 2018, among patients with lateral temporal lobe epilepsy (LTLE) who underwent resective surgery in a university-affiliated hospital of South Korea. Sixty-four patients were included in the study. The main results were: 1) statistically significant prognostic factors for postsurgical outcomes were the duration of epilepsy before surgery and focal cortical dysplasia on postoperative histopathology at the 5-year follow-up; 2) cortical thinning was found in ipsilateral cingulate gyrus and contralateral parietal lobe in poor surgical group compared to good surgical group. The Authors also propose a model for predicting seizure outcomes 5 years after surgery using a nomogram. As a minor observation (at page IX, lines 200-201) the Authors state that "there was no difference between the groups, except for the preoperative disease duration" Anyway, reading Table 1, also follow-up after surgery resulted statistically different in the two groups. So, the Authors should correct this sentence. There are several typos in the text. For example at page XVIII, line 378, "...better tools are need..." should be changed in " ...better tools are needed..."; at the same page, line 384, "...the ppor surgical..." should be written "...the poor surgical...". The Authors should read agian their manuscript in order to correct typos. Response) Thank you for your comments. According to your recommendations, we revised some sentences including them. Reviewer #3: This research aimed to evaluate the long-term surgical outcomes and identify possible prognostic factors in patients with lateral temporal lobe epilepsy. Retrospective analysis of sixty-four patients showed FCD was the significant prognostic factors for postsurgical outcomes at the 5-year follow-up. Cortical thinning was observed in ipsilateral cingulate gyrus and contralateral parietal lobe in poor surgical group compared to good surgical group. This study lacked of innovation and interesting. It seems that meaningful conclusions cannot be drawn from the results of this study I have the following opinions： 1. In the part of abstract, the author should provide a more detailed method such as MRI analysis and clarify conclusions from the results. Response) Thank you for comments. We revised the abstract. (page ii, line 30-34) Methods: This retrospective cohort study was conducted between January 1995 and December 2018 among patients who underwent resective surgery in a university-affiliated hospital. Patients were classified as LTLE if ictal onset zone was in lateral temporal area. Surgical outcomes were evaluated at 2 and 5 years. We subdivided based on outcomes and compared clinical and neuroimaging data including cortical thickness between two groups. (page ii, line 46-48) Conclusions: The identified predictors of unfavorable surgical outcomes may help in selecting optimal candidates and identifying the optimal timing for surgery among patients with LTLE. Additionally, cortical thinning was more extensive in the poor surgical group. 2. In the part of cortical thickness, the author may add to MRI-negative image with same age as another control group. Response) Thank you for comments. We also hoped to analyze cortical thickness compared to healthy controls, but there was no available MRI data. These are our limitations and described in discussion. (page xx, line 439-440) Fourthly, the absence of healthy controls in the cortical thickness analysis is another limitation. 3. Based on this study, I think the researchers used voxel based morphology to analyze cortical thickness. If so, voxel-wise FWE correction and threshold with FDR corrected should be used. Response) Thank you for comments. We used voxel-wise FEW correction and threshold with FDR corrected at first, but we could not get meaningful results. Although the analysis was not ideal, we still believe that we would get significant results in larger participants. 4. A significant English editing is necessary. Response) Thank you for comments. We already got English editing service, but we checked our manuscript over in general and revised some parts. Reviewer #4: This is a retrospective, single center cohort study aiming to evaluate the short-term and long-term seizure outcomes following resective surgery in patients with lateral temporal lobe epilepsy. This study focused on interesting and important issue in resective epilepsy surgery. However, several limitations unfortunately dampen the enthusiasm for this study. 1. The definition of lateral temporal lobe epilepsy is unclear. It is based on electro-clinical findings? Imaging findings? The authors should clarify. Response) Thank you for comments. We defined LTLE based on the invasive study. If the seizure onset zone was in lateral temporal area, not mesial temporal structures (hippocampus, amygdala or parahippocampal gyrus) and basal temporal area, we diagnosed as LTLE. We described in method section. (page iv, line 89-92) Patients were diagnosed with LTLE if the seizure onset zone was in the lateral temporal area, not in mesial temporal structures or basal temporal area based on an invasive study. The seizure onset zone was defined as any paroxysmal ictal pattern that was distinct from background activity with clinical symptoms. 2. How many parents were underwent invasive EEG diagnostic with subdural or depth electrodes? Were these findings supported by clinical or imaging diagnosis? Response) Thank you for comments. All enrolled participants were underwent invasive study with subdural electrodes in some cases. We proceeded invasive monitoring, if clinical or imaging diagnosis suggested LTLE. Therefore, presurgical diagnostics supported LTLE and invasive study confirmed it. 3. It is remarkable, that in this study, the long-term seizure outcome is improved compared to the short-term outcome. What is the reason for this observation? The authors should discuss it more extensively. Response) Thank you for comments. According to your recommendations, we additionally described in our discussion. (page xvi, line 327-333) Interestingly, our study showed surgical outcome improved over time. This may be related to study population. As reported by Tellez-Zenteno[24], long-term seizure freedom was highest in patients with tumor, but patients older than 50 years at time of surgery was lowest compared to short-term seizure freedom in temporal lobe surgery. We included patients with tumorous lesions and the average age of surgery was 29.0 years. There are also results that surgical outcomes improved patients with FCD[25], and it is agreement with our results. 4. Since the authors found FCD is significant factor for unfavorable outcome, it is important to know what kind of FCD (classification) was predominantly detected in this cohort. Response) Thank you for the comment. We tried to report types of FCD, but it was tough. Because more than half of participants were performed epilepsy surgery before 2011, there was no available data of FCD classification. Among available data, 30% (3/10) of each was type 1 and 2 and remaining 40% (4/10) was type 3. So we thought interpretation of it might lead to bias due to limited data, we did not describe it in the manuscript. 5. What is the reason for worse outcome in patients with FCD in this cohort? The authors should explain this noteworthy observation Response) Thank you for comments. According to your recommendations, we additionally described in our discussion. (page xvi-xvii, line 347-352) However, the predictive value of FCD has been controversial, which could be attributed to differences in the study population [8, 27]. Some studies have suggested that complete resection, including dysplasia, is more predictable than FCD itself [28, 29]. This may be one of the reasons why FCD attributes to worse prognosis in our study. In patients with non-lesional MRI, resection margin was determined only by ictal onset zone. It might lead to incomplete resection and seizure recurrence. 6. The subgroup analysis indicates patients with mesial abnormalities and co-existing FCD. This observation is presuming for including of patients with dual pathologies in this study. This could bias both, the findings and the conclusion made by the authors. Response) Thank you for comments. Although there were MRI abnormalities in some patients, all ictal onset was seen in lateral temporal areas suggesting LTLE. So, we described reasons of signal changes as seizure related changes or kindling in our discussion. (page xix, line 408-419) As confirmed by invasive monitoring, ictal onset zones were in the lateral temporal area in all patients including the subgroup. As a result, signal changes observed in the mesial temporal area could be attributed to other mechanisms. First, seizures can induce signal changes in MRI, which are transient abnormalities that occur after seizure activity in the epileptogenic zone or distinct regions connected by an epileptic network[43]. In some cases, MRI scans were performed after clustering seizures on the last day of EMU monitoring, which could impact the observed signal changes on MRI. Second, the kindling model might be related to these alterations. Kindling refers to a change in seizure characteristics and behaviors resulting from recurrent seizures due to focal electrical stimulation.[44] Limbic circuits, including the hippocampus and amygdala, are highly vulnerable to kindling, which can eventually lead to epileptogenicity in affected regions. One study showed changes observed in the mesial temporal area may be due to the kindling process.[45] ________________________________________ 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. 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Reviewer #1: No Reviewer #2: No Reviewer #4: No ********** 10.1371/journal.pone.0288054.r004 Acceptance letter Martino Tommaso Academic Editor © 2023 Tommaso Martino 2023 Tommaso Martino https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 21 Jun 2023 PONE-D-23-07317R1 Identifying important factors for successful surgery in patients with lateral temporal lobe epilepsy Dear Dr. Joo: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Tommaso Martino Academic Editor PLOS ONE ==== Refs References 1 de Tisi J , Bell GS , Peacock JL , McEvoy AW , Harkness WF , Sander JW , et al . The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet. 2011;378 (9800 ):1388–95. doi: 10.1016/S0140-6736(11)60890-8 .22000136 2 Tellez-Zenteno JF , Hernandez-Ronquillo L . A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res Treat. 2012;2012 :630853. 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