Transcriptional features of low-grade neuroepithelial tumors with the BRAF V600E mutation associated with epileptogenicity.

Low-grade neuroepithelial tumors are major causes of drug-resistant focal epilepsy. Clinically, these tumors are defined as low-grade epilepsy-associated neuroepithelial tumors (LEATs). The BRAF V600E mutation is frequently observed in LEAT and linked to poor seizure outcomes. However, its molecular role in epileptogenicity remains elusive. To understand the molecular mechanism underlying the epileptogenicity in LEAT with the BRAF V600E genetic mutation (BRAF V600E-LEAT), we conducted RNA sequencing (RNA-seq) analysis using surgical specimens of BRAF V600E-LEAT obtained and stored at a single institute. We obtained 21 BRAF V600E-LEAT specimens and 4 control specimens, including 24 from Japanese patients and 1 from a patient of Central Asian origin, along with comprehensive clinical data. We submitted the transcriptome dataset of 21 BRAF V600E-LEAT plus 4 controls, as well as detailed clinical information, to a public database. Preliminary bioinformatics analysis using this dataset identified 2134 differentially expressed genes between BRAF V600E-LEAT and control. Additionally, gene set enrichment analysis provided novel insights into the association between estrogen response-related pathways and the epileptogenicity of BRAF V600E-LEAT patients. Our datasets and findings will contribute toward the understanding of the pathology of epilepsy caused by LEAT and the identification of new therapeutic targets.

Focal ictal direct current shifts by a time constant of 2 seconds were clinically useful for resective epilepsy surgery.

OBJECTIVE: Ictal direct current shifts (icDCs) and ictal high-frequency oscillations (icHFOs) have been reported as surrogate markers for better surgical outcomes in epilepsy surgery. icDCs have been classified into two types: rapid and slow development. icDCs have been investigated with a time constant of 10 s (TC10s); however, many institutes use electroencephalography with a time constant of 2 s (TC2s). This study aimed to evaluate whether icDCs can be observed adequately with TC2s; moreover, it examined the relationship between the resected core area of icDCs or icHFOs and surgical outcomes, occurrence rate of each type of icDCs, and relationship between each type of icDCs and pathology. METHODS: Twenty-five patients with intractable focal epilepsy were analyzed retrospectively. icDCs and icHFOs were defined according to common metrics. The amplitude of icDCs was defined at >200 µV and even <200 µV. The two electrodes producing the most prominent icDCs and icHFOs were defined as core electrodes. The correlation between the resected core electrode area and degree of seizure control after surgery was analyzed. icDCs were classified into two types based on a peak latency value cutoff of 8.9 s, and the occurrence rates of both patterns were investigated. RESULTS: icDCs (142/147 seizures [96.6%]) and icHFOs (135/147 seizures [91.8%]) occurred in all patients (100%). Compared with the amplitude of icDCs with TC10s reported in previous studies, the amplitude of icDCs with TC2s was attenuated in the current study. A significant positive correlation was observed between the resected core electrode area and degree of seizure control in both icDCs and icHFOs. A rapid development pattern was observed in 202 of 264 electrodes (76.5%). SIGNIFICANCE: Similar to icDCs with TC10s, those with TC2s were observed adequately. Furthermore, favorable outcomes are expected using TC2s, which is currently available worldwide.

Added value of corpus callosotomy following vagus nerve stimulation in children with Lennox-Gastaut syndrome: A multicenter, multinational study.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe form of epileptic encephalopathy, presenting during the first years of life, and is very resistant to treatment. Once medical therapy has failed, palliative surgeries such as vagus nerve stimulation (VNS) or corpus callosotomy (CC) are considered. Although CC is more effective than VNS as the primary neurosurgical treatment for LGS-associated drop attacks, there are limited data regarding the added value of CC following VNS. This study aimed to assess the effectiveness of CC preceded by VNS. METHODS: This multinational, multicenter retrospective study focuses on LGS children who underwent CC before the age of 18 years, following prior VNS, which failed to achieve satisfactory seizure control. Collected data included epilepsy characteristics, surgical details, epilepsy outcomes, and complications. The primary outcome of this study was a 50% reduction in drop attacks. RESULTS: A total of 127 cases were reviewed (80 males). The median age at epilepsy onset was 6 months (interquartile range [IQR] = 3.12-22.75). The median age at VNS surgery was 7 years (IQR = 4-10), and CC was performed at a median age of 11 years (IQR = 8.76-15). The dominant seizure type was drop attacks (tonic or atonic) in 102 patients. Eighty-six patients underwent a single-stage complete CC, and 41 an anterior callosotomy. Ten patients who did not initially have a complete CC underwent a second surgery for completion of CC due to seizure persistence. Overall, there was at least a 50% reduction in drop attacks and other seizures in 83% and 60%, respectively. Permanent morbidity occurred in 1.5%, with no mortality. SIGNIFICANCE: CC is vital in seizure control in children with LGS in whom VNS has failed. Surgical risks are low. A complete CC has a tendency toward better effectiveness than anterior CC for some seizure types.

Chorea-acanthocytosis: Time-dependent changes of symptoms and imaging findings.

BACKGROUND AND PURPOSE: Chorea-acanthocytosis, a rare neurodegenerative disease, affects both the striatum and the medial temporal lobe which may cause involuntary movements and epilepsy, respectively. We examined the imaging changes of the hippocampus/amygdala and the striatum as well as clinical symptoms. MATERIALS AND METHODS: We retrospectively reviewed 29 MRI and 13 SPECT studies and the clinical findings of seven genetically confirmed chorea-acanthocytosis patients. We evaluated the time-dependent imaging changes of the hippocampus/amygdala and striatum and examined the relationships among these images and symptoms. RESULTS: The initial symptom was epilepsy in four patients and involuntary movements in three patients. These symptoms were eventually noted in five and all seven patients, respectively. On MRI, most patients showed striatum atrophy before a hippocampus/amygdala abnormality emerged, but one patient showed a hippocampus/amygdala abnormality before striatum atrophy. Abnormal MRI findings of hippocampus/amygdala were noted in five patients and atrophy of striatum in all seven patients. SPECT demonstrated hypoperfusion of hippocampus/amygdala in three patients and that of striatum in all five available patients. Four patients demonstrated hypoperfusion of striatum earlier than that of hippocampus/amygdala and one patient showed hypoperfusion of both simultaneously. Many imaging abnormal lesions were accompanied by their corresponding symptoms, but not always so. CONCLUSION: Striatum abnormalities were the initial imaging findings in many chorea-acanthocytosis patients, but epilepsy or hippocampus/amygdala imaging abnormalities may be the only findings at the early stage. It is important to understand the detailed clinical and imaging time courses for the diagnosis of chorea-acanthocytosis.

Systemic metabolism and energy consumption after microsurgical clipping and endovascular coiling for aneurysmal subarachnoid hemorrhage.

BACKGROUND: The postoperative metabolic states of subarachnoid hemorrhage (SAH) patients were investigated using indirect calorimetry (IDC) and various nutritional evaluations to establish any difference in perioperative metabolic and nutritional states between microsurgical and endovascular treatment. METHODS: This study included 30 acute aneurysmal SAH patients with ruptured intracranial aneurysms treated by surgical clipping (n = 16) or coil embolization (n = 14) at a single institute. The resting energy expenditure (REE) and respiratory quotient were measured using IDC on days 1, 4, 7, 10, 14, and 17-21 after the operation. Various blood tests, including C-reactive protein (CRP) and prealbumin, were evaluated on the same days. RESULTS: The clipping group showed a significant increase in REE/basal energy expenditure (BEE) compared with the coiling group on days 1 and 4 (p = 0.04 and 0.03, respectively). No significant differences were found on days 7, 10, 14, and 17-21. The mean REE/BEE on days 1-14 and 1-21 showed no significant differences between the groups with repeated measures analysis of variance. The clipping group showed a significant decrease of prealbumin on day 4 and significant increase in CRP on days 1, 4, and 7. CONCLUSIONS: The clipping group was in the hypermetabolic state compared with the coiling group during the very early postoperative period. However, the difference associated with the treatment modality was relatively small compared to the effects of the SAH and of the sequelae.

Transplanted microvascular endothelial cells promote oligodendrocyte precursor cell survival in ischemic demyelinating lesions.

We previously showed that transplantation of brain microvascular endothelial cells (MVECs) greatly stimulated remyelination in the white matter infarct of the internal capsule (IC) induced by endothelin-1 injection and improved the behavioral outcome. In the present study, we examined the effect of MVEC transplantation on the infarct volume using intermittent magnetic resonance image and on the behavior of oligodendrocyte lineage cells histochemically. Our results in vivo show that MVEC transplantation reduced the infarct volume in IC and apoptotic death of oligodendrocyte precursor cells (OPCs). These results indicate that MVECs have a survival effect on OPCs, and this effect might contribute to the recovery of the white matter infarct. The conditioned-medium from cultured MVECs reduced apoptosis of cultured OPCs, while the conditioned medium from cultured fibroblasts did not show such effect. These results suggest a possibility that transplanted MVECs increased the number of OPCs through the release of humoral factors that prevent their apoptotic death. Identification of such humoral factors may lead to the new therapeutic strategy against ischemic demyelinating diseases.

Surgical treatment may improve depressive and hysterical traits in temporal lobe epilepsy with hippocampal sclerosis: Study using the Minnesota Multiphasic Personality Inventory.

Aim: The influence of surgeries on psychiatric symptoms and personality traits is not well known in patients with intractable temporal lobe epilepsy (TLE). We investigated changes in personality traits with respect to postoperative seizure outcomes, etiology, side of surgery, and sex differences. Methods: Clinical information was retrospectively collected for 44 patients whose Minnesota Multiphasic Personality Inventory (MMPI) was examined before and 1 year after surgical treatment for drug-resistant TLE. Postoperative changes in MMPI T-scores were analyzed using a paired t-test. Participants were divided into two groups based on postoperative seizure outcome, the presence or absence of hippocampal sclerosis (HS) as the etiology, side of surgery, and sex differences. The effect of these clinical factors on postoperative changes in MMPI T-scores was evaluated using analysis of covariance (P-values < 0.05). Results: The hypochondria (Hs) scale decreased significantly in all patients (p = 0.022). The postoperative seizure-free group had a significant decrease in the depression (D) scale (p = 0.037). The HS group had significant decreases in the D scale and the hysteria (Hy) scale (p = 0.016 and 0.004, respectively), and a significant increase in the masculinity-femininity (Mf) scale (p = 0.009). No significant differences existed between the sides of surgery or sex. Conclusion: Depressive traits were improved in patients with postoperative seizure freedom. Depressive and hysterical traits were improved in patients with HS, which may be attributed to a reduction in anxiety and fear associated with aura. Most personality traits are not significantly changed or exacerbated by surgical treatment of TLE.

Treatment odyssey to epilepsy surgery in children with focal cortical dysplasia: Risk factors for delayed surgical intervention.

OBJECTIVE: To elucidate the patient's journey to epilepsy surgery and identify the risk factors contributing to surgical delay in pediatric patients with drug-resistant epilepsy (DRE) due to focal cortical dysplasia (FCD). METHODS: A retrospective review was conducted of 93 pediatric patients who underwent curative epilepsy surgery for FCD between January 2012 and March 2023 at a tertiary epilepsy center. The Odyssey plot demonstrated the treatment process before epilepsy surgery, including key milestones of epilepsy onset, first hospital visit, epilepsy diagnosis, MRI diagnosis, DRE diagnosis, and surgery. The primary outcome was surgical delay; the duration from DRE to surgery. Multivariate linear regression models were used to examine the association between surgical delay and clinical, investigative, and treatment characteristics. RESULTS: The median age at seizure onset was 1.3 years (interquartile range [IQR] 0.14-3.1), and at the time of surgery, it was 6 years (range 1-11). Notably, 46% experienced surgical delays exceeding two years. The Odyssey plot visually highlighted that surgical delay comprised a significant portion of the patient journey. Although most patients underwent MRI before referral, MRI abnormalities were identified before referral only in 39% of the prolonged group, compared to 70% of the non-prolonged group. Multivariate analyses showed that delayed notification of MRI abnormalities, longer duration from epilepsy onset to DRE, older age at onset, number of antiseizure medications tried, and moderate to severe intellectual disability were significantly associated with prolonged surgical delay. CONCLUSION: Pediatric DRE patients with FCD experienced a long journey until surgery. Early and accurate identification of MRI abnormalities is important to minimize surgical delays.

Intraventricular hemorrhage volume and younger age at surgery may be risk factors for postoperative hydrocephalus after hemispherotomy in children.

OBJECTIVE: Hemispherotomy is an effective treatment for intractable hemispheric epilepsy; however, hydrocephalus remains a common complication of the procedure. The causes of hydrocephalus following hemispherotomy have not been fully elucidated; therefore, the purpose of this study was to identify the risk factors associated with the condition. METHODS: The authors investigated the records of all patients aged < 18 years who underwent hemispherotomy at their institution between 2003 and 2020 and were monitored for hydrocephalus for at least 1 year after the procedure. To identify the risk factors for hydrocephalus, the following information about each patient was collected: sex, corrected age at surgery, body weight at surgery, previous intracranial surgery, etiology of epilepsy, results of PET for hypermetabolism, side of surgery, type of operation (vertical or horizontal approach), operation time, blood loss during surgery, use of intraventricular drainage, occurrence of intraventricular hemorrhage (IVH) on the 1st postoperative day, duration of postoperative fever of > 38°C, and maximum C-reactive protein level after the operation. Multivariate logistic regression analyses were performed. RESULTS: This study included 51 children who underwent hemispherotomies for drug-resistant epilepsy at our hospital. Seven patients (13.7%) experienced hydrocephalus and were treated with ventricular or subdural peritoneal shunts or fenestration. Multivariate logistic analysis using the Bayesian information criterion revealed that 3 factors were associated with the occurrence of hydrocephalus: age at surgery, postoperative IVH volume, and duration of postoperative fever of > 38°C. CONCLUSIONS: This study showed that younger age at surgery, postoperative IVH volume, and duration of postoperative fever of > 38°C might be risk factors for hydrocephalus after hemispherotomy. The risk of hydrocephalus should be considered in cases of early surgical indication in children. Intraoperative hemostasis and postoperative use of anti-inflammatory measures may reduce the risk of hydrocephalus.

MRI detection of mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE) on T1WI-CHESS.

Mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE) is a recently proposed epileptogenic entity that is difficult to detect on MRI. We present a case of MOGHE that was successfully detected on T1WI-chemical shift-selective saturation (CHESS) MRI. The clinical presentation, MRI including T1WI-CHESS, functional images, and pathology findings of a 14-year-old Japanese girl diagnosed with MOGHE are described. T1WI-CHESS revealed an abnormal high signal along the affected lesion, whereas the findings shown by the other MR sequences were less obvious; interictal fluorodeoxyglucose-positron emission tomography indicated slightly decreased accumulation in the lesion, and subtraction ictal single photon emission computed tomography co-registered to MRI showed an increased blood flow. Together these observations suggest that T1WI-CHESS may be a useful MR sequence for detecting the lesions in patients with MOGHE.

Microvascular decompression of the root emerging zone for hemifacial spasm: evaluation by fusion magnetic resonance imaging and technical considerations.

OBJECT: The root exit zone (RExZ) of the facial nerve has been considered to be the target in microvascular decompression (MVD) for hemifacial spasm. However, more proximal segments with oligodendrocyte-derived myelin, where the facial nerve root emerges at the pontomedullary sulcus and adheres to the brainstem surface (root emerging zone [REmZ]), may also be susceptible to neurovascular compression. This study evaluated the predictive value of magnetic resonance (MR) imaging in detecting and assessing the features of vascular compression, especially in the pontomedullary sulcus, and describes the technical considerations of MVD procedures for the more proximal segments of the facial nerve. METHODS: Twenty patients treated with MVD underwent three-dimensional constructive interference in steady-state MR imaging and three-dimensional time-of-flight MR angiography. Their fusion images were used to evaluate the anatomical neurovascular relationships and intraoperative findings were analyzed. RESULTS: Most offending arteries at the REmZ and the RExZ of the facial nerve were correctly identified by fusion MR imaging. During surgery, neurovascular contacts were identified at one or more segments of the facial nerve in all patients. The REmZ of the facial nerve was affected in 55 % of the patients. The most common offending vessel at the REmZ was the posterior inferior cerebellar artery rather than the anterior inferior cerebellar artery. The key procedure to explore the deep-seated REmZ in the pontomedullary sulcus was full dissection of the lower cranial nerves to the brainstem origin. CONCLUSIONS: Our definition more correctly describes the specific anatomical relationship of the facial nerve origin from the brainstem and the clinically relevant target for MVD surgery. Fusion MR imaging is very useful to identify neurovascular contacts at both the RExZ and the REmZ of the facial nerve.

Safety, Feasibility, and Efficacy of Additional Extraventricular Anterior Commissurotomy With Corpus Callosotomy.

BACKGROUND: Corpus callosotomy (CC) is a palliative neurosurgical procedure for patients with intractable epilepsy and without resectable focal epileptogenic lesions. Anterior commissurotomy (AC) has been historically performed with CC. However, the efficacy and safety of adding AC to CC remain unknown. OBJECTIVE: To describe the surgical technique of extraventricular AC and retrospectively investigate its clinical efficacy and safety by assessing patients who underwent CC with and without AC. METHODS: AC has been added to CC at our institution since 2018. Fifty-five consecutive patients who received total callosotomy from 2016 to 2020 were included and categorized into 2 groups: 26 patients with additional AC and 29 patients without additional AC. Seizure outcome 1 year after surgery were compared between groups for assessing the efficacy of adding AC. The perioperative factors were compared for assessing the safety and feasibility. RESULTS: Seizure reduction rate (50% and 60%; P = .60) and disappearance of drop attacks (42% and 58%; P = .25) were not significantly different between CC and CC + AC groups. No statistical group differences were found in intraoperative estimated blood loss, number of days to first oral intake, duration of postoperative intravenous hydration, and length of hospital stay. CONCLUSION: Disconnection of the anterior commissure is a feasible and relatively safe procedure. This study failed to show the significant efficacy of adding AC to CC. However, further investigation is needed to prove its efficacy in ameliorating epilepsy.

Sevoflurane-induced high-frequency oscillations, effective connectivity and intraoperative classification of epileptic brain areas.

OBJECTIVE: To determine how sevoflurane anesthesia modulates intraoperative epilepsy biomarkers on electrocorticography, including high-frequency oscillation (HFO) effective connectivity (EC), and to investigate their relation to epileptogenicity and anatomical white matter. METHODS: We studied eight pediatric drug-resistant focal epilepsy patients who achieved seizure control after invasive monitoring and resective surgery. We visualized spatial distributions of the electrocorticography biomarkers at an oxygen baseline, three time-points while sevoflurane was increasing, and at a plateau of 2 minimum alveolar concentration (MAC) sevoflurane. HFO EC was combined with diffusion-weighted imaging, in dynamic tractography. RESULTS: Intraoperative HFO EC diffusely increased as a function of sevoflurane concentration, although most in epileptogenic sites (defined as those included in the resection); their ability to classify epileptogenicity was optimized at sevoflurane 2 MAC. HFO EC could be visualized on major white matter tracts, as a function of sevoflurane level. CONCLUSIONS: The results strengthened the hypothesis that sevoflurane-activated HFO biomarkers may help intraoperatively localize the epileptogenic zone. SIGNIFICANCE: Our results help characterize how HFOs at non-epileptogenic and epileptogenic networks respond to sevoflurane. It may be warranted to establish a normative HFO atlas incorporating the modifying effects of sevoflurane and major white matter pathways, as critical reference in epilepsy presurgical evaluation.

Glioma facilitates the epileptic and tumor-suppressive gene expressions in the surrounding region.

Patients with glioma often demonstrate epilepsy. We previously found burst discharges in the peritumoral area in patients with malignant brain tumors during biopsy. Therefore, we hypothesized that the peritumoral area may possess an epileptic focus and that biological alterations in the peritumoral area may cause epileptic symptoms in patients with glioma. To test our hypothesis, we developed a rat model of glioma and characterized it at the cellular and molecular levels. We first labeled rat C6 glioma cells with tdTomato, a red fluorescent protein (C6-tdTomato), and implanted them into the somatosensory cortex of VGAT-Venus rats, which specifically expressed Venus, a yellow fluorescent protein in GABAergic neurons. We observed that the density of GABAergic neurons was significantly decreased in the peritumoral area of rats with glioma compared with the contralateral healthy side. By using a combination technique of laser capture microdissection and RNA sequencing (LCM-seq) of paraformaldehyde-fixed brain sections, we demonstrated that 19 genes were differentially expressed in the peritumoral area and that five of them were associated with epilepsy and neurodevelopmental disorders. In addition, the canonical pathways actively altered in the peritumoral area were predicted to cause a reduction in GABAergic neurons. These results suggest that biological alterations in the peritumoral area may be a cause of glioma-related epilepsy.

Low EEG Gamma Entropy and Glucose Hypometabolism After Corpus Callosotomy Predicts Seizure Outcome After Subsequent Surgery.

Background: Patients with generalized epilepsy who had lateralized EEG abnormalities after corpus callosotomy (CC) occasionally undergo subsequent surgeries to control intractable epilepsy. Objectives: This study evaluated retrospectively the combination of EEG multiscale entropy (MSE) and FDG-PET for identifying lateralization of the epileptogenic zone after CC. Methods: This study included 14 patients with pharmacoresistant epilepsy who underwent curative epilepsy surgery after CC. Interictal scalp EEG and FDG-PET obtained after CC were investigated to determine (1) whether the MSE calculated from the EEG and FDG-PET findings was lateralized to the surgical side, and (2) whether the lateralization was associated with seizure outcomes. Results: Seizure reduction rate was higher in patients with lateralized findings to the surgical side than those without (MSE: p < 0.05, FDG-PET: p < 0.05, both: p < 0.01). Seizure free rate was higher in patients with lateralized findings in both MSE and FDG-PET than in those without (p < 0.05). Conclusions: This study demonstrated that patients with lateralization of MSE and FDG-PET to the surgical side had better seizure outcomes. The combination of MSE and conventional FDG-PET may help to select surgical candidates for additional surgery after CC with good postoperative seizure outcomes.

Predictors of Seizure Outcome after Repeat Pediatric Epilepsy Surgery: Reasons for Failure, Sex, Electrophysiology, and Temporal Lobe Surgery.

Considering that seizure freedom is one of the most important goals in the treatment of epilepsy, repeat epilepsy surgery could be considered for patients who continue to experience drug-resistant seizures after epilepsy surgery. However, the chance of seizure freedom is reported to be below 50% after reoperation for failed epilepsy surgery. This study aimed to elucidate the predictive factors for seizure outcomes after repeat pediatric epilepsy surgery. In all, 39 pediatric patients who underwent repeat curative epilepsy surgery between 2008 and 2020 at our institution were retrospectively studied. The relationship between preoperative clinical factors and postoperative seizure freedom at the last follow-up was statistically evaluated. The mean age at the first surgery was 5.5 years (0-16). The etiology of epilepsy was malformation of cortical development in 33 patients. The average time to seizure recurrence after the first surgery was 6.4 months (range, 0-26 months). In all, 16 patients (41.0%) achieved seizure freedom after the second surgery. Seven patients underwent a third surgery, and three (42.9%) achieved seizure freedom. Overall, 19 patients achieved seizure freedom after repeat epilepsy surgery (48.7%). Female sex, surgical failure due to technical limitations, congruent electroencephalography (EEG) findings, lesional magnetic resonance imaging (MRI) and Rt-sided surgery were predictive of seizure freedom, and surgery limited to the temporal lobe was predictive of residual seizures, as determined in the multivariate analysis. The reoperation of failed epilepsy surgery is challenging. Consideration of the above predictive factors can be helpful in deciding whether to reoperate on pediatric patients whose initial surgical intervention failed.

Volume-Based Radiofrequency Thermocoagulation for Pediatric Insulo-Opercular Epilepsy: A Feasibility Study.

BACKGROUND: Stereotactic ablation surgeries including radiofrequency thermocoagulation (RFTC) and laser interstitial thermal therapy are recent less invasive treatment methods for insular epilepsy. Volume-based RFTC after stereoelectroencephalography was first proposed by a French group as a more effective method for seizure relief in insular epilepsy patients than stereoelectroencephalography-guided RFTC. OBJECTIVE: To describe the feasibility and technical details about volume-based RFTC in patients with insulo-opercular epilepsy. METHODS: We successfully treated 3- and 6-year-old patients with medically refractory insulo-opercular epilepsy with volume-based RFTC, in which the target volume of coagulation was flexibly designed by combining multiple spherical models of 5-mm diameter which is smaller than reported previously. RESULTS: The insula was targeted by oblique trajectory from the frontoparietal area in one case, and the opercular cortex was targeted by perpendicular trajectories from the perisylvian cortex in the other case. The use of the small sphere model required more trajectories and manipulations but enabled more exhaustive coagulation of the epileptogenic zone, with 70% to 78% of the planned target volume coagulated without complications, and daily seizures disappeared after RFTC in both patients. CONCLUSION: Volume-based RFTC planned with small multiple sphere models may improve the completeness of lesioning for patients with insulo-opercular epilepsy. Careful planning is necessary to reduce the risks of vascular injuries.