Impact of epilepsy surgery on developmental trajectories of children under 3 years of age.

AIM: To investigate the developmental effects of epilepsy surgery in young children. METHOD: This study retrospectively reviewed 315 consecutive children under 3 years of age, and ultimately included 89 children (48 males, 41 females) with pre- and postsurgery developmental evaluations. RESULTS: The mean general quotient before surgery was 46.7 (SD 24.7). Before surgery, the general quotient decreased in 77.6% of patients, while after surgery it increased in 55.1%. Furthermore, 70% of those 20 patients whose presurgical general quotient decreased by more than 10 points experienced positive changes. General quotient scores decreased in 15 out of the 22 patients classified in the normal/marginal presurgical category. Children who underwent surgery before the age of 12 months had a median gain in general quotient score by 7.6. Short-term general quotient scores were highly correlated with long-term scores (r = 0.909, p < 0.001). INTERPRETATION: Surgical intervention was more inclined to positively impact developmental trajectories within a short postsurgical period, particularly among those affected by severe epileptic activity. However, in children with relatively typical development, certain developmental setbacks may arise. Postsurgical short-term developmental outcomes could predict longer-term outcomes.

The heterogeneity effect of surveillance intervals on progression free survival.

Progression-free survival (PFS) is an increasingly important surrogate endpoint in cancer clinical trials. However, the true time of progression is typically unknown if the evaluation of progression status is only scheduled at given surveillance intervals. In addition, comparison between treatment arms under different surveillance schema is not uncommon. Our aim is to explore whether the heterogeneity of the surveillance intervals may interfere with the validity of the conclusion of efficacy based on PFS, and the extent to which the variation would bias the results. We conduct comprehensive simulation studies to explore the aforementioned goals in a two-arm randomized control trial. We introduce three steps to simulate survival data with predefined surveillance intervals under different censoring rate considerations. We report the estimated hazard ratios and examine false positive rate, power and bias under different surveillance intervals, given different baseline median PFS, hazard ratio and censoring rate settings. Results show that larger heterogeneous lengths of surveillance intervals lead to higher false positive rate and overestimate the power, and the effect of the heterogeneous surveillance intervals may depend upon both the life expectancy of the tumor prognoses and the censoring proportion of the survival data. We also demonstrate such heterogeneity effect of surveillance intervals on PFS in a phase III metastatic colorectal cancer trial. In our opinions, adherence to consistent surveillance intervals should be favored in designing the comparative trials. Otherwise, it needs to be appropriately taken into account when analyzing data.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Surgical treatment for drug-resistant epilepsy due to early brain injury in children.

BACKGROUND: The study aimed to summarize the indications and clinical features of pediatric drug-resistant epilepsy associated with early brain injury, surgical outcomes, and prognostic factors. METHODS: We retrospectively analyzed children diagnosed with drug-resistant epilepsy due to early brain injury, who had undergone surgery at the Pediatric Epilepsy Center of Peking University First Hospital from May 2014 to May 2021. Clinical data of vasculogenic and non-vasculogenic injuries from early brain damage were compared and analyzed. The surgical outcomes were assessed using the Engel grading system. RESULTS: The median ages at acquiring injury, seizure onset, and surgery among 65 children were 19.0 (0-120) days, 8.6 (0-136.5) months, and 62.9 (13.5-234) months, respectively. Of the 14 children with non-vasculogenic injuries, 12 had posterior ulegyria. Unilateral or bilateral synchronous interictal epileptiform discharges were located mainly in the posterior quadrant in 10 children (71 %), and unilateral posterior quadrant or non-lateralized ictal region in eight children (57 %). The surgical approach was mainly temporo-parieto-occipital or parieto-occipital disconnection in nine children. Of 49 children with vasculogenic injuries, magnetic resonance imaging revealed hemispheric abnormalities in 38. Unilaterally hemispheric or bilateral interictal epileptiform discharges were observed in 36 children (73 %), whereas 42 (86 %) had unilateral hemispheric or non-lateralized ictal onset. The surgical procedure involved hemispherotomy in 38 children (78 %) and lobectomy or disconnection, multilobectomy or disconnection and hemispherotomy in 5, 20, and 40 children, respectively. Fifty-five patients (84.6 %) achieved remission from seizure during follow-up at 5.4 years. Age at surgery (odds ratio = 1.022, 95 % confidence interval = 1.003-1.042, P = 0.023) and etiology (odds ratio = 17.25, 95 % confidence interval = 2.778-107.108, P = 0.002) affected the seizure outcomes. CONCLUSION: Children with drug-resistant epilepsy due to early brain injury can successfully be treated with surgery after rigorous preoperative screening. Good surgical outcomes are associated with an early age at surgery and an etiology of vasculogenic injury.

Long-term seizure and developmental outcomes of epilepsy surgery in children under 3 years old: A single-center study of 113 patients.

AIMS: To investigate the clinical characteristics, surgical strategy, developmental and seizure outcomes, and predictors of surgical outcome in children with drug-resistant epilepsy (DRE) under 3 years old. METHODS: One hundred thirteen consecutive children younger than 3 years of age with DRE underwent curative surgical treatment after multidisciplinary preoperative evaluation using the strategy developed in the pediatric epilepsy center of Peking University First Hospital (PKFHPEC) between 2014 and 2018. These patients were selected for retrospective study. The relevant clinical data were collected and analyzed. The surgical prognoses were classified using the Engel classification, and the developmental assessment results were collected. Statistical analysis of the clinical data was performed to analyze the predictors of seizure outcomes and their correlation with developmental outcomes. RESULTS: All the patients were followed up for more than 3 years, and 98 (86.7%) patients had no seizure recurrence. One year after surgery, the seizure-free rate was 86.7%, which was as high as that at the last follow-up. Cortical dysplasia was the most frequent etiology of DRE in this cohort, accounting for 77.0%. According to the Engel classification, acute postoperative seizure (APOS; p < 0.001) was a predictor of seizure recurrence. No deaths occurred. No unpredicted long-term severe complications occurred except for one ventricular peritoneal shunt. The patients' neurodevelopmental statuses were improved after successful surgery, while the scores of the pre- and postoperative developmental assessments were closely correlated. CONCLUSIONS: For children who are younger than 3 years old and have DRE and structural abnormalities, early curative treatment can lead to long-term good seizure outcomes and a low complication rate. The development of appropriate strategies for both presurgical evaluation and resection is crucial for the success of surgery.

Enhanced focal cortical dysplasia detection in pediatric frontal lobe epilepsy with asymmetric radiomic and morphological features.

Objective: Focal cortical dysplasia (FCD) is the most common pathological cause for pediatric epilepsy, with frontal lobe epilepsy (FLE) being the most prevalent in the pediatric population. We attempted to utilize radiomic and morphological methods on MRI and PET to detect FCD in children with FLE. Methods: Thirty-seven children with FLE and 20 controls were included in the primary cohort, and a five-fold cross-validation was performed. In addition, we validated the performance in an independent site of 12 FLE children. A two-stage experiments including frontal lobe and subregions were employed to detect the lesion area of FCD, incorporating the asymmetric feature between the left and right hemispheres. Specifically, for the radiomics approach, we used gray matter (GM), white matter (WM), GM and WM, and the gray-white matter boundary regions of interest to extract features. Then, we employed a Multi-Layer Perceptron classifier to achieve FCD lesion localization based on both radiomic and morphological methods. Results: The Multi-Layer Perceptron model based on the asymmetric feature exhibited excellent performance both in the frontal lobe and subregions. In the primary cohort and independent site, the radiomics analysis with GM and WM asymmetric features had the highest sensitivity (89.2 and 91.7%) and AUC (98.9 and 99.3%) in frontal lobe. While in the subregions, the GM asymmetric features had the highest sensitivity (85.6 and 79.7%). Furthermore, relying on the highest sensitivity of GM and WM asymmetric features in frontal lobe, when integrated with the subregions results, our approach exhibited overlaps with GM asymmetric features (55.4 and 52.4%), as well as morphological asymmetric features (54.4 and 53.8%), both in the primary cohort and at the independent site. Significance: This study demonstrates that a two-stage design based on the asymmetry of radiomic and morphological features can improve FCD detection. Specifically, incorporating regions of interest for GM, WM, GM, and WM, and the gray-white matter boundary significantly enhances the localization capabilities for lesion detection within the radiomics approach.

Epilepsy Outcome and Pathology Analysis for Ganglioglioma: A Series of 51 Pediatric Patients.

BACKGROUND: The postoperative epilepsy outcome and clinicopathological features in children with ganglioglioma (GG) are not well understood. METHODS: Data from 51 consecutive pediatric patients diagnosed with GGs who underwent surgery were collected. The correlations between the expression of CD34 and BRAF V600E mutations and clinical features were analyzed. The related factors affecting the outcome of epilepsy were analyzed. RESULTS: The average follow-up was 44.2 months, and 48 patients were seizure-free. A high proportion of BRAF V600E mutation (78.8%) and CD34 expression (77.8%) was detected in GG. The onset age of epilepsy with the BRAF V600E mutation was earlier than that without. The expression of CD34 increased with the age of onset, the duration of epilepsy, and the age of operation. Focal cortical dysplasia (FCD) I was found in 62.7% of patients, and FCD II was found in 11.8% of patients approximately in the cortex surrounding GG. There was no significant correlation between the outcome of epilepsy and BRAF V600E mutation, CD34 expression, and combination with FCD. CONCLUSIONS: The overall outcome of GG and epilepsy in children is optimistic, and the outcome is not closely related to the presence of BRAF V600E mutation and CD34 (+). The FCD surrounding GG could be type I or type II. Incomplete resection of the surrounding FCD has the risk of unsatisfactory control of epilepsy. Children with the BRAF V600E mutation may be prone to early-onset epilepsy. The expression of CD34 is more likely to be detected in children with older age and a long duration of epilepsy.

Disconnection Surgery in Pediatric Epilepsy: A Single Center's Experience With 185 Cases.

BACKGROUND AND OBJECTIVES: Lobar and multilobar disconnections have gradually become common surgical methods in pediatric epilepsy surgery in recent years. However, the surgical procedures, postoperative epilepsy outcomes, and complications reported by each center are quite different. To review and analyze the clinical data from lobar disconnection in treating intractable pediatric epilepsy and study the characteristics, surgical outcomes, and safety of different disconnection surgeries. METHODS: This was a retrospective analysis of 185 children with intractable epilepsy who underwent various lobar disconnections at the Pediatric Epilepsy Center, Peking University First Hospital. Clinical information was grouped according to their characteristics. The differences in the abovementioned characteristics among the different lobar disconnections were summarized, and risk factors affecting the surgical outcome and postsurgical complications were explored. RESULTS: Among the 185 patients, 149 patients (80.5%) achieved seizure freedom with a follow-up of 2.1 years. There were 145 patients (78.4%) with malformations of cortical development (MCD). The seizure onset time (median 6 months, P = .001) and surgery time (median 34 months, P = .000) of the MCD group were smaller. Differences were found in etiology, resection of the insular lobe and epilepsy outcome among different disconnection approaches. Both parieto-occipital disconnection ( P = .038, odds ratio = 8.126) and MRI abnormalities larger than the disconnection extent ( P = .030, odds ratio = 2.670) affected the epilepsy outcome. Early postoperative complications were observed in 43 patients (23.3%), and long-term postoperative complications were observed in 5 patients (2.7%). CONCLUSION: The most common etiology of epilepsy in children undergoing lobar disconnection is MCD, whose onset and operative ages are the youngest. Disconnection surgery obtained good seizure outcomes in the treatment of pediatric epilepsy with a low incidence of long-term complications. With advances in presurgical evaluation, disconnection surgery will play a more important role in young children with intractable epilepsy.

Seizure features and outcomes in 50 children with GATOR1 variants: A retrospective study, more favorable for epilepsy surgery.

OBJECTIVES: To summarize the clinical features of epilepsy related to DEPDC5, NPRL2, and NPRL3 genes encoding the GATOR1 complex in children and to evaluate the factors affecting the prognosis of these epilepsies. METHODS: In this retrospective study, we reviewed the clinical and genetic characteristics of children with epilepsy related to GATOR1 variants who were admitted to the Peking University First Hospital between January 2016 and December 2021. Potential prognostic factors were assessed by comparing children with and without ongoing seizures. RESULTS: Fifty probands, including 31 boys and 19 girls were recruited. The median age at onset of epilepsy was 4 months, and 64% of patients had early-onset epilepsy (≤1 year). The most frequent epileptic seizure type was focal seizure (86%). Among the 50 patients, only six were with de novo variants. According to the novel classification framework for GATOR1 variants, 36 patients were with pathogenic variants and 14 with likely pathogenic variants. DEPDC5 variants were found in 37 patients, NPRL3 in 9, and NPRL2 in 4. The phenotype was similar among the probands, with variants in DEPDC5, NRPL2, or NPRL3. 76% (38/50) of epilepsy related to GATOR1 variants was neuroimaging positive, including brain MRI positive in 31 patients, and MRI combined F-18-fluorodeoxyglucose positron emission tomography positive in the other seven patients. Twenty-seven patients underwent epilepsy surgery. In total, after initial antiseizure medications alone, 92% (46/50) of patients were drug-resistant epilepsies, only 8% (4/50) of the probands became seizure-free but seizure-free (≥6 m) occurred in 92.6% (25/27) of patients with drug-resistant epilepsy after epilepsy surgery at the last follow-up. Patients undergoing epilepsy surgery had better epilepsy prognosis. SIGNIFICANCE: Epilepsy related to GATOR1 variants had high possibility to be drug-resistant epilepsy and to have positive neuroimaging finding. Epilepsy surgery is the only favorable factor for better seizure prognosis in this kind epilepsy.

Clinical characteristics and surgical outcomes in children with mild malformation of cortical development and oligodendroglial hyperplasia in epilepsy.

OBJECTIVE: Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a new and rare histopathological entity of cortical developmental malformations. The clinical characteristics of MOGHE remain challenging. METHODS: Children with histologically confirmed MOGHE were retrospectively studied. The clinical findings, electroclinical and imaging features, and postoperative outcomes were analyzed, and previously published studies were reviewed up to June 2022. RESULTS: Thirty-seven children were included in our cohort. Clinical characteristics included early onset in infancy (94.6% before 3 years), multiple seizure types, and moderate or severe delay. Epileptic spasm is the most common seizure type and initial manifestation. The lesions were mainly multilobar (59.5% multiple lobes and 8.1% hemispheres), and predominance in the frontal lobe was observed. The interictal EEG pattern was circumscribed or widespread. The prominent MRI characteristics were cortical thickening, cortical/subcortical hyperintense T2/FLAIR signal, and blurring at the GM and WM transition. Among the 21 children followed up for more than 1 year after surgery, 76.2% were seizure-free. Preoperative interictal circumscribed discharges and larger resections were significantly associated with a good postoperative outcome. The clinical features of 113 patients in the reviewed studies were similar to those we reported, but the lesions were mainly unilobar (73.5%) and Engel I was achieved in only 54.2% after surgery. SIGNIFICANCE: Distinct clinical characteristics in MOGHE, especially age at onset, epileptic spasm, and age-related MRI characteristics, can help in early diagnosis. Preoperative interictal discharge and surgical strategy may be predictors of postoperative outcomes.

Pediatric epilepsy surgery in patients with Lennox-Gastaut syndrome after viral encephalitis.

Objective: To analyse the surgical outcomes of pediatric patients with Lennox-Gastaut syndrome (LGS) secondary to viral encephalitis. Methods: We retrospectively analyzed the data of four patients with LGS secondary to viral encephalitis who underwent surgery at the pediatric epilepsy center of Peking University First Hospital from January 2014 to December 2019. Preoperative evaluations included a detailed history, long-term video electroencephalography (VEEG), brain magnetic resonance imaging (MRI), positron emission tomography (PET) and a neuropsychological test. All patients were followed up at 1, 3, and 6 months and then yearly. The surgical outcome was evaluated according to the Engel classification. Results: Among the four children, the surgeries were right temporo-parieto-occipital disconnection (case 1), corpus callosotomy (case 2), left temporo-parieto-occipital disconnection (case 3), and left temporal lobectomy (case 4). The pathology was gliosis secondary to viral encephalitis. The median follow-up time was 4 years (3-5 years). At the last follow-up, one case had Engel I, two cases had Engel III, and one case had Engel IV. Conclusions: Preliminary observations shows that surgical treatment may be challenging for patients with LGS secondary to viral encephalitis. However, suitable surgical candidacy and approaches have a significant impact on the prognosis of the patients.

Efficacy of vagus nerve stimulation in 95 children of drug-resistant epilepsy with structural etiology.

Vagus nerve stimulation (VNS) is one of the treatment options for drug-resistant epilepsy (DRE). To analyze the efficacy of VNS in children of DRE with structural etiology, we conducted a cohort study including 95 patients of DRE with structural etiology who underwent VNS treatment. Patients were followed up every 3 months at the outpatient department or via a remote programming platform. The median follow-up period was 2.6 years (range 1.0-4.6 years). The respective responder rates at 6, 12, 18, and 24 months of follow-up were 40.0% (38/95), 52.6% (50/95), 56.0% (47/84), and 59.7% (37/62). The respective seizure-free rates at 12, 18, and 24 months of follow-up were 8.4% (8/95), 9.5% (8/84), and 9.7% (6/62). The patients were divided into four groups based on etiologies: malformations of cortical development (n = 26), post-encephalitic lesions (n = 36), perinatal brain injury lesions (n = 31), and hippocampal sclerosis (n = 2). The respective responder rates at 12 months of follow-up in these groups were 53.8% (14/26), 52.8% (19/36), 51.6% (16/31), and 50.0% (1/2). There were no significant differences in gender, age at onset, age at stimulator implantation, epilepsy duration prior to VNS implantation, number of anti-seizure medications ever tried before VNS treatment, pulse amplitude of VNS, specific structural etiologies, lobe distribution or hemispheric side of structural lesions between responders and non-responders. Of the 95 patients, 8 (8.4%) underwent lesion surgery or hemispherectomy before VNS implantation, and 6/8 (75%) of these patients had a >50% reduction in seizure frequency. One patient who had a corpus callosotomy before VNS implantation had no response to VNS treatment. In conclusion, VNS is an effective treatment in children of DRE with structural etiology. There was no significant difference in VNS efficacy in patients with different structural etiologies. Vagus nerve stimulation treatment may also control seizures well in some patients with poor outcomes after lesion resection or hemispherectomy before VNS implantation.

Safety and efficacy of rapid withdrawal of antiseizure medications during long-term video-electroencephalogram monitoring in children with drug-resistant epilepsy: A retrospective study.

OBJECTIVE: Performing long-term video-electroencephalographic monitoring (LTVEM) to obtain the ictal electroencephalogram (EEG) is important for presurgical evaluation. This study aimed at investigating the safety and efficacy of our protocol developed at Peking University First Hospital (PUFH) for rapid withdrawal of antiseizure medications (ASMs) during LTVEM to induce seizures in children with drug-resistant epilepsy (DRE) exhibiting nondaily seizures. METHODS: Children with DRE who followed the PUFH protocol for rapid withdrawal of ASMs during LTVEM between 2018 and 2021 were enrolled. The occurrence of seizures, number of ASMs withdrawn, seizure onset time after ASM tapering initiation, changes in interictal epileptiform discharge (IED), and adverse events were evaluated during LTVEM. RESULTS: Among 80 children evaluated in this study, seizures were induced successfully in 72 (90%) children. Furthermore, no change in IED sites was observed in these 72 children following the initiation of ASM tapering while 2 children exhibited secondary bilateral tonic-clonic seizures. The median time from ASM tapering initiation to the onset of the first seizure was found to be 3 days (2-4), while the median number of ASMs withdrawn was 2 (1-2). Finally, 66 children (91.7%) had habitual seizures while 6 children had nonhabitual seizure semiology. SIGNIFICANCE: The PUFH protocol can be used for the rapid withdrawal of ASMs during LTVEM in children with DRE. Using this protocol, ictal EEG patterns can be obtained in a relatively short time for most patients with fewer adverse effects during LTVEM, which may provide meaningful electro-clinical information for presurgical evaluation.

Regional efficacy evaluation in multi-regional clinical trials using a discounting factor weighted Z test.

Multi-regional clinical trial (MRCT) is an efficient design to accelerate drug approval globally. Once the global efficacy of test drug is demonstrated, each local regulatory agency is required to prove effectiveness of test drug in their own population. Meanwhile, the ICH E5/E17 guideline recommends using data from other regions to help evaluate regional drug efficacy. However, one of the most challenges is how to manage to bridge data among multiple regions in an MRCT since various intrinsic and extrinsic factors exist among the participating regions. Furthermore, it is critical for a local agency to determine the proportion of information borrowing from other regions given the ethnic differences between target region and non-target regions. To address these issues, we propose a discounting factor weighted Z statistic to adaptively borrow information from non-target regions. In this weighted Z statistic, the weight is derived from a discounting factor in which the discounting factor denotes the proportion of information borrowing from non-target regions. We consider three ways to construct discounting factors based on the degree of congruency between target and non-target regions either using control group data, or treatment group data, or all data. We use the calibrated power prior to construct discounting factor based on scaled Kolmogorov-Smirnov statistic. Comprehensive simulation studies show that our method has desirable operating characteristics. Two examples are used to illustrate the applications of our proposed approach.

Vagus nerve stimulation in children with drug-resistant epilepsy of monogenic etiology.

Vagus nerve stimulation (VNS) is an effective treatment for drug-resistant epilepsy (DRE). The present study evaluated the efficacy of VNS in pediatric patients with DRE of monogenic etiology. A total of 20 patients who received VNS treatment at our center were followed up every 3 months through outpatient visits or a remote programming platform. The median follow-up time was 1.4 years (range: 1.0-2.9). The rate of response to VNS at 12 months of follow-up was 55.0% (11/20) and the seizure-free rate was 10.0% (2/20). We found that 75.0% (3/4) of patients with an SCN1A variant had a >50% reduction in seizure frequency. Patients with pathogenic mutations in the SLC35A2, CIC, DNM1, MBD5, TUBGCP6, EEF1A2, and CHD2 genes or duplication of X q28 (MECP2 gene) had a >50% reduction in seizure frequency. Compared with the preoperative electroencephalography (EEG), at 6, 12, 18, and 24 months after stimulator implantation, the percentage of the patients whose background frequency increased >1.5 Hz was respectively, 15.0% (3/20), 50.0% (10/20), 58.3% (7/12) and 62.5% (5/8); the percentage of the patients whose interictal EEG showed a >50% decrease in spike number was respectively 10% (2/20), 40.0% (8/20), 41.6% (5/12) and 50.0% (4/8). In the 9 patients with no response to VNS treatment, there was no difference in terms of spike number and background frequency between preoperative and postoperative EEG. Five of the 20 children (25.0%) reached new developmental milestones or acquired new skills after VNS compared to the preoperative evaluation. The efficacy of VNS in pediatric patients with DRE of monogenic etiology is consistent with that in the overall population of pediatric DRE patients. Patients with Dravet syndrome (DS), tuberous sclerosis complex (TSC), or Rett syndrome/MECP2 duplication syndrome may have a satisfactory response to VNS, but it is unclear whether patients with rare variants of epilepsy-related genes can benefit from the treatment.

Lesional Intractable Epileptic Spasms in Children: Electroclinical Localization and Postoperative Outcomes.

To analyze the influence of seizure semiology, electroencephalography (EEG) features and magnetic resonance imaging (MRI) change on epileptogenic zone localization and surgical prognosis in children with epileptic spasm (ES) were assessed. Data from 127 patients with medically intractable epilepsy with ES who underwent surgical treatment were retrospectively analyzed. ES semiology was classified as non-lateralized, bilateral asymmetric, and focal. Interictal epileptiform discharges were divided into diffusive or multifocal, unilateral, and focal. MRI results showed visible local lesions for all patients, while the anatomo-electrical-clinical value of localization of the epileptogenic zone was dependent on the surgical outcome. During preoperative video EEG monitoring, among all 127 cases, 53 cases (41.7%) had ES only, 46 (36.2%) had ES and focal seizures, 17 (13.4%) had ES and generalized seizures, and 11 (8.7%) had ES with focal and generalized seizures. Notably, 35 (27.6%) and 92 cases (72.4%) showed simple and complex ES, respectively. Interictal EEG showed that 22 cases (17.3%) had bilateral multifocal discharges or hypsarrhythmia, 25 (19.7%) had unilateral dominant discharges, and 80 (63.0%) had definite focal or regional discharges. Ictal discharges were generalized/bilateral in 71 cases (55.9%) and definite/lateralized in 56 cases (44.1%). Surgically resected lesions were in the hemisphere (28.3%), frontal lobe (24.4%), temporal lobe (16.5%), temporo-parieto-occipital region (14.2%), and posterior cortex region (8.7%). Seizure-free rates at 1 and 4 years postoperatively were 81.8 and 72.7%, respectively. There was no significant difference between electroclinical characteristics of ES and seizure-free rate. Surgical treatment showed good outcomes in most patients in this cohort. Semiology and ictal EEG change of ES had no effect on localization, while focal or lateralized epileptiform discharges of interictal EEG may affect lateralization and localization. Complete resection of epileptogenic lesions identified via MRI was the only factor associated with a positive surgical outcome.

Sensorimotor outcomes after resection for perirolandic drug-resistant epilepsy: a systematic review and individual patient data meta-analysis.

OBJECTIVE: The prevalence of long-term postoperative sensorimotor deficits in children undergoing perirolandic resective epilepsy surgery is unclear. The risk of developing these deficits must be weighed against the potential reduction in seizure frequency after surgery. In this study, the authors investigated the prevalence of sensorimotor deficits after resective surgery at ≥ 1 year postoperatively. METHODS: A systematic review and individual patient data meta-analysis was conducted using PubMed, Embase, and Scopus databases. Subgroups of patients were identified and categorized according to their outcomes as follows: group A patients were denoted as seizure free with no postoperative sensorimotor deficits; group B patients experienced seizure recurrence with no deficit; group C patients were seizure free with deficits; and group D patients were not seizure free and with deficits. Rates of sensory deficits were examined in patients undergoing postcentral gyrus resection, and rates of motor deficits were aggregated in patients undergoing precentral gyrus resection. RESULTS: Of 797 articles resulting from the database searches, 6 articles including 164 pediatric patients at a mean age of 7.7 ± 5.2 years with resection for drug-resistant perirolandic epilepsy were included in the study. Seizure freedom was observed in 118 (72.9%) patients at a mean follow-up of 3.4 ± 1.8 years. In total, 109 (66.5%) patients did not develop sensorimotor deficits at last follow-up, while 55 (33.5%) had permanent deficits. Ten (14.3%) of 70 patients with postcentral gyrus resection had permanent sensory deficits. Of the postcentral gyrus resection patients, 41 (58.6%) patients were included in group A, 19 (27.1%) in group B, 7 (10.0%) in group C, and 3 (4.3%) in group D. Forty (37.7%) of 106 patients with precentral resections had permanent motor deficits. Of the precentral gyrus resection patients, 50 (47.2%) patients were in group A, 16 (15.1%) in group B, 24 (22.6%) in group C, and 16 (15.1%) in group D. Patients without focal cortical dysplasia were more likely to have permanent motor deficits relative to those with focal cortical dysplasia in the precentral surgery cohort (p = 0.02). CONCLUSIONS: In total, 58.6% of patients were seizure free without deficit, 27.1% were not seizure free and without deficit, 10.0% were seizure free but with deficit, and 4.3% were not seizure free and with deficit. Future studies with functional and quality-of-life data, particularly for patients who experience seizure recurrence with no deficits (as in group B in the present study) and those who are seizure free with deficits (as in group C) after treatment, are necessary to guide surgical decision-making.

Subtotal hemispherotomy for intractable lesional hemispheric epilepsy without hemiparesis in children.

PURPOSE: We analyzed the surgical indications, outcomes, and prognostic factors of subtotal hemispherotomy for intractable lesional hemispheric epilepsy in children with almost normal motor function and summarized its surgical strategies. METHODS: We retrospectively analyzed 20 children who underwent subtotal hemispherotomy (hemispheric disconnection sparing sensorimotor cortex) between March 2015 and May 2021. The children were divided into seizure-free group and residual seizures group according to their surgical outcomes. The surgical outcome was based on International League Against Epilepsy (ILAE) classification (class 1-6). All presurgical evaluation data were collected and analyzed. RESULTS: Among the 20 children, the mean age at the time of seizure onset, mean age at the time of surgery, and mean follow-up time was 3.2 ± 2.8, 7.5 ± 4.4, and 3.5 ± 2.1 years, respectively. All children had hemispheric lesion on MRI. At the last follow-up evaluation, 75% (15/20) of children remained seizure-free. Univariate analyses revealed that the electrocorticogram finding of epileptiform discharges in the central cortex after disconnection were poor prognostic factors for seizure outcomes (P < 0.05). Disconnection of the central operculum and insula was a poor prognostic factor for motor function after surgery (P < 0.05). CONCLUSIONS: For intractable lesional hemispheric epilepsy with no hemiparesis, subtotal hemispherotomy can be performed with favorable seizure outcome. Disconnection of the central operculum and insula may increase the possibility of motor function injury.

Brain Somatic Variant in Ras-Like Small GTPase RALA Causes Focal Cortical Dysplasia Type II.

Purpose: In our group's previous study, we performed deep whole-exome sequencing and targeted amplicon sequencing in the postoperative brain tissue of epilepsy patients with focal cortical dysplasia type II (FCD II). We identified the first somatic variant of RALA in the brain tissue of a child with FCD type IIb. RALA encodes a small GTPase of the Ras superfamily. To date, the role of RALA in brain development is not yet known. In this study, we reported that the RALA somatic variant led to FCD type II through activation of the mammalian target of rapamycin (mTOR) pathways. Materials and Methods: HEK293T cells were transfected in vitro to analyze the expression of the RalA protein, as well as phosphorylated S6 (P-S6), one of the major markers of mTOR pathway activation, RalA GTPase activity, and the interaction between RalA and its downstream binding effectors. In vivo, wild-type, and mutant RALA plasmids were transfected into the local cortex of mice using in utero electroporation to evaluate the effect of RALA c.G482A on neuronal migration. Results: The RALA c.G482A mutation increased RalA protein expression, the abnormal activation of the mTOR pathways, RalA GTPase activity, and binding to downstream effectors. RALA c.G482A local transfection in the embryonic brain in utero induced abnormal cortical neuron migration in mice. Conclusion: This study demonstrated for the first time that the somatic gain-of-function variant of RALA activates the mTOR pathway and leads to neuronal migration disorders in the brain, facilitating the development of FCD II. Therefore, RALA brain somatic mutation may be one of the pathogenic mechanisms leading to FCD II, which is always related to drug-resistant epilepsy in children. However, more somatic variations of this gene are required to be confirmed in more FCD II patient brain samples.

A comprehensive prognostic and immune analysis of enhancer RNA identifies IGFBP7-AS1 as a novel prognostic biomarker in Uterine Corpus Endometrial Carcinoma.

BACKGROUND: Long non-coding RNAs (lncRNA) have been implicated in a hand of studies that supported an involvement and co-operation in Uterine Corpus Endometrial Carcinoma (UCEC). Enhancer RNAs (eRNA), a functional subtype of lncRNA, have a key role throughout the genome to guide protein production, thus potentially associated with diseases. METHODS: In this study, we mainly applied the Cancer Genome Atlas (TCGA) dataset to systematically discover crucial eRNAs involving UCEC. For the key eRNAs in UCEC, we employed RT-qPCR to compare eRNA expression levels in tumor tissues and paired normal adjacent tissues from UCEC patients for validation. Furthermore, the relationships between the key eRNAs and immune activities were measured from several aspects, including the analysis for tumor microenvironment, immune infiltration cells, immune check point genes, tumor mutation burden, and microsatellite instability, as well as m6A related genes. Finally, the key eRNAs were verified by a comprehensive pan-cancer analysis. RESULTS: IGFBP7 Antisense RNA 1 (IGFBP7-AS1) was identified as the key eRNA for its expression patterns of low levels in tumor tissues and favorable prognostic value in UCEC correlated with its target gene IGFBP7. In RT-qPCR analysis, IGFBP7-AS1 and IGFBP7 had down-regulated expression in tumor tissues, which was consistent with previous analysis. Moreover, IGFBP7-AS1 was found closely related with immune response in relevant immune analyses. Besides, IGFBP7-AS1 and its target gene IGFBP7 correlated with a multi-omics pan-cancer analysis. CONCLUSIONS: Finally, we suggested that IGFBP7-AS1 played a key role in impacting on clinical outcomes of UCEC patients for its possible influence on immune activity.