Characterizing Frontal Lobe Seizure Semiology in Children.

OBJECTIVE: The objective was to analyze seizure semiology in pediatric frontal lobe epilepsy patients, considering age, to localize the seizure onset zone for surgical resection in focal epilepsy. METHODS: Fifty patients were identified retrospectively, who achieved seizure freedom after frontal lobe resective surgery at Great Ormond Street Hospital. Video-electroencephalography recordings of preoperative ictal seizure semiology were analyzed, stratifying the data based on resection region (mesial or lateral frontal lobe) and age at surgery (≤4 vs >4). RESULTS: Pediatric frontal lobe epilepsy is characterized by frequent, short, complex seizures, similar to adult cohorts. Children with mesial onset had higher occurrence of head deviation (either direction: 55.6% vs 17.4%; p = 0.02) and contralateral head deviation (22.2% vs 0.0%; p = 0.03), ictal body-turning (55.6% vs 13.0%; p = 0.006; ipsilateral: 55.6% vs 4.3%; p = 0.0003), and complex motor signs (88.9% vs 56.5%; p = 0.037). Both age groups (≤4 and >4 years) showed hyperkinetic features (21.1% vs 32.1%), contrary to previous reports. The very young group showed more myoclonic (36.8% vs 3.6%; p = 0.005) and hypomotor features (31.6% vs 0.0%; p = 0.003), and fewer behavioral features (36.8% vs 71.4%; p = 0.03) and reduced responsiveness (31.6% vs 78.6%; p = 0.002). INTERPRETATION: This study presents the most extensive semiological analysis of children with confirmed frontal lobe epilepsy. It identifies semiological features that aid in differentiating between mesial and lateral onset. Despite age-dependent differences, typical frontal lobe features, including hyperkinetic seizures, are observed even in very young children. A better understanding of pediatric seizure semiology may enhance the accuracy of onset identification, and enable earlier presurgical evaluation, improving postsurgical outcomes. ANN NEUROL 2024;95:1138-1148.

Long-term neuropsychological trajectories in children with epilepsy: does surgery halt decline?

Neuropsychological impairments are common in children with drug-resistant epilepsy. It has been proposed that epilepsy surgery might alleviate these impairments by providing seizure freedom; however, findings from prior studies have been inconsistent. We mapped long-term neuropsychological trajectories in children before and after undergoing epilepsy surgery, to measure the impact of disease course and surgery on functioning. We performed a retrospective cohort study of 882 children who had undergone epilepsy surgery at Great Ormond Street Hospital (1990-2018). We extracted patient information and neuropsychological functioning [obtained from IQ tests (domains: full-scale IQ, verbal IQ, performance IQ, working memory and processing speed) and tests of academic attainment (reading, spelling and numeracy)] and investigated changes in functioning using regression analyses. We identified 500 children (248 females) who had undergone epilepsy surgery [median age at surgery = 11.9 years, interquartile range = (7.8, 15.0)] and neuropsychological assessment. These children showed declines in all domains of neuropsychological functioning in the time leading up to surgery (all P-values ≤0.001; e.g. ßFSIQ = -1.9, SEFSIQ = 0.3, PFSIQ < 0.001). Children lost on average one to four points per year, depending on the domain considered; 27%-43% declined by ≥10 points from their first to their last preoperative assessment. At the time of presurgical evaluation, most children (46%-60%) scored one or more standard deviations below the mean (<85) on the different neuropsychological domains; 37% of these met the threshold for intellectual disability (full-scale IQ < 70). On a group level, there was no change in performance from pre- to postoperative assessment on any of the domains (all P-values ≥0.128). However, children who became seizure free through surgery showed higher postoperative neuropsychological performance (e.g. rrb-FSIQ = 0.37, P < 0.001). These children continued to demonstrate improvements in neuropsychological functioning over the course of their long-term follow-up (e.g. ßFSIQ = 0.9, SEFSIQ = 0.3, PFSIQ = 0.004). Children who had discontinued antiseizure medication treatment at 1-year follow-up showed an 8- to 13-point advantage in postoperative working memory, processing speed and numeracy, and greater improvements in verbal IQ, working memory, reading and spelling (all P-values ≤0.034) over the postoperative period compared with children who were seizure free and still receiving antiseizure medication. In conclusion, by providing seizure freedom and the opportunity for antiseizure medication cessation, epilepsy surgery might not only halt but reverse the downward trajectory that children with drug-resistant epilepsy display in neuropsychological functioning. To halt this decline as soon as possible or, potentially, to prevent it from occurring in the first place, children with focal epilepsy should be considered for epilepsy surgery as early as possible after diagnosis.

Lesion detection in epilepsy surgery: Lessons from a prospective evaluation of a machine learning algorithm.

AIM: To evaluate a lesion detection algorithm designed to detect focal cortical dysplasia (FCD) in children undergoing stereoelectroencephalography (SEEG) as part of their presurgical evaluation for drug-resistant epilepsy. METHOD: This was a prospective, single-arm, interventional study (Idea, Development, Exploration, Assessment, and Long-Term Follow-Up phase 1/2a). After routine SEEG planning, structural magnetic resonance imaging sequences were run through an FCD lesion detection algorithm to identify putative clusters. If the top three clusters were not already sampled, up to three additional SEEG electrodes were added. The primary outcome measure was the proportion of patients who had additional electrode contacts in the SEEG-defined seizure-onset zone (SOZ). RESULTS: Twenty patients (median age 12 years, range 4-18 years) were enrolled, one of whom did not undergo SEEG. Additional electrode contacts were part of the SOZ in 1 out of 19 patients while 3 out of 19 patients had clusters that were part of the SOZ but they were already implanted. A total of 16 additional electrodes were implanted in nine patients and there were no adverse events from the additional electrodes. INTERPRETATION: We demonstrate early-stage prospective clinical validation of a machine learning lesion detection algorithm used to aid the identification of the SOZ in children undergoing SEEG. We share key lessons learnt from this evaluation and emphasize the importance of robust prospective evaluation before routine clinical adoption of such algorithms. WHAT THIS PAPER ADDS: The focal cortical dysplasia detection algorithm collocated with the seizure-onset zone (SOZ) in 4 out of 19 patients. The algorithm changed the resection boundaries in 1 of 19 patients undergoing stereoelectroencephalography for drug-resistant epilepsy. The patient with an altered resection due to the algorithm was seizure-free 1 year after resective surgery. Overall, the algorithm did not increase the proportion of patients in whom SOZ was identified.

Predicting seizure outcome after epilepsy surgery: Do we need more complex models, larger samples, or better data?

OBJECTIVE: The accurate prediction of seizure freedom after epilepsy surgery remains challenging. We investigated if (1) training more complex models, (2) recruiting larger sample sizes, or (3) using data-driven selection of clinical predictors would improve our ability to predict postoperative seizure outcome using clinical features. We also conducted the first substantial external validation of a machine learning model trained to predict postoperative seizure outcome. METHODS: We performed a retrospective cohort study of 797 children who had undergone resective or disconnective epilepsy surgery at a tertiary center. We extracted patient information from medical records and trained three models-a logistic regression, a multilayer perceptron, and an XGBoost model-to predict 1-year postoperative seizure outcome on our data set. We evaluated the performance of a recently published XGBoost model on the same patients. We further investigated the impact of sample size on model performance, using learning curve analysis to estimate performance at samples up to N = 2000. Finally, we examined the impact of predictor selection on model performance. RESULTS: Our logistic regression achieved an accuracy of 72% (95% confidence interval [CI] = 68%-75%, area under the curve [AUC] = .72), whereas our multilayer perceptron and XGBoost both achieved accuracies of 71% (95% CIMLP = 67%-74%, AUCMLP = .70; 95% CIXGBoost own = 68%-75%, AUCXGBoost own = .70). There was no significant difference in performance between our three models (all p > .4) and they all performed better than the external XGBoost, which achieved an accuracy of 63% (95% CI = 59%-67%, AUC = .62; pLR = .005, pMLP = .01, pXGBoost own = .01) on our data. All models showed improved performance with increasing sample size, but limited improvements beyond our current sample. The best model performance was achieved with data-driven feature selection. SIGNIFICANCE: We show that neither the deployment of complex machine learning models nor the assembly of thousands of patients alone is likely to generate significant improvements in our ability to predict postoperative seizure freedom. We instead propose that improved feature selection alongside collaboration, data standardization, and model sharing is required to advance the field.

Seizure outcome determinants in children after surgery for single unilateral lesions on magnetic resonance imaging: Role of preoperative ictal and interictal electroencephalography.

OBJECTIVE: To determine whether an ictal electroencephalographic (EEG) recording as part of presurgical evaluation of children with a demarcated single unilateral magnetic resonance imaging (MRI) lesion is indispensable for surgical decision-making, we investigated the relationship of interictal/ictal EEG and seizure semiology with seizure-free outcome. METHODS: Data were obtained retrospectively from consecutive patients (≤18 years old) undergoing epilepsy surgery with a single unilateral MRI lesion at our institution over a 6-year period. Video-telemetry EEG (VT-EEG) was classified as concordant or nonconcordant/noninformative in relation to the MRI lesion location. The odds of seizure-free outcome associated with nonconcordant versus concordant for semiology, interictal EEG, and ictal EEG were compared separately. Multivariate logistic regression was conducted to correct for confounding variables. RESULTS: After a median follow-up of 26 months (interquartile range = 17-37.5), 73 (69%) of 117 children enrolled were seizure-free. Histopathological diagnoses included low-grade epilepsy-associated tumors, n = 46 (39%); focal cortical dysplasia (FCD), n = 33 (28%); mesial temporal sclerosis (MTS), n = 23 (20%); polymicrogyria, n = 3 (3%); and nondiagnostic findings/gliosis, n = 12 (10%). The odds of seizure freedom were lower with a nonconcordant interictal EEG (odds ratio [OR] = .227, 95% confidence interval [CI] = .079-.646, p = .006) and nonconcordant ictal EEG (OR = .359, 95% CI = .15-.878, p = .035). In the multivariate logistic regression model, factors predicting lower odds for seizure-free outcome were developmental delay/intellectual disability and higher number of antiseizure medications tried, with a nonsignificant trend for "nonconcordant interictal EEG." In the combined subgroup of patients with FCD and tumors (n = 79), there was no significant relationship of VT-EEG factors and seizure outcomes, whereas in children with MTS and acquired lesions (n = 25), a nonconcordant EEG was associated with poorer seizure outcomes (p = .003). SIGNIFICANCE: An ictal EEG may not be mandatory for presurgical evaluation, particularly when a well-defined single unilateral MRI lesion has been identified and the interictal EEG is concordant.

Proportion of resected seizure onset zone contacts in pediatric stereo-EEG-guided resective surgery does not correlate with outcome.

OBJECTIVE: We aimed to determine whether the proportion of putative seizure onset zone (SOZ) contacts resected associates with seizure outcome in a cohort of children undergoing stereoelectroencephalography (SEEG)-guided resective epilepsy surgery. METHODS: Patients who underwent SEEG-guided resective surgery over a six-year period were included. The proportion of SOZ contacts resected was determined by co-registration of pre- and post-operative imaging. Outcome was classified as seizure free (SF, Engel class I) or not seizure-free (NSF, Engel class II-IV) at last clinical follow-up. RESULTS: Twenty-nine patients underwent resection of whom 22 had sufficient imaging data for analysis (median age at surgery of 10 years, range 5-18). Fifteen (68.2%) were SF at median follow-up of 19.5 months (range 12-46). On univariate analysis, histopathology, was the only significant factor associated with SF (p < 0.05). The percentage of defined SOZ contacts resected ranged from 25-100% and was not associated with SF (p = 0.89). In a binary logistic regression model, it was highly likely that histology was the only independent predictor of outcome. CONCLUSIONS: The percentage of SOZ contacts resected was not associated with SF in children undergoing SEEG-guided resective epilepsy surgery. SIGNIFICANCE: Factors such as spatial organisation of the epileptogenic zone, neurophysiological biomarkers and the prospective identification of pathological tissue may therefore play an important role.

Seizure outcomes of large volume temporo-parieto-occipital and frontal surgery in children with drug-resistant epilepsy.

OBJECTIVE: In this study, we investigate the seizure outcomes of temporo-parieto-occipital (TPO) and frontal disconnections or resections in children with drug-resistant epilepsy (DRE) in order to determine factors which may predict surgical results. METHODS: Children with DRE, who underwent either TPO or frontal disconnection or resection at Great Ormond Street Hospital for Children between 2000 and 2017, were identified from a prospectively collated operative database. Demographic data, age at surgery, type of surgery, scalp EEGs and operative histopathology were collected. Magnetic resonance imaging (MRI) was assessed to determine completeness of disconnection and presence of radiological lesion beyond the disconnection margins. Seizure outcome at 6, 12, and 24 months post-surgery was assessed using the Engel Scale (ES). Logistic regression was used to identify relationships between data variables and seizure outcome. RESULTS: 46 children (males = 28, females = 18; age range 0.5-16.6 years) who underwent TPO (n = 32, including a re-do disconnection) or frontal disconnection or resection (n = 15) were identified. Patients in the TPO treatment group had more favourable seizure outcomes than those in the frontal treatment group (ES I-II in 56 %vs 47 % at 6 months, 52 % vs 46 % at 12 months). Presence of the lesion beyond disconnection boundaries and older age at the time of surgery were associated with poorer seizure outcome. Gender, surgery type, completeness of disconnection, scalp EEG findings and underlying pathology were not related to seizure outcome, but subgroup numbers were small. CONCLUSIONS: Both TPO and frontal disconnection are effective treatments for selected children with posterior multi-lobar or diffuse frontal lobe epilepsy. Confinement of the MRI lesion within the disconnection margins and a younger age at surgery are associated with favourable seizure outcomes. Further studies are required to elucidate these findings.

Stereo-EEG exploration in the insula/operculum in paediatric patients with refractory epilepsy.

PURPOSE: Failure to recognise involvement of the insula / opercula (I/O) region is associated with poor outcome in epilepsy surgery. Recognition is challenging due to high connectivity with adjacent structures resulting in variable and misleading semiology, often subjective and therefore likely to be underreported by children. In this study we explored prevalence and characteristics of I/O involvement in paediatric patients undergoing sEEG exploration. METHOD: We retrospectively included all consecutive patients undergoing sEEG at our centre between 11/2014 and 01/2018 with at least three contacts within I/O and excluded those with undetermined seizure onset zone (SOZ) by sEEG. We divided patients into three groups: 1) SOZ in I/O, 2) spread to I/O and 3) no I/O involvement. We compared pre-invasive characteristics, sEEG results, surgery and outcome for each group. RESULTS: 29 of all 53 consecutive patients had an identified SOZ by sEEG and at least three contacts within the I/O and were included. 41% had I/O SOZ, 38% had I/O spread and 21% had no I/O involvement. Insula associated symptoms described in adult literature were not statistically different between the three groups. Complications due to sEEG were low (2 of 53 patients). Following I/O surgery, 63% were seizure free while an additional 26% of patients achieved seizure reduction. Postoperative deficits were seen in 75% of the patients but completely resolved in all but one patient. CONCLUSIONS: Our data suggest an important role of the I/O region with frequent onset or propagation to the I/O region (at least 64% of all 53 sEEG cases). Semiology appears less specific than in adults. Insula depth electrode insertion is safe with subsequent good surgical outcomes albeit common transient deficits.

Reproducibility of interictal EEG-fMRI results in patients with epilepsy.

PURPOSE: Combined electroencephalography (EEG) and functional MRI (EEG-fMRI) can be useful in the evaluation of epilepsy patients. The reproducibility of EEG-fMRI findings needs to be established to consider it as a clinically valuable method. We addressed the intrasubject reproducibility of EEG-fMRI and the possible superiority of higher magnetic field strength in patients who were scanned twice. METHODS: Fifteen patients were studied: Seven had one 1.5T and one 3T scan and eight had two 3T EEG-fMRI studies. Equal numbers of events of the same interictal epileptic discharge (IED) were included, and IED-related blood oxygenation level dependent (BOLD) results were compared. KEY FINDINGS: In 1.5T-3T comparisons, five patients had BOLD responses in both studies, but in four there was a better response (higher maximum t-score and larger cluster) in 3T studies. One patient had a BOLD response in the 3T study only. The remaining patient had no BOLD response in either study. In 3T-3T comparisons, results were reproducible in five of eight patients, and one patient had no response in both studies. The two remaining patients had previous extensive surgery and extremely frequent IEDs. Some of the reproduced patterns in other patients, however, differed in terms of maximum t-score and cluster size. SIGNIFICANCE: EEG-fMRI appears to provide reasonable reproducibility, although repeated studies may show differences. The absence of BOLD response seems to be reproducible as well. EEG-fMRI results tend to benefit from higher field scanners (3T over 1.5T). Further studies are needed to determine if reproducibility depends on specific clinical, electrographic, or anatomic findings.

Independent component analysis reveals dynamic ictal BOLD responses in EEG-fMRI data from focal epilepsy patients.

INTRODUCTION: Seizures occur rarely during EEG-fMRI acquisitions of epilepsy patients, but can potentially offer a better estimation of the epileptogenic zone than interictal activity. Independent component analysis (ICA) is a data-driven method that imposes minimal constraints on the hemodynamic response function (HRF). In particular, the investigation of HRFs with clear peaks, but varying latency, may be used to differentiate the ictal focus from propagated activity. METHODS: ICA was applied on ictal EEG-fMRI data from 15 patients. Components related to seizures were identified by fitting an HRF to the component time courses at the time of the ictal EEG events. HRFs with a clear peak were used to derive maps of significant BOLD responses and their associated peak delay. The results were then compared with those obtained from a general linear model (GLM) method. Concordance with the presumed epileptogenic focus was also assessed. RESULTS: The ICA maps were significantly correlated with the GLM maps for each patient (Spearman's test, p<0.05). The ictal BOLD responses identified by ICA always included the presumed epileptogenic zone, but were also more widespread, accounting for 20.3% of the brain volume on average. The method provided a classification of the components as a function of peak delay. BOLD response clusters associated with early HRF peaks were concordant with the suspected epileptogenic focus, while subsequent HRF peaks may correspond to ictal propagation. CONCLUSION: ICA applied to EEG-fMRI can detect areas of significant BOLD response to ictal events without having to predefine an HRF. By estimating the HRF peak time in each identified region, the method could also potentially provide a dynamic analysis of ictal BOLD responses, distinguishing onset from propagated activity.

Evaluation of epileptogenic networks in children with tuberous sclerosis complex using EEG-fMRI.

PURPOSE: Ninety percent of patients with tuberous sclerosis complex (TSC) have epilepsy. Identification of epileptogenic areas can be difficult and studies are needed to characterize the epileptogenic network in more detail. METHODS: Five children with TSC and focal epilepsy were studied using simultaneous EEG and functional MRI recordings. Tubers were marked by a neuroradiologist on the anatomical MRI. Spike-associated BOLD (blood oxygenation level-dependent) responses were superimposed with lesions. RESULTS: Thirteen different types of interictal epileptiform discharges (IED) were analyzed with 12 showing a BOLD response, all involving more than one tuber. Five studies had tubers with activations exclusively within the lesion, three studies had lesional activations extending to perilesional areas, and two studies had activations involving exclusively perilesional areas of at least one tuber. Deactivations exclusively within a tuber were found in six studies, lesional deactivations extending to perilesional areas were found in four studies, and tubers with exclusively perilesional deactivations were found in five studies. A BOLD response was found in at least one tuber in the lobe of IED generation and presumed seizure onset (according to telemetry) in all patients. In four patients, the same tubers were involved following different IED localizations. The observed changes were always multifocal, sometimes involving tubers distant from the IED field. DISCUSSION: These findings suggest extended epileptogenic networks in patients with TSC, which exceed networks described in PET and SPECT studies. It was possible to identify specific interictally active tubers. EEG-fMRI provides a noninvasive method to select tubers and areas at their borders for further presurgical investigations.