Screening for serum antineuronal antibodies in pediatric epilepsy.

Epileptogenic lesions in focal epilepsy can be subtle or remain undetected on conventional MRI. Ultra-high field (7T) MRI offers higher spatial resolution, contrast, and signal-to-noise ratio compared with conventional field strengths and has shown promise in adult presurgical evaluation. However, its utility in pediatric focal epilepsy, where malformations of cortical development are common, remains unclear. In this study, we directly compared 7T and 3T MRI in children with drug-resistant focal epilepsy, evaluating (1) scan tolerability, (2) image quality, and (3) lesion detection yield. In this prospective cohort study, patients were recruited from outpatient clinics at 3 large epilepsy centers in London. Eligible participants were aged 8-17 years and had no contraindications to MRI. Scanning was conducted in 2 separate sessions at 3T and 7T. Safety and tolerability were assessed using age-specific questionnaires and analyzed using the Mann-Whitney test for differences between age groups and the McNemar χ2 test for within-participant cross-field comparisons. Image quality was evaluated by a pediatric neuroradiologist and estimated quantitatively by comparing cortical thickness between field strengths. Lesion detection yield of 7T MRI was assessed by joint review with a multidisciplinary team. A total of 63 children were assessed: 41 patients (mean age 12.6 ± 2.4 years, 22 were male) and 22 healthy controls (8-17 years, mean age 11.7 ± 2.7 years, 15 were male). Both field strengths were well tolerated, and side effects were transient. These included higher dizziness-related discomfort at 7T (p = 0.02, Cohen h = 0.89), with side effects more frequently noted in younger children (scanner noise: p = 0.02, Cohen r = -0.36; metallic taste: p = 0.02, Cohen r = -0.37). Cortical thickness was significantly thinner at 7T for both right (t = 5.65, p < 0.001, Cohen d = -0.72) and left (t = 5.01, p < 0.001, Cohen d = -0.64) hemispheres, with thinner boundaries in temporo-parietal/sensory regions. Although 7T images had increased reported inhomogeneity and artifacts, new lesions were detected in 6 of 26 patients (23%), influencing surgical management in 4 of 26 (15%) (odds ratio 1.86). 7T MRI in children with epilepsy is well tolerated and associated with a 23% improvement in lesion detection, directly affecting clinical management and surgical outcomes. Although limited by a preselected cohort with extensive diagnostic workups, our findings underscore the transformative potential of 7T MRI in presurgical planning for pediatric epilepsy.

Localization and duration dependent effects of pediatric refractory epilepsy on language function.

ObjectiveThe thalamus is a key hub in seizure propagation, and its nuclei are emerging targets for neuromodulation. However, the contributions of individual nuclei to epileptic networks remain unclear, particularly in children, who are less studied than adults. We investigated structural and functional thalamic alterations across different pediatric focal epilepsies and their associations with clinical features and postsurgical outcomes.MethodsWe retrospectively studied children with temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), and posterior quadrant epilepsy (PQE) and healthy controls. The thalamus was segmented into four nuclei groups (anterior, lateral, medial, pulvinar) using the THOMAS pipeline on T1‐weighted magnetic resonance imaging (MRI) to estimate volumes. Functional connectivity was assessed with functional MRI using node strength, capturing total thalamic connectivity across the brain. We compared patients with controls and evaluated associations with hippocampal sclerosis, history of focal to bilateral tonic–clonic seizures, and postsurgical seizure freedom.ResultsAmong 136 children with focal epilepsy (81 TLE, 36 FLE, 19 PQE; mean age = 13.0 years) and 70 controls (mean age = 13.4 years), ipsilateral thalamic volume reductions were observed in the following: anterior and lateral nuclei and pulvinar in TLE, anterior and lateral nuclei in FLE, and pulvinar in PQE (Cohen d = .52–.70, all Bonferroni‐corrected p < .05). In contrast, medial nuclei volume increase was associated with history of seizure generalization (partial η2 = .06). Functional connectivity was bilaterally reduced across epilepsy groups (partial η2 = .03), most consistently in the pulvinar (Cohen d = .25–.68). Within TLE, hippocampal sclerosis was associated with increased anterior nucleus connectivity (partial η2 = .17), distinguishing it from other pathologies.SignificanceWe demonstrate both shared and syndrome‐specific thalamic abnormalities in pediatric focal epilepsy. Common patterns included ipsilateral thalamic volume loss, indicating cumulative disease burden, and reduced bilateral functional connectivity, particularly in the pulvinar, likely reflecting thalamocortical decoupling. These findings advance understanding of seizure networks beyond the epileptogenic zone and provide a foundation for personalized thalamic‐targeted neuromodulation strategies.

Objective: Focal epilepsy is the most frequent type of epilepsy in childhood, particularly after the first year of life. This study aims to analyze the clinical aspects, electrophysiological and neuroimaging findings, and genetic predispositions in pediatric focal epilepsy. Specifically, we investigate the association between these parameters and evaluate their impact on therapeutic decisions. Methods: This is a retrospective study, in which we enrolled 39 patients currently receiving follow-up in our unit, 20 male and 19 female. Using the Chi-squared test, we compared them considering several genetic traits, pre/peri/postnatal risk factors, family history, clinical and instrumental features, and treatments. Differences are considered significant with a p value < 0.005. Results: Our findings highlight the multifactorial nature of focal epilepsy, with a combination of genetic and environmental contributions. EEG demonstrated the highest sensitivity among diagnostic tools, being non-significant in only 12.8% of cases, while MRI (p < 0.001), CT (p < 0.04), and brain ultrasound had lower detection rates. MRI findings were significant in 43.6% of patients, predominantly showing vascular malformations (35.8%). MRI-negative findings were more common in temporal and occipital epilepsy, whereas MRI-positive results were observed in 100% of frontal seizures. Importantly, some MRI-negative cases may still be lesional, particularly in temporal lobe epilepsy, where focal cortical dysplasia could be present but undetected with standard imaging. Valproic acid remains the most commonly used anti-seizure medication, and, despite guideline recommendations, it was still prescribed as a first-line treatment in 34.3% of cases and is being used in 23.5% of female patients, raising concerns about its appropriateness. Conclusions: This study highlights the role of genetic and environmental risk factors in pediatric focal epilepsy. EEG showed superior diagnostic sensitivity over MRI, particularly in MRI-negative cases. While high-resolution MRI (3T or 7T) could improve lesion detection, its cost limits accessibility. Valproate was the most prescribed drug, despite its recommended use in generalized epilepsy, emphasizing the need for improved adherence to treatment guidelines. Together with other studies, these findings can contribute to optimizing diagnostic and therapeutic strategies for pediatric focal epilepsy.

Nonfebrile seizures.

Learning and memory are essential for academic success and everyday functioning, but the pattern of memory skills and its relationship to executive functioning in children with focal epilepsy is not fully delineated. We address a gap in the literature by examining the relationship between memory and executive functioning in a pediatric focal epilepsy population. Seventy children with focal epilepsy and 70 typically developing children matched on age, intellectual functioning, and gender underwent neuropsychological assessment, including measures of intelligence (Wechsler Abbreviated Scale of Intelligence [WASI]/Differential Ability Scales [DAS]), as well as visual Children's Memory Scale (CMS Dot Locations) and verbal episodic memory (Wide Range Assessment of Memory and Learning [WRAML] Story Memory and California Verbal Learning Test for Children [CVLT-C]). Executive functioning was measured directly (WISC-IV Digit Span Backward; Clinical Evaluation of Language Fundamentals, Fourth Edition (CELF-IV) Recalling Sentences) and by parent report (Behavior Rating Inventory of Executive Function [BRIEF]). Children with focal epilepsy had lower delayed free-recall scores than controls across visual and verbal memory tasks (p = 0.02; partial η2 = 0.12). In contrast, recognition memory performance was similar for patients and controls (p = 0.36; partial η2 = 0.03). Children with focal epilepsy demonstrated difficulties in working memory (p = 0.02; partial η2 = 0.08) and planning/organization (p = 0.02) compared to controls. Working memory predicted 9-19% of the variance in delayed free recall for verbal and visual memory; organization predicted 9-10% of the variance in verbal memory. Patients with both left and right focal epilepsy demonstrated more difficulty on verbal versus visual tasks (p = 0.002). Memory performance did not differ by location of seizure foci (temporal vs. extratemporal, frontal vs. extrafrontal). Children with focal epilepsy demonstrated memory ability within age-level expectations, but delayed free recall was inefficient compared to typically developing controls. Memory difficulties were not related to general cognitive impairment or seizure localization. Executive functioning accounted for significant variance in memory performance, suggesting that poor executive control negatively influences memory retrieval.

To clarify the clinical picture of mesial temporal lobe epilepsy (MTLE) in childhood, we carried out a clinical, electroencephalographic, and neuroradiologic study of 19 patients. MTLE was noted in 19 (0.82%) of 2,319 epileptic patients with childhood onset. Three types of initial seizure were recognized: febrile convulsion, afebrile generalized convulsion, and complex partial seizure (CPS). As presumed causes, various prolonged convulsions (persisting for > 30 min) were found in 12 (63.2%) cases. Regardless of the presence of preceding convulsions (febrile or afebrile), the clinical course was not uniform, with CPS in the early period temporarily controlled in some cases and intractable from the early period in others. Unilateral hippocampal abnormalities were confirmed on magnetic resonance imaging (MRI) before the age of 5 years in two cases, suggesting that mesial temporal sclerosis (MTS) is formed within a relatively short period in some cases. Seizures were controlled for > 6 months in only two (10.5%) cases and persisted in 17. In four (21.1%) cases, surgical treatment was considered to be available.

EPILEPSY

Febrile seizures and hippocampal sclerosis: Frequent and related findings in intractable temporal lobe epilepsy of childhood

Research priorities in epilepsy for the next decade—A representative view of the European scientific community: Summary of the ILAE Epilepsy Research Workshop, Brussels, 17–18 January 2008

Background Epilepsy has a high prevalence of 1%, which makes it the most common serious neurological disorder. The most difficult to treat type of epilepsy is temporal lobe epilepsy (TLE) with its most commonly associated lesion being hippocampal sclerosis (HS). About 30-50% of all patients undergoing resective surgery of epileptogenic tissue continue to have seizures postoperatively. Indication for this type of surgery is only given when lesions are clearly visible on magnetic resonance images (MRI). About 30% of all patients with focal epilepsy do not show an underlying structural lesion upon qualitative neuroradiological MRI assessment (MRI-negative). Objectives The work presented in this thesis uses MRI data to quantitatively investigate structural differences between brains of patients with focal epilepsy and healthy controls using automated imaging preprocessing and analysis methods. Methods All patients studied in this thesis had electrophysiological evidence of focal epilepsy, and underwent routine clinical MRI prior to participation in this study. There were two datasets and both included a cohort of age-matched controls: (i) Patients with TLE and associated HS who later underwent selective amygdalahippocampectomy (cohort 1) and (ii) MRI-negative patients with medically refractory focal epilepsy (cohort 2). The participants received high- resolution routine clinical MRI as well as additional sequences for gray and white matter (GM/WM) structural imaging. A neuroradiologist reviewed all images prior to analysis. Hippocampal subfield volume and automated tractography analysis was performed in patients with TLE and HS and related to post-surgical outcomes, while images of MRI- negative patients were analyzed using voxel-based morphometry (VBM) and manual/automated tractography. All studies were designed to detect quantitative differences between patients and controls, except for the hippocampal subfield analysis as control data was not available and comparisons were limited to patients with persistent postoperative seizures and those without. Results 1. Automated hippocampal subfield analysis (cohort 1): The high-resolution hippocampal subfield segmentation technique cannot establish a link between hippocampal subfield volume loss and post-surgical outcome. Ipsilateral and contralateral hippocampal subfield volumes did not correlate with clinical variables such as duration of epilepsy and age of onset of epilepsy. 2. Automated WM diffusivity analysis (cohort 1): Along-the-tract analysis showed that ipsilateral tracts of patients with right/left TLE and HS were more extensively affected than contralateral tracts and the affected regions within tracts could be specified. The extent of hippocampal atrophy (HA) was not related to (i) the diffusion alterations of temporal lobe tracts or (ii) clinical characteristics of patients, whereas diffusion alterations of ipsilateral temporal lobe tracts were significantly related to age at onset of epilepsy, duration of epilepsy and epilepsy burden.Patients without any postoperative seizure symptoms (excellent outcomes) had more ipsilaterally distributed WM tract diffusion alterations than patients with persistent postoperative seizures (poorer outcomes), who were affected bilaterally. 3. Automated epileptogenic lesion detection (cohort 2): Comparison of individual patients against the controls revealed that focal cortical dysplasia (FCD) can be detected automatically using statistical thresholds. All sites of dysplasia reported at the start of the study were detected using this technique. Two additional sites in two different patients, which had previously escaped neuroradiological assessment, could be identified. When taking these statistical results into account during re-assessment of the dedicated epilepsy research MRI, the expert neuroradiologist was able to confirm these as lesions. 4. Manual and automated WM diffusion tensor imaging (DTI) analysis (cohort 2): The analysis of consistency across approaches revealed a moderate to good agreement between extracted tract shape, morphology and space and a strong correlation between diffusion values extracted with both methods. While whole-tract DTI-metrics determined using Automated Fiber Quantification (AFQ) revealed correlations with clinical variables such as age of onset and duration of epilepsy, these correlations were not found using the manual technique. The manual approach revealed more differences than AFQ in group comparisons of whole-tract DTI-metrics. Along-the-tract analysis provided within AFQ gave a more detailed description of localized diffusivity changes along tracts, which correlated with clinical variables such as age of onset and epilepsy duration. Conclusions While hippocampal subfield volume loss in patients with TLE and HS was not related with any clinical variables or to post-surgical outcomes, WM tract diffusion alterations were more bilaterally distributed in patients with persistent postoperative seizures, compared to patients with excellent outcomes. This may indicate that HS as an initial precipitating injury is not affected by clinical features of the disorder and automated hippocampal subfield mapping based on MRI is not sufficient to stratify patients according to outcome. Presence of persisting seizures may depend on other pathological processes such as seizure propagation through WM tracts and WM integrity. Automated and time-efficient three-dimensional voxel-based analysis may complement conventional visual assessments in patients with MRI-negative focal epilepsy and help to identify FCDs escaping routine neuroradiological assessment. Furthermore, automated along-the-tract analysis may identify widespread abnormal diffusivity and correlations between WM integrity loss and clinical variables in patients with MRI-negative epilepsy. However, automated WM tract analysis may differ from results obtained with manual methods and therefore caution should be exercised when using automated techniques.

Levetiracetam (LEV) and carbamazepine (CBZ) are effective monotherapies for focal epilepsy in children. However, the best drug remains controversial. Therefore, we performed a systematic review and meta-analysis comparing LEV and CBZ monotherapy in the management of pediatric focal epilepsy (PFE). We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCTs) published until February 2024 comparing LEV and CBZ monotherapy in PFE. Statistical analysis was performed using R version 4.2.2, heterogeneity was assessed using I2 statistics, and the risk of bias was evaluated using the RoB-2 tool. Risk Ratios (RR) with p < 0.05 were considered significant. The outcomes of interest were seizure freedom, any adverse events, adverse events leading to treatment discontinuation, dermatologic adverse events, and the frequency of at least one seizure, defined as the proportion of patients experiencing one or more seizures during the treatment period. Four RCTs comprising 381 children with a mean age of 7.32 to 9.28 years were included, of whom 186 (48.8%) received LEV monotherapy. There was no significant difference between groups (RR: 1.15; 95% CI 0.88–1.50; p = 0.31; I2 = 90%) regarding seizure freedom. The frequency of at least one seizure (RR: 0.71; 95% CI 0.52–0.97; p = 0.03; I2 = 8%) and dermatologic adverse events (RR: 0.24; 95% CI 0.09–0.64; p < 0.01; I2 = 0%) were both significantly lower in the LEV group. There were no significant differences in the presence of any adverse events (RR: 0.58; 95% CI 0.33–1.01; p = 0.05; I2 = 36%) or adverse events leading to treatment discontinuation (RR: 0.67; 95% CI 0.13–3.42; p = 0.63; I2 = 30%).Conclusion: In monotherapy, LEV was more advantageous than CBZ for PFE, with a lower frequency of seizures and fewer dermatological adverse events. However, both drugs are equally effective in achieving seizure freedom, adverse events without specification, and those that lead to treatment discontinuation. Our findings have important implications for clinical practice and decision-making in this condition.What is Known:• Both LEV and CBZ are effective monotherapies for pediatric focal epilepsy.• The use of LEV or CBZ monotherapy for the management of children with focal epilepsy remains controversial.What is New:• No significant differences were observed between the LEV and CBZ groups in terms of overall seizure freedom, safety, and tolerance.• However, LEV resulted in a lower frequency of at least one seizure and fewer dermatological adverse events than CBZ.

Childhood epilepsy can be frequently associated with impaired cognitive functioning. Previous research has suggested an increased risk of cognitive impairment that may be related to the etiology, the electro-clinical pattern and the load of anti-seizure medications (ASMs). The aim of this study was to evaluate the impact of different clinical features on the global intellectual functioning in a cohort of children and adolescents with epilepsy. We studied eighty patients diagnosed and followed in a tertiary care center. These factors were examined: 1. Etiology of epileptic syndrome; 2. Type of seizure; 3. Number of ASMs; 4. Seizure frequency; 5. Age at seizure onset; 6. Total duration of epilepsy; and 7. Active duration of epilepsy. Multiple regression analysis showed that the etiology and the total duration of epilepsy were the best indicators of intellectual functioning. The present data indicate that children with symptomatic epilepsy (SE) have lower IQ scores (M = 63.5), while children with self-limited focal epilepsy and generalized idiopathic epilepsy, i.e. age-related epileptic syndromes (ARES), have a higher IQ (M = 100.0; p < 0.01). Children with epilepsy of unknown etiology (UEE) (M = 75.1; p < 0.05) are positioned at an intermediate level between the SE and the ARES group (p < 0.01). Increased duration of epilepsy was associated with decreased intellectual functioning. In conclusion, knowledge about the risks associated with etiologic factors and the duration of the disease may guide the definition of optimal neuropsychological rehabilitation strategies.

Neurofeedback impacts cognition and quality of life in pediatric focal epilepsy: An exploratory randomized double-blinded sham-controlled trial

Background: This study was designed to investigate the difference in the prevalence of neuronal autoantibodies in patients diagnosed with established temporal lobe epilepsy (TLE) of unknown cause with mesial temporal sclerosis (MTS) and patients with TLE without MTS.Methods: In an observational cohort study design, we included thirty-three consecutive adult patients and divided them into two groups with and without MTS. We evaluated anti-neuronal and nuclear antibodies with immunofluorescence (IF) and enzyme-linked immunosorbent assay (ELISA), respectively.Results: From the thirty-three consecutive patients with epilepsy 17 (51.1%) had MTS of which 12 had unilateral and 5 had bilateral MTS. No significant difference was detected between seropositive and seronegative patients in MTS versus non-MTS groups. The studied autoantibodies were present in 16 patients, including gamma-aminobutyric acid receptor (GABA-R) antibodies being the most common in 11 (33.3%), followed by N-methyl-D-aspartate receptor (NMDA-R) in 2 (6.1%), glutamic acid decarboxylase receptor (GAD-R) in 1 (3.0%), anti-phospholipid (APL) antibody in 1 (3.0%), CV2 in 1 (3.0%), Tr in 1 (3.0%), recoverin in 1 (3.0%), and double-stranded deoxyribonucleic acid (dsDNA) antibody in 1 (3.0%) of our patients with focal epilepsy. In both MTS and non-MTS groups, eight patients were positive for antibodies; four patients were positive for GABA in the MTS group and seven for GABA in the non-MTS group.Conclusion: Neuronal antibodies were presented in half of patients with focal epilepsy, GABA antibody being the leading one. No specific magnetic resonance imaging (MRI) findings were found in the seropositive group. Our results suggest that screening for relevant antibodies may enable us to offer a possible treatment to this group of patients.