Distinguishing drug-resistant temporal lobe epilepsy (TLE) caused by isolated hippocampal sclerosis (iHS) from focal cortical dysplasia type IIIa (FCD IIIa) remains a presurgical challenge. This study aimed to compare the clinical characteristics, electrophysiological data, and postsurgical seizure outcomes between these pathologies. We retrospectively analyzed a cohort of 50 consecutive TLE patients (mean duration of disease of 22 years) who underwent surgery. The histopathology confirmed either iHS (n = 22) or FCD IIIa (n = 28) and a minimum follow-up of 12 months. The groups were compared on complex presurgical data, surgery type, and outcome. A history of febrile seizures (p = 0.02, OR = 4.7) was more frequent in the FCD IIIa group, which also had significantly lower intelligence quotient (IQ) scores in all domains. The mean total IQ score for FCD IIIa/iHS was 86/94 (p = 0.02); verbal IQ was 85/92 (p = 0.03); performance IQ was 89/98 (p = 0.02). The effect size was considered medium for all three (Cohen's d = 0.7, 0.63 and 0.68 respectively). Scalp EEG showed shorter seizures in FCD IIIa (p = 0.03), in SEEG, the temporal pole was more implanted in this group (p = 0.02, 50 % difference, OR = ∞). At a mean follow-up of 8.5 years, similar seizure-freedom rates was found between groups (82 % for FCD IIIa, 95 % for iHS; p = 0.48). Follow-up EEG and neuropsychological assessment at 6 months post-surgery showed no statistical differences. FCD IIIa and iHS exhibit several distinct electro-clinical features. The most important is a more impaired general cognitive profile associated with FCD IIIa, without differences in language or global memory.

Focal cortical dysplasia (FCD) type IIIa, distinct from isolated FCD in drug-resistant epilepsy, is typically confirmed via postoperative histopathology. This study aimed to evaluate the diagnostic utility of preoperative noninvasive 18F-fludeoxyglucose (FDG) PET/MRI co-registration in localizing the epileptogenic zone (EZ) in FCD type IIIa. We performed a retrospective study that included 60 patients with FCD type IIIa who underwent resection for drug-resistant epilepsy. The sensitivity of each modality for localizing the EZ was calculated, with invasive stereoelectroencephalography (SEEG) as a reference. Diagnostic accuracy and value of each modality were further assessed with respect to SEEG and postoperative outcomes for all patients and MRI negative/doubtful patients. We analyzed the diagnostic value of the different non-invasive diagnostic techniques with respect to concordance with SEEG findings and postsurgical seizure outcomes. For all included patients, 18F-FDG PET/MRI showed the highest sensitivity (75.7 %) for localizing the EZ across all modalities. We also found that 18F-FDG PET/MRI demonstrated the best accuracy and diagnostic value for localizing the EZ (60.0 %). Among MRI-doubtful/negative patients, 18F-FDG PET/MRI not only showed the highest sensitivity (79.3 %) but also achieved most promising accuracy and diagnostic value for identifying the EZ (61.7 % accuracy) across all modalities. 18F-FDG PET/MRI coregistration appears to be overwhelmingly rewarding in affording localization of EZ for patients with FCD type IIIa. This technique is potentially valuable as a noninvasive method to identify the EZ in patients with drug-resistant epilepsy due to FCD type IIIa, especially for MRI-negative/doubtful patients.

We comprehensively characterized a large pediatric cohort with focal cortical dysplasia (FCD) type 1 to expand the phenotypic spectrum and to identify predictors of postsurgical outcomes. We included pediatric patients with histopathological diagnosis of isolated FCD type 1 and at least 1 year of postsurgical follow-up. We systematically reanalyzed clinical, electrophysiological, and radiological features. The results of this reanalysis served as independent variables for subsequent statistical analyses of outcome predictors. All children (N = 31) had drug-resistant epilepsy with varying impacts on neurodevelopment and cognition (presurgical intelligence quotient [IQ]/developmental quotient scores = 32-106). Low presurgical IQ was associated with abnormal slow background electroencephalographic (EEG) activity and disrupted sleep architecture. Scalp EEG showed predominantly multiregional and often bilateral epileptiform activity. Advanced epilepsy magnetic resonance imaging (MRI) protocols identified FCD-specific features in 74.2% of patients (23/31), 17 of whom were initially evaluated as MRI-negative. In six of eight MRI-negative cases, fluorodeoxyglucose-positron emission tomography (PET) and subtraction ictal single photon emission computed tomography coregistered to MRI helped localize the dysplastic cortex. Sixteen patients (51.6%) underwent invasive EEG. By the last follow-up (median = 5 years, interquartile range = 3.3-9 years), seizure freedom was achieved in 71% of patients (22/31), including seven of eight MRI-negative patients. Antiseizure medications were reduced in 21 patients, with complete withdrawal in six. Seizure outcome was predicted by a combination of the following descriptors: age at epilepsy onset, epilepsy duration, long-term invasive EEG, and specific MRI and PET findings. This study highlights the broad phenotypic spectrum of FCD type 1, which spans far beyond the narrow descriptions of previous studies. The applied multilayered presurgical approach helped localize the epileptogenic zone in many previously nonlesional cases, resulting in improved postsurgical seizure outcomes, which are more favorable than previously reported for FCD type 1 patients.

Hippocampal sclerosis (HS) is a common surgical substrate in adult epilepsy surgery cohorts but variably reported in various pediatric cohorts. We aimed to study the epilepsy phenotype, radiological and pathological variability, seizure and neurocognitive outcomes in children with drug-resistant epilepsy and hippocampal sclerosis (HS) with or without additional subtle signal changes in anterior temporal lobe who underwent surgery. This retrospective study enrolled children with drug-resistant focal epilepsy and hippocampal sclerosis with or without additional subtle T2-Fluid Attenuated Inversion Recovery (FLAR)/Proton Density (PD) signal changes in anterior temporal lobe who underwent anterior temporal lobectomy with amygdalohippocampectomy. Their clinical, EEG, neuropsychological, radiological and pathological data were reviewed and summarized. Thirty-six eligible patients were identified. The mean age at seizure onset was 3.7 years; 25% had daily seizures at time of surgery. Isolated HS was noted in 22 (61.1%) cases and additional subtle signal changes in ipsilateral temporal lobe in 14 (38.9%) cases. Compared to the normative population, the group mean performance in intellectual functioning and most auditory and visual memory tasks were significantly lower than the normative sample. The mean age at surgery was 12.3 years; 22 patients (61.1%) had left hemispheric surgeries. ILAE class 1 outcomes was seen in 28 (77.8%) patients after a mean follow up duration of 2.3 years. Hippocampal sclerosis was noted pathologically in 32 (88.9%) cases; type 2 (54.5%) was predominant subtype where further classification was possible. Additional pathological abnormalities were seen in 11 cases (30.6%); these had had similar rates of seizure freedom as compared to children with isolated hippocampal sclerosis/gliosis (63.6% vs 84%, p=0.21). Significant reliable changes were observed across auditory and visual memory tasks at an individual level post surgery. Favourable seizure outcomes were seen in most children with isolated radiological hippocampal sclerosis. Patients with additional pathological abnormalities had similar rates of seizure freedom as compared to children with isolated hippocampal sclerosis/gliosis.

Recent studies have identified brain somatic variants as a cause of focal epilepsy. These studies relied on resected tissue from epilepsy surgery, which is not available in most patients. The use of trace tissue adherent to depth electrodes used for stereo electroencephalography (EEG) has been proposed as an alternative but is hampered by the low cell quality and contamination by nonbrain cells. Here, we use our improved depth electrode harvesting technique that purifies neuronal nuclei to achieve molecular diagnosis in a patient with focal cortical dysplasia (FCD). Depth electrode tips were collected, pooled by brain region and seizure onset zone, and nuclei were isolated and sorted using fluorescence-activated nuclei sorting (FANS). Somatic DNA was amplified from neuronal and astrocyte nuclei using primary template amplification followed by exome sequencing of neuronal DNA from the affected pool, unaffected pool, and saliva. The identified variant was validated using droplet digital polymerase chain reaction (PCR). An 11-year-old male with drug-resistant genetic-structural epilepsy due to left anterior insula FCD had seizures from age 3 years. Stereo EEG confirmed seizure onset in the left anterior insula. The two anterior insula electrodes were combined as the affected pool and three frontal electrodes as the unaffected pool. FANS isolated 140 neuronal nuclei from the affected and 245 neuronal nuclei from the unaffected pool. A novel somatic missense MTOR variant (p.Leu489Met, CADD score 23.7) was identified in the affected neuronal sample. Droplet digital PCR confirmed a mosaic gradient (variant allele frequency = .78% in affected neuronal sample; variant was absent in all other samples). Our findings confirm that harvesting neuronal DNA from depth electrodes followed by molecular analysis to identify brain somatic variants is feasible. Our novel method represents a significant improvement compared to the previous method by focusing the analysis on high-quality cells of the cell type of interest.