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.

Brain somatic mutations in mTOR pathway genes are a major genetic etiology of focal cortical dysplasia type II (FCDII). Despite a greater ability to detect low-level somatic mutations in the brain by deep sequencing and analytics, about 40% of cases remain genetically unexplained. We included 2 independent cohorts consisting of 21 patients with mutation-negative FCDII without apparent mutations on conventional deep sequencing of bulk brain. To find ultra-low level somatic variants or structural variants, we isolated cells exhibiting phosphorylation of the S6 ribosomal protein (p-S6) in frozen brain tissues using fluorescence-activated cell sorting (FACS). We then performed deep whole-genome sequencing (WGS; >90×) in p-S6+ cells in a cohort of 11 patients with mutation-negative. Then, we simplified the method to whole-genome amplification and target gene sequencing of p-S6+ cells in independent cohort of 10 patients with mutation-negative followed by low-read depth WGS (10×). We found that 28.6% (6 of 21) of mutation-negative FCDII carries ultra-low level somatic mutations (less than 0.2% of variant allele frequency [VAF]) in mTOR pathway genes. Our method showed ~34 times increase of the average mutational burden in FACS mediated enrichment of p-S6+ cells (average VAF = 5.84%) than in bulky brain tissues (average VAF = 0.17%). We found that 19% (4 of 21) carried germline structural variations in GATOR1 complex undetectable in whole exome or targeted gene sequencing. Our method facilitates the detection of ultra-low level somatic mutations, in specifically p-S6+ cells, and germline structural variations and increases the genetic diagnostic rate up to ~80% for the entire FCDII cohort. ANN NEUROL 2023;93:1082-1093.

To evaluate the patients who had epilepsy surgery and pathologically proven focal cortical dysplasia (FCD) in order to further classify and discuss electroencephalography (EEG) findings in different pathological subtypes. This study included 19 refractory epilepsy patients who underwent surgery between 1999 and 2017 in the Istanbul Faculty of Medicine. Demographic data, preoperative examinations, scalp video EEGs, and postoperative outcomes were evaluated retrospectively. In this study, 36.8% of the patients were female. The mean age was 21.89 ± 14.64 years. Rhythmic epileptiform discharges (RED) were observed in 31.6%. 37.5% of the patients with isolated intermittent spike/sharp waves were type I, 50% were type II, and 12.5% were type III. 100% of the patients with normal background activity were FCD type II. 67% of the patients with asymmetric slowing were FCD type I, 22% was FCD type II, 11% were FCD type III. 71% of the patients with symmetrical slowing were FCD type I, 29% were FCD type II. One patient had Frontal Intermittent Rhythmic Activity, one patient had Electrical Status Epilepticus in Slow Sleep, two patients had "burst suppression," and one patient had a "switch of" sign. The frequency of focal epileptogenic activity was higher when there was an FCD lesion on magnetic resonance imaging. The findings obtained in this study did not reveal any distinctive electrophysiological features in FCD and subgroups of FCD. The incidence of REDs did not differ between types. The frequency of isolated intermittent sharp/spike waves was higher in type II than I. Intermittent and continuous EEG slowing was more commonly seen among FCD Type I patients.