Anti-seizure gene therapy for focal cortical dysplasia.

Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. Focal cortical dysplasia type II is typically caused by somatic mutations resulting in mammalian target of rapamycin (mTOR) hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe focal cortical dysplasia. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established focal cortical dysplasia model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human Ras homolog enriched in brain (RHEB) plasmid, an activator of mTOR complex 1. We characterized the model by quantifying electrocorticographic and behavioural abnormalities, both in mice developing spontaneous generalized seizures and in mice only exhibiting interictal discharges. Injection of AAV9-CAMK2A-EKC in the dysplastic region resulted in a robust decrease (∼64%) in the frequency of seizures. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal discharges or behaviour in mice without generalized seizures. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.

Potential of focal cortical dysplasia in migraine pathogenesis.

Focal cortical dysplasias are abnormalities of the cerebral cortex associated with an elevated risk of neurological disturbances. Cortical spreading depolarization/depression is a correlate of migraine aura/headache and a trigger of migraine pain mechanisms. However, cortical spreading depolarization/depression is associated with cortical structural changes, which can be classified as transient focal cortical dysplasias. Migraine is reported to be associated with changes in various brain structures, including malformations and lesions in the cortex. Such malformations may be related to focal cortical dysplasias, which may play a role in migraine pathogenesis. Results obtained so far suggest that focal cortical dysplasias may belong to the causes and consequences of migraine. Certain focal cortical dysplasias may lower the threshold of cortical excitability and facilitate the action of migraine triggers. Migraine prevalence in epileptic patients is higher than in the general population, and focal cortical dysplasias are an established element of epilepsy pathogenesis. In this narrative/hypothesis review, we present mainly information on cortical structural changes in migraine, but studies on structural alterations in deep white matter and other brain regions are also presented. We develop the hypothesis that focal cortical dysplasias may be causally associated with migraine and link pathogeneses of migraine and epilepsy.

Focal cortical dysplasia II caused by brain somatic mutation of IRS-1 is associated with ERK signaling pathway activation.

Somatic mutations have been identified in 10% to 63% of focal cortical dysplasia type II samples, primarily linked to the mTOR pathway. When the causative genetic mutations are not identified, this opens the possibility of discovering new pathogenic genes or pathways that could be contributing to the condition. In our previous study, we identified a novel candidate pathogenic somatic variant of IRS-1 c.1791dupG in the brain tissue of a child with focal cortical dysplasia type II. This study further explored the variant's role in causing type II focal cortical dysplasia through in vitro overexpression in 293T and SH-SY5Y cells and in vivo evaluation via in utero electroporation in fetal brains, assessing effects on neuronal migration, morphology, and network integrity. It was found that the mutant IRS-1 variant led to hyperactivity of p-ERK, increased cell volume, and was predominantly associated with the MAPK signaling pathway. In vivo, the IRS-1 c.1791dupG variant induced abnormal neuron migration, cytomegaly, and network hyperexcitability. Notably, the ERK inhibitor GDC-0994, rather than the mTOR inhibitor rapamycin, effectively rescued the neuronal defects. This study directly highlighted the ERK signaling pathway's role in the pathogenesis of focal cortical dysplasia II and provided a new therapeutic target for cases of focal cortical dysplasia II that are not treatable by rapamycin analogs.

Mouse model of focal cortical dysplasia type II generates a wide spectrum of high-frequency activities.

High-frequency oscillations (HFOs) represent an electrographic biomarker of endogenous epileptogenicity and seizure-generating tissue that proved clinically useful in presurgical planning and delineating the resection area. In the neocortex, the clinical observations on HFOs are not sufficiently supported by experimental studies stemming from a lack of realistic neocortical epilepsy models that could provide an explanation of the pathophysiological substrates of neocortical HFOs. In this study, we explored pathological epileptiform network phenomena, particularly HFOs, in a highly realistic murine model of neocortical epilepsy due to focal cortical dysplasia (FCD) type II. FCD was induced in mice by the expression of the human pathogenic mTOR gene mutation during embryonic stages of brain development. Electrographic recordings from multiple cortical regions in freely moving animals with FCD and epilepsy demonstrated that the FCD lesion generates HFOs from all frequency ranges, i.e., gamma, ripples, and fast ripples up to 800 Hz. Gamma-ripples were recorded almost exclusively in FCD animals, while fast ripples occurred in controls as well, although at a lower rate. Gamma-ripple activity is particularly valuable for localizing the FCD lesion, surpassing the utility of fast ripples that were also observed in control animals, although at significantly lower rates. Propagating HFOs occurred outside the FCD, and the contralateral cortex also generated HFOs independently of the FCD, pointing to a wider FCD network dysfunction. Optogenetic activation of neurons carrying mTOR mutation and expressing Channelrhodopsin-2 evoked fast ripple oscillations that displayed spectral and morphological profiles analogous to spontaneous oscillations. This study brings experimental evidence that FCD type II generates pathological HFOs across all frequency bands and provides information about the spatiotemporal properties of each HFO subtype in FCD. The study shows that mutated neurons represent a functionally interconnected and active component of the FCD network, as they can induce interictal epileptiform phenomena and HFOs.

Spatial omics reveals molecular changes in focal cortical dysplasia type II.

Focal cortical dysplasia (FCD) represents a group of diverse localized cortical lesions that are highly epileptogenic and occur due to abnormal brain development caused by genetic mutations, involving the mammalian target of rapamycin (mTOR). These somatic mutations lead to mosaicism in the affected brain, posing challenges to unravel the direct and indirect functional consequences of these mutations. To comprehensively characterize the impact of mTOR mutations on the brain, we employed here a multimodal approach in a preclinical mouse model of FCD type II (Rheb), focusing on spatial omics techniques to define the proteomic and lipidomic changes. Mass Spectrometry Imaging (MSI) combined with fluorescence imaging and label free proteomics, revealed insight into the brain's lipidome and proteome within the FCD type II affected region in the mouse model. MSI visualized disrupted neuronal migration and differential lipid distribution including a reduction in sulfatides in the FCD type II-affected region, which play a role in brain myelination. MSI-guided laser capture microdissection (LMD) was conducted on FCD type II and control regions, followed by label free proteomics, revealing changes in myelination pathways by oligodendrocytes. Surgical resections of FCD type IIb and postmortem human cortex were analyzed by bulk transcriptomics to unravel the interplay between genetic mutations and molecular changes in FCD type II. Our comparative analysis of protein pathways and enriched Gene Ontology pathways related to myelination in the FCD type II-affected mouse model and human FCD type IIb transcriptomics highlights the animal model's translational value. This dual approach, including mouse model proteomics and human transcriptomics strengthens our understanding of the functional consequences arising from somatic mutations in FCD type II, as well as the identification of pathways that may be used as therapeutic strategies in the future.

Ultra-Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II.

OBJECTIVE: 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. METHODS: 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×). RESULTS: 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. CONCLUSIONS: 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.

[18F]SynVesT-1 and [18F]FDG quantitative PET imaging in the presurgical evaluation of MRI-negative children with focal cortical dysplasia type II.

PURPOSE: MRI-negative children with focal cortical dysplasia type II (FCD II) are one of the most challenging cases in surgical epilepsy management. We aimed to utilize quantitative positron emission tomography (QPET) analysis to complement [18F]SynVesT-1 and [18F]FDG PET imaging and facilitate the localization of epileptogenic foci in pediatric MRI-negative FCD II patients. METHODS: We prospectively enrolled 17 MRI-negative children with FCD II who underwent [18F]SynVesT-1 and [18F]FDG PET before surgical resection. The QPET scans were analyzed using statistical parametric mapping (SPM) with respect to healthy controls. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of [18F]SynVesT-1 PET, [18F]FDG PET, [18F]SynVesT-1 QPET, and [18F]FDG QPET in the localization of epileptogenic foci were assessed. Additionally, we developed a multivariate prediction model based on dual trace PET/QPET assessment. RESULTS: The AUC values of [18F]FDG PET and [18F]SynVesT-1 PET were 0.861 (sensitivity = 94.1%, specificity = 78.2%, PPV = 38.1%, NPV = 98.9%) and 0.908 (sensitivity = 82.4%, specificity = 99.2%, PPV = 93.3%, NPV = 97.5%), respectively. [18F]FDG QPET showed lower sensitivity (76.5%) and NPV (96.6%) but higher specificity (95.0%) and PPV (68.4%) than visual assessment, while [18F]SynVesT-1 QPET exhibited higher sensitivity (94.1%) and NPV (99.1%) but lower specificity (97.5%) and PPV (84.2%). The multivariate prediction model had the highest AUC value (AUC = 0.996, sensitivity = 100.0%, specificity = 96.6%, PPV = 81.0%, NPV = 100%). CONCLUSIONS: The multivariate prediction model based on [18F]SynVesT-1 and [18F]FDG PET/QPET assessments holds promise in noninvasively identifying epileptogenic regions in MRI-negative children with FCD II. Furthermore, the combination of visual assessment and QPET may improve the sensitivity and specificity of diagnostic tests in localizing epileptogenic foci and achieving a preferable surgical outcome in MRI-negative FCD II.

Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitability via overactivation of neuronal GluN2C N-methyl-D-aspartate receptors.

OBJECTIVE: Genetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood. Previously, the role of upregulated GluN2C-containing glutamate-gated N-methyl-D-aspartate receptors (NMDARs) has been demonstrated for germline defects in the TSC genes. Here, we questioned whether this mechanism would expand to other mTORopathies in the different context of a somatic genetic variation of the MTOR protein recurrently found in FCD type II. METHODS: We used a rat model of FCD created by in utero electroporation of neural progenitors of dorsal telencephalon with expression vectors encoding either the wild-type or the pathogenic MTOR variant (p.S2215F). In this mosaic configuration, patch-clamp whole-cell recordings of the electroporated, spiny stellate neurons and extracellular recordings of the electroporated areas were performed in neocortical slices. Selective inhibitors were used to target mTOR activity and GluN2C-mediated currents. RESULTS: Neurons expressing the mutant protein displayed an excessive activation of GluN2C NMDAR-mediated spontaneous excitatory postsynaptic currents. GluN2C-dependent increase in spontaneous spiking activity was detected in the area of electroporated neurons in the mutant condition and was restricted to a critical time window between postnatal days P9 and P20. SIGNIFICANCE: Somatic MTOR pathogenic variant recurrently found in FCD type II resulted in overactivation of GluN2C-mediated neuronal NMDARs in neocortices of rat pups. The related and time-restricted local hyperexcitability was sensitive to subunit GluN2C-specific blockade. Our study suggests that GluN2C-related pathomechanisms might be shared in common by mTOR-related brain disorders.

Identification of a mosaic MTOR variant in purified neuronal DNA in a patient with focal cortical dysplasia using a novel depth electrode harvesting technique.

OBJECTIVE: 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). METHODS: 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). RESULTS: 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). SIGNIFICANCE: 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.

Combining magnetic resonance fingerprinting with voxel-based morphometric analysis to reduce false positives for focal cortical dysplasia detection.

OBJECTIVE: We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis. METHODS: We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level. RESULTS: MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients. SIGNIFICANCE: This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy.

Multimodal mapping of regional brain vulnerability to focal cortical dysplasia.

Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.

Epileptogenesis and drug-resistant in focal cortical dysplasias: Update on clinical, cellular, and molecular markers.

Focal cortical dysplasia (FCD) is a cortical malformation in brain development and is considered as one of the major causes of drug-resistant epilepsiesin children and adults. The pathogenesis of FCD is yet to be fully understood. Imaging markers such as MRI are currently the surgeons major obstacle due to the difficulty in delimiting the precise dysplasic area and a mosaic brain where there is epileptogenic tissue invisible to MRI. Also increased gene expression and activity may be responsible for the alterations in cell proliferation, migration, growth, and survival. Altered expressions were found, particularly in the PI3K/AKT/mTOR pathway. Surgery is still considered the most effective treatment option, due to drug-resistance, and up to 60 % of patients experience complete seizure control, varying according to the type and location of FCD. Both genetic and epigenetic factors may be involved in the pathogenesis of FCD, and there is no conclusive evidence whether these alterations are inherited or have an environmental origin.

Neuropsychological outcome after frontal surgery for pediatric-onset epilepsy with focal cortical dysplasia in adolescent and young adult.

OBJECTIVE: We investigated neuropsychological outcome in patients with pharmacoresistant pediatric-onset epilepsy caused by focal cortical dysplasia (FCD), who underwent frontal lobe resection during adolescence and young adulthood. METHODS: Twenty-seven patients were studied, comprising 15 patients who underwent language-dominant side resection (LDR) and 12 patients who had languagenondominant side resection (n-LDR). We evaluated intelligence (language function, arithmetic ability, working memory, processing speed, visuo-spatial reasoning), executive function, and memory in these patients before and two years after resection surgery. We analyzed the relationship between neuropsychological outcome and resected regions (side of language dominance and location). RESULTS: Although 75% of the patients showed improvement or no change in individual neuropsychological tests after surgical intervention, 25% showed decline. The cognitive tests that showed improvement or decline varied between LDR and n-LDR. In patients who had LDR, decline was observed in Vocabulary and Phonemic Fluency (both 5/15 patients), especially after resection of ventrolateral frontal cortex, and improvement was observed in WCST-Category (7/14 patients), Block Design (6/15 patients), Digit Symbol (4/15 patients), and Delayed Recall (3/9 patients). In patients who underwent n-LDR, improvement was observed in Vocabulary (3/12 patients), but decline was observed in Block Design (2/9 patients), and WCST-Category (2/9 patients) after resection of dorsolateral frontal cortex; and Arithmetic (3/10 patients) declined after resection of dorsolateral frontal cortex or ventrolateral frontal cortex. General Memory (3/8 patients), Visual Memory (3/8 patients), Delayed Recall (3/8 patients), Verbal Memory (2/9 patients), and Digit Symbol (3/12 patients) also declined after n-LDR. CONCLUSION: Postoperative changes in cognitive function varied depending on the location and side of the resection. For precise presurgical prediction of neuropsychological outcome after surgery, further prospective studies are needed to accumulate data of cognitive changes in relation to the resection site.

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.

A radiomics nomogram based on multiparametric MRI for diagnosing focal cortical dysplasia and initially identifying laterality.

BACKGROUND: Focal cortical dysplasia (FCD) is the most common epileptogenic developmental malformation. The diagnosis of FCD is challenging. We generated a radiomics nomogram based on multiparametric magnetic resonance imaging (MRI) to diagnose FCD and identify laterality early. METHODS: Forty-three patients treated between July 2017 and May 2022 with histopathologically confirmed FCD were retrospectively enrolled. The contralateral unaffected hemispheres were included as the control group. Therefore, 86 ROIs were finally included. Using January 2021 as the time cutoff, those admitted after January 2021 were included in the hold-out set (n = 20). The remaining patients were separated randomly (8:2 ratio) into training (n = 55) and validation (n = 11) sets. All preoperative and postoperative MR images, including T1-weighted (T1w), T2-weighted (T2w), fluid-attenuated inversion recovery (FLAIR), and combined (T1w + T2w + FLAIR) images, were included. The least absolute shrinkage and selection operator (LASSO) was used to select features. Multivariable logistic regression analysis was used to develop the diagnosis model. The performance of the radiomic nomogram was evaluated with an area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration and clinical utility. RESULTS: The model-based radiomics features that were selected from combined sequences (T1w + T2w + FLAIR) had the highest performances in all models and showed better diagnostic performance than inexperienced radiologists in the training (AUCs: 0.847 VS. 0.664, p = 0.008), validation (AUC: 0.857 VS. 0.521, p = 0.155), and hold-out sets (AUCs: 0.828 VS. 0.571, p = 0.080). The positive values of NRI (0.402, 0.607, 0.424) and IDI (0.158, 0.264, 0.264) in the three sets indicated that the diagnostic performance of Model-Combined improved significantly. The radiomics nomogram fit well in calibration curves (p > 0.05), and decision curve analysis further confirmed the clinical usefulness of the nomogram. Additionally, the contrast (the radiomics feature) of the FCD lesions not only played a crucial role in the classifier but also had a significant correlation (r = -0.319, p < 0.05) with the duration of FCD. CONCLUSION: The radiomics nomogram generated by logistic regression model-based multiparametric MRI represents an important advancement in FCD diagnosis and treatment.

Focal cortical dysplasia is a frequent coexistent pathology in patients with Rasmussen's encephalitis.

INTRODUCTION: Rasmussen's encephalitis (RE) is a rare, predominantly pediatric epilepsy disorder of unknown etiology. It classically affects one of the cerebral hemispheres and histologically shows cortical chronic inflammation, gliosis, and neuronal loss. The etiopathogenesis of RE remains unknown, with genetic, infectious, and autoimmune factors all speculated to play a role. Although the histologic findings in RE are well described, few studies have investigated a large cohort of cases looking for the coexistence of RE with focal cortical dysplasia (FCD). DESIGN: The study is a retrospective review of RE patients who underwent surgical resection of brain tissue between 1979 and 2021. Relevant patient history was retrieved, and available histologic slides were reviewed. The histologic severity of RE was described according to the Pardo criteria. In cases where FCD was present, the observed patterns of FCD (namely Ia, Ib, IIa, IIb, etc.) were described using the International League Against Epilepsy (ILAE) classification. RESULTS: Thirty-eight resection specimens from 31 patients formed the study cohort. Seventeen patients (54.8 %) were male; average age at surgery was 8 years (range: 2-28 years). Twenty-seven resection specimens (71.1 %) from 23 patients (74 %) showed evidence of coexistent FCD. Most cases with FCD resembled the ILAE type Ib (n = 23) pattern. Cases of RE that did not show FCD were either Pardo stage 1 (n = 5) or 4 (n = 6), with all Pardo stage 2 and 3 cases demonstrating FCD. CONCLUSIONS: FCD was found in most patients with RE (74 %). The most observed pattern of FCD was ILAE Ib.

[Diagnostic value of high frequency oscillation in localization of type â ¡ focal cortical dysplasia epilepsy].

Retrospective analysis was conducted on 9 patients with type Ⅱ focal cortical dysplasia (FCD) who underwent stereo-electroencephalography (SEEG) implantation in the Department of Neurosurgery of the First Affiliated Hospital of Fujian Medical University from November 2020 to February 2023. The onset area, onset time, and frequency of high-frequency oscillations (HFO) were analyzed and the correlation of HFOs with interictal, preictal, and ictal periods. SEEG recordings of 80-500 Hz HFOs were observed in both interictal and ictal periods in 9 patients, with 6 patients exhibiting fast ripples (FR) in the range of 250-500 Hz. Surgical resection of the seizure onset area and FR-generating electrodes was performed, and postoperative follow-up for over 2 years indicated Engel I in 5 cases. 6 patients showed continuous discharge during the preictal period, and the distribution index of continuous discharge was positively correlated with seizure frequency. HFOs in the range of 80-500 Hz were present in all four seizure onset patterns during the ictal period. The onset area and FR-emitting electrode were surgically removed in 6 patients with continuous discharge and overlapping HFOs during the preictal period, with 5 cases of Engel I. Type Ⅱ FCD discharges exhibited complexity, high discharge indices, and a close association with HFOs. Compared with the spike wave, the electrode range of HF is more limited, and the incidence of HF before attack is significantly increased, which is closely correlated with the onset area. The simultaneous occurrence of HFO and the spike waves has higher diagnostic value than the individual occurrence, effectively enhancing surgical efficacy.

[Focal cortical dysplasia: visual assessment of MRI and MR morphometry data]. / Fokal'naya kortikal'naya displaziya: sravnitel'nyi analiz vizual'noi otsenki dannykh magnitno-rezonansnoi tomografii i magnitno-rezonansnoi morfometrii.

OBJECTIVE: Assessing the diagnostic significance of MR morphometry in determining the localization of focal cortical dysplasias (FCD). MATERIAL AND METHODS: The study included 13 children after surgery for drug-resistant epilepsy caused by FCD type II and stable postoperative remission of seizures (Engel class IA, median follow-up 56 months). We analyzed the results of independent expert assessment of native MR data by three radiologists (HARNESS protocol) and MR morphometry data regarding accuracy of FCD localization. We considered 2 indicators, i.e. local cortical thickening and gray-white matter blurring. RESULTS: FCD detection rate was higher after MR morphometry compared to visual analysis of native MR data using the HARNESS protocol. MR morphometry also makes it possible to more often identify gray-white matter blurring as a sign often missed by radiologists (p<0.05). CONCLUSION: MR morphometry is an additional non-invasive method for assessing the localization of FCD.

SLC35A2 somatic variants in drug resistant epilepsy: FCD and MOGHE.

De novo somatic (post-zygotic) gene mutations affecting neuroglial progenitor cell types in embryonic cerebral cortex are increasingly identified in patients with drug resistant epilepsy (DRE) associated with malformations of cortical development, in particular, focal cortical dysplasias (FCD). Somatic variants in at least 16 genes have been linked to FCD type II, all encoding components of the mechanistic target of rapamycin (mTOR) pathway. FCD type II is characterized histopathologically by cytomegalic dysmorphic neurons and balloon cells. In contrast, the molecular pathogenesis of FCD I subtypes is less well understood, and histological features are characterized by alterations in columnar or laminar organization without cytomegalic dysmorphic neurons or balloon cells. In 2018, we reported somatic mutations in Solute Carrier Family 35 member A2 (SLC35A2) linked to DRE underlying FCD type I and subsequently to a new histopathological phenotype: excess oligodendrocytes and heterotopic neurons in subcortical white matter known as MOGHE (mild malformation of cortical development with oligodendroglial hyperplasia). These discoveries opened the door to studies linking somatic mutations to FCD. In this review, we discuss the biology of SLC35A2 somatic mutations in epilepsy in FCD and MOGHE, and insights into SLC35A2 epilepsy pathogenesis, describing progress to date and critical areas for investigation.

The clinico-pathological characterisation of focal cortical dysplasia type IIb genetically defined by MTOR mosaicism.

AIMS: Focal cortical dysplasia (FCD) is a major cause of drug-resistant paediatric epilepsy and is amenable to successful neurosurgical resection. FCD ILAE Type IIb is the most common FCD subtype, and brain somatic mutations affecting the mTOR pathway play a major pathogenic role. The aim of this study was to comprehensively describe the genotype-phenotype association of 20 patients with histopathologically confirmed FCDIIb using next generation sequencing (NGS) of paired blood-brain samples. METHODS: Clinical and neuropathological data were retrospectively reviewed from the hospital archive. The NGS panel included 11 mTOR-pathway-related genes with maximum coverage of 2000×. The detected variants were validated by digital droplet PCR. RESULTS: Pathogenic MTOR variants were identified in 10 patients (50%). Further comparison with MTOR-wildtype FCDIIb suggested a profound genotype-phenotype association characterised by (1) a non-temporal lobe lesion on MRI, (2) a larger lesion volume occupying grey and white matter (3.032 ± 1.859 cm3 vs 1.110 ± 0.856 cm3 , p = 0.014), (3) more balloon cells (50.20 ± 14.40 BC/mm2 vs 31.64 ± 30.56 BC/mm2 , p = 0.099) and dysmorphic neurons (48.72 ± 19.47DN/mm2 vs 15.28 ± 13.95DN/mm2 , p = 0.000) and (4) a positive correlation between VAF and the lesion volume (r = 0.802, p = 0.017). CONCLUSIONS: Our study identified frequent MTOR mutations in the cell-rich FCDIIb phenotype, clinically characterised by a non-temporal location and large lesion volume. Comprehensive genotype-phenotype associations will help us further explore and define the broad spectrum of FCD lesions to make more targeted therapies available in the realm of epileptology.