Mild Malformation Of Cortical Development Research Articles

Mouse models of Slc35a2 brain mosaicism reveal mechanisms of mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy.

Brain somatic variants in SLC35A2 were recently identified as a genetic marker for mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). The role of SLC35A2 in cortical development and the contributions of abnormal neurons and oligodendrocytes to seizure activity in MOGHE remain largely unexplored. Here, we generated a novel Slc35a2 floxed allele, which we used to develop two Slc35a2 conditional knockout mouse lines targeting (1) the Emx1 dorsal telencephalic lineage (excitatory neurons and glia) and (2) the Olig2 lineage (oligodendrocytes). We examined brain structure, behavior, and seizure activity. Knockout of Slc35a2 from the Emx1 lineage, which targets both cortical neurons and oligodendrocytes, resulted in early lethality and caused abnormal cortical development, increased oligodendroglial cell density, early onset seizures, and developmental delays akin to what is observed in patients with MOGHE. By tracing neuronal development with 5-Ethynyl-2'-deoxyuridine (EdU) birthdating experiments, we found that Slc35a2 deficiency disrupts corticogenesis by delaying radial migration of neurons from the subventricular zone. To discern the contributions of oligodendrocytes to these phenotypes, we knocked out Slc35a2 from the Olig2 lineage. This recapitulated the increased oligodendroglial cell density and resulted in abnormal electroencephalographic activity, but without a clear seizure phenotype, suggesting Slc35a2 deficiency in neurons is required for epileptogenesis. This study presents two novel Slc35a2 conditional knockout mouse models and characterizes the effects on brain development, behavior, and epileptogenesis. Together, these results demonstrate a direct causal role for SLC35A2 in MOGHE-like phenotypes, including a critical role in neuronal migration during brain development, and identify neurons as key contributors to SLC35A2-related epileptogenesis.

A deep-learning-based histopathology classifier for focal cortical dysplasia (FCD) unravels a complex scenario of comorbid FCD subtypes.

Recently, we developed a first artificial intelligence (AI)-based digital pathology classifier for focal cortical dysplasia (FCD) as defined by the ILAE classification. Herein, we tested the usefulness of the classifier in a retrospective histopathology workup scenario. Eighty-six new cases with histopathologically confirmed FCD ILAE type Ia (FCDIa), FCDIIa, FCDIIb, mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE), or mild malformations of cortical development were selected, 20 of which had confirmed gene mosaicism. The classifier always recognized the correct histopathology diagnosis in four or more 1000 × 1000-μm digital tiles in all cases. Furthermore, the final diagnosis overlapped with the largest batch of tiles assigned by the algorithm to one diagnostic entity in 80.2% of all cases. However, 86.2% of all cases revealed more than one diagnostic category. As an example, FCDIIb was identified in all of the 23 patients with histopathologically assigned FCDIIb, whereas the classifier correctly recognized FCDIIa tiles in 19 of these cases (83%), that is, dysmorphic neurons but no balloon cells. In contrast, the classifier misdiagnosed FCDIIb tiles in seven of 23 cases histopathologically assigned to FCDIIa (33%). This mandates a second look by the signing histopathologist to either confirm balloon cells or differentiate from reactive astrocytes. The algorithm also recognized coexisting architectural dysplasia, for example, vertically oriented microcolumns as in FCDIa, in 22% of cases classified as FCDII and in 62% of cases with MOGHE. Microscopic review confirmed microcolumns in the majority of tiles, suggesting that vertically oriented architectural abnormalities are more common than previously anticipated. An AI-based diagnostic classifier will become a helpful tool in our future histopathology laboratory, in particular when large anatomical resections from epilepsy surgery require extensive resources. We also provide an open access web application allowing the histopathologist to virtually review digital tiles obtained from epilepsy surgery to corroborate their final diagnosis.

Slc35a2 mosaic knockout impacts cortical development, dendritic arborisation, and neuronal firing

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an important cause of drug-resistant epilepsy. A significant subset of individuals diagnosed with MOGHE display somatic mosaicism for loss-of-function variants in SLC35A2, which encodes the UDP-galactose transporter. We developed a mouse model to investigate how disruption of this transporter leads to a malformation of cortical development. We used in utero electroporation and CRISPR/Cas9 to knockout Slc35a2 in a subset of layer 2/3 cortical neuronal progenitors in the developing brains of male and female fetal mice to model mosaic expression. Mosaic Slc35a2 knockout was verified through next-generation sequencing and immunohistochemistry of GFP-labelled transfected cells. Histology of brain tissue in mosaic Slc35a2 knockout mice revealed the presence of upper layer-derived cortical neurons in the white matter. Reconstruction of single filled neurons identified altered dendritic arborisation with Slc35a2 knockout neurons having increased complexity. Whole-cell electrophysiological recordings revealed that Slc35a2 knockout neurons display reduced action potential firing, increased afterhyperpolarisation duration and reduced burst-firing when compared with control neurons. Mosaic Slc35a2 knockout mice also exhibited significantly increased epileptiform spiking and increased locomotor activity. We successfully generated a mouse model of mosaic Slc35a2 deficiency, which recapitulates features of the human phenotype, including impaired neuronal migration. We show that knockout in layer 2/3 cortical neuron progenitors is sufficient to disrupt neuronal excitability, increase epileptiform activity and cause hyperactivity in mosaic mice. Our mouse model provides an opportunity to further investigate the disease mechanisms that contribute to MOGHE and facilitate the development of precision therapies.

Frontal Disconnection for Treating Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE) in the Frontal Lobe.

Malformation of cortical development is an important cause of drug-resistant epilepsy in young children. Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) has been added to the last focal cortical dysplasia (FCD) classification and commonly involves the frontal lobe. The semiology at the onset of epilepsy is dominated by non-lateralizing infantile spasm; the boundaries of the malformation are usually difficult to determine by magnetic resonance imaging (MRI) and positron emission tomography (PET), and electroencephalography (EEG) findings are often widespread. Therefore, the traditional concept and strategy of preoperative evaluation to determine the extent of the epileptogenic zone by comprehensive anatomo-electro-clinical methods are difficult to implement. Frontal disconnection is an effective surgical method for the treatment of epilepsy, but there are few related reports. A total of 8 children with histo-pathologically confirmed MOGHE were retrospectively studied. MOGHE was located in the frontal lobe in all patients, and frontal disconnection was performed. The periinsular approach was used in the disconnective procedures, divided into several surgical steps: the partial inferior frontal gyrus resection, the frontobasal and intrafrontal disconnection, and the anterior corpus callosotomy. One patient presented with a short-term postoperative speech disorder, while another patient exhibited transient postoperative limb weakness. No long-term postoperative complications were observed. At 2 years after surgery, 75% of patients were seizure-free, with cognitive improvement in half of them. This finding suggested that frontal disconnection is an effective and safe surgical procedure for the treatment of MOGHE instead of extensive resection in the frontal lobe.

Clinical characteristics and multimodal imaging can help diagnosing and treating mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy.

Mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE) is a recently described, histopathologically and molecularly defined (SLC35A2-mutated) type of cortical malformation. Although increasingly recognized, the diagnosis of MOGHE remains a challenge. We present the characteristics of the first six patients diagnosed in Bulgaria, with the aim to facilitate identification, proper presurgical evaluation, and surgical treatment approach in this disease. Revision of histopathological specimens of 202 patients operated on for drug-resistant focal epilepsy identified four cases with MOGHE. Another two were suggested, based on clinical characteristics and subsequently, were histologically confirmed. Sanger SLC35A2 sequencing on paraffin-embedded or fresh-frozen brain tissue was performed. Analysis of seizure types, neuropsychological profiles, electroencephalographic (EEG), imaging features and epilepsy surgery outcomes was done. Three out of the six cases (50%) harbored pathogenic SLC35A2 mutations. One patient had a heterozygous somatic variant with uncertain significance. Clinical characteristics included epilepsy onset in infancy (in 100% under 3 years of age), multiple seizure types, and moderate or severe intellectual/developmental delay. Epileptic spasms with hypsarrhythmia on EEG were the initial seizure type in five patients. The subsequent seizure types resembled those in Lennox-Gastaut syndrome. The majority of the patients (n = 4) presented prominent and persisting autistic features. Magnetic resonance imaging (MRI) showed multilobar (n = 6) and bilateral (n = 3) lesions, affecting the frontal lobes (n = 5; bilaterally in three) and characterized by increased signal on T2/fluid-attenuated inversion recovery (FLAIR). Voxel-based morphometric MRI post-processing and positron emission tomography helped determining the localization and extent of the lesions and presumed epileptogenic zones. After surgery, four patients (66.7%) were seizure-free ≥2 years. Interestingly, all seizure-free patients carried somatic SLC35A2-alterations. Epileptic spasms, early prominent neuropsychological disturbances, MRI-T2/FLAIR hyperintense lesions with cortico-subcortical blurring, frequently multilobar and especially frontal, can preoperatively help to suspect MOGHE. Epilepsy surgery is still the only successful treatment option in MOGHE.

Updates from the International League Against Epilepsy Classification of Epilepsy (2017) and Focal Cortical Dysplasias (2022): Imaging Phenotype and Genetic Characterization.

The International League Against Epilepsy (ILAE) is an organization of 120 national chapters providing the most widely accepted and updated guidelines on epilepsy. In 2022, the ILAE Task Force revised the prior (2011) classification of focal cortical dysplasias to incorporate and update clinicopathologic and genetic information, with the aim to provide an objective classification scheme. New molecular-genetic information has led to the concept of "integrated diagnosis" on the same lines as brain tumors, with a multilayered diagnostic model providing a phenotype-genotype integration. Major changes in the new update were made to type II focal cortical dysplasias, apart from identification of new entities, such as mild malformations of cortical development and cortical malformation with oligodendroglial hyperplasia. No major changes were made to type I and III focal cortical dysplasias, given the lack of significant new genetic information. This review provides the latest update on changes to the classification of focal cortical dysplasias with discussion about the new entities. The ILAE in 2017 updated the classification of seizure and epilepsy with 3 levels of diagnosis, including seizure type, epilepsy type, and epilepsy syndrome, which are also briefly discussed here.

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

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. 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-testswere 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. 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. This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting invivo pathological changes. © 2024 International League Against Epilepsy.

Neuropathology and epilepsy surgery - 2024 update.

Neuropathology-based studies in neurosurgically resected brain tissue obtained from carefully examined patients with focal epilepsies remain a treasure box for excellent insights into human neuroscience, including avenues to better understand the neurobiology of human brain organization and neuronal hyperexcitability at the cellular level including glio-neuronal interaction. It also allows to translate results from animal models in order to develop personalized treatment strategies in the near future. A nice example of this is the discovery of a new disease entity in 2017, termed mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy or MOGHE, in the frontal lobe of young children with intractable seizures. In 2021, a brain somatic missense mutation of the galactose transporter SLC35A2 leading to altered glycosylation of lipoproteins in the Golgi apparatus was detected in 50 % of MOGHE samples. In 2023, the first clinical trial evaluated galactose supplementation in patients with histopathologically confirmed MOGHE carrying brain somatic SLC35A2 mutations that were not seizure free after surgery. The promising results of this pilot trial are an example of personalized medicine in the arena of epileptology. Besides this, neuropathological studies of epilepsy samples have revealed many other fascinating results for the main disease categories in focal epilepsies, such as the first deep-learning based classifier for Focal Cortical Dysplasia, or the genomic landscape of cortical malformations showing new candidate genes such as PTPN11, which is associated with ganglioglioma and adverse clinical outcome. This update will also ask why common pathogenic variants accumulate in certain brain regions, e.g., MTOR in the frontal lobe, and BRAF in the temporal lobe. Finally, I will highlight the ongoing discussion addressing commonalities between temporal lobe epilepsy and Alzheimer's disease, the impact of adult neurogenesis and gliogenesis for the initiation and progression of temporal lobe seizures in the human brain as well as the immunopathogenesis of glutamic acid decarboxylase antibody associated temporal lobe epilepsy as a meaningful disease entity. This review will update the reader on some of these fascinating publications from 2022 and 2023 which were selected carefully, yet subjectively, by the author.

Bilateral and asymmetrical localization of language function identified by the superselective infusion of propofol in an epilepsy patient with a mild malformation of cortical development: illustrative case.

Atypical localization of language function can result in unexpected postsurgical deficits after cortical resection, but it is difficult to predict the risk in the presurgical evaluation. The authors experienced a rare case of the bilateral and independent existence of different components of language function identified by segmented evaluation of anatomical anterior and posterior language areas using the superselective infusion of propofol. A 32-year-old right-handed female presented with drug-resistant epilepsy. Comprehensive epilepsy evaluation suggested that the epileptic foci involved the whole left frontal lobe but provided less evidence of structural abnormality. To estimate the extent of functional deterioration likely to be caused by an extended left frontal lobectomy, the authors evaluated segmented cortical function in the ipsi- and contralateral hemispheres by the superselective infusion of propofol into the branches of the intracranial artery. The results revealed bilateral and asymmetrical localization of language function because the patient presented with different components of aphasia in each hemisphere. Based on the authors' assessment of her functional tolerance, an extended left frontal lobectomy was performed and resulted in neurological deficits within the anticipated range. An accurate understanding of the correlations between vascular and functional anatomy and the highly specific evaluation of language function provides more advanced presurgical assessment, allowing more tailored planning of cortical resection.

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.

D-galactose Supplementation for the Treatment of Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE): A Pilot Trial of Precision Medicine After Epilepsy Surgery.

MOGHE is defined as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Approximately half of the patients with histopathologically confirmed MOGHE carry a brain somatic variant in the SLC35A2 gene encoding a UDP-galactose transporter. Previous research showed that D-galactose supplementation results in clinical improvement in patients with a congenital disorder of glycosylation due to germline variants in SLC35A2. We aimed to evaluate the effects of D-galactose supplementation in patients with histopathologically confirmed MOGHE, with uncontrolled seizures or cognitive impairment and epileptiform activity at the EEG after epilepsy surgery (NCT04833322). Patients were orally supplemented with D-galactose for 6months in doses up to 1.5g/kg/day and monitored for seizure frequency including 24-h video-EEG recording, cognition and behavioral scores, i.e., WISC, BRIEF-2, SNAP-IV, and SCQ, and quality of life measures, before and 6months after treatment. Global response was defined by > 50% improvement of seizure frequency and/or cognition and behavior (clinical global impression of "much improved" or better). Twelve patients (aged 5-28years) were included from three different centers. Neurosurgical tissue samples were available in all patients and revealed a brain somatic variant in SLC35A2 in six patients (non-present in the blood). After 6months of supplementation, D-galactose was well tolerated with just two patients presenting abdominal discomfort, solved after dose spacing or reduction. There was a 50% reduction or higher of seizure frequency in 3/6 patients, with an improvement at EEG in 2/5 patients. One patient became seizure-free. An improvement of cognitive/behavioral features encompassing impulsivity (mean SNAP-IV - 3.19 [- 0.84; - 5.6]), social communication (mean SCQ - 2.08 [- 0.63; - 4.90]), and executive function (BRIEF-2 inhibit - 5.2 [- 1.23; - 9.2]) was observed. Global responder rate was 9/12 (6/6 in SLC35A2-positive). Our results suggest that supplementation with D-galactose in patients with MOGHE is safe and well tolerated and, although the efficacy data warrant larger studies, it might build a rationale for precision medicine after epilepsy surgery.

Clinical characteristics and surgical outcomes in children with mild malformation of cortical development and oligodendroglial hyperplasia in epilepsy.

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a new and rare histopathological entity of cortical developmental malformations. The clinical characteristics of MOGHE remain challenging. Children with histologically confirmed MOGHE were retrospectively studied. The clinical findings, electroclinical and imaging features, and postoperative outcomes were analyzed, and previously published studies were reviewed up to June 2022. Thirty-seven children were included in our cohort. Clinical characteristics included early onset in infancy (94.6% before 3 years), multiple seizure types, and moderate or severe delay. Epileptic spasm is the most common seizure type and initial manifestation. The lesions were mainly multilobar (59.5% multiple lobes and 8.1% hemispheres), and predominance in the frontal lobe was observed. The interictal EEG pattern was circumscribed or widespread. The prominent MRI characteristics were cortical thickening, cortical/subcortical hyperintense T2/FLAIR signal, and blurring at the GM and WM transition. Among the 21 children followed up for more than 1 year after surgery, 76.2% were seizure-free. Preoperative interictal circumscribed discharges and larger resections were significantly associated with a good postoperative outcome. The clinical features of 113 patients in the reviewed studies were similar to those we reported, but the lesions were mainly unilobar (73.5%) and Engel I was achieved in only 54.2% after surgery. Distinct clinical characteristics in MOGHE, especially age at onset, epileptic spasm, and age-related MRI characteristics, can help in early diagnosis. Preoperative interictal discharge and surgical strategy may be predictors of postoperative outcomes.

Pathomorphological Diagnostic Criteria for Focal Cortical Dysplasias and Other Common Epileptogenic Lesions-Review of the Literature.

Focal cortical dysplasia (FCD) represents a heterogeneous group of morphological changes in the brain tissue that can predispose the development of pharmacoresistant epilepsy (recurring, unprovoked seizures which cannot be managed with medications). This group of neurological disorders affects not only the cerebral cortex but also the subjacent white matter. This work reviews the literature describing the morphological substrate of pharmacoresistant epilepsy. All illustrations presented in this study are obtained from brain biopsies from refractory epilepsy patients investigated by the authors. Regarding classification, there are three main FCD types, all of which involve cortical dyslamination. The 2022 revision of the International League Against Epilepsy (ILAE) FCD classification includes new histologically defined pathological entities: mild malformation of cortical development (mMCD), mild malformation of cortical development with oligodendroglial hyperplasia in frontal lobe epilepsy (MOGHE), and "no FCD on histopathology". Although the pathomorphological characteristics of the various forms of focal cortical dysplasias are well known, their aetiologic and pathogenetic features remain elusive. The identification of genetic variants in FCD opens an avenue for novel treatment strategies, which are of particular utility in cases where total resection of the epileptogenic area is impossible.

A deep learning-based histopathology classifier for Focal Cortical Dysplasia

A light microscopy-based histopathology diagnosis of human brain specimens obtained from epilepsy surgery remains the gold standard to confirm the underlying cause of a patient’s focal epilepsy and further inform postsurgical patient management. The differential diagnosis of neocortical specimens in the realm of epilepsy surgery remains, however, challenging. Herein, we developed an open access, deep learning-based classifier to histopathologically assess whole slide microscopy images (WSI) and to automatically recognize various subtypes of Focal Cortical Dysplasia (FCD), according to the ILAE consensus classification update of 2022. We trained a convolutional neuronal network (CNN) with fully digitalized WSI of hematoxylin–eosin stainings obtained from 125 patients covering the spectrum of mild malformation of cortical development (mMCD), mMCD with oligodendroglial hyperplasia in epilepsy (MOGHE), FCD ILAE Type 1a, 2a and 2b using 414 formalin-fixed and paraffin-embedded archival tissue blocks. An additional series of 198 postmortem tissue blocks from 59 patients without neurological disorders served as control to train the CNN for homotypic frontal, temporal and occipital areas and heterotypic Brodmann areas 4 and 17, entorhinal cortex and dentate gyrus. Special stains and immunohistochemical reactions were used to comprehensively annotate the region of interest. We then programmed a novel tile extraction pipeline and graphical dashboard to visualize all areas on the WSI recognized by the CNN. Our deep learning-based classifier is able to compute 1000 × 1000 µm large tiles and recognizes 25 anatomical regions and FCD categories with an accuracy of 98.8% (F1 score = 0.82). Microscopic review of regions predicted by the network confirmed these results. This deep learning-based classifier will be made available as online web application to support the differential histopathology diagnosis in neocortical human brain specimens obtained from epilepsy surgery. It will also serve as blueprint to build a digital histopathology slide suite addressing all major brain diseases encountered in patients with surgically amenable focal epilepsy.

Epilepsy with SLC35A2 Brain Somatic Mutations in Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE)

Purpose: This study presents the characteristics of patients with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) with SLC35A2 somatic variants in the brain who underwent epilepsy surgery and showed clinical improvement in seizures. Methods: We collected 10 patients with SLC35A2 somatic mutations in the brain who underwent surgery to treat drug-resistant epilepsy at Severance Children’s Hospital from 2014 to 2019 and retrospectively reviewed their genetic profiles, neuropathologic results, clinical features, pre-operative evaluations, and post-operative outcomes.Results: Six of the 10 patients with SCL35A2 somatic mutations in the brain had Lennox Gastaut syndrome (LGS) evolving from infantile spasms (IS), three had LGS, and one had IS. The median value of variant allele frequencies (VAFs) was 5.7% (1.7% to 5.8%; range, 1.4% to 22.9%). Nonsense mutations were the most common (50%), followed by missense mutations (40%) and a splicing site mutation (10%). Eight patients (80%) had good post-operative outcomes, with freedom from disabling seizures in five (Engel class I) and rare disabling seizures in three (Engel class II). Four of the eight patients who could be assessed for social quotient (SQ) after surgery showed SQ improvements by 12.2±6.4. Although all patients were finally diagnosed with MOGHE, seven (70%) were initially diagnosed with gliosis, two with mild malformation of cortical development, and one with no abnormality.Conclusion: All patients with SCL35A2 brain somatic mutations, even with low VAFs, had refractory epilepsy such as LGS or IS, and were finally diagnosed with MOGHE. This report is the first in Korea to our knowledge.

The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission.

Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico‐pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular‐genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro‐clinical‐imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico‐pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and “no definite FCD on histopathology” as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi‐layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options.

Neuropathology findings in KCNQ2 neonatal epileptic encephalopathy.

PurposeKCNQ2-epileptic encephalopathy (EE) is a neonatal epilepsy syndrome characterized by a typical clinical presentation and EEG recording, but without any brain or cortical abnormal development on MRI. Most of the patients have a severe developmental impairment. The epileptogenic mechanisms are thought to be the result of the changes of the M-current density causing a change of brain excitability. Although recent studies allow us to better understand the physiopathology of KCNQ2-EE, the neuropathology of this ion channel dysfunction has only been previously described in a single case report. MethodsWe report the neuropathology study of a case of KCNQ2-EE with a typical electro-phenotype due to a de novo heterozygous single nucleotide pathogenic variant in the exon 5 of the KCNQ2 gene (NM_172107.2:c.802C>T; p.Leu268Phe). ResultsAt the macroscopic level, the brain had a normal structure with a normal neocortical gyral pattern. At the histological level, the cortex had a usual six-layer lamination in all lobes but blurred gray-white matter boundaries due to excessive heterotopic neurons in deep white matter were observed. This diffuse mild malformation of cortical development is suggestive of a neuronal migration disorder. ConclusionIn recent years, our understanding of the role of ion channel dysfunctions in early brain development has expanded from the occurrence of EE to brain malformation. Through this rare neuropathological report, we emphasize the role of KCNQ2 channels in the process of cortical development. As for other genetic neonatal onset epilepsies, more reports are needed to further delineate the range of neuropathological abnormalities for KCNQ2-EE.

Focal cortical dysplasia: Updates.

Focal cortical dysplasias (FCDs) represent the third most frequent cause of drug-resistant focal epilepsy in adults (after hippocampal sclerosis and tumours) submitted to surgery, and the most common in the pediatric age group. The International League Against Epilepsy (ILAE) classification of focal cortical dysplasia is still a reference and consists of a three-tiered system: FCD type I refers to isolated abnormalities in cortical layering; FCD type II refers to cases with abnormalities in cortical architecture and dysmorphic neurons with or without balloon cells; and FCD type III refers to abnormalities in cortical layering associated with other lesions. Recent studies have demonstrated that somatic mutations occurring post-zygotically during embryonal development and leading to mosaicism, underlie most brain malformations. The molecular pathogenesis of FCD type II is associated with activation of the mTOR pathway. Pathogenic variants in this pathway are recognized in up to 63% of cases and may occur both through single activating variants in activators of the mTOR signaling pathway or double-hit inactivating variants in repressors of the signaling pathway. The newly described mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy, has been found to show recurrent pathogenic variants in SLC35A2 with mosaicism. The present review describes the lesions of FCD and discusses the molecular pathogenesis and proposal for a revised classification.

Neuropathology and epilepsy surgery: 2022 update.

The impact of a precise histopathology diagnosis and molecular workup for surgical patient management remains a controversial issue in epileptology with a lack of diagnostic agreement as root cause. Very recent advances in genotype-phenotype characterization of epilepsy-associated developmental brain lesions, including the first diagnostically useful DNA methylation studies, opened new avenues and will help to finally resolve these issues. A series of most recent articles were decisively selected by the author to exemplify the areas of improvement in neuropathology and epilepsy surgery. These topics include the progress in genotype-phenotype association studies of Focal Cortical Dysplasia (FCD) leading to the discovery of new molecularly defined entities, i.e. mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE), SLC35A2 altered. These studies also triggered the first update of the international FCD consensus classification scheme from 2011, which will hopefully support diagnostic agreement in clinical practice and research. The dilemma of new tumor entities proposed by the 5th edition of the WHO classification primarily associated with early seizure onset yet not well introduced to the epileptology community will also be discussed in the light of emerging experimental evidence when transfecting the developing murine brain with the single most important genetic alteration for both carcino- and epileptogenesis, i.e. BRAF V600E.

A case of mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE)

Recently, in the scientist community of specialists dealing with structural epilepsy, it has been noticed an increasing interest in a special form of cortical development disorder not to be included in the ILAE Classification of the epilepsies the 2017 revision. It is so-called mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE). There are a number of publications devoted to the neuroimaging features of MOGHE, which are possible to distinguish from other epileptogenic substrates in comparisons with clinical/anamnestic data and dynamic observation. Our paper describes the case of a patient under 6 years suffering from pharmacoresistant epilepsy with histologically confirmed MOGHE, and having undergone the procedure of epileptic surgery. MRI showed an increased intensity of the T2/FLAIR signal from the white matter in combination with signs of laminar hyperintensivity, regional sulcation disturbance, smoothness of gray-white matter demarcation in the right frontal lobe. A signal intensification from the white matter with the formation similarity of the «transmantl» sign and further pronounced smoothness of the gray-white matter demarcation was observed on dynamic MRI. These changes were estimated as focal cortical dysplasia. Pre-surgical examination revealed a correlation of epileptiform activity with MRI changes. The subtotal resection of the right frontal lobe and the morphological conclusion established the presence of MOGHE was performed.