In childhood drug-resistant focal epilepsy, the identification of a magnetic resonance imaging lesion significantly affects the management and prognosis, although it is often challenging. Herein we report the preliminary results of a modified MR sequence, in which both magnetization transfer and chemical shift selective preparation pulses are added to a 3D fast spin echo T1-weighted sequence to recognize focal cortical dysplasia. The scan time is short, and the images have expected uniform suppression of the background normal gray and white matter. We report four children with focal epilepsy, in whom the focal cortical and subcortical lesions are superiorly conspicuous on the aforementioned MR sequence compared to the high-resolution fluid-attenuated inversion recovery images obtained with typical epilepsy MR protocols.

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.
CONCLUSIONS: The radiomics nomogram generated by logistic regression model-based multiparametric MRI represents an important advancement in FCD diagnosis and treatment.

UNASSIGNED: Focal cortical dysplasia (FCD) is a significant cause of drug-resistant epilepsy, often necessitating surgical intervention. Type IIb FCD poses challenges due to its strong association with drug-resistant seizures. Effective management involves advanced imaging, intraoperative neurophysiological monitoring, and precise surgical techniques. This case study illustrates these strategies in an 11-year-old female with drug-resistant epilepsy attributed to Type IIb FCD.
UNASSIGNED: The patient, an 11-year-old female, had drug-resistant seizures despite various anticonvulsant treatments. Preoperative 3 Tesla (3T) MRI revealed an ill-defined lesion in the right frontal operculum. The surgical team used neuro-navigation for intraoperative guidance and electrocorticography for lesionectomy. Pathology confirmed Type IIb FCD with rare concentric calcifications.
UNASSIGNED: Drug-resistant seizures in FCD often require surgery when medications fail. This case highlights the importance of comprehensive preoperative evaluations and advanced imaging, such as 3T MRI, to accurately identify lesions. Intraoperative neurophysiological monitoring, including electrocorticography, ensures precise resection of the epileptogenic zone. The unusual finding of concentric calcifications in Type IIb FCD is noteworthy, suggesting the need for further research to understand their impact on the disease.
UNASSIGNED: Microsurgical lesionectomy is crucial for managing drug-resistant seizures in Type IIb FCD. Combining advanced imaging with intraoperative monitoring improves surgical precision and outcomes. The rare pathological finding of calcifications highlights the diversity of FCD manifestations, warranting further study. These techniques can significantly enhance seizure control and quality of life in patients with drug-resistant epilepsy.

Introduction: The NPRL3 gene is a critical component of the GATOR1 complex, which negatively regulates the mTORC1 pathway, essential for neurogenesis and brain development. Located on chromosome 16p13.3, NPRL3 is situated near the α-globin gene cluster. Haploinsufficiency of NPRL3, either by deletion or a pathogenic variant, is associated with a variable phenotype of focal epilepsy, with or without malformations of cortical development, with known decreased penetrance. Case Description: This work details the diagnostic odyssey of a neurotypical 10-year-old boy who presented at age 2 with unusual nocturnal episodes and a history of microcytic anemia, as well as a review of the existing literature on NPRL3-related epilepsy, with an emphasis on individuals with deletions who also present with α-thalassemia trait. The proband\'s episodes were mistaken for gastroesophageal reflux disease for several years. He had molecular testing for his α-thalassemia trait and was noted to carry a deletion encompassing the regulatory region of the α-thalassemia gene cluster. Following the onset of overt focal motor seizures, genetic testing revealed a heterozygous loss of NPRL3, within a 106 kb microdeletion on chromosome 16p13.3, inherited from his mother. This deletion encompassed the entire NPRL3 gene, which overlaps the regulatory region of the α-globin gene cluster, giving him the dual diagnosis of NPRL3-related epilepsy and α-thalassemia trait. Brain imaging postprocessing showed left hippocampal sclerosis and mid-posterior para-hippocampal focal cortical dysplasia, leading to the consideration of epilepsy surgery. Conclusions: This case underscores the necessity of early and comprehensive genetic assessments in children with epilepsy accompanied by systemic features, even in the absence of a family history of epilepsy or a developmental delay. Recognizing phenotypic overlaps is crucial to avoid diagnostic delays. Our findings also highlight the impact of disruptions in regulatory regions in genetic disorders: any individual with full gene deletion of NPRL3 would have, at a minimum, α-thalassemia trait, due to the presence of the major regulatory element of α-globin genes overlapping the gene\'s introns.

Somatic mosaicism in a fraction of brain cells causes neurodevelopmental disorders, including childhood intractable epilepsy. However, the threshold for somatic mosaicism leading to brain dysfunction is unknown. In this study, we induced various mosaic burdens in focal cortical dysplasia type II (FCD II) mice, featuring mTOR somatic mosaicism and spontaneous behavioral seizures. The mosaic burdens ranged from approximately 1,000 to 40,000 neurons expressing the mTOR mutant in the somatosensory (SSC) or medial prefrontal (PFC) cortex. Surprisingly, approximately 8,000 to 9,000 neurons expressing the MTOR mutant, which are extrapolated to constitute 0.08-0.09% of total cells or roughly 0.04% of variant allele frequency (VAF) in the mouse hemicortex, were sufficient to trigger epileptic seizures. The mutational burden was correlated with seizure frequency and onset, with a higher tendency for electrographic inter-ictal spikes and beta- and gamma-frequency oscillations in FCD II mice exceeding the threshold. Moreover, mutation-negative FCD II patients in deep sequencing of their bulky brain tissues revealed somatic mosaicism of the mTOR pathway genes as low as 0.07% in resected brain tissues through ultra-deep targeted sequencing (up to 20 million reads). Thus, our study suggests that extremely low levels of somatic mosaicism can contribute to brain dysfunction.

OBJECTIVE: To evaluate the diagnostic capabilities of modifying the standard MRI protocol as part of an interdisciplinary presurgical examination of patients with epileptogenic substrates of unknown etiology.
METHODS: The results of dynamic MRI of 8 patients with a referral diagnosis of focal cortical dysplasia (FCD) were analyzed. In 7 patients, epilepsy was the reason for a standard MRI of the brain; in another patient with myasthenia, MRI was performed as part of a comprehensive examination. All patients, in addition to standard MRI, underwent a modification of the real-time scanning protocol to include contrast, tractography (DTI), and perfusion techniques (ASL/DSC). In 1 case, with questionable results, the results of a modification of the standard MRI protocol, high-resolution MRI (HR MRI) and hybrid positron emission CT with 11C-methionine (PET/CT with 11C-MET) were combined.
RESULTS: Seven patients underwent epileptic surgery and 1 patient was operated on for a tumor. In 4 out of 8 patients, based on the results of a modification of the standard MRI protocol, radiological signs of a neoplastic process were identified, which suggested a low-grade tumor. One of them needed PET/CT to confirm the assumption. The results of pathomorphological examination correlated with the direct diagnosis for surgical treatment. One of the 4 patients was suspected to have dysembryoplastic neuroepithelial tumor (DNET) based on the results of the protocol modification, which was also confirmed by pathological examination. In another 4 patients in whom it was possible to narrow the differential between FCD type II and DNET based on the results of the modification, FCD IIb was pathomorphologically verified.
CONCLUSIONS: The proposed modification of the standard MRI protocol can significantly facilitate the differential diagnosis between the neoplastic and dysplastic origin of an epileptogenic substrate of unknown etiology, which in turn affects the patient\'s management tactics.
UNASSIGNED: Оценить диагностические возможности модификации стандартного протокола МРТ в рамках междисциплинарного прехирургического обследования пациентов с эпилептогенными субстратами неясной этиологии.
UNASSIGNED: Проанализированы результаты динамических МРТ 8 пациентов с предположительным диагнозом «фокальная кортикальная дисплазия» (ФКД). У 7 пациентов поводом для проведения стандартной МРТ головного мозга явилась эпилепсия, у 1 пациента с миастенией МРТ проведена в ходе комплексного обследования. Всем пациентам дополнительно к стандартной МРТ выполнен модифицированный протокол сканирования в режиме реального времени, включая контрастирование, трактографию (DTI), оценку перфузии (ASL/DSC). При сомнительных результатах у 1 больного проведено совмещение результатов модифицированного протокола стандартной МРТ, МРТ высокого разрешения (МРТ ВР) и гибридной позитронно-эмиссионной КТ с 11C-метионином (ПЭТ/КТ с 11С-МЕТ).
UNASSIGNED: Процедуру эпилептической хирургии прошли 7 пациентов, 1 — прооперирован по поводу опухоли. У 4 из 8 пациентов по результатам модифицированного протокола стандартной МРТ были выявлены радиологические признаки неопластического процесса, позволившие предположить опухоль низкой степени злокачественности. Одному пациенту понадобилось проведение ПЭТ/КТ для подтверждения диагноза. Результаты патоморфологического исследования коррелировали с направляющим диагнозом на хирургическое лечение. У 1 из 4 пациентов была предположена дизэмбриопластическая нейроэпителиальная опухоль (ДНЭО), основываясь на результатах модифицированного протокола, что было подтверждено при патоморфологическом исследовании. Еще у 4 пациентов, у которых удалось сузить дифференциально диагностический ряд между ФКД II типа и ДНЭО, по результатам модифицированной МРТ патоморфологически верифицирована ФКД IIb.
UNASSIGNED: Предложенная модификация стандартного протокола МРТ может существенно облегчить проведение дифференциальной диагностики между неопластическим и диспластическим происхождением эпилептогенного субстрата неясной этиологии, что влияет на тактику ведения пациента.

OBJECTIVE: Assessing the diagnostic significance of MR morphometry in determining the localization of focal cortical dysplasias (FCD).
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).
CONCLUSIONS: MR morphometry is an additional non-invasive method for assessing the localization of FCD.
UNASSIGNED: Оценка диагностической значимости магнитно-резонансной (МР) морфометрии в определении локализации фокальных кортикальных дисплазий (ФКД).
UNASSIGNED: В исследование включены 13 детей, оперированных по поводу фармакорезистентной структурной эпилепсии, обусловленной ФКД II типа, с исходом в стойкую ремиссию приступов (Engel class IA, медиана катамнеза 56 мес). Проведен сравнительный анализ результатов экспертной независимой оценки трех рентгенологов нативных МР-данных по протоколу HARNESS с данными МР-морфометрии в точности локализации ФКД по двум показателям: локальному утолщению коры и размытости перехода серого и белого вещества.
UNASSIGNED: Частота выявления зон с ФКД была выше после проведения МР-морфометрии по сравнению с визуальным анализом нативных МР-данных по протоколу HARNESS. МР-морфометрия также позволяет чаще выявлять зоны размытости перехода серого вещества в белое — признак, часто пропускаемый врачами-рентгенологами (p<0,05).
UNASSIGNED: Метод МР-морфометрии является дополнительным неинвазивным методом оценки локализации ФКД.

OBJECTIVE: To elucidate the patient\'s journey to epilepsy surgery and identify the risk factors contributing to surgical delay in pediatric patients with drug-resistant epilepsy (DRE) due to focal cortical dysplasia (FCD).
METHODS: A retrospective review was conducted of 93 pediatric patients who underwent curative epilepsy surgery for FCD between January 2012 and March 2023 at a tertiary epilepsy center. The Odyssey plot demonstrated the treatment process before epilepsy surgery, including key milestones of epilepsy onset, first hospital visit, epilepsy diagnosis, MRI diagnosis, DRE diagnosis, and surgery. The primary outcome was surgical delay; the duration from DRE to surgery. Multivariate linear regression models were used to examine the association between surgical delay and clinical, investigative, and treatment characteristics.
RESULTS: The median age at seizure onset was 1.3 years (interquartile range [IQR] 0.14-3.1), and at the time of surgery, it was 6 years (range 1-11). Notably, 46% experienced surgical delays exceeding two years. The Odyssey plot visually highlighted that surgical delay comprised a significant portion of the patient journey. Although most patients underwent MRI before referral, MRI abnormalities were identified before referral only in 39% of the prolonged group, compared to 70% of the non-prolonged group. Multivariate analyses showed that delayed notification of MRI abnormalities, longer duration from epilepsy onset to DRE, older age at onset, number of antiseizure medications tried, and moderate to severe intellectual disability were significantly associated with prolonged surgical delay.
CONCLUSIONS: Pediatric DRE patients with FCD experienced a long journey until surgery. Early and accurate identification of MRI abnormalities is important to minimize surgical delays.

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.

UNASSIGNED: Infantile epileptic spasms syndrome (IESS) is a common developmental and epileptic encephalopathy with poor long-term outcomes. A substantial proportion of patients with IESS have a potentially surgically remediable etiology. Despite this, epilepsy surgery is underutilized in this patient group. Some surgically remediable etiologies, such as focal cortical dysplasia and malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE), are under-diagnosed in infants and young children. Even when a surgically remediable etiology is recognised, for example, tuberous sclerosis or focal encephalomalacia, epilepsy surgery may be delayed or not considered due to diffuse EEG changes, unclear surgical boundaries, or concerns about operating in this age group.
UNASSIGNED: In this review, the authors discuss the common surgically remediable etiologies of IESS, their clinical and EEG features, and the imaging techniques that can aid in their diagnosis. They then describe the surgical approaches used in this patient group, and the beneficial impact that early epilepsy surgery can have on developing brain networks.
UNASSIGNED: Epilepsy surgery remains underutilized even when a potentially surgically remediable cause is recognized. Overcoming the barriers that result in under-recognition of surgical candidates and underutilization of epilepsy surgery in IESS will improve long-term seizure and developmental outcomes.