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.

暂无摘要。

Focal cortical dysplasia type I (FCD I) is the most common cause of pharmaco-resistant epilepsy with the poorest prognosis. To understand the epileptogenic mechanisms of FCD I, we obtained tissue resected from patients with FCD I epilepsy, and from tumor patients as control. Using whole-cell patch clamp in acute human brain slices, we investigated the cellular properties of fast-spiking interneurons (FSINs) and pyramidal neurons (PNs) within the ictal onset zone. In FCD I epilepsy, FSINs exhibited lower firing rates from slower repolarization and action potential broadening, while PNs had increased firing. Importantly, excitatory synaptic drive of FSINs increased progressively with the scale of cortical activation as a general property across species, but this relationship was inverted towards net inhibition in FCD I epilepsy. Further comparison with intracranial electroencephalography (iEEG) from the same patients revealed that the spatial extent of pathological high-frequency oscillations (pHFO) was associated with synaptic events at FSINs.

Brain malformations represent a heterogeneous group of abnormalities of neural morphogenesis, often associated with aberrations of neuronal connectivity and brain volume. Prenatal detection of brain malformations requires a clear understanding of embryology and developmental morphology through the various stages of gestation. This expert panel review is written with the central aim of providing an easy-to-understand roadmap to improve prenatal detection and characterization of structural malformations based on the current understanding of normal and aberrant brain development. The utility of each available neuroimaging modality including prenatal multiplanar neurosonography, anatomical magnetic resonance imaging (MRI), and advanced MRI techniques, as well as further insights from post-mortem imaging have been highlighted for every developmental stage.

Malformations of cortical development (MCD) are a group of developmental disorders characterized by abnormal cortical structures caused by genetic or harmful environmental factors. Many kinds of MCD are caused by genetic variation. MCD is the common cause of intellectual disability and intractable epilepsy. With rapid advances in imaging and sequencing technologies, the diagnostic rate of MCD has been increasing, and many potential genes causing MCD have been successively identified. However, the high genetic heterogeneity of MCD makes it challenging to understand the molecular pathogenesis of MCD and to identify effective targeted drugs. Thus, in this review, we outline important events of cortical development. Then we illustrate the progress of molecular genetic studies about MCD focusing on the PI3K/PTEN/AKT/mTOR pathway. Finally, we briefly discuss the diagnostic methods, disease models, and therapeutic strategies for MCD. The information will facilitate further research on MCD. Understanding the role of the PI3K/PTEN/AKT/mTOR pathway in MCD could lead to a novel strategy for treating MCD-related diseases.

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.

CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.