[Malformations of cortical development: what's new?] / Malformaciones del desarrollo cortical: ¿qué hay de nuevo?

Malformations of cortical development (MCDs) are structural abnormalities that disrupt the normal process of cortical development in utero. MCDs include microcephaly with simplified gyral pattern/microlyssencephaly, hemimegalencephaly, focal cortical dysplasia, lissencephaly, heterotopia, polymicrogyria, and schizencephaly. The debut of MCD can be with pharmacoresistant epilepsy, developmental delay, neurologic deficits, or cognitive impairment. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and etiology. Although the definitive diagnosis of MCD depends on histopathology, neuroimages have an important role in this process. Furthermore, knowing the disturbance of the molecular pathway involved is important. Increased understanding of the molecular biology and recent advances in genetic testing have caused rapid growth in the knowledge of the genetic causes of MCDs, allowing for information on prognosis, recurrence risk, and prediction of treatment outcomes.

Las malformaciones del desarrollo cortical (MDC) son alteraciones estructurales que interrumpen el proceso normal de desarrollo cortical in utero. Se incluyen la microcefalia, con patrón giral simplificado/microlisencefalia, hemimegalencefalia, displasia cortical focal, lisencefalia, heterotopía, polimicrogiria y esquizencefalia. Se presentan con epilepsia farmacorresistente, retraso del desarrollo, déficit neurológico o compromiso cognitivo. El diagnóstico es complejo debido a la amplia variedad en su presentación y etiología. Aunque el diagnóstico definitivo es por anatomía patológica, las neuroimágenes cumplen un rol fundamental. Además, es sumamente importante conocer la alteración en el mecanismo molecular involucrado en la fisiopatogenia de la malformación. El creciente desarrollo de la biología molecular y de los estudios genéticos han mejorado el conocimiento de las causas genéticas de las MDC. Esto permitirá mejorar el pronóstico, consejo genético y probablemente las opciones terapéuticas.

Focally Enlarged Perivascular Spaces in Pediatric and Adolescent Patients with Polymicrogyria-an MRI Study.

PURPOSE: Polymicrogyria (PMG) is a cortical malformation frequently associated with epilepsy. Our aim was to investigate the frequency and conspicuity of enlarged perivascular spaces (EPVS) underneath dysplastic cortex as a potentially underrecognized feature of PMG in pediatric and adolescent patients undergoing clinical magnetic resonance imaging (MRI). METHODS: We analyzed data from 28 pediatric and adolescent patients with PMG and a matched control group, ranging in age from 2 days to 21 years, who underwent MRI at 1.5T or 3T. T2-weighted MR images were examined for the presence of EPVS underneath the dysplastic cortex. The quantity of EPVS was graded from 0 to 4 (0: none, 1: < 10, 2: 11-20, 3: 21-40, 4: > 40 EPVS). We then compared the presence and quantity of EPVS to the matched controls in terms of total EPVS scores, and EPVS scores underneath the dysplastsic cortex depending on the age groups, the localization of PMG, and the MRI field strength. RESULTS: In 23/28 (82%) PMG patients, EPVS spatially related to the dysplastic cortex were identified. EPVS scores were significantly higher in PMG patients compared to controls, independent from age or PMG location. No significant differences were observed in EPVS scores in patients examined at 1.5T compared to those examined at 3T. CONCLUSION: EPVS underneath the dysplastic cortex were identified in 82% of patients. EPVS may serve as an important clue for PMG and a marker for cortical malformation.

The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development.

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.

Prenatal assessment of brain malformations on neuroimaging: an expert panel review.

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.

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.

A spectrum of AKT3 activating mutations cause focal malformations of cortical development (FMCDs) in cortical organoids.

Focal malformations of cortical development (FMCDs) are brain disorders mainly caused by hyperactive mTOR signaling due to both inactivating and activating mutations of genes in the PI3K-AKT-mTOR pathway. Among them, mosaic and somatic activating mutations of the mTOR pathway activators are more frequently linked to severe form of FMCDs. A human stem cell-based FMCDs model to study these activating mutations is still lacking. Herein, we genetically engineer human embryonic stem cell lines carrying these activating mutations to generate cortical organoids. Mosaic and somatic expression of AKT3 activating mutations in cortical organoids mimicking the disease presentation with overproliferation and the formation of dysmorphic neurons. In parallel comparison of various AKT3 activating mutations reveals that stronger mutation is associated with more severe neuronal migratory and overgrowth defects. Together, we have established a feasible human stem cell-based model for FMCDs that could help to better understand pathogenic mechanism and develop novel therapeutic strategy.

CT Scan Data Analysis in Malformations of Cortical Development.

Malformations of cortical development (MCDs) are a diverse group of disorders that result from abnormal neuronal migration, proliferation, and differentiation during brain development. Head computed tomography (CT) has limited use in the diagnosis of MCDs and should be reserved for selected cases with specific indications or when magnetic resonance imaging is not available or contraindicated. CT can detect brain calcifications associated with MCDs, thus helping in the differential diagnosis between acquired and genetic MCDs or in the identification of different genetic patterns. Moreover, CT can provide high-resolution images of the skull and bones, thus identifying associated malformations, such as craniosynostosis, inner and middle ear malformations, and vertebral anomalies. In this chapter, we review the CT scan technique, data analysis, and indications in the investigation of MCDs.

MRI Data Analysis in Malformations of Cortical Development.

Brain magnetic resonance imaging (MRI) is a noninvasive imaging modality that utilizes powerful magnets and radio waves to generate detailed images of the brain, making it a valuable tool for investigating malformations of cortical development (MCD). Various MRI techniques, including 3D T1-weighted, multiplanar thin-sliced T2-weighted, and 3D fluid-attenuated inversion recovery (FLAIR) sequences, can provide high-resolution images with excellent spatial and contrast resolution, allowing for a detailed visualization of cortical anatomy and abnormalities. Almost all MCD can be detected and characterized using MRI. Advanced techniques, such as arterial spin labeling MR perfusion, diffusion tensor imaging (DTI), and functional MRI (fMRI), may be used to improve the detection rate of these malformations and to plan surgery in case of drug-resistant epilepsy. However, there are also limitations related to high cost, relatively low availability, need for sedation or anesthesia, and limited sensitivity for detecting subtle focal cortical malformations. Despite these limitations, brain MRI plays a crucial role in the investigation of MCD, providing valuable information for diagnosis, treatment planning, and patient management.

Malformations of cortical development: Fetal imaging and genetics.

BACKGROUND: Malformations of cortical development (MCD) are a group of congenital disorders characterized by structural abnormalities in the brain cortex. The clinical manifestations include refractory epilepsy, mental retardation, and cognitive impairment. Genetic factors play a key role in the etiology of MCD. Currently, there is no curative treatment for MCD. Phenotypes such as epilepsy and cerebral palsy cannot be observed in the fetus. Therefore, the diagnosis of MCD is typically based on fetal brain magnetic resonance imaging (MRI), ultrasound, or genetic testing. The recent advances in neuroimaging have enabled the in-utero diagnosis of MCD using fetal ultrasound or MRI. METHODS: The present study retrospectively reviewed 32 cases of fetal MCD diagnosed by ultrasound or MRI. Then, the chromosome karyotype analysis, single nucleotide polymorphism array or copy number variation sequencing, and whole-exome sequencing (WES) findings were presented. RESULTS: Pathogenic copy number variants (CNVs) or single-nucleotide variants (SNVs) were detected in 22 fetuses (three pathogenic CNVs [9.4%, 3/32] and 19 SNVs [59.4%, 19/32]), corresponding to a total detection rate of 68.8% (22/32). CONCLUSION: The results suggest that genetic testing, especially WES, should be performed for fetal MCD, in order to evaluate the outcomes and prognosis, and predict the risk of recurrence in future pregnancies.

Disproportion of Corpus Callosum in Fetuses With Malformations of Cortical Development.

OBJECTIVE: To evaluate corpus callosum (CC) size in fetuses with malformations of cortical development (MCD) and to explore the diagnostic value of three CC length (CCL) ratios in identifying cortical abnormalities. METHODS: This is a single-center retrospective study in singleton fetuses at 20-37 weeks of gestation between April 2017 and August 2022. The midsagittal plane of the fetal brain was obtained and evaluated for the following variables: length, height, area of the corpus callosum, and relevant markers, including the ratios of corpus callosum length to internal cranial occipitofrontal dimension (CCL/ICOFD), corpus callosum length to femur length (CCL/FL), and corpus callosum length to cerebellar vermian diameter (CCL/VD). Intra-class correlation coefficient (ICC) was used to evaluate measurement consistency. The accuracy of biometric measurements in prediction of MCD was assessed using the area under the receiver-operating-characteristics curves (AUC). RESULTS: Fetuses with MCD had a significantly decreased CCL, height (genu and splenium), and area as compared with those of normal fetuses (P < .05), but there was no significant difference in body height (P = .326). The CCL/ICOFD, CCL/FL, and CCL/VD ratios were significantly decreased in fetuses with MCD when compared with controls (P < .05). The CCL/ICOFD ratio offered the highest predictive accuracy for MCD, yielding an AUC of 0.856 (95% CI: 0.774-0.938, P < .001), followed by CCL/FL ratio (AUC, 0.780 (95% CI: 0.657-0.904), P < .001), CCL/VD ratio (AUC, 0.677 (95% CI: 0.559-0.795), P < .01). CONCLUSION: The corpus callosum biometric parameters in fetuses with MCD are reduced. The CCL/ICOFD ratio derived from sonographic measurements is considered a promising tool for the prenatal detection of cortical malformations. External validation of these findings and prospective studies are warranted.

Diagnóstico de malformación del desarrollo cortical en embarazo gemelar monocorial: reporte de caso / Diagnosis of malformation of the cortical development in a monochorial twin pregnancy: case report

Introducción: Las malformaciones del desarrollo cortical se deben a alteraciones en la migración del neuroblasto durante la formación de la corteza cerebral. Se desconoce su frecuencia en embarazos monocoriales. Objetivo: Reportar el caso de un embarazo monocorial con diagnóstico de malformación del desarrollo cortical en uno de los fetos y revisar la literatura referente a su diagnóstico y pronóstico. Método: Mujer de 19 años, embarazo monocorial biamniótico de 26 semanas, que acudió con estudio ecográfico y resonancia fetal que evidenció en uno de los fetos asimetría de los hemisferios cerebrales, hipoplasia de la cisura de Silvio izquierda con simplificación del patrón giral por focos de paquigiria y polimicrogiria, con confirmación posnatal de alteración en la migración neuronal asociada a hipoplasia vermiana. Resultados: Se encontraron en la literatura tres casos de embarazo múltiple monocorial con trastorno de la migración neuronal con recién nacidos vivos. Los hallazgos más comunes fueron microcefalia, lisencefalia e hipoplasia cerebelosa. Conclusiones: El diagnóstico prenatal del trastorno de la migración neuronal se realiza con ecografía y resonancia fetal. La más frecuente es la alteración de la migración neuronal tipo II. El pronóstico depende del tipo de alteración; sin embargo, la mayoría de los casos presentan trastornos epileptiformes con alteraciones del neurodesarrollo.

Introduction: Malformations of cortical development are the result from alterations in the neuroblast migration during the cerebral cortex formation. Its frequency in monochorial multiple pregnancies remains unknown. Objective: To report a case of monochorial multiple pregnancy with diagnosis of malformation of the cortical development in one of the fetuses. In addition, to review the literature regarding the diagnosis and prognosis of this entity. Method: A 19-year-old female with a monochorial diamniotic pregnancy of 26 weeks gestation, arrived with an ultrasound anatomy scan visit, and fetal magnetic resonance imaging, we detected asymmetry in the cerebral hemispheres one of the fetuses, hypoplasia of the left sulcus of Sylvius with simplification of the gyrus pattern due to clusters of pachygyria and polymicrogyria. Those findings were confirmed afterbirth, with a definite diagnosis of neuronal migration disorder associated with vermian hypoplasia. Results: Three cases of monochorial pregnancy with neuronal migration disorder with live newborn, common findings like microcephaly, lissencephaly and vermian hypoplasia. Conclusions: Prenatal diagnosis with neuronal migration disorder is done via ultrasound and magnetic resonance imaging. Neuronal migration disorders type II are the most common of them. Prognosis depends on the type of disorder; however, most patients have epileptiform activity and neurodevelopment impairment.

The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions.

The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype-phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.

Prenatal Diagnosis of Hemimegalencephaly Using Radiological Methods: A Case Report.

Hemimegalencephaly is a rare congenital anomaly characterized by an increase in the size and dysplastic involvement of one cerebral hemisphere, which can be partial or complete. It may also be associated with anomalies in the cerebellum and brainstem and, in some cases, be a part of different syndromes. The result of these abnormalities leads to intractable epilepsy and developmental delay. Diagnosis is typically made through imaging studies in the postnatal period, but it can also be done before birth. We present the case of a 23-week pregnant patient in whom a prenatal diagnosis of hemimegalencephaly was made, highlighting the need for fetal magnetic resonance imaging (MRI) to confirm the diagnosis.

Deep learning-based automated lesion segmentation on pediatric focal cortical dysplasia II preoperative MRI: a reliable approach.

OBJECTIVES: Focal cortical dysplasia (FCD) represents one of the most common causes of refractory epilepsy in children. Deep learning demonstrates great power in tissue discrimination by analyzing MRI data. A prediction model was built and verified using 3D full-resolution nnU-Net for automatic lesion detection and segmentation of children with FCD II. METHODS: High-resolution brain MRI structure data from 65 patients, confirmed with FCD II by pathology, were retrospectively studied. Experienced neuroradiologists segmented and labeled the lesions as the ground truth. Also, we used 3D full-resolution nnU-Net to segment lesions automatically, generating detection maps. The algorithm was trained using fivefold cross-validation, with data partitioned into training (N = 200) and testing (N = 15). To evaluate performance, detection maps were compared to expert manual labels. The Dice-Sørensen coefficient (DSC) and sensitivity were used to assess the algorithm performance. RESULTS: The 3D nnU-Net showed a good performance for FCD lesion detection at the voxel level, with a sensitivity of 0.73. The best segmentation model achieved a mean DSC score of 0.57 on the testing dataset. CONCLUSION: This pilot study confirmed that 3D full-resolution nnU-Net can automatically segment FCD lesions with reliable outcomes. This provides a novel approach to FCD lesion detection. CRITICAL RELEVANCE STATEMENT: Our fully automatic models could process the 3D T1-MPRAGE data and segment FCD II lesions with reliable outcomes. KEY POINTS: • Simplified image processing promotes the DL model implemented in clinical practice. • The histopathological confirmed lesion masks enhance the clinical credibility of the AI model. • The voxel-level evaluation metrics benefit lesion detection and clinical decisions.

Fetal indusium griseum is a possible biomarker of the regularity of brain midline development in 3T MR imaging: A retrospective observational study.

INTRODUCTION: This study aimed to assess the visibility of the indusium griseum (IG) in magnetic resonance (MR) scans of the human fetal brain and to evaluate its reliability as an imaging biomarker of the normality of brain midline development. MATERIAL AND METHODS: The retrospective observational study encompassed T2-w 3T MR images from 90 post-mortem fetal brains and immunohistochemical sections from 41 fetal brains (16-40 gestational weeks) without cerebral pathology. Three raters independently inspected and evaluated the visibility of IG in post-mortem and in vivo MR scans. Weighted kappa statistics and regression analysis were used to determine inter- and intra-rater agreement and the type and strength of the association of IG visibility with gestational age. RESULTS: The visibility of the IG was the highest between the 25 and 30 gestational week period, with a very good inter-rater variability (kappa 0.623-0.709) and excellent intra-rater variability (kappa 0.81-0.93). The immunochemical analysis of the histoarchitecture of IG discloses the expression of highly hydrated extracellular molecules in IG as the substrate of higher signal intensity and best visibility of IG during the mid-fetal period. CONCLUSIONS: The knowledge of developmental brain histology and fetal age allows us to predict the IG-visibility in magnetic resonance imaging (MRI) and use it as a biomarker to evaluate the morphogenesis of the brain midline. As a biomarker, IG is significant for post-mortem pathological examination by MRI. Therefore, in the clinical in vivo imaging examination, IG should be anticipated when an assessment of the brain midline structures is needed in mid-gestation, including corpus callosum thickness measurements.

Metabolic heterogeneity in different subtypes of malformations of cortical development causing epilepsy: a proton magnetic resonance spectroscopy study.

Background: The most common subtypes of malformations of cortical development (MCDs) are gray matter heterotopia (GMH), focal cortical dysplasia (FCD), and polymicrogyria (PMG). This study aimed to characterize the possible neurometabolic abnormalities and heterogeneity in different MCDs subtypes using proton magnetic resonance spectroscopy (1H-MRS). Methods: In this prospective cross-sectional study, we recruited 29 patients with MCDs and epilepsy, including ten with GMH, ten with FCD, and nine with PMG, as well as 25 age- and sex-matched healthy controls (HC) from the Epilepsy Center of West China Hospital of Sichuan University between August 2018 and November 2021. Inclusion criteria for the patients were based upon typical magnetic resonance imaging (MRI) findings of MCDs and full clinical assessment for epilepsy. Single-voxel point-resolved spectroscopy was used to acquire data from both the lesion and the normal-appearing contralateral side (NACS) in patients and from the frontal lobe in HC. Metabolite measures, including N-acetyl aspartate (NAA), myoinositol (Ins), choline (Cho), creatine (Cr), and glutamate + glutamine (Glx) concentrations, were quantitatively estimated with linear combination model (LCModel) software and corrected for the partial volume effect of cerebrospinal fluid (CSF). Results: The NAA concentration was lower and the Ins concentration was higher in the MCDs lesions than in the NACS and in HC (P=0.002-0.007), and the Cho and Cr concentrations were higher in MCDs lesions than in HC (P=0.001-0.016). Moreover, the Cho concentration was higher in NACS than in HC (P=0.015). In the GMH lesions, the only metabolic alteration was an NAA reduction (GMH_lesion vs. HC: P=0.001). In the FCD lesions, there were more metabolite abnormalities than in the other two subtypes, particularly a lower NAA and a higher Ins than in HC and NACS (P=0.012-0.042). In the PMG lesions, Cr (lesion vs. HC or NACS: P=0.017-0.021) and Glx (lesion vs. NACS: P=0.043) were increased, while NAA was normal. Correlation analysis revealed that the Cr concentration in MCDs lesions was positively correlated with seizure frequency (r=0.411; P=0.027). Conclusions: Based upon 1H-MRS, our study demonstrated that different MCDs subtypes exhibited variable metabolic features, which may be associated with distinct functional and cytoarchitectural properties.

Cutting-edge applications of fetal MR neuro-imaging in clinical routine: a pictorial essay.

Over time, fetal MR neuro-imaging has undergone continuous improvement; presently, it plays a pivotal role in the diagnosis of an expanding array of complex neurological conditions. Within this pictorial essay, our focus will be exclusively directed towards those cutting-edge clinical applications, which currently yield valuable diagnostic insights on a single case basis. Specifically, the pictorial examples will center on some abnormal entities and their features at an earlier fetal stage.

Genetic testing in children enrolled in epilepsy surgery program. A real-life study.

OBJECTIVE: Although genetic causes of drug-resistant focal epilepsy and selected focal malformations of cortical development (MCD) have been described, a limited number of studies comprehensively analysed genetic diagnoses in patients undergoing pre-surgical evaluation, their outcomes and the effect of genetic diagnosis on surgical strategy. METHODS: We analysed a prospective cohort of children enrolled in epilepsy surgery program over January 2018-July 2022. The majority of patients underwent germline and/or somatic genetic testing. We searched for predictors of surgical outcome and positive result of germline genetic testing. RESULTS: Ninety-five patients were enrolled in epilepsy surgery program and 64 underwent resective epilepsy surgery. We ascertained germline genetic diagnosis in 13/74 patients having underwent germline gene testing (pathogenic or likely pathogenic variants in CHRNA4, NPRL3, DEPDC5, FGF12, GRIA2, SZT2, STXBP1) and identified three copy number variants. Thirty-five patients underwent somatic gene testing; we detected 10 pathogenic or likely pathogenic variants in genes SLC35A2, PTEN, MTOR, DEPDC5, NPRL3. Germline genetic diagnosis was significantly associated with the diagnosis of focal epilepsy with unknown seizure onset. SIGNIFICANCE: Germline and somatic gene testing can ascertain a definite genetic diagnosis in a significant subgroup of patients in epilepsy surgery programs. Diagnosis of focal genetic epilepsy may tip the scales against the decision to proceed with invasive EEG study or surgical resection; however, selected patients with genetic focal epilepsies associated with MCD may benefit from resective epilepsy surgery and therefore, a genetic diagnosis does not disqualify patients from presurgical evaluation and epilepsy surgery.

The "cortical invagination sign": a midtrimester sonographic marker of unilateral cortical focal dysgyria in fetuses with complete agenesis of the corpus callosum.

BACKGROUND: Agenesis of the corpus callosum is associated with several malformations of cortical development. Recently, features of focal cortical dysgyria have been described in fetuses with agenesis of the corpus callosum. OBJECTIVE: This study aimed to describe the "cortical invagination sign," a specific sonographic feature of focal cortical dysgyria, which is consistently seen at midtrimester axial brain ultrasound in fetuses with complete agenesis of the corpus callosum. STUDY DESIGN: This was a retrospective analysis of prospectively collected data from 2018 to 2021, including patients referred to 5 fetal medicine centers in the second trimester of pregnancy (19 0/7 to 22 0/7 weeks of gestation) with suspected complete agenesis of the corpus callosum. All cases with the diagnosis of complete agenesis of the corpus callosum were submitted to an axial sonographic assessment of the fetal brain on the transventricular plane. In this scanning section, the mesial profile of both cerebral hemispheres at the level of the frontal-parietal cortex was investigated. In this area, the operator looked for an abnormal invagination of the cortical surface along the widened interhemispheric fissure, which was referred to as the "cortical invagination sign." All fetuses were submitted to dedicated antenatal magnetic resonance imaging to reassess the ultrasound findings. Cases with additional brain anomalies, which did not involve the cortex, were excluded. The final diagnosis was confirmed at postnatal brain magnetic resonance imaging or postmortem examination, for cases undergoing termination of pregnancy. The primary outcome of this study was to evaluate the presence and laterality of the "cortical invagination sign" in fetuses with complete agenesis of the corpus callosum at antenatal ultrasound and magnetic resonance imaging. RESULTS: During the study period, 64 cases of complete agenesis of the corpus callosum were included; of those cases, 50 (78.1%) resulted in termination of pregnancy, and 14 (21.9%) resulted in a live birth. The "cortical invagination sign" was detected at ultrasound in 13 of 64 cases (20.3%) and at targeted brain magnetic resonance imaging in 2 additional cases (23.4%), all of which were electively terminated. Moreover, the "cortical invagination sign" was found to be exclusively unilateral and on the left cerebral hemisphere in all the cases. There was a predominant number, although nonsignificant, of male fetuses (80.0% of cases; P=.06) in the group of complete agenesis of the corpus callosum with the "cortical invagination sign." CONCLUSION: The "cortical invagination sign" is a specific marker of focal cortical dysgyria, which seems to characterize at midtrimester of pregnancy in a large group of fetuses with complete agenesis of the corpus callosum. The etiology, pathophysiology, and prognostic significance of this finding remain to be elucidated.

Clinical and Surgical Approach for Cerebral Cortical Dysplasia.

The present article describes pathophysiological and clinical aspects of congenital malformations of the cerebral tissue (cortex and white matter) that cause epilepsy and very frequently require surgical treatment. A particular emphasis is given to focal cortical dysplasias, the most common pathology among these epilepsy-related malformations. Specific radiological and surgical features are also highlighted, so a thorough overview of cortical dysplasias is provided.