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OBJECTIVES: To develop a multiparametric machine-learning (ML) framework using high-resolution 3 dimensional (3D) magnetic resonance (MR) fingerprinting (MRF) data for quantitative characterization of focal cortical dysplasia (FCD). MATERIALS: We included 119 subjects, 33 patients with focal epilepsy and histopathologically confirmed FCD, 60 age- and gender-matched healthy controls (HCs), and 26 disease controls (DCs). Subjects underwent whole-brain 3 Tesla MRF acquisition, the reconstruction of which generated T1 and T2 relaxometry maps. A 3D region of interest was manually created for each lesion, and z-score normalization using HC data was performed. We conducted 2D classification with ensemble models using MRF T1 and T2 mean and standard deviation from gray matter and white matter for FCD versus controls. Subtype classification additionally incorporated entropy and uniformity of MRF metrics, as well as morphometric features from the morphometric analysis program (MAP). We translated 2D results to individual probabilities using the percentage of slices above an adaptive threshold. These probabilities and clinical variables were input into a support vector machine for individual-level classification. Fivefold cross-validation was performed and performance metrics were reported using receiver-operating-characteristic-curve analyses. RESULTS: FCD versus HC classification yielded mean sensitivity, specificity, and accuracy of 0.945, 0.980, and 0.962, respectively; FCD versus DC classification achieved 0.918, 0.965, and 0.939. In comparison, visual review of the clinical magnetic resonance imaging (MRI) detected 48% (16/33) of the lesions by official radiology report. In the subgroup where both clinical MRI and MAP were negative, the MRF-ML models correctly distinguished FCD patients from HCs and DCs in 98.3% of cross-validation trials for the magnetic resonance imaging negative group and MAP negative group. Type II versus non-type-II classification exhibited mean sensitivity, specificity, and accuracy of 0.835, 0.823, and 0.83, respectively; type IIa versus IIb classification showed 0.85, 0.9, and 0.87. In comparison, the transmantle sign was present in 58% (7/12) of the IIb cases. INTERPRETATION: The MRF-ML framework presented in this study demonstrated strong efficacy in noninvasively classifying FCD from normal cortex and distinguishing FCD subtypes. ANN NEUROL 2024.
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OBJECTIVE: Perineuronal nets (PNN) are specialized extracellular matrix (ECM) components of the central nervous system, frequently accumulating at the surface of inhibitory GABAergic interneurons. While an altered distribution of PNN has been observed in neurological disorders including Alzheimer's disease, schizophrenia and epilepsy, their anatomical distribution also changes during physiological brain maturation and aging. Such an age-dependent shift was experimentally associated also with hippocampal engram formation during brain maturation. Our aim was to histopathologically assess PNN in the hippocampus of adult and pediatric patients with temporal lobe epilepsy (TLE) compared to age-matched post-mortem control subjects and to compare PNN-related changes with memory impairment observed in our patient cohort. METHODS: Sixty-six formalin-fixed and paraffin-embedded tissue specimens of the human hippocampus were retrieved from the European Epilepsy Brain Bank. Twenty-nine patients had histopathologically confirmed hippocampal sclerosis (HS), and eleven patients suffered from TLE without HS. PNN were immunohistochemically visualized using an antibody directed against aggrecan and manually counted from hippocampus subfields and the subiculum. RESULTS: PNN density increased with age in both human controls and TLE patients. However, their density was significantly higher in all HS patients compared to age-matched controls. Intriguingly, TLE patients presented presurgically with better memory when their hippocampal PNN density was higher (p < 0.05). SIGNIFICANCE: Our results were compatible with age-dependent ECM specialization in the human hippocampus and its precocious aging in the epileptic condition. These observations confirm recent experimental animal models and also support the notion that PNN play a role in memory formation in the human brain. PLAIN LANGUAGE SUMMARY: "Perineuronal nets" (PNN) are a specialized compartment of the extracellular matrix (ECM), especially surrounding highly active neurons of the mammalian brain. There is evidence that PNN play a role in memory formation, brain maturation, and in some pathologies like Alzheimer's disease, schizophrenia or epilepsy. In this study, we investigated the role of PNN in patients suffering from drug-resistant focal epilepsy compared to controls. We found that with increasing age, more neurons are surrounded by PNN. Similarly, all epilepsy patients but especially patients with better memory performance also had more PNN. This study raises further interest in studying ECM molecules in the human brain under physiological and pathophysiological conditions.
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Envejecimiento , Epilepsia del Lóbulo Temporal , Matriz Extracelular , Hipocampo , Humanos , Hipocampo/patología , Masculino , Femenino , Adulto , Matriz Extracelular/patología , Epilepsia del Lóbulo Temporal/patología , Envejecimiento/patología , Persona de Mediana Edad , Adulto Joven , Niño , Adolescente , Anciano , EsclerosisRESUMEN
OBJECTIVE: To assess the need for an epilepsy educational curriculum for primary healthcare providers formulated by the International League Against Epilepsy (ILAE) and the importance attributed to its competencies by epilepsy specialists and primary care providers and across country-income settings. METHODS: The ILAE primary care epilepsy curriculum was translated to five languages. A structured questionnaire assessing the importance of its 26 curricular competencies was posted online and publicized widely to an international community. Respondents included epilepsy specialists, primary care providers, and others from three World Bank country-income categories. Responses from different groups were compared with univariate and ordinal logistic regression analyses. RESULTS: Of 785 respondents, 60% noted that a primary care epilepsy curriculum did not exist or they were unaware of one in their country. Median ranks of importance for all competencies were high (very important to extremely important) in the entire sample and across different groups. Fewer primary care providers than specialists rated the following competencies as extremely important: definition of epilepsy (p = .03), recognition of seizure mimics (p = .02), interpretation of test results for epilepsy care (p = .001), identification of drug-resistant epilepsy (0.005) and management of psychiatric comorbidities (0.05). Likewise, fewer respondents from LMICs in comparison to UMICs rated 15 competencies as extremely important. SIGNIFICANCE: The survey underscores the unmet need for an epilepsy curriculum in primary care and the relevance of its competencies across different vocational and socioeconomic settings. Differences across vocational and country income groups indicate that educational packages should be developed and adapted to needs in different settings.
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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.
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OBJECTIVE: We aim to improve focal cortical dysplasia (FCD) detection by combining high-resolution, three-dimensional (3D) magnetic resonance fingerprinting (MRF) with voxel-based morphometric magnetic resonance imaging (MRI) analysis. METHODS: We included 37 patients with pharmacoresistant focal epilepsy and FCD (10 IIa, 15 IIb, 10 mild Malformation of Cortical Development [mMCD], and 2 mMCD with oligodendroglial hyperplasia and epilepsy [MOGHE]). Fifty-nine healthy controls (HCs) were also included. 3D lesion labels were manually created. Whole-brain MRF scans were obtained with 1 mm3 isotropic resolution, from which quantitative T1 and T2 maps were reconstructed. Voxel-based MRI postprocessing, implemented with the morphometric analysis program (MAP18), was performed for FCD detection using clinical T1w images, outputting clusters with voxel-wise lesion probabilities. Average MRF T1 and T2 were calculated in each cluster from MAP18 output for gray matter (GM) and white matter (WM) separately. Normalized MRF T1 and T2 were calculated by z-scores using HCs. Clusters that overlapped with the lesion labels were considered true positives (TPs); clusters with no overlap were considered false positives (FPs). Two-sample t-tests were performed to compare MRF measures between TP/FP clusters. A neural network model was trained using MRF values and cluster volume to distinguish TP/FP clusters. Ten-fold cross-validation was used to evaluate model performance at the cluster level. Leave-one-patient-out cross-validation was used to evaluate performance at the patient level. RESULTS: MRF metrics were significantly higher in TP than FP clusters, including GM T1, normalized WM T1, and normalized WM T2. The neural network model with normalized MRF measures and cluster volume as input achieved mean area under the curve (AUC) of .83, sensitivity of 82.1%, and specificity of 71.7%. This model showed superior performance over direct thresholding of MAP18 FCD probability map at both the cluster and patient levels, eliminating ≥75% FP clusters in 30% of patients and ≥50% of FP clusters in 91% of patients. SIGNIFICANCE: This pilot study suggests the efficacy of MRF for reducing FPs in FCD detection, due to its quantitative values reflecting in vivo pathological changes. © 2024 International League Against Epilepsy.
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Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical , Humanos , Imagen por Resonancia Magnética/métodos , Femenino , Masculino , Adulto , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/patología , Adolescente , Adulto Joven , Epilepsias Parciales/diagnóstico por imagen , Epilepsias Parciales/patología , Persona de Mediana Edad , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/patología , Imagenología Tridimensional/métodos , Niño , Reacciones Falso Positivas , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Procesamiento de Imagen Asistido por Computador/métodos , Displasia Cortical FocalRESUMEN
Objective: Heterozygous mutations within the voltage-gated sodium channel α subunit (SCN1A) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of SCN1A are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches. Methods: We investigated SCN1A mRNA expression and expression of two SCN1A related antisense RNAs in brain tissues in different age groups of pediatric non-Dravet patients who underwent surgery for drug resistant epilepsy. The effect of different antisense oligonucleotides (ASOs) directed against SCN1A specific antisense RNAs on SCN1A expression was tested. Results: The SCN1A related antisense RNAs SCN1A-dsAS (downstream antisense, RefSeq identifier: NR_110598) and SCN1A-usAS (upstream AS, SCN1A-AS, RefSeq identifier: NR_110260) were widely expressed in the brain of pediatric patients. Expression patterns revealed a negative correlation of SCN1A-dsAS and a positive correlation of lncRNA SCN1A-usAS with SCN1A mRNA expression. Transfection of SK-N-AS cells with an ASO targeted against SCN1A-dsAS was associated with a significant enhancement of SCN1A mRNA expression and reduction in SCN1A-dsAS transcripts. Conclusion: These findings support the role of SCN1A-dsAS in the suppression of SCN1A mRNA generation. Considering the haploinsufficiency in genetic SCN1A related DS, SCN1A-dsAS is an interesting target candidate for the development of ASOs (AntagoNATs) based precision medicine therapeutic approaches aiming to enhance SCN1A expression in DS.
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Focal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype-phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study. Clinical data were directly available from each contributing centre. Histopathological analyses were performed from formalin-fixed, paraffin-embedded tissue samples using haematoxylin-eosin and immunohistochemistry for NF-SMI32, NeuN, pS6, p62, and vimentin. Ten individuals carried loss-of-function variants in the GATOR1 complex encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function variants in MTOR (n = 7). Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e., lack of balloon cells, individuals with MTOR variants presented with both histopathology subtypes, FCDIIa and FCDIIb. Interestingly, 50% of GATOR1-positive cases showed a unique and predominantly vacuolizing phenotype with p62 immunofluorescent aggregates in autophagosomes. All cases with GATOR1 alterations had neurosurgery in the frontal lobe and the majority was confined to the cortical ribbon not affecting the white matter. This pattern was reflected by subtle or negative MRI findings in seven individuals with GATOR1 variants. Nonetheless, all individuals were seizure-free after surgery except four individuals carrying a DEPDC5 variant. We describe a yet underrecognized genotype-phenotype correlation of GATOR1 variants with FCDIIa in the frontal lobe. These lesions were histopathologically characterized by abnormally vacuolizing cells suggestive of an autophagy-altered phenotype. In contrast, individuals with FCDIIb and brain somatic MTOR variants showed larger lesions on MRI including the white matter, suggesting compromised neural cell migration.
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Epilepsia Refractaria , Epilepsia , Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Niño , Humanos , Epilepsia/genética , Serina-Treonina Quinasas TOR/genética , Proteínas Activadoras de GTPasa/genética , Genotipo , Malformaciones del Desarrollo Cortical/genéticaRESUMEN
Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a contributing factor to regeneration failure in mammals. We demonstrate that the SLRPs chondroadherin, fibromodulin, lumican, and prolargin are enriched in rodent and human but not zebrafish CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer mechano-structural properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as inhibitory ECM factors that impair axon regeneration by modifying tissue mechanics and structure, and identifies their enrichment as a feature of human brain and spinal cord lesions. These findings imply that SLRPs may be targets for therapeutic strategies to promote CNS regeneration.
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Proteoglicanos , Proteoglicanos Pequeños Ricos en Leucina , Animales , Humanos , Proteoglicanos Tipo Condroitín Sulfato , Pez Cebra , Decorina , Axones , Regeneración Nerviosa , Proteínas de la Matriz Extracelular , Sistema Nervioso Central , MamíferosRESUMEN
Focal Cortical Dysplasia (FCD) is a frequent cause of drug-resistant focal epilepsy in children and young adults. The international FCD classifications of 2011 and 2022 have identified several clinico-pathological subtypes, either occurring isolated, i.e., FCD ILAE Type 1 or 2, or in association with a principal cortical lesion, i.e., FCD Type 3. Here, we addressed the DNA methylation signature of a previously described new subtype of FCD 3D occurring in the occipital lobe of very young children and microscopically defined by neuronal cell loss in cortical layer 4. We studied the DNA methylation profile using 850 K BeadChip arrays in a retrospective cohort of 104 patients with FCD 1 A, 2 A, 2B, 3D, TLE without FCD, and 16 postmortem specimens without neurological disorders as controls, operated in China or Germany. DNA was extracted from formalin-fixed paraffin-embedded tissue blocks with microscopically confirmed lesions, and DNA methylation profiles were bioinformatically analyzed with a recently developed deep learning algorithm. Our results revealed a distinct position of FCD 3D in the DNA methylation map of common FCD subtypes, also different from non-FCD epilepsy surgery controls or non-epileptic postmortem controls. Within the FCD 3D cohort, the DNA methylation signature separated three histopathology subtypes, i.e., glial scarring around porencephalic cysts, loss of layer 4, and Rasmussen encephalitis. Differential methylation in FCD 3D with loss of layer 4 mapped explicitly to biological pathways related to neurodegeneration, biogenesis of the extracellular matrix (ECM) components, axon guidance, and regulation of the actin cytoskeleton. Our data suggest that DNA methylation signatures in cortical malformations are not only of diagnostic value but also phenotypically relevant, providing the molecular underpinnings of structural and histopathological features associated with epilepsy. Further studies will be necessary to confirm these results and clarify their functional relevance and epileptogenic potential in these difficult-to-treat children.
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Epilepsia Refractaria , Epilepsia , Displasia Cortical Focal , Malformaciones del Desarrollo Cortical , Niño , Adulto Joven , Humanos , Preescolar , Estudios Retrospectivos , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/genética , Metilación de ADN , Epilepsia/genética , Epilepsia Refractaria/patología , Imagen por Resonancia MagnéticaRESUMEN
Epilepsy is a common medical condition that affects people of all ages, races, social classes, and geographical regions. Diagnosis of epilepsy remains clinical, and ancillary investigations (electroencephalography, imaging, etc) are of aid to determine the type, cause, and prognosis. Antiseizure medications represent the mainstay of epilepsy treatment: they aim to suppress seizures without adverse events, but they do not affect the underlying predisposition to generate seizures. Currently available antiseizure medications are effective in around two-thirds of patients with epilepsy. Neurosurgical resection is an effective strategy to reach seizure control in selected individuals with drug-resistant focal epilepsy. Non-pharmacological treatments such as palliative surgery (eg, corpus callosotomy), neuromodulation techniques (eg, vagus nerve stimulation), and dietary interventions represent therapeutic options for patients with drug-resistant epilepsy who are not suitable for resective brain surgery.
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Epilepsia Refractaria , Epilepsia , Humanos , Adulto , Resultado del Tratamiento , Epilepsia/terapia , Epilepsia/tratamiento farmacológico , Convulsiones , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/terapia , PronósticoRESUMEN
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 6 months in doses up to 1.5 g/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 6 months 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 5-28 years) 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 6 months 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.
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Epilepsia , Galactosa , Humanos , Medicina de Precisión , Hiperplasia , Proyectos Piloto , Calidad de Vida , Epilepsia/terapia , Convulsiones , Electroencefalografía/métodosRESUMEN
Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.
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Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Epilepsia , Neocórtex , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Epilepsia del Lóbulo Temporal/cirugía , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Estudios Retrospectivos , Hipocampo/patología , Epilepsia/patologíaRESUMEN
The human brain has a highly complex structure both on the microscopic and on the macroscopic scales. Increasing evidence has suggested the role of mechanical forces for cortical folding - a classical hallmark of the human brain. However, the link between cellular processes at the microscale and mechanical forces at the macroscale remains insufficiently understood. Recent findings suggest that an additional proliferating zone, the outer subventricular zone (OSVZ), is decisive for the particular size and complexity of the human cortex. To better understand how the OSVZ affects cortical folding, we establish a multifield computational model that couples cell proliferation in different zones and migration at the cell scale with growth and cortical folding at the organ scale by combining an advection-diffusion model with the theory of finite growth. We validate our model based on data from histologically stained sections of the human fetal brain and predict 3D pattern formation. Finally, we address open questions regarding the role of the OSVZ for the formation of cortical folds. The presented framework not only improves our understanding of human brain development, but could eventually help diagnose and treat neuronal disorders arising from disruptions in cellular development and associated malformations of cortical development.
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Ventrículos Laterales , Neuronas , Humanos , Diferenciación Celular , Neurogénesis/fisiología , Proliferación Celular , Corteza CerebralRESUMEN
Introduction: Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2022 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gray and white matters of surgical FCD type II specimens. We aimed to contribute to pathophysiology and tissue characterization. Methods: We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation employing digital analyses. Results: We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. Cholesterol biosynthesis was among the main enriched cellular pathways in both IIa and IIb gray matter. Particularly, the genes HMGCS1, HMGCR, and SQLE were upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed, respectively, compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Discussion: Overall, our study contributed to identifying cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to a neuroprotective response to seizures. Moreover, specific analyses in either the gray or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively.
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OBJECTIVE: Completeness as a predictor of seizure freedom is broadly accepted in epilepsy surgery. We focused on the requirements for a complete hemispherotomy and hypothesized that the disconnection of the insula contributes to a favorable postoperative seizure outcome. We analyzed surgical and nonsurgical predictors influencing long-term seizure outcome before and after a modification of our hemispherotomy technique. METHODS: We retrospectively studied surgical procedures, electroclinical parameters, magnetic resonance imaging (MRI) results, and follow-up data in all children who had undergone hemispherotomy between 2001 and 2018 at our institution. We used logistic regression models to analyze the influence of different factors on seizure outcome. RESULTS: A total of 152 patients were eligible for seizure outcome analysis only. Of these, 140 cases had complete follow-up data for ≥24 months and provide the basis for the following results. The median age at surgery was 4.3 years (range = .3-17.9 years). Complete disconnection (including the insular tissue) was achieved in 63.6% (89/140). At 2-year follow-up, seizure freedom (Engel class IA) was observed in 34.8% (8/23) with incomplete insular disconnection, whereas this was achieved in 88.8% (79/89) with complete surgical disconnection (p < .001, odds ratio [OR] = 10.41). In the latter group (n = 89), a potentially epileptogenic contralateral MRI lesion was the strongest predictor for postoperative seizure recurrence (OR = 22.20). SIGNIFICANCE: Complete surgical disconnection is the most important predictor of seizure freedom following hemispherotomy and requires disconnection of the insular tissue at the basal ganglia level. Even if the hemispherotomy is performed surgically completely, a potentially epileptogenic contralateral lesion on preoperative MRI significantly reduces the chances of postoperative seizure freedom.
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Epilepsia , Hemisferectomía , Humanos , Niño , Preescolar , Adolescente , Estudios Retrospectivos , Resultado del Tratamiento , Hemisferectomía/métodos , Convulsiones/diagnóstico por imagen , Convulsiones/cirugía , Epilepsia/diagnóstico por imagen , Epilepsia/cirugía , Epilepsia/patología , Imagen por Resonancia Magnética , ElectroencefalografíaRESUMEN
Correctly diagnosing and classifying seizures and epilepsies is paramount to ensure the delivery of optimal care to patients with epilepsy. Focal seizures, defined as those that originate within networks limited to one hemisphere, are primarily subdivided into focal aware, focal impaired awareness, and focal to bilateral tonic-clonic seizures. Focal epilepsies account for most epilepsy cases both in children and adults. In children, focal epilepsies are typically subdivided in three groups: self-limited focal epilepsy syndromes (e.g., self-limited epilepsy with centrotemporal spikes), focal epilepsy of unknown cause but which do not meet criteria for a self-limited focal epilepsy syndrome, and focal epilepsy of known cause (e.g., structural lesions-developmental or acquired). In adults, focal epilepsies are often acquired and may be caused by a structural lesion such as stroke, infection and traumatic brain injury, or brain tumors, vascular malformations, metabolic disorders, autoimmune, and/or genetic causes. In addition to seizure semiology, neuroimaging, neurophysiology, and neuropathology constitute the cornerstones of a diagnostic evaluation. Patients with focal epilepsy who become drug-resistant should promptly undergo assessment in an epilepsy center. After excluding pseudo-resistance, these patients should be considered for presurgical evaluation as a means to identify the location and extent of the epileptogenic zone and assess their candidacy for a surgical procedure. The goal of this seminar in epileptology is to summarize clinically relevant information concerning focal epilepsies. This contributes to the ILAE's mission to ensure that worldwide healthcare professionals, patients, and caregivers continue to have access to high-quality educational resources concerning epilepsy.
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Epilepsias Parciales , Epilepsia , Síndromes Epilépticos , Adulto , Niño , Humanos , Epilepsias Parciales/cirugía , Convulsiones/diagnóstico , Epilepsia/complicaciones , Síndromes Epilépticos/complicaciones , Neuroimagen , ElectroencefalografíaRESUMEN
Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.
Asunto(s)
Epilepsia , Ganglioglioma , Humanos , Epilepsia/patología , Ganglioglioma/genética , Ganglioglioma/patología , Mutación/genética , Fenotipo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Genes ras , Sistema de Señalización de MAP QuinasasRESUMEN
OBJECTIVE: MRI-negative drug-resistant epilepsy presents a challenge when it comes to surgical planning, and surgical outcome is worse than in cases with an identified lesion. Although increasing implementation of more powerful MRI scanners and artificial intelligence has led to the detection of previously unrecognizable lesions, in some cases even postoperative pathological evaluation of electrographically epileptogenic zones shows no structural alterations. While in temporal lobe epilepsy a standardized resection approach can usually be performed, the surgical management of extra-temporal lesions is always individual. Here we present a strategy for treating patients with extra-temporal MRI-negative epilepsy focus and report our histological findings and patient outcome. METHODS: Patients undergoing epilepsy surgery in the Department of Neurosurgery at the University Hospital Erlangen between 2012 and 2020 were included in the study. Inclusion criteria were: (1) failure to identify a structural lesion on preoperative high-resolution 3 Tesla MRI with a standardized epilepsy protocol and (2) preoperative intracranial EEG (iEEG) diagnostics. RESULTS: We identified 8 patients corresponding to the inclusion criteria. Second look MRI analysis by an experienced neuroradiologist including the most recent analysis algorithm utilized in our clinic revealed a possible lesion in two patients. One of the patients with a clear focal cortical dysplasia (FCD) finding on a second look was excluded from further analysis. Of the other 7 patients, in one patient iEEG was performed with subdural electrodes, whereas the other 6 were evaluated with depth electrodes. MEG was performed preoperatively in all but one patient. An MEG focus was implemented in resection planning in 3 patients. FDG PET was performed in all, but only implemented in one patient. Histopathological evaluation revealed one non-lesional case, 4 cases of FCD and 2 cases with mild developmental malformation. All patients were free from permanent neurological deficits and presented with Engel 1A or 1B outcome on the last follow-up. CONCLUSION: We demonstrate that extra-temporal MRI-negative epilepsy can be treated successfully provided an extensive preoperative planning is performed. The most important diagnostic was stereo-EEG, whereas additional data from MEG was helpful and FDG PET was rarely useful in our cohort.