The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission.

To investigate the clinicopathologic features of focal cortical dysplasia (FCD) in patients with refractory epilepsy. The clinical, radiologic and pathologic features of 38 cases of FCD receiving surgical treatment in 2005 were reviewed retrospectively. The mean age of disease onset was 9.2 years. The disease lasted for 11.9 years on average and often presented as complex partial seizure. Radiologic examination revealed hippocampal sclerosis, or abnormal signals in the grey matter in 21 cases. According to Palmini's classification system, the following pathologic subgroups were identified: FCD type IA (3/38), FCD type IB (20/38), FCD type IIA (5/38) and FCD type IIB (5/38). The remaining 5 cases were classified as mild cortical dysplasia. Topographically, FCD type II was often seen in the extratemporal region (8/10), predominantly in the frontal lobe (5/8). Dual pathology was identified only in cases with FCD type IB. Immunohistochemical study showed that the giant neurons, immature neurons and dysmorphic neurons were strongly positive for NeuN. A small number of balloon cells expressed nestin. FCD is a common cause of refractory epilepsy. FCD type IB is the predominant pathologic subtype. Associated hippocampal sclerosis is sometimes seen. Clinicopathologic differences between FCD type I and FCD type II are observed.

Objective: To investigate the expression of cation chloride cotransporter (NKCC1/KCC2) in the neurons from cerebral lesions of children with focal cortical dysplasia (FCD) type Ⅱ, to provide a morphological basis for revealing the possible mechanism of epilepsy. Methods: Eight cases of FCD type Ⅱ diagnosed at Beijing Haidian Hospital, Beijing, China and 12 cases diagnosed at Xuanwu Hospital, Capital Medical University, Beijing, China from February 2017 to December 2019 were included. The expression of NKCC1 and KCC2 in FCD type Ⅱa and FCD type Ⅱb was detected using immunohistochemistry and double immunohistochemical stains. The average optical density of NKCC1 in dysmorphic neurons and normal neurons was also determined using immunohistochemical staining in FCD type Ⅱa (10 cases). Results: The patients were all younger than 14 years of age. Ten cases were classified as FCD type IIa, and 10 cases as FCD type Ⅱb. NKCC1 was expressed in the cytoplasm of normal cerebral cortex neurons and KCC2 expressed on cell membranes. In dysmorphic neurons of FCD type Ⅱa, expression of NKCC1 increased, which was statistically higher than that of normal neurons (P<0.01). Aberrant expression of KCC2 in dysmorphic neurons was also noted in the cytoplasm. In the FCD Ⅱb type, the expression pattern of NKCC1/KCC2 in dysmorphic neurons was the same as that of FCD type Ⅱa. The aberrant expression of NKCC1 in balloon cells was negative or weakly positive on the cell membrane, while the aberrant expression of KCC2 was absent. Conclusions: The expression pattern of NKCC1/KCC2 in dysmorphic neurons and balloon cells is completely different from that of normal neurons. The NKCC1/KCC2 protein-expression changes may affect the transmembrane chloride flow of neurons, modify the effect of inhibitory neurotransmitters γ-aminobutyric acid and increase neuronal excitability. These effects may be related to the occurrence of clinical epileptic symptoms.

Background: The Notch signaling pathway is an important regulator of stem cell activity in various tissues, including the central nervous system. It has been implicated in neurodevelopmental processes, including neuronal differentiation and synaptic plasticity. Research suggests that its expression may be associated with certain epileptogenic lesions, particularly those with neurodevelopmental origin. The aim of this study was to investigate the expression of Notch-1 in brain biopsies from various cases of pharmacoresistant epilepsy. Methods: Here, we used immunohistochemistry staining to retrospectively analyze 128 developmental lesions associated with pharmacoresistant epilepsy, including 13 cases with focal cortical dysplasia (FCD) type I, 39 with FCD type II, 37 with hippocampal sclerosis (HS), 23 with FCD IIIc, 9 with mild malformations of cortical development (MCD), 4 cases with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE), and 3 with tuberous sclerosis (TS). The tissues were stained for Neurofilament protein, Vimentin, S-100 protein, NeuN, and GFAP, as well as the stem cell marker Notch-1. Tissue that stained positively for Notch-1 was further characterized. Results: A positive Notch-1 reaction was found in all cases of FCD type IIb and TS, where it appeared in balloon cells but not in dysmorphic neurons, and in a single case of meningioangiomatosis (FCD IIIc), where it stained spider-like cells. Notch-1-positive cells showed a stem-like, glio-neuronal precursor immunophenotype. No staining was observed in the remaining cases with FCD type I, type III, HS, mild MCD, and MOGHE. Conclusions: Notch-1 displays a distinct pattern of expression in some epileptogenic lesions, potentially highlighting a stem cell-like origin or neurodevelopmental abnormalities contributing to pharmacoresistant epilepsy; however, it is not a general marker of such lesions. Its differential expression may prove useful in distinguishing between different types of FCD or other cortical malformations, which could assist in both their diagnosis and potentially in the development of more targeted therapeutic approaches. Further studies with different stem cell markers are needed in this direction.

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

Focal cortical dysplasia (FCD) is the most frequent pathological finding in pediatric epilepsy surgery patients. Several histopathological types of FCD are distinguished. The aim of the study was to define distinctive features of FCD subtypes. We retrospectively reviewed clinical, electroencephalographic, magnetic resonance imaging, neuropsychological, and surgical variables, and seizure outcome data in 200 children. Cortical malformations were histopathologically confirmed in all patients, including mild malformation of cortical development type II (mMCD) in 36, FCD type Ia in 55, FCD type Ib in 39, FCD type IIa in 35, and FCD type IIb in 35 subjects. Perinatal risk factors were more frequent in mMCD/FCD type I than FCD type II. Children with FCD type IIb had more localized ictal electroencephalographic patterns and magnetic resonance imaging changes. Increased cortical thickness, abnormal gyral/sulcal patterns, gray/white matter junction blurring, and gray matter signal abnormality in fluid-attenuated inversion recovery and T2-weighted sequences occurred more often in FCD type II, were infrequent in FCD type I, and rare in mMCD. Lobar hypoplasia/atrophy was common in FCD type I. Hippocampal sclerosis was most frequent in FCD type I. Neuropsychological testing demonstrated no significant differences between the groups. There was a trend toward better surgical outcomes in FCD type II compared with FCD type I patients. Different histopathological types of mMCD/FCD have distinct clinical and imaging characteristics. The ability to predict the subtype before surgery could influence surgical planning. Invasive electroencephalographic study should be considered when mMCD/FCD type I is expected based on noninvasive tests.

Objective To analyze the MR imaging features of epileptogenic focal cortical dysplasia (FCD)and to optimize the scanning protocols by correlating MRI appearance with pathological findings.Methods MRI findings and the relative scanning protocols in 36 patients with surgically and pathologically proved 40 lesions of FCD were retrospectively analyzed. According to Palmini classification system,all 40 lesions were pathologically categorized as FCD type Ⅰ (including FCD Ⅰ A and FCD Ⅰ B) and FCD type Ⅱ (including FCD Ⅱ A and FCD ⅡB ). The distribution of cerebral or dual lesions accompanied hippocampal sclerosis were observed.Differences of the distribution of cerebral in FCD type Ⅰ and FCD type Ⅱ were compared by using Fisher exact probabilities. MR scans in all patients consisted of routine and optimized protocols.Axial FSE T2WI,axial SET1WI and axial FLAIR were recognized as routine scanning protocols,while adding oblique coronal FSE T2WI and FLAIR were recognized as optimization scanning protocols.Both routine and optimization scanning protocols were performed in all patients.The conspicuity of main findings of FCD on different imaging plane and sequences of each protocol were assessed.The detection of cerebral or dual lesion and the accompanied hippocampal sclerosis were compared between the routine protocol and the optimized protocol by using McNemar test.Results Forty lesions were found in 36 cases with FCD,29 had temporal lobe lesion (72.5％ ),9 had frontal lobe lesion(22.5％ ) and 2 had parietal lobe lesion (5.0％).According to Palmini classification system,29 lesions in 27 patients (72.5％ ) were FCD type Ⅰ,11 lesions in 10 patients (27.5％) were FCD type Ⅱ lesions.There were 25 temporal lobe lesions in FCD type Ⅰ,while 4 in FCD type Ⅱ.There were statistically significant differences between FCD type Ⅰ group and FCD type Ⅱ group in the distribution of cerebral (P =0.002 ).Fourteen cases were found to have hippocampal sclerosis simultaneously,with 13 cases found in FCD type Ⅰ patients and 1 case in type Ⅱ patients.The detection rate of temporal lobe lesion was 65.5 ％ (19/29) and 44.8 ％ ( 13/29 ) respectively on optimized protocol and routine protocol.There was statistically significant difference ( x2 =4.167,P =0.031 ).The detection rate of hippocampal sclerosis was 85.7％ (12/14) and 42.9％ (6/14) respectively on optimized protocol and routine protocol respectively.There was statistically significant difference ( x2 =4.167,P =0.031 ).The detection rate of frontal lobe lesion showed no statistically significant difference between optimized protocols and routine protocols (x2 =0.304,P =1.000 ).Conclusions FCD was frequently involved the temporal lobe,followed by the frontal lobe.FCD type Ⅰ lesion was frequently found in the temporal lobe,with a higher incidence of concomitant hippocampal sclerosis. The optimized whole temporal lobe scanning with imaging plane perpendicular to the hippocampus long axis was a highly desired scanning protocol specifically for FCD,which is helpful for the detection of the FCD lesions. Key words: Cerebral cortex; Nervous system abnormalities; Magnetic resonance imaging

Focal cortical dysplasia (FCD) type II is the leading cause of drug-resistant focal epilepsy in children. While surgical resection offers the only definitive cure, its success is hindered by the challenge of precisely identifying the lesion and its boundaries. Despite advancements in neuroimaging, FCD type II often remains elusive, complicating surgical planning and outcome optimization. Enhanced detection methods are crucial to improving the precision of resection and, ultimately, achieving seizure freedom in affected patients. Advanced techniques for detecting FCD type II margins during surgery are critically needed to enhance postoperative outcomes. Spontaneous Raman spectroscopy is a label-free optical method that allows the characterization of the tissue's biochemical composition. The goal of this proof-of-concept study was to compare-in pediatric patients-the spectral signature of abnormal cells in FCD tissue with cells associated with the normal cortex. A Raman microspectroscopy imaging workflow was developed and applied to 70 surgical specimens from 30 focal epilepsy patients diagnosed with FCD type II. Raman spectra from individual cells were recorded from FCD type II specimens (dysmorphic neurons and balloon cells) and normal brains (neurons). Machine learning models (support vector machines) were trained, validated, and tested to distinguish FCD tissue from the normal brain as well as to distinguish between two disease subtypes, i.e., FCD types IIa and IIb. A total of 1420 single-cell spectra were acquired and spectral differences determined between FCD type II and normal cortex, as well as between FCD type IIa and type IIb. Machine learning distinguished FCD type II from the normal cortex with 96% accuracy, 100% sensitivity, and 95% specificity. FCD types IIa and IIb specimens were distinguished with 92% accuracy, 100% sensitivity, and 86% specificity. The Raman spectroscopy signature of single cells associated with FCD tissue was established. This provides credence to the hypothesis that Raman spectroscopy as a technique-if implemented using a fiber optics system-has the potential for safely optimizing the extent of FCD type II resection in pediatric focal epilepsy surgery. In addition, this technique provides insights into multiple biochemical alterations within dysplastic tissues, which may contribute to the underlying mechanisms of epileptogenesis.

Increased expression of fibroblast growth factor 13 in cortical lesions of the focal cortical dysplasia

Focal cortical dysplasias (FCDs) are increasingly recognized as important causes of medically intractable epilepsy. To understand the potential role of the interleukin 17 (IL-17) system in the epileptogenesis of FCDs, we studied the expression patterns of the IL-17 system in 15 FCD type Ia (FCDIa), 12 FCD type IIa (FCDIIa), and 12 FCD type IIb (FCDIIb) cortical lesions and compared the results with those in cerebral cortex from 10 control patients. Protein levels of IL-17, IL-17 receptor (IL-17R), and downstream factors of the IL-17 pathway (nuclear factor-κB activator 1 [NFκB; ACT1] and NFκB-p65) were markedly elevated in FCDIa, FCDIIa, and FCDIIb. Moreover, protein levels of IL-17 and IL-17R positively correlated with the frequency of seizures in FCD patients. Immunostaining indicated that IL-17 and IL-17R are highly expressed in neuronal microcolumns, dysmorphic neurons, balloon cells, astrocytes, and vascular endothelial cells. Nuclear factor-κB activator 1 and NFκB-p65 were diffusely expressed in FCDs. In addition, we detected a few IL-17-positive, CD4-positive T lymphocytes in FCDIIa and FCDIIb but not in FCDIa. Taken together, these findings suggest that the overexpression of the IL-17 system and the activation of the IL-17 signal transduction pathway may be involved in the epileptogenicity of cortical lesions in FCDs, thus representing a novel potential target for antiepileptic therapy.

Focal cortical dysplasia (FCD) is the main cause of medically intractable pediatric epilepsy. Previous studies have suggested that alteration of cortical interneurons and abnormal cytoarchitecture have been linked to initiation and development for seizure. However, whether each individual subpopulation of cortical interneurons is linked to distinct FCD subtypes remains largely unknown. Here, we retrospectively analyzed both control samples and epileptic specimens pathologically diagnosed with FCD types Ia, IIa, or IIb. We quantified three major interneuron (IN) subpopulations, including parvalbumin (PV)-, somatostatin (Sst)-, and vasoactive intestinal peptide (Vip)-positive INs across all the subgroups. Additionally, we calculated the ratio of the subpopulations of INs to the major INs (mINs) by defining the total number of the PV-, Sst-, and Vip-INs as mINs. Compared with the control, the density of the PV-INs in FCD type IIb was significantly lower, and the ratio of PV/mINs was lower in the superficial part of the cortex of the FCD type Ia and IIb groups. Interestingly, we found a significant increase in the ratio of Vip/mINs only in FCD type IIb. Overall, these results suggest that in addition to a reduction in PV-INs, the increase in Vip/mINs may be related to the initiation of epilepsy in FCD type IIb. Furthermore, the increase in Vip/mINs in FCD type IIb may, from the IN development perspective, indicate that FCD type IIb forms during earlier stages of pregnancy than FCD type Ia.

Focal cortical dysplasia (FCD) is known as a common cause of chronic refractory epilepsy, but the underlying mechanisms of the factors that lead to FCD-related epilepsy are unclear. Previous studies have shown that canonical transient receptor potential channels (TRPCs) might be involved in the process of epileptogenesis. Canonical transient receptor potential channel 1 (TRPC1), which is ubiquitously expressed in the brain, has been shown to be involved in epileptiform bust firing in knockout mice. In this study, we examined the expression of TRPC1 in FCD type Ia (FCDIa), FCD type IIa (FCDIIa), and FCD type IIb (FCDIIb) surgical specimens from patients and age-matched autopsy control samples. Real-time quantitative PCR and western blotting indicated that TRPC1 mRNA and protein levels were increased in FCDIa, FCDIIa, and FCDIIb samples compared to control samples. Immunohistochemistry results revealed that TRPC1 was mainly distributed in microcolumns, dysmorphic neurons, and balloon cells. Further double immunofluorescent staining showed that TRPC1 was co-localized with glutamatergic and GABAergic markers. Taken together, our results demonstrate that the overexpression and specific cellular location of TRPC1 might be related to the epileptogenesis of FCD.

Surgery: All Ages

Objective To summarize MRI findings of focal cortical dysplasia (FCD), analyze MRI characteristics of various pathological subtypes of focal cortical dysplasia. Methods Forty-four patients with FCD were collected. Their MRI findings were analyzed retrospectively. According to pathologic findings, these patients were divided into FCD type Ⅰ group and FCD type Ⅱ group. The following MR signs were observed in the two types of FCD: ( 1 ) Focal thickening of the cortex. ( 2 ) Blurring of the gray matter-white matter junction. ( 3 ) Tapering of white matter signal intensity alteration toward the ventricle on FLAIR and on T2WI. (4)Focal brain hypoplasia. (5)Increased signal intensity of gray matter on FLAIR. (6)Increased signal intensity of gray matter on T2 WI. ( 7 ) Increased signal intensity of subcortical white matter on FLAIR.(8) Increased signal intensity of subeortical white matter on T2WI. (9) Decreased signal intensity of subcortical white matter on T1 WI. The χ2 tests and corrected χ2 tests were used for comparison between the two groups. Results In the 44 cases, there were 30 cases with FCD type Ⅰ and 14 cases with FCD type Ⅱ. FCD was identified by MRI in 32 cases. Blurring of the gray-white matter junction is the most common sign of FCD (23 cases). There were 21 cases identified by MRI in FCD type Ⅰ group. Focal brain hypoplasia is a typical sign of FCD type Ⅰ , which was found in 11 cases in FCD type Ⅰ group but none in FCD type Ⅱ group. There was statistically significant difference between the two groups (continuity corrected χ2 =5. 0286,P =0. 0249) . In FCD type Ⅱ group, 11 cases were identified by MRI. Increased cortical thickness was found in 10 eases in FCD type Ⅱ group and 11 cases in FCD type Ⅰ group ( χ2 =4. 6234 ,P =0. 0315). Increased signal intensity of subcortical white matter on FLAIR was found in 9 cases in FCD type Ⅱ group and 7 cases in FCD type Ⅰ group (χ2 =6.9180,P =0.0085). Tapering of white matter signal intensity alteration toward the ventricle was found in 4 cases in FCD type Ⅱ group and none in FCD type Ⅰ group ( continuity corrected χ2 = 6. 2883, P = 0. 0122). The above-mentioned three MRI findings showed statistically significant difference between the two groups and were features of FCD type Ⅱ.All of the other MRI findings showed no statistically significant difference between the two groups. Conclusions Different pathological subtypes of FCD have different MRI characteristics. It is helpful to make preoperative diagnosis and planning. Key words: Cerebral cortex; Nervous system abnormalities; Magnetic resonance imaging

In the histopathological examination of treatment-resistant epilepsy, focal cortical dysplasia (FCD) is the most common diagnosis in the pediatric group. FCD is classified histopathologically according to the International League Against Epilepsy (ILAE) classification. In the last decade since the ILAE classification has been released, molecular genetic studies have revealed mTOR pathway-related mutations as a major etiology. The objective of this study was to determine the incidence of FCD in treatment-resistant epilepsy patients, explore histomorphological and immunohistochemical features, examine clinicopathological correlation, demonstrate mTOR pathway activation using a pS6 antibody immunohistochemically, and try to introduce a candidate for possible targeted therapies. Paraffin blocks and slides of tissue from patients with treatment-resistant epilepsy were reexamined retrospectively. Histopathological subtypes of FCD were determined according to the ILAE classification. NeuN and neurofilament H (NF-H) staining were performed, and additionally a pS6 antibody was used to demonstrate mTOR pathway activation. In 32 cases diagnosed with FCD, or 17.5% of 183 surgical epilepsy materials, there were no significant differences in the statistical analysis of clinical variables between the ILAE FCD subtypes. Recommended antibody NeuN revealed microcolumnar alignment in the FCD type Ia and IIIa groups and the loss of lamination in the type Ib group. Another recommended antibody, NF-H, was not found to be useful in discriminating between normal and dysmorphic neurons. pS6 expression, showing mTOR pathway activation, was observed in dysmorphic neurons and balloon cells in all FCD type II cases. Significant pS6 expression in FCD type II represents the genomic nature of the disease noted in the literature. Nevertheless, the known MTOR gene and mTOR pathway-related mutations remain behind proportionally to explain the mTOR pathway activation in all FCD type II cases. Clinicopathologically and genetically integrated classification and usage of mTOR pathway inhibitors in treatment are expected as a recent evolution.

Post-surgical outcome for epilepsy associated with type I focal cortical dysplasia subtypes