Altered expression of the Plexin-B2 system in tuberous sclerosis complex and focal cortical dysplasia IIb lesions.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb are the predominant causes of drug-refractory epilepsy in children. Dysmorphic neurons (DNs), giant cells (GCs), and balloon cells (BCs) are the most typical pathogenic profiles in cortical lesions of TSC and FCD IIb patients. However, mechanisms underlying the pathological processes of TSC and FCD IIb remain obscure. The Plexin-B2-Sema4C signalling pathway plays critical roles in neuronal morphogenesis and corticogenesis during the development of the central nervous system. However, the role of the Plexin-B2 system in the pathogenic process of TSC and FCD IIb has not been identified. In the present study, we investigated the expression and cell distribution characteristics of Plexin-B2 and Sema4C in TSC and FCD IIb lesions with molecular technologies. Our results showed that the mRNA and protein levels of Plexin-B2 expression were significantly increased both in TSC and FCD IIb lesions versus that in the control cortex. Notably, Plexin-B2 was also predominantly observed in GCs in TSC epileptic lesions and BCs in FCD IIb lesions. In contrast, the expression of Sema4C, the ligand of Plexin-B2, was significantly decreased in DNs, GCs, and BCs in TSC and FCD IIb epileptic lesions. Additionally, Plexin-B2 and Sema4C were expressed in astrocytes and microglia cells in TSC and FCD IIb lesions. Furthermore, the expression of Plexin-B2 was positively correlated with seizure frequency in TSC and FCD IIb patients. In conclusion, our results showed the Plexin-B2-Sema4C system was abnormally expressed in cortical lesions of TSC and FCD IIb patients, signifying that the Plexin-B2-Sema4C system may play a role in the pathogenic development of TSC and FCD IIb.

Vascular endothelial growth factor-C modulates cortical NMDA receptor activity in cortical lesions of young patients and rat model with focal cortical dysplasia.

Emergence of dysmorphic neurons is the primary pathology in focal cortical dysplasia (FCD) associated pediatric intractable epilepsy; however, the etiologies related to the development and function of dysmorphic neurons are not fully understood. Our previous studies revealed that the expression of vascular endothelial growth factor-C (VEGF-C) and corresponding receptors VEGFR-2, VEGFR-3 was increased in the epileptic lesions of patients with tuberous sclerosis complex or mesial temporal lobe epilepsy. Here, we showed that the expression of VEGF-C, VEGFR-2, and VEGFR-3 was increased at both mRNA and protein levels in patients with cortical lesions of type I, IIa, and IIb FCD. The immunoreactivity of VEGF-C, VEGFR-2 and VEGFR-3 was located in the micro-columnar neurons in FCD type I lesions, dysplastic neurons (DNs) in FCD type IIa lesions, balloon cells (BCs) and astrocytes in FCD type IIb lesions. Additionally, the amplitude of evoked-EPSCs (eEPSC) mediated by NMDA receptor, the ratio of NMDA receptor- and AMPA receptor-mediated eEPSC were increased in the dysmorphic neurons of FCD rats established by prenatal X-ray radiation. Furthermore, NMDA receptor mediated current in dysmorphic neurons was further potentiated by exogenous administration of VEGF-C, however, could be antagonized by ki8751, the blocker of VEGFR-2. These results suggest that VEGF-C system participate in the pathogenesis of cortical lesions in patients with FCD in association with modulating NMDA receptor-mediated currents.

Predictors of Seizure Freedom in Patients Undergoing Surgery for Central Nervous System Infection-Related Epilepsy: A Systematic Review and Meta-Analysis.

Objective: Central nervous system infections (CNSIs), especially viral encephalitis and meningitis, are well-recognized causes of medically refractory epilepsy. Although surgery is an effective and durable intervention against these infections, the seizure control outcomes described in previous surgical series have been variable. Accordingly, it is not clear which variables are most valuable in predicting seizure control following surgery for CNSI. The aim of this meta-analysis was to identify the predictors of favorable surgical outcomes in CNSI-related epilepsy. Methods: The PubMed, EMBASE, Cochrane Library, WANGFANG, VIP, CBM, and CNKI databases were searched for studies according to the inclusion criteria. Prognostic factors, surgical outcomes, and patient characteristics were extracted. Heterogeneity was detected by the I2 and Q statistics. Results: Seventeen studies were included in our meta-analysis. Eight predictors of favorable outcomes (Engel Class I/II) were determined, including abnormal MRI findings, meningitis, temporal location only, regional ictal pattern, unilateral ictal pattern, older age at epilepsy, longer silent period, and longer time from infection, as follows: OR = 3.34 (95% CI 1.44-7.74), OR = 0.31 (95% CI 0.13-0.70), OR = 0.34 (95% CI 0.16-0.74), OR = 5.65 (95% CI 1.75-18.30), and OR = 9.53 (95% CI 2.36-38.48), respectively, and MD = 2.15 (95% CI 0.20-4.11), MD = 2.40 (95% CI 0.09-4.70), and MD = 8.49 (95% CI 1.50-15.48), respectively. A subgroup analysis found the following associations: regional and unilateral ictal patterns in viral encephalitis, a younger age at infection in parasitic encephalopathy, an older age at surgery, a longer time from onset, and a longer time from infection in unexplained meningitis. A sensitivity analysis restricted to studies that included each variable yielded robust results. Little evidence of publication bias was observed. Conclusions: This meta-analysis suggests that abnormal MRI findings, meningitis, temporal location only, regional and unilateral ictal patterns, older age at epilepsy, longer silent period, and longer time from infection are predictive factors in patients with favorable surgical outcomes in CNSI-related epilepsy. In addition, different infective agents influenced the results in regional and unilateral ictal patterns in ictal electroencephalography, as well as the relationship between age at infection and surgery and the time from epilepsy onset and infection.

A novel de novo TSC2 nonsense mutation detected in a pediatric patient with tuberous sclerosis complex.

PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems. The TSC1 and TSC2 genes have been identified as the genetic basis of TSC. Two gene tests were used for definitive genetic diagnosis. METHODS: In our study, the case of a Chinese pediatric patient with seizures, hypomelanotic macules, hyperpigmented patches, multiple parenchymal lesions in the ventricle, and developmental retardation is detailed. Whole-genome sequencing (WGS) and multiplex ligation-dependent probe amplification (MLPA) were employed to detect genetic variations and copy number variations of TSC1 and TSC2. RESULTS: A novel heterozygous nonsense mutation in the TSC2 gene (c.3751A>T, p.Lys1251Ter) was identified in a Chinese pediatric patient suffering from TSC, whose unaffected parents did not carry this mutation. The mutation was classified as "pathogenic" according to the American College of Medical Genetics (ACMG) guidelines. CONCLUSION: WGS was carried out to definitively diagnose and detect variations in the exon and noncoding region of the gene and copy number variations in the whole genome simultaneously. For diseases with complex genetic mechanisms, WGS as the first-line test can be efficient and cost-effective for clinical diagnosis.

Expression of TRPC3 in cortical lesions from patients with focal cortical dysplasia.

Focal cortical dysplasia (FCD) is one of the main causes of medically intractable epilepsy. Some studies have reported that transient receptor potential canonical channel 3 (TRPC3) may play an important role in the occurrence of seizures. In this study, we investigated the expression patterns of TRPC3 in different types of FCD. Forty-five FCD specimens and 12 control samples from autopsies were used in our study. Western blotting, immunohistochemistry, and immunofluorescence staining were employed to detect protein expression and distribution. The amount of TRPC3 protein was markedly elevated in the FCD group. The immunohistochemistry results revealed that TRPC3 staining was strong in the malformed cells and microcolumns. Most of the TRPC3-positive cells were colabeled with glutamatergic and GABAergic markers. The overexpression and altered cellular distribution of TRPC3 in the FCD samples suggest that TRPC3 may be related to epileptogenesis in FCD.

Differential Expression Hallmarks of Interneurons in Different Types of Focal Cortical Dysplasia.

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.

Predictors of seizure recurrence in patients with surgery for focal cortical dysplasia: pairwise and network meta-analysis and trial sequential analysis.

OBJECT: The aim of this study was to determine the predictors of seizure recurrence in surgery for focal cortical dysplasia (FCD) by conducting a meta-analysis. METHODS: Publications that met the pre-stated inclusion criteria were selected from PubMed and CNKI databases. Two authors extracted data independently about prognostic factors, surgical outcome, and clinical characteristics of participants. A fixed-effects model was used to calculate the summary of odds ratio (OR) with 95% confidence interval (CI). RESULTS: Forty-eight studies were included in our meta-analysis. Three predictors of seizure recurrence (Engel class III/IV)-histological FCD type I, incomplete resection, and extratemporal location were determined; combined OR with 95% CI were 1.94 (95%CI 1.53-2.46), 12.06 (95%CI 7.32-19.88), and 1.91 (95%CI 1.06-3.44), respectively. Trial sequential analysis revealed that the outcomes had a sufficient sample size to reach firm conclusions. Furthermore, seizure location was not substantially modified by geographic region, while histological FCD type I and incomplete resection showed a significant association with seizure recurrence in different continents except Asia for incomplete resection. Sensitivity analyses restricted to studies for each variable yielded robust results. Little evidence of publication bias was observed. Meanwhile, the difference in the standard for outcome failed to influence the results for prognosis. Network meta-analysis including 13 trials comparing subtypes of FCD found the FCD IIb had the lowest seizure recurrence rate. CONCLUSIONS: This meta-analysis suggests that histological FCD type I, incomplete resection, and extratemporal location are recurrence factors in patients with epilepsy surgery for FCD. In addition, FCD IIb is associated with the highest rates of postoperative seizure control among the subtypes of FCD, type I and type II.

Elevated Expression of TRPC4 in Cortical Lesions of Focal Cortical Dysplasia II and Tuberous Sclerosis Complex.

Focal cortical dysplasia type II (FCD II) and tuberous sclerosis complex (TSC) are well-known causes of chronic refractory epilepsy in children. Canonical transient receptor potential channels (TRPCs) are non-selective cation channels that are commonly activated by phospholipase C (PLC) stimulation. Previous studies found that TRPC4 may participate in the process of epileptogenesis. This study aimed to examine the expression and distribution of TRPC4 in FCD II (n = 24) and TSC (n = 11) surgical specimens compared with that in age-matched autopsy control samples (n = 12). We found that the protein levels of TRPC4 and its upstream factor, PLC delta 1 (PLCD1), were elevated in FCD II and TSC samples compared to those of control samples. Immunohistochemistry assays revealed that TRPC4 staining was stronger in malformed cells, such as dysmorphic neurons, balloon cells and giant cells. Moderate-to-strong staining of the upstream factor PLCD1 was also identified in abnormal neurons. Moreover, double immunofluorescence staining revealed that TRPC4 was colocalised with glutamatergic and GABAergic neuron markers. Taken together, our results indicate that overexpression of TRPC4 protein may be involved in the epileptogenesis of FCD II and TSC.

Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex.

BACKGROUND: Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are well-recognized causes of chronic intractable epilepsy in children. Accumulating evidence suggests that activation of the microglia/macrophage and concomitant inflammatory response in FCD IIb and TSC may contribute to the initiation and recurrence of seizures. The membrane glycoproteins CD47 and CD200, which are highly expressed in neurons and other cells, mediate inhibitory signals through their receptors, signal regulatory protein α (SIRP-α) and CD200R, respectively, in microglia/macrophages. We investigate the levels and expression pattern of CD47/SIRP-α and CD200/CD200R in surgically resected brain tissues from patients with FCD IIb and TSC, and the potential effect of soluble human CD47 Fc and CD200 Fc on the inhibition of several proinflammatory cytokines associated with FCD IIb and TSC in living epileptogenic brain slices in vitro. The level of interleukin-4 (IL-4), a modulator of CD200, was also investigated. METHODS: Twelve FCD IIb (range 1.8-9.5 years), 13 TSC (range 1.5-10 years) patients, and 6 control cases (range 1.5-11 years) were enrolled. The levels of CD47/SIRP-α and CD200/CD200R were assessed by quantitative real-time polymerase chain reaction and western blot. The expression pattern of CD47/SIRP-α and CD200/CD200R was investigated by immunohistochemical analysis, and the cytokine concentrations were measured by enzyme-linked immune-sorbent assays. RESULTS: Both the messenger RNA and protein levels of CD47, SIRP-α, and CD200, as well as the mRNA level of IL-4, were downregulated in epileptogenic lesions of FCD IIb and TSC compared with the control specimens, whereas CD200R levels were not significantly changed. CD47, SIRP-α, and CD200 were decreasingly expressed in dysmorphic neuron, balloon cells, and giant cells. CD47 Fc and CD200 Fc could inhibit IL-6 release but did not suppress IL-1ß or IL-17 production. CONCLUSIONS: Our results suggest that microglial activation may be partially caused by CD47/SIRP-α- and CD200/CD200R-mediated reductions in the immune inhibitory pathways within FCD IIb and TSC cortical lesions where chronic neuroinflammation has been established. Upregulation or activation of CD47/SIRP-α and CD200/CD200R may have therapeutic potential for controlling neuroinflammation in human FCD IIb and TSC.

Increased Expression of Transient Receptor Potential Vanilloid 4 in Cortical Lesions of Patients with Focal Cortical Dysplasia.

AIM: Focal cortical dysplasia (FCD) represents a well-known cause of medically intractable epilepsy. Studies found that transient receptor potential vanilloid receptor 4 (TRPV4) may participate in the occurrence of seizures. This study investigated the expression patterns of TRPV4 in FCD and the cascade that regulate functional state of TRPV4 in cortical neurons. METHODS: Thirty-nine surgical specimens from FCD patients and 10 age-matched control samples from autopsies were included in this study. Protein expression and distribution were detected by Western blot, immunohistochemistry, and immunofluorescence staining. Calcium imaging was used to detect the TRPV4-mediated Ca(2+) influx in cortical neurons. RESULTS: (1) The protein levels of TRPV4 and of an upstream factor, protein kinase C (PKC), were markedly elevated in FCD. (2) TRPV4 staining was stronger in the dysplastic cortices of FCD and mainly observed in neuronal microcolumns and malformed cells. (3) The activation of TRPV4 was central for [Ca(2+)]i elevation in cortical neurons, and this activity of TRPV4 in cortical neurons was regulated by the PKC, but not the PKA, pathway. CONCLUSION: The overexpression and altered cellular distribution of TRPV4 in FCD suggest that TRPV4 may potentially contribute to the epileptogenesis of FCD.

Increased Expression and Cellular Localization of P2X7R in Cortical Lesions of Patients With Focal Cortical Dysplasia.

Focal cortical dysplasias (FCDs) are major brain malformations that commonly lead to medically intractable epilepsy. The purinergic ionotropic P2X7 receptor (P2X7R) is an atypical P2X subtype that gates calcium and sodium ions. Previous animal studies have suggested that P2X7R is a contributing factor in epileptogenesis. This study aimed to define the distribution and expression of P2X7R in 35 FCD patient-surgical-resection specimens relative to autopsy control samples (n = 8). Immunohistochemical colocalization assays revealed that P2X7R was primarily expressed in neurons, astrocytes, and microglia. In FCD samples, P2X7R protein levels were increased in abnormal cell types such as dysmorphic neurons and balloon cells, which are characteristic of FCD. By real-time PCR and Western blotting, P2X7R mRNA and protein expression levels were elevated in FCD patient samples vs control samples; P2X7R expression was also higher in FCDII vs FCDIa patient samples. Because interleukin-1ß is a downstream factor of the P2X7R signaling pathway, we determined that there was also moderate-to-strong interleukin-1ß expression in the dysmorphic neurons, balloon cells, and microglia in FCD patient lesions. These results indicate that increasing P2X7R levels may contribute to the pathogenesis of human FCD and that P2X7R represents a potential anti-epileptogenic target.

Clinical outcomes and quality of life following surgical treatment for refractory epilepsy: a systematic review and meta-analysis.

Surgery for refractory epilepsy is widely used but the efficacy of this treatment for providing a seizure-free outcome and better quality of life remains unclear.This study aimed to update current evidence and to evaluate the effects of surgery on quality of life in patients with refractory epilepsy.A systematic review and meta-analysis of the literature were conducted and selected studies included 2 groups of refractory epilepsy patients, surgical and nonsurgical.The studies were assessed using the Newcastle-Ottawa Scale. The primary outcome was the seizure-free rate. The secondary outcome was quality of life. Adverse events were also reviewed.After screening, a total of 20 studies were selected: 8 were interventional, including 2 randomized controlled trials, and 12 were observational. All of the studies comprised 1959 patients with refractory epilepsy. The seizure-free rates were significantly higher for patients who received surgery compared with the patients who did not; the combined odds ratio was 19.35 (95% CI = 12.10-30.95, P < 0.001). After adjusting for publication bias the combined odds ratio was 10.25 (95% CI = 5.84-18.00). In both the interventional and observational studies, patients treated surgically had a significantly better quality of life compared with the patients not treated surgically. Complications were listed in 3 studies and the rates were similar in surgical and nonsurgical patients.Our meta-analysis found that for patients with refractory epilepsy, surgical treatment appears to provide a much greater likelihood of seizure-free outcome than nonsurgical treatment, although there is a need for more studies, particularly randomized studies, to confirm this conclusion. Based on more limited data, surgical treatment also appeared to provide a better quality of life and did not seem to increase complications.

Down-regulated expression of acid-sensing ion channel 1a in cortical lesions of patients with focal cortical dysplasia.

Focal cortical dysplasia (FCD) represents a well-recognized cause of medically intractable epilepsy. Previous studies have indicated that seizures can reduce brain pH and then eliminate seizure discharges. Acid-sensing ion channels (ASICs) are H(+)-gated cation channels that are widely expressed in the central and peripheral nervous systems. To understand the potential roles of ASIC1a in the epileptogenesis of FCD, we investigated the expression and distribution patterns of ASIC1a in surgical specimens from patients with FCD and age-matched normal cortices (CTX). Decreased ASIC1a messenger RNA (mRNA) and protein expression were detected in FCD compared with CTX. Moreover, the expression of ASIC1a was significantly lower in FCD type II than FCD type I. Immunohistochemistry results indicated that the overall immunoreactivity of the ASIC1a staining was diminished in the dysplastic cortices of FCD compared to the CTX samples. In FCD, ASIC1a immunoreactivity was mainly observed in reactive astrocytes and a minority of malformed cells, including hypertrophic neurons, dysmorphic neurons, and balloon cells. Confocal analysis demonstrated that most malformed cells expressing ASIC1a were co-labeled with neuronal rather than astrocytic markers, indicating a neuronal lineage. In conclusion, the downregulation and altered cellular distribution of ASIC1a in FCD suggest that ASIC1a may potentially contribute to the epileptogenesis of FCD.

Expression and cellular distribution of the interleukin 2 signaling system in cortical lesions from patients with focal cortical dysplasia.

Focal cortical dysplasia (FCD) is a well-known cause of medically intractable epilepsy. To understand the potential role of the inflammatory cytokine interleukin 2 (IL-2) in the pathogenesis of FCD, we investigated the expression patterns of IL-2 and its receptors (IL-2Rs) in FCD and control samples that included epileptic neocortex from mesial temporal lobe epilepsy patients and nonepileptic normal cortex (CTX). Greater mRNA and protein levels of IL-2 and IL-2Rs were observed in FCD versus CTX samples. Moreover, the expression of IL-2 and IL-2Rs was significantly higher in FCD II than FCD I. In situ hybridization and immunohistochemistry results indicated that IL-2 and IL-2Rs were strongly expressed in hypertrophic neurons and neuronal microcolumns in FCD I and highly expressed in malformed cells in FCD II. In addition, the protein levels of Janus kinase 1, Janus kinase 3, phosphorylated signal transducer and activator of transcription 5, which are important downstream factors in the IL-2 signaling pathway, were increased in FCD lesions. Soluble IL-2R was decreased in FCD compared with that in CTX samples. These results suggest that upregulation of IL-2 and IL-2Rs combined with activation of IL-2-dependent signaling pathways may contribute to the pathogenesis of FCD.

Endogenous subventricular zone neural progenitors contribute to the formation and hyperexcitability of experimental model of focal microgyria.

Microgyria is associated with epilepsy and due to developmental disruption of neuronal migration. However, the role of endogenous subventricular zone-derived neural progenitors (SDNPs) in formation and hyperexcitability has not been fully elucidated. Here, we establish a neonatal cortex freeze-lesion (FL) model, which was considered as a model for focal microgyria, and simultaneously label SDNPs by CM-DiI. Morphological investigation showed that SDNPs migrated into FL and differentiated into neuronal and glia cell types, suggesting the involvement of endogenous SDNPs in the formation of FL-induced microgyria. Patch-clamp recordings in CM-DiI positive (CM-DiI(+)) pyramidal neurons within FL indicated an increase in frequency of spontaneous action potentials, while the resting membrane potential did not differ from the controls. We also found that spontaneous excitatory postsynaptic currents (EPSCs) increased in frequency but not in amplitude compared with controls. The evoked EPSCs showed a significant increase of 10-90% in rise time and decay time in the CM-DiI(+) neurons. Moreover, paired-pulse facilitation was dramatically larger in CM-DiI(+) pyramidal neurons. Western blotting data showed that AMPA and NMDA receptors were increased to some extent in the FL cortex compared with controls, and the NMDA/AMPA ratio of eEPSCs at CM-DiI(+) pyramidal neurons was significantly increased. Taken together, our findings provide novel evidence for the contribution of endogenous SDNPs in the formation and epileptogenicity of FL-induced focal microgyria.

Expression of the interleukin 17 in cortical tubers of the tuberous sclerosis complex.

The role of interleukin 17 (IL-17) to epilepsy-associated cortical tubers of tuberous sclerosis complex (TSC) is unknown. We investigated the expression patterns of the IL-17 and IL-17 receptor (IL-17R) in cortical tubers of TSC compared with normal control cortex (CTX). We found that IL-17 and IL-17R were clearly upregulated in cortical tubers at the protein levels. Immunostaining indicated that IL-17 was specifically distributed in the innate immunity cells (DNs, GCs, astrocytes, and microglia) and adaptive immunity cells (T-lymphocytes) as well as the endothelial cells of blood vessels. The overexpression and distribution patterns of IL-17 may be involved in the epileptogenicity of cortical tubers in TSC.

The interleukin 17 system in cortical lesions in focal cortical dysplasias.

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.

Expression of TRPV1 in cortical lesions from patients with tuberous sclerosis complex and focal cortical dysplasia type IIb.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCDIIb) are recognized as causes of intractable epilepsy. Transient receptor potential vanilloid receptor 1 (TRPV1), a member of the transient receptor potential family, is the capsaicin receptor and is known to be involved in peripheral nociception. Recent evidence suggested that TRPV1 may be a contributing factor in epileptogenicity. Here, we evaluated the expression of TRPV1 in the cortical lesions of TSC and FCDIIb relative to normal control cortex. TRPV1 was studied in epilepsy surgery cases with TSC (cortical tubers; n=12) and FCDIIb (n=12) using immunocytochemistry, confocal analysis, and Western blotting (WB). Immunohistochemical location of the TRPV1 was predominately detected in the abnormal cell types, such as dysmorphic neurons, balloon cells (BCs) and giant cells. Co-localization assays further revealed that cells expressing TRPV1 mainly had a neuronal lineage, apart from some BCs in FCDIIb, which obviously were of astrocytic lineage. The increased TRPV1 expression within the dysplastic cortex of TSC and FCDIIb was confirmed by WB. Interestingly, both immunohistochemical and WB data indicated that TRPV1 might have both cytoplasm and nuclear distribution, suggesting a potential nuclear role of TRPV1. The over-expression of TRPV1 in cortical lesions of TSC and FCDIIb suggested the possible involvement of TRPV1 in the intrinsic and increased epileptogenicity of malformations of cortical development associated epilepsy diseases and may represent a potential antiepileptogenic target. However, the current data are merely descriptive, and further electrophysiological investigation is needed in the future.

Expression of the Nogo-A system in cortical lesions of pediatric patients with tuberous sclerosis complex and focal cortical dysplasia type IIb.

The reticulon protein Nogo-A is an important regulator of neurite growth, axonal plasticity, and cell migration in the central nervous system. Previous studies have shown markedly elevated levels of Nogo-A in human temporal lobe epilepsy. In the present study, we examined the expression pattern of the Nogo-A system in cortical lesions of pediatric patients with tuberous sclerosis complex and focal cortical dysplasia type IIb. These disorders are characterized by malformations of cortical development and are frequently associated with intractable epilepsy. We found that the messenger RNA and protein levels of the Nogo-A receptor (NgR) and the downstream targets of Nogo-A, LINGO-1, TROY, and RhoA but not P75 were upregulated in the cortices of patients compared with autopsy control samples. Immunohistochemical analyses indicated that Nogo-A and NgR were strongly expressed in misshapen cells, particularly dysmorphic neurons, balloon cells, and giant cells. TROY was diffusely expressed in the malformations of cortical development. Most of theNogo-A/NgR-positive misshapen cells were colabeled with neuronal rather than astrocytic markers. Taken together, our results suggestthat the activation of Nogo-A via the NgR/LINGO-1/TROY signal transduction pathways, but not NgR/LINGO-1/P75, may be involved in the development and/or seizure activity of cortical lesions in tuberous sclerosis complex and focal cortical dysplasia type IIb.

Surgical treatment of patients with Lennox-Gastaut syndrome phenotype.

Lennox-Gastaut syndrome (LGS) is a devastating and refractory generalized epilepsy affecting children and adolescents. In this study we report the results of resective surgery in 18 patients with LGS phenotype who underwent single-lobe/lesionectomy or multilobe resection plus multiple subpial transection and/or callosotomy. After surgery, seven patients became completely seizure-free (Engel Class I) and five almost seizure-free (Engel Class II). Additional four had significant seizure control (Engel Class III), and two had no change in seizure frequency (Engel Class IV). Of the 4 patients without any lesion on brain MRI, 2 ended with Engel Class II, 1 with III and the other with IV in Engels' classification. Mean intelligence quotient (IQ) increased from 56.1 ± 8.1 (mean ± SD) before operation to 67.4 ± 8.2 (mean ± SD) after operation, a significant improvement (P = 0.001). Results also indicated that the younger the patient at surgery, or the shorter the interval between onset of seizure and resective operation, the better the intellectual outcome. Our data suggest that resective epilepsy surgery can be successful in patients with LGS phenotype as long as the EEG shows dominance of discharges in one hemisphere and corresponding ipsilateral imaging findings, even with contralateral ictal discharges.