Glioma-associated Epilepsy Research Articles

Unexplained Causes of Glioma-Associated Epilepsies: A Review of Theories and an Area for Research

Approximately 30% of glioma patients are able to survive beyond one year postdiagnosis. And this short time is often overshadowed by glioma-associated epilepsy. This condition severely impairs the patient’s quality of life and causes great suffering. The genetic, molecular and cellular mechanisms underlying tumour development and epileptogenesis remain incompletely understood, leading to numerous unanswered questions. The various types of gliomas, namely glioblastoma, astrocytoma and oligodendroglioma, demonstrate distinct seizure susceptibility and disease progression patterns. Patterns have been identified in the presence of IDH mutations and epilepsy, with tumour location in cortical regions, particularly the frontal lobe, showing a more frequent association with seizures. Altered expression of TP53, MGMT and VIM is frequently detected in tumour cells from individuals with epilepsy associated with glioma. However, understanding the pathogenesis of these modifications poses a challenge. Moreover, hypoxic effects induced by glioma and associated with the HIF-1a factor may have a significant impact on epileptogenesis, potentially resulting in epileptiform activity within neuronal networks. We additionally hypothesise about how the tumour may affect the functioning of neuronal ion channels and contribute to disruptions in the blood–brain barrier resulting in spontaneous depolarisations.

CNSC-29. NKCC1 SIGNALING IN GLIOBLASTOMA REGULATES NEURONAL HYPEREXCITABILITY THROUGH GABAERGIC TONE

Abstract Over 90% of patients with glioma experience tumor-associated epilepsy, however first-line treatment fails to control seizures in most patients. Thus, there is a critical need to identify novel drivers of glioblastoma-induced neuronal hyperexcitability. We therefore used high-density electrode arrays to record local field potentials in vivo from gliomas. We then developed cerebral organoid and mouse models using primary glioblastoma cells from patients and neurons derived from induced pluripotent stem cells. Single-cell RNA sequencing (13,730 cells analyzed) in this system identified genes elevated in glioma-intrinsic neurons, including the sodium-potassium-chloride co-transporter 1 (NKCC1), which mediates chloride (Cl-) influx into cells. This elevated NKCC1 expression and subsequent increase of intracellular Cl- sets the reversal potential of GABAAR-mediated currents promoting depolarizing excitatory GABAergic responses. Electrophysiological analysis of glioma-neuron co-cultures using multi-electrode array and live-cell calcium imaging demonstrated increased network burst synchrony in the presence of NKCC1-high expressing tumor cells. Single-nucleus sequencing (54,000 cells analyzed) of embryonic neurons in co-culture with GBM cells further confirmed the elevated expression of circuit assembly genes including neuronal NKCC1. Live-cell imaging of iPSC-induced neuron organoids co-cultured with NKCC1-high-and low-GBM cells revealed increased migration and integration of NKCC1-elevated tumor cells. Mechanistic and functional studies validating therapeutic vulnerabilities to NKCC1 silencing by shRNA knockdown and by the FDA-approved diuretic drug, bumetanide was performed in vitro. The reduction in neuronal synchrony induced by NKCC1 downregulation correlated with a decrease in extracellular GABA and glutamate, suggesting a strong association between excitatory GABAergic and glutamate signaling with neuronal hypersynchrony in glioblastoma. Patient-derived xenograft in vivo experiments evaluated the effect of NKCC1 on tumor growth and progression and NKCC1-high GBM cells exhibited greater tumor burden compared to control mice. Collectively, these findings reveal a novel mechanism driving neuronal hyperactivity in glioblastoma and identifies potential therapeutic vulnerabilities for the treatment of glioma-associated epilepsy.

A novel deep learning model for glioma epilepsy associated with the identification of human cytomegalovirus infection injuries based on head MR.

In this study, a deep learning model was established based on head MRI to predict a crucial evaluation parameter in the assessment of injuries resulting from human cytomegalovirus infection: the occurrence of glioma-related epilepsy. The relationship between glioma and epilepsy was investigated, which serves as a significant indicator of labor force impairment. This study enrolled 142 glioma patients, including 127 from Shengjing Hospital of China Medical University, and 15 from the Second Affiliated Hospital of Dalian Medical University. T1 and T2 sequence images of patients' head MRIs were utilized to predict the occurrence of glioma-associated epilepsy. To validate the model's performance, the results of machine learning and deep learning models were compared. The machine learning model employed manually annotated texture features from tumor regions for modeling. On the other hand, the deep learning model utilized fused data consisting of tumor-containing T1 and T2 sequence images for modeling. The neural network based on MobileNet_v3 performed the best, achieving an accuracy of 86.96% on the validation set and 75.89% on the test set. The performance of this neural network model significantly surpassed all the machine learning models, both on the validation and test sets. In this study, we have developed a neural network utilizing head MRI, which can predict the likelihood of glioma-associated epilepsy in untreated glioma patients based on T1 and T2 sequence images. This advancement provides forensic support for the assessment of injuries related to human cytomegalovirus infection.

SDPS-45 PROGNOSTIC CHARACTERIZATION OF GENETIC MARKERS IN GLIOMA-ASSOCIATED EPILEPSY

Abstract BACKGROUND High-grade gliomas are often associated with seizures, which impair quality of life and cause deleterious neurocognitive effects. Few molecular markers characterized in high-grade gliomas have prognostic capacity for glioma-associated epilepsy. Mutations in isocitrate-dehydrogenase 1 (IDH1) have been associated with glioma-associated epilepsy (Chen et al. Neurology 2017;88(19):1805–13), but other genetic and cell proliferation markers in glioma biopsies have inconclusive connections with glioma-associated epilepsy. Current AAN guidelines advise against prophylactic administration of anti-seizure medications in patients with newly diagnosed brain tumors. We sought to characterize common molecular markers in high-grade glioma-associated epilepsy. METHODS We retrospectively reviewed 241 patients diagnosed with grade IV gliomas between 2018 and 2021 at our institution. Analysis of genetic biomarkers in tumor biopsies included chromosome 1p/19q deletion, ki-67 expression, p53 expression, MGMT methylation, IDH1 mutation, and EGFR amplification. Multiple logistic regressions were utilized to examine the association between genetic biomarkers and seizure incidence at three intervals: preoperative, postoperative, and six months post-surgery. Other variables examined were age, tumor location (lobe, laterality, eloquence), and treatment type (radiation therapy, chemotherapy, immunotherapy). RESULTS Of 241 patients analyzed, 104 (43%) patients experienced seizures. EGFR amplification in high-grade gliomas was associated with preoperative seizures (β = .92, p = .013) but was not associated with postoperative seizures nor seizures six months post-surgery. Chromosome 1p/19q deletion, ki-67 expression, p53 expression, MGMT methylation, and IDH1 mutation were all not associated with seizure incidence. CONCLUSION The study results indicate that EGFR amplification is associated with preoperative seizures, suggesting EGFR to promote glioma epileptiform activity. As EGFR amplification is characteristic of the classical subtype of glioblastoma, these results further suggest that the pathogenesis of glioma-associated epilepsy is likely related to specific molecular tumor characteristics. These preliminary results will be expanded upon with further analyses that increase sample size and include next-generation sequencing RESULTS

Infraclavicular de novo placement of a responsive neurostimulator for a patient with eloquent glioma-associated epilepsy: illustrative case.

The authors present a 50-year-old female with high-grade glioma involving the motor cortex as the cause of her drug-resistant epilepsy (DRE). Responsive neurostimulation (RNS) was chosen for epilepsy treatment. Due to concerns regarding the generator impeding the regular imaging surveillance required for treatment and monitoring of her glioma, surgeons placed the internal pulse generator (IPG) within an infraclavicular chest pocket. Implantation of the RNS device and IPG within the infraclavicular pocket was uneventful. However, both subdural and depth electrodes were used and connected to the IPG, and subdural electrodes are considerably shorter than depth electrodes (37 vs 44 cm). The shorter strip leads presumably generated significant tension, leading to fracture of the leads. Therefore, surgery was repeated using only depth electrodes for more length and less tension. The device has good-quality electrocorticography signals that continue to be used for device programming. The seizure burden was reduced, and quality of life improved for the patient. The RNS system with infraclavicular IPG placement reduced the seizure burden and improved the quality of life of a patient with glioma-associated epilepsy. Surgeons may consider the infraclavicular location as an alternative site for implantation for RNS candidates who require recurrent intracranial magnetic resonance imaging.

Interactions between astrocytes and extracellular matrix structures contribute to neuroinflammation-associated epilepsy pathology.

Often considered the "housekeeping" cells of the brain, astrocytes have of late been rising to the forefront of neurodegenerative disorder research. Identified as crucial components of a healthy brain, it is undeniable that when astrocytes are dysfunctional, the entire brain is thrown into disarray. We offer epilepsy as a well-studied neurological disorder in which there is clear evidence of astrocyte contribution to diseases as evidenced across several different disease models, including mouse models of hippocampal sclerosis, trauma associated epilepsy, glioma-associated epilepsy, and beta-1 integrin knockout astrogliosis. In this review we suggest that astrocyte-driven neuroinflammation, which plays a large role in the pathology of epilepsy, is at least partially modulated by interactions with perineuronal nets (PNNs), highly structured formations of the extracellular matrix (ECM). These matrix structures affect synaptic placement, but also intrinsic neuronal properties such as membrane capacitance, as well as ion buffering in their immediate milieu all of which alters neuronal excitability. We propose that the interactions between PNNs and astrocytes contribute to the disease progression of epilepsy vis a vis neuroinflammation. Further investigation and alteration of these interactions to reduce the resultant neuroinflammation may serve as a potential therapeutic target that provides an alternative to the standard anti-seizure medications from which patients are so frequently unable to benefit.

Potentials of miR-9-5p in promoting epileptic seizure and improving survival of glioma patients

BackgroundEpilepsy affects over 70 million people worldwide; however, the underlying mechanisms remain unclear. MicroRNAs (miRNAs) have essential functions in epilepsy. miRNA-9, a brain-specific/enriched miRNA, plays a role in various nervous system diseases and tumors, but whether miRNA-9 is involved in epilepsy and glioma-associated epilepsy remains unknown. Therefore, we aimed to explore the potential role of miR-9-5p in seizures and its effect on the survival of glioma patients, in order to provide new targets for the treatment of epilepsy and glioma.MethodsThe YM500v2 database was used to validate the expression of hsa-miR-9-5p in tissues. Moreover, qRT-PCR was performed to investigate the expression of miR-9-5p in temporal lobe epilepsy patients and rats with lithium-pilocarpine-induced seizures. Recombinant adeno-associated virus containing miR-9-5p was constructed to overexpress miR-9-5p in vivo. The effects of miR-9-5p on the behavior and electroencephalographic activities of the lithium-pilocarpine rat model of epilepsy were tested. Bioinformatics analysis was used to predict the targets of miR-9-5p and explore its potential role in epilepsy and glioma-associated epilepsy.ResultsThe expression of miR-9-5p increased at 6 h and 7 days after lithium-pilocarpine-induced seizures in rats. Overexpression of miR-9-5p significantly shortened the latency of seizures and increased seizure intensity at 10 min and 20 min after administration of pilocarpine (P < 0.05). Predicted targets of miR-9-5p were abundant and enriched in the brain, and affected various pathways related to epilepsy and tumor. Survival analysis revealed that overexpression of miR-9-5p significantly improved the survival of patients from with low-grade gliomas and glioblastomas. The involvement of miR-9-5p in the glioma-associated epileptic seizures and the improvement of glioma survival may be related to multiple pathways, including the Rho GTPases and hub genes included SH3PXD2B, ARF6, and ANK2.ConclusionsmiR-9-5p may play a key role in promoting epileptic seizures and improving glioma survival, probably through multiple pathways, including GTPases of the Rho family and hub genes including SH3PXD2B, ARF6 and ANK2. Understanding the roles of miR-9-5p in epilepsy and glioma and the underlying mechanisms may provide a theoretical basis for the diagnosis and treatment of patients with epilepsy and glioma.

Does epilepsy always indicate worse outcomes? A longitudinal follow-up analysis of 485 glioma patients

BackgroundEpilepsy is one of the most common glioma complications, and the two may be connected in more ways than we understand. We aimed to investigate the clinical features of glioma-associated epilepsy and explore the risk factors associated with it.MethodsWe collected clinical information from 485 glioma patients in the Nanjing Brain Hospital and conducted 4 periodic follow-up visits. Based on the collected data, we analyzed the clinical characteristics of glioma patients with or without epilepsy and their relationship with survival.ResultsAmong glioma patients, younger people were more likely to have epilepsy. However, epilepsy incidence was independent of gender. Patients with grade II gliomas were most likely to develop epilepsy, while those with grade IV gliomas were least likely. There was no difference in Karnofsky Performance Status scores between patients with glioma-associated epilepsy and those without epilepsy. Additionally, epilepsy was independently associated with longer survival in the World Health Organization grade IV glioma patients. For grades II, III, and IV tumors, the 1-year survival rate of the epilepsy group was higher than that of the non-epilepsy group.ConclusionsEpilepsy did not lead to worse admission performance and correlated with a better prognosis for patients with grade IV glioma.

Radiomics Nomogram Improves the Prediction of Epilepsy in Patients With Gliomas.

PurposeTo investigate the association between clinic-radiological features and glioma-associated epilepsy (GAE), we developed and validated a radiomics nomogram for predicting GAE in WHO grade II~IV gliomas.MethodsThis retrospective study consecutively enrolled 380 adult patients with glioma (266 in the training cohort and 114 in the testing cohort). Regions of interest, including the entire tumor and peritumoral edema, were drawn manually. The semantic radiological characteristics were assessed by a radiologist with 15 years of experience in neuro-oncology. A clinic-radiological model, radiomic signature, and a combined model were built for predicting GAE. The combined model was visualized as a radiomics nomogram. The AUC was used to evaluate model classification performance, and the McNemar test and Delong test were used to compare the performance among the models. Statistical analysis was performed using SPSS software, and p < 0.05 was regarded as statistically significant.ResultsThe combined model reached the highest AUC with the testing cohort (training cohort, 0.911 [95% CI, 0.878–0.942]; testing cohort, 0.866 [95% CI, 0.790–0.929]). The McNemar test revealed that the differences among the accuracies of the clinic-radiological model, radiomic signature, and combined model in predicting GAE in the testing cohorts (p > 0.05) were not significantly different. The DeLong tests showed that the difference between the performance of the radiomic signature and the combined model was significant (p < 0.05).ConclusionThe radiomics nomogram predicted seizures in patients with glioma non-invasively, simply, and practically. Compared with the radiomics models, comprehensive clinic-radiological imaging signs observed by the naked eye have non-discriminatory performance in predicting GAE.

Radiomics for the Prediction of Epilepsy in Patients With Frontal Glioma.

ObjectiveThis study was conducted in order to investigate the association between radiomics features and frontal glioma-associated epilepsy (GAE) and propose a reliable radiomics-based model to predict frontal GAE.MethodsThis retrospective study consecutively enrolled 166 adult patients with frontal glioma (111 in the training cohort and 55 in the testing cohort). A total 1,130 features were extracted from T2 fluid-attenuated inversion recovery images, including first-order statistics, 3D shape, texture, and wavelet features. Regions of interest, including the entire tumor and peritumoral edema, were drawn manually. Pearson correlation coefficient, 10-fold cross-validation, area under curve (AUC) analysis, and support vector machine were adopted to select the most relevant features to build a clinical model, a radiomics model, and a clinical–radiomics model for GAE. The receiver operating characteristic curve (ROC) and AUC were used to evaluate the classification performance of the models in each cohort, and DeLong’s test was used to compare the performance of the models. A two-sided t-test and Fisher’s exact test were used to compare the clinical variables. Statistical analysis was performed using SPSS software (version 22.0; IBM, Armonk, New York), and p <0.05 was set as the threshold for significance.ResultsThe classification accuracy of seven scout models, except the wavelet first-order model (0.793) and the wavelet texture model (0.784), was <0.75 in cross-validation. The clinical–radiomics model, including 17 magnetic resonance imaging-based features selected among the 1,130 radiomics features and two clinical features (patient age and tumor grade), achieved better discriminative performance for GAE prediction in both the training [AUC = 0.886, 95% confidence interval (CI) = 0.819–0.940] and testing cohorts (AUC = 0.836, 95% CI = 0.707–0.937) than the radiomics model (p = 0.008) with 82.0% and 78.2% accuracy, respectively.ConclusionRadiomics analysis can non-invasively predict GAE, thus allowing adequate treatment of frontal glioma. The clinical–radiomics model may enable a more precise prediction of frontal GAE. Furthermore, age and pathology grade are important risk factors for GAE.

Angiocentric glioma-associated seizures: The possible role of EATT2, pyruvate carboxylase and glutamine synthetase

PurposeOur purpose was to better understand the pathogenesis of seizures associated with angiocentric glioma. Angiocentric glioma is an indolent and rare low-grade glioma. Its typical clinical presentation is with epileptic seizures. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathomechanisms, the increased neurotoxic concentrations of the glutamate has been proposed. Glutamate transporters, pyruvate carboxylase and glutamine synthetase are involved in maintaining the physiological concentration of glutamate in the inter synaptic spaces. MethodsWe evaluated the immunohistochemical expression of EAAT2 (the most important glutamate transporter), pyruvate carboxylase and glutamine synthetase in 17 angiocentric gliomas. ResultsEAAT2 was never expressed (0%) in the neoplastic cells in none of the cases studied. Pyruvate carboxylase was expressed in the cytoplasm of the neoplastic cells in 16/17 cases (94 %). Glutamine synthetase was expressed in the cytoplasm of the neoplastic cells in 15/17 cases (88 %). ConclusionThe net result of this enzymatic expression, in particular considering the loss of EAAT2, could be an increased glutamate concentration in the synaptic clef, which might increase local network excitability initially involving intratumoral neurons. The observation that the angiocentric glioma-associated epilepsy might be at least in part related to EAAT2 deficiency opens up interesting therapeutic perspectives.

Molecular insights into the role of AMPA receptors in the synaptic plasticity, pathogenesis and treatment of epilepsy: therapeutic potentials of perampanel and antisense oligonucleotide (ASO) technology.

Glutamate is considered as the predominant excitatory neurotransmitter in the mammalian central nervous systems (CNS). Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the main glutamate-gated ionotropic channels that mediate the majority of fast synaptic excitation in the brain. AMPARs are highly dynamic that constitutively move into and out of the postsynaptic membrane. Changes in the postsynaptic number of AMPARs play a key role in controlling synaptic plasticity and also brain functions such as memory formation and forgetting development. Impairments in the regulation of AMPAR function, trafficking, and signaling pathway may also contribute to neuronal hyperexcitability and epileptogenesis process, which offers AMPAR as a potential target for epilepsy therapy. Over the last decade, various types of AMPAR antagonists such as perampanel and talampanel have been developed to treat epilepsy, but they usually show limited efficacy at low doses and produce unwanted cognitive and motor side effects when administered at higher doses. In the present article, the latest findings in the field of molecular mechanisms controlling AMPAR biology, as well as the role of these mechanism dysfunctions in generating epilepsy will be reviewed. Also, a comprehensive summary of recent findings from clinical trials with perampanel, in treating epilepsy, glioma-associated epilepsy and Parkinson's disease is provided. Finally, antisense oligonucleotide therapy as an alternative strategy for the efficient treatment of epilepsy is discussed.

Perampanel attenuates epileptiform phenotype in C6 glioma

Epileptic seizures are frequent in patients with glioma, and anticonvulsive treatment is often indicated. Glioma cells release glutamate via the Xc- antiporter system, which appears to be a major pathomechanism of glioma-associated seizures and excitotoxicity. In addition, the proliferation and survival of the tumor cells are promoted. Therefore, anticonvulsants that attenuate glutamate-mediated receptor activation could be especially effective. In this study, we investigated the effects of AMPA receptor antagonist perampanel in rat C6 glioma model. In first pilot experiments, perampanel reduced glucose uptake but had no impact of extracellular glutamate level in vitro. To analyze the effects of perampanel in vivo, we injected C6 cells orthotopically into the neocortex of Wistar rats in order to establish a model of glioma-associated epilepsy. Spontaneous recurrent discharges in brain slices were abolished upon perfusion with the AMPA receptor blocker perampanel, supporting the major role of glutamatergic excitation. With respect to the tumor progression, no effect of perampanel on survival of the animals or on glioma size was determined. Our data demonstrate that perampanel inhibit epileptiform discharges in organotypic brain slices of glioma, but failed to attenuate tumor growth or promote animal survival.

P18. Effekte von Perampanel auf die Gliom-assoziierte Epilepsie

Seizures are a well-recognized symptom of glioblastoma, and anticonvulsive treatment is common. While clinical guidelines recommend all approved anticonvulsants, so far there is a lack of data that allow a well-founded differential therapy. Based on pathophysiological knowledge about both mechanisms of glioma-associated seizures and tumor progression, it is conceivable that some certain anti-seizure medication could be more preferable than others in the sense of a combined anti-convulsive and anti-tumoral efficacy. Thus, glioma cells release glutamate via the Xc− antiport system, which appears to be a major pathomechanism of glioma-associated seizures and excitotoxicity. In addition, the proliferation and survival of the tumor cells are promoted. Therefore, anticonvulsants that attenuate glutamate-mediated receptor activation could be especially effective. In a first in vitro approach, perampanel had antiproliferative effects. In addition, AMPA receptor-mediated epileptiform activity was effectively reduced in rat glioma brain slices using perampanel. In our current studies, rat glioma cells are injected orthotopically into the neocortex of Fischer rats. Thus, both tumor disease and glioma-associated epilepsy can be simulated in a clinically relevant in vivo model. In this model, the efficacy of perampanel in combination with standard radio-chemotherapy on the survival of the animals is examined. Epileptiform activity is recorded with video EEG monitoring in vivo and additionally analyzed in an in vitro epilepsy model (Mg2+ withdrawal, GABAA receptor inhibition). On the side of the tumor disease, the morphology of the gliomas is determined and the expression of relevant proteins is quantified. To gain further insights into the mechanisms of glutamate-mediated pathophysiology of human gliomas, patient-generated low-passage glioblastoma cell lines were established from more than 50 surgical brain tumor resectants. In 15 of these cell lines, we quantified the expression of various epilepsy-associated genes by RT-PCR. As expected, the genes SLC7A11, EAAT2, GLUL, BCAT1 and IDH1 were expressed differently in the cells. To validate these findings, four cell lines with a pro-epileptogenic phenotype were selected. In addition, the efficacy of perampanel on glutamate release and cell proliferation was tested. It could be shown that perampanel mediate an overall reduction of glutamate release cross all cell lines. With our combined in vitro and in vivo approach, we aim to investigate the efficacy of glutamate receptor antagonists such as perampanel on glioblastoma cells with respect to seizure development and tumor progression. Our results suggest that anticonvulsants that inhibit glutamate receptor activation may be particularly suitable.

LGI1 tumor tissue expression and serum autoantibodies in patients with primary malignant glioma

ObjectivesThe Leucine-rich glioma inactivated 1 (LGI1) protein is thought to be implicated in malignant progression of glioma tumors, and mutations in the encoding gene, LGI1, cause autosomal dominant lateral temporal epilepsy, a genetic focal epilepsy syndrome. The aim of this study was to investigate the possible involvement of LGI1 in high-grade glioma-associated epilepsy by analyzing its expression in tumor specimens of patients with and without epilepsy and by searching for LGI1 autoantibodies in the sera these patients. Patients and methodsWe examined tumor tissue samples from 24 patients with high-grade gliomas (12 with and 12 without epilepsy) by immunoblot and detected variable amounts of LGI1 in tumor tissues from 9/24 (37%) patients. ResultsLGI1 was detected in 7/12 (58%) patients with epilepsy and in 2/12 (16%) patients without epilepsy (p = 0.0894; Fisher’s exact test). Moreover, testing blood sera of five patients for antibodies against LGI1 revealed LGI1 autoantibodies in two patients, both suffering from epilepsy and expressing LGI1 in tumor tissue. ConclusionOur findings suggest that there may be a preferential expression of LGI1 in high-grade glioma tumors of patients with epilepsy. We also unveil the presence of serum LGI1 autoantibodies in some patients with high-grade gliomas, where they might play an epileptogenic role.

IDH1 and IDH2 mutations in postoperative diffuse glioma-associated epilepsy

ObjectiveIsocitrate dehydrogenase 1 and 2 mutations (IDH1/2) have an established association with preoperative seizures in patients with grades II–IV diffuse gliomas. Here, we examined if IDH1/2 mutations are a biomarker of postoperative seizure frequency. MethodsThis was a retrospective study. Patients with grades II–IV supratentorial diffuse glioma, immunohistochemistry results of IDH1-R132H, and antiepileptic drug (AED) prescribed postoperatively were included. The primary outcome was seizure frequency over the first 12 postoperative months: Group A — postoperative seizure freedom; Group B — 1–11 seizures over 12months (less than one seizure per month); and Group C — greater than one seizure per month. Rates of IDH1-R132H mutation were compared between the three outcome groups in univariate and multivariate analyses. Subgroup analysis was performed in 64 patients with IDH1/2 pyrosequencing data. ResultsOne hundred cases were included in the analysis: 30.0% grade II, 20.0% grade III, and 50.0% grade IV gliomas. Group B patients averaged 1 seizure over 12months, compared with 2 seizures per month in Group C. Isocitrate dehydrogense 1-R132H mutation was present in 29.3% (17/58) of Group A, 18.2% (14/22) of Group B, and 70.0% (14/20) of Group C patients (p=0.001). On multivariate analysis, after controlling for preoperative seizure, grade, and temporal tumor location, IDH1-R132H was associated with Group C when compared with both Group A (RR 4.75, p=0.032) and Group B (RR 9.70, p=0.012). In the subgroup with IDH1/2 molecular data, an IDH1/2 mutation was present in 64.7% (22/34) of Group A, 28.6% (4/14) of Group C, and 87.5% (14/16) of Group C patients (p=0.004). SignificanceIn patients with supratentorial diffuse gliomas, IDH1-R132H mutations are associated with a more severe phenotype of postoperative epilepsy. These findings support further research into IDH mutations, and the potential for an antiepileptic therapeutic effect of their inhibitors, in patients with glioma-associated epilepsy.

Glioma-associated epilepsy: toward mechanism-based treatment

: Epilepsy is common in glioma patients, and glioma-related epilepsy has a strong impact on patients’ quality of life. Glioma-related epilepsy has a unfavorable clinical course when compared to other types of symptomatic epilepsy, with low rates of seizure freedom, common relapses of seizures after seizure-free periods, and a severe outcome in case of intractable seizures (status epilepticus). Translational research is starting to elucidate the specific pathophysiological mechanisms in this disease: the molecular-biological characteristics of the tumor result in metabolic changes in the glioma and the peritumoral region. These changes lead to abnormal neuronal and non-neuronal signaling changes in the tumor’s surroundings and in the brain’s global functional network (“connectome”). Anti-neoplastic treatments often cause amelioration of epilepsy, possibly by reverting the pathophysiological pro-epileptogenic processes in the tumor. Further research should focus on these pathophysiological mechanisms and on the possibilities for new mechanism-based anti-epileptic treatments. Clinical trials for gliomas should incorporated epilepsy as an outcome measure.

Predictors and mechanisms of epilepsy occurrence in cerebral gliomas: What to look for in clinicopathology

Gliomas, especially low-grade gliomas, are highly epileptogenic brain tumors. Histopathological information is valuable in evaluating the diagnosis and/or biologic behavior of various gliomas. Here we explored the clinical data and histopathological predictors of the occurrence of epilepsy in patients with gliomas. A retrospective study examined 310 consecutive patients who had undergone surgical treatment for gliomas in our institution from January 2013 to January 2015. Clinical data and pathological examination results were analyzed. Literatures regarding the predictors and etiology of glioma associated epileptic seizures in the period of 1995–2015 were also reviewed. A total of 234 (75.5%) astrocytic tumors and 76 (24.5%) oligodendrial tumors were included. At diagnosis, 33.6% of patients had epileptic seizures. Multivariate analysis revealed cortex involvement (OR=7.991, 95%CI=1.599–39.926), lower World Health Organization grade (OR=3.584, 95%CI=1.032–12.346) and topoisomerase II (TopoII) positivity (OR=0.943, 95%CI=0.903–0.982) were strong predictors for preoperative epileptic seizures. Gender, disease course, tumor classification, location or volume did not significantly affect epileptic seizure occurrence. Forty-three publications involved glioma-associated epilepsy were found in PubMed online database and key data were extracted and summarized. The present studies on glioma-related epilepsy are relatively limited and inconsistent. Low-grade gliomas, cortex involvement and TopoII positivity were independent predictors of a history of epileptic seizures at diagnosis. Further studies to examine the underlying mechanism of topoisomerase II as well as other molecules in epilepsy occurrence in brain gliomas are needed in the future.

Dysregulation of microRNA-128 expression in WHO grades 2 glioma is associated with glioma-associated epilepsy: Down-regulation of miR-128 induces glioma-associated seizure

ObjectiveApproximately 80% of glioma patients will experience at least one seizure activity during the course of the disease, and because the etiology of glioma-related seizure is most likely multifactorial and complex, it remains poorly understood. MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators. MicroRNA-128 was found to be decreased in glioblastoma, and knockout of the microRNA-128a gene could induce epilepsy in mice. Based on the Chinese Glioma Genome Atlas and previous study, we hypothesized that dysregulation of miR-128 expression may play a role in the pathogenesis of TAE in low-grade glioma. MethodsFifty-three low-grade glioma samples were analyzed for the expression levels of miR-128 using qRT-PCR, and candidate targets of miR-128 (Cacnge2, GRIK3, and GRIN2D) were detected by the 3′-UTR luciferase reporter assay. Four other miRs (miR-9, miR-192a, miR-92a, and miR-451) that showed dysregulation of glioblastoma in the CGGA data were also analyzed. ResultsThe microRNA-128 expression levels were down-regulated in low-grade glioma tissue (t-test; p=0.009). Dysregulation of miR-128 expression in low-grade glioma is associated with glioma-associated epilepsy (p=0.006). No statistical significance of miR-9, miR-192a, miR-92a, and miR-451 was found to be associated with LGG. ConclusionOur results here, together with other recent lines of evidence, indicate that miR-128 is an extremely attractive target for therapy in glioma patients with seizure.

Seizures in oligodendroglial tumors.

Epilepsy develops in more than 70-90% of oligodendroglial tumors and represents a favorable indicator for long-term survival if present as the first clinical sign. Presence of IDH1 mutation is frequently associated with seizures in oligodendrogliomas, next to alterations of glutamate and GABA metabolism in the origin of glioma-associated epilepsy. Treatment by surgery or radiotherapy results in seizure freedom in about two-thirds of patients, and chemotherapy to a seizure reduction in about 50%. Symptomatic anticonvulsive therapy with levetiracetam and valproic acid as monotherapy are both evidence-based drugs for the partial epilepsies, and their effective use in brain tumors is supported by a large amount of additional data. Pharmacoresistance against anticonvulsants is more prevalent among oligodendrogliomas, occurring in about 40% despite polytherapy with two anticonvulsants or more. Toxic signs of anticonvulsants in brain tumors involve cognition, bone marrow and skin. Previous neurosurgery, radiation therapy or chemotherapy add to the risks of cognitive dysfunction.