Search Results (14)

Background/Objectives: Late epilepsy occurring in the late stage after glioblastoma (GBM) resection is suggested to be caused by increased extracellular glutamate (Glu). To elucidate the mechanism underlying postoperative late epilepsy, the present study aimed to investigate the expressions and relations of molecules related to Glu metabolism in tumor tissues from GBM patients and cultured glioma stem-like cells (GSCs). Methods: Expressions of CD44, xCT and excitatory amino acid transporter (EAAT) 2 and extracellular Glu concentration in GBM patients with and without epilepsy were examined and their relationships were analyzed. For the study using GSCs, expressions and relationships of the same molecules were analyzed and the effects of CD44 knock-down on xCT, EAAT2, and Glu were investigated. In addition, the effects of hypoxia on the expressions of these molecules were investigated. Results: Tumor tissues highly expressed CD44 and xCT in the periphery of GBM with epilepsy, whereas no significant difference in EAAT2 expression was seen between groups with and without epilepsy. Extracellular Glu concentration was higher in patients with epilepsy than those without epilepsy. GSCs displayed reciprocal expressions of CD44 and xCT. Concentrations of extracellular Glu coincided with the degree of xCT expression, and CD44 knock-down elevated xCT expression and extracellular Glu concentrations. Hypoxia of 1% O₂ elevated expression of CD44, while 5% O₂ increased xCT and extracellular Glu concentration. Conclusions: Late epilepsy after GBM resection was related to extracellular Glu concentrations that were regulated by reciprocal expression of CD44 and xCT, which were stimulated by differential hypoxia for each molecule. Full article

Background: Angiocentric glioma (AG) is a rare, benign, and slow-growing tumor. First described in 2005, it is now gaining attention with respect to the possibility of being diagnosed. Even with no statistical differences between sex, it has been reported both in children and the elderly. A total of 120 cases have been described in the literature. The aim of this study is to provide new data for a new statistical assessment of the prevalence and incidence of AG in populations. Case report: An 8-year-old male patient with no history of epilepsy and no need for antiepileptic therapy underwent surgery for a left-parietal brain lesion, revealed through MRI. Imaging was acquired after his first absence episode. The lesion was completely resected. Histological findings indicated angiocentric glioma. No signs of recurrency after two years of follow-up. Conclusion: AG is usually an epilepsy-related low-grade glioma. Few cases exhibit disease progression and exitus. Surgical management should aim for a gross total resection to avoid recurrence and persisting epilepsy. Surgery represents the gold standard in diagnosis and treatment and must be performed as soon as possible in consideration of its healing properties and its useful diagnosis. Full article

Background: A cortical electroencephalogram (ECoG) is often used for the intraoperative monitoring of epilepsy surgery, and propofol is an important intravenous anesthetic, but its effect on EEGs is unclear. Objectives: To further clarify the effect of propofol on cortical ECoGs during glioma-related epilepsy surgery and to clarify the possible clinical value. Methods: A total of 306 patients with glioma were included in the study. Two hundred thirty-nine with glioma-related epilepsy were included in the epilepsy group, and 67 without glioma-related epilepsy were included in the control group. All patients experienced continuous, real-time ECoG monitoring and long-term follow-up after surgery. Results: After injection of low-dose propofol, the rate of activated ECoGs in the epilepsy group (74%) was significantly higher than in the control group (9%). Furthermore, compared with patients in the untreated group, patients in the treated group had lower rates of early and long-term postoperative seizure frequencies and fewer interictal epileptiform discharges (IEDs). Conclusions: Low-dose infusion of propofol can specifically activate ECoGs in epilepsy patients. Therefore, activated ECoGs might provide an accurate and reliable method for identifying potential epileptic zones during glioma-related epilepsy surgery, resulting in better early and long-term prognoses after epilepsy surgery. Full article

Glioblastoma (GBM) is characterized by fast-growing cells, genetic and phenotypic heterogeneity, and radio-chemo-therapy resistance, contributing to its dismal prognosis. Various medical comorbidities are associated with the natural history of GBM. The most disabling and greatly affecting patients’ quality of life are neurodegeneration, cognitive impairment, and GBM-related epilepsy (GRE). Hallmarks of GBM include molecular intrinsic mediators and pathways, but emerging evidence supports the key role of non-malignant cells within the tumor microenvironment in GBM aggressive behavior. In this context, hyper-excitability of neurons, mediated by glutamatergic and GABAergic imbalance, contributing to GBM growth strengthens the cancer-nervous system crosstalk. Pathogenic mechanisms, clinical features, and pharmacological management of GRE with antiepileptic drugs (AEDs) and their interactions are poorly explored, yet it is a potentially promising field of research in cancer neuroscience. The present review summarizes emerging cooperative mechanisms in oncogenesis and epileptogenesis, focusing on the neuron-to-glioma interface. The main effects and efficacy of selected AEDs used in the management of GRE are discussed in this paper, as well as their potential beneficial activity as antitumor treatment. Overall, although still many unclear processes overlapping in GBM growth and seizure onset need to be elucidated, this review focuses on the intriguing targeting of GBM-neuron mutual interactions to improve the outcome of the so challenging to treat GBM. Full article

(1) Background: Glioma is the most common primary tumor in the central nervous system, and glioma-related epilepsy (GRE) is one of its common symptoms. The abnormalities of white matter fiber tracts are involved in attributing changes in patients with epilepsy (Rudà, R, 2012).This study aimed to assess frontal lobe gliomas’ effects on the cerebral white matter fiber tracts. (2) Methods: Thirty patients with frontal lobe glioma were enrolled and divided into two groups (Ep and nEep). Among them, five patients were excluded due to apparent insular or temporal involvement. A set of 14 age and gender-matched healthy controls were also included. All the enrolled subjects underwent preoperative conventional magnetic resonance images (MRI) and diffusion tensor imaging (DTI). Furthermore, we used tract-based spatial statistics to analyze the characteristics of the white matter fiber tracts. (3) Results: The two patient groups showed similar patterns of mean diffusivity (MD) elevations in most regions; however, in the ipsilateral inferior fronto-occipital fasciculus (IFOF), superior longitudinal fasciculus (SLF), and superior corona radiata, the significant voxels of the EP group were more apparent than in the nEP group. No significant fractional anisotropy (FA) elevations or MD degenerations were found in the current study. (4) Conclusions: Gliomas grow and invade along white matter fiber tracts. This study assessed the effects of GRE on the white matter fiber bundle skeleton by TBSS, and we found that the changes in the white matter skeleton of the frontal lobe tumor-related epilepsy were mainly concentrated in the IFOF, SLF, and superior corona radiata. This reveals that GRE significantly affects the white matter fiber microstructure of the tumor. Full article

The infiltrative character of supratentorial lower grade glioma makes it possible for eloquent neural pathways to remain within tumoural tissue, which renders complete surgical resection challenging. Neuromodulation-Induced Cortical Prehabilitation (NICP) is intended to reduce the likelihood of premeditated neurologic sequelae that otherwise would have resulted in extensive rehabilitation or permanent injury following surgery. This review aims to conceptualise current approaches involving Repetitive Transcranial Magnetic Stimulation (rTMS-NICP) and extraoperative Direct Cortical Stimulation (eDCS-NICP) for the purposes of inducing cortical reorganisation prior to surgery, with considerations derived from psychiatric, rehabilitative and electrophysiologic findings related to previous reports of prehabilitation. Despite the promise of reduced risk and incidence of neurologic injury in glioma surgery, the current data indicates a broad but compelling possibility of effective cortical prehabilitation relating to perisylvian cortex, though it remains an under-explored investigational tool. Preliminary findings may prove sufficient for the continued investigation of prehabilitation in small-volume lower-grade tumour or epilepsy patients. However, considering the very low number of peer-reviewed case reports, optimal stimulation parameters and duration of therapy necessary to catalyse functional reorganisation remain equivocal. The non-invasive nature and low risk profile of rTMS-NICP may permit larger sample sizes and control groups until such time that eDCS-NICP protocols can be further elucidated. Full article

Background: Awake craniotomy with intraoperative stimulation has been utilized in glioma surgical resection to preserve the quality of life. Epilepsy may occur in 5–20% of cases, leading to severe consequences. This study aimed to discuss the mechanism of intraoperative stimulation-related epilepsy (ISE) using DTI-based graph theoretical analysis. Methods: Twenty patients with motor-area glioma were enrolled and divided into two groups (Ep and nEp) according to the presence of ISE. Additionally, a group of 10 healthy participants matched by age, sex, and years of education was also included. All participants underwent T1, T2, and DTI examinations. Graph theoretical analysis was applied to reveal the topological characteristics of white matter networks. Results: Three connections were found to be significantly lower in at least one weighting in the Ep group. These connections were between A1/2/3truL and A4ulL, A1/2/3truR and A4tR, and A6mL and A6mR. Global efficiency was significantly decreased, while the shortest path length increased in the Ep group in at least one weighting. Ten nodes exhibited significant differences in nodal efficiency and degree centrality analyses. The nodes A6mL and A6mR showed a marked decrease in total four weightings in the Ep group. Conclusions: The hub nodes A6mL and A6mR are disconnected in patients with ISE, causing subsequent lower efficiency of global and regional networks. These findings provide a basis for presurgical assessment of ISE, for which caution should be taken when it involves hub nodes during intraoperative electrical stimulation. Full article

The progression of glioblastomas is associated with a variety of neurological impairments, such as tumor-related epileptic seizures. Seizures are not only a common comorbidity of glioblastoma but often an initial clinical symptom of this cancer entity. Both, glioblastoma and tumor-associated epilepsy are closely linked to one another through several pathophysiological mechanisms, with the neurotransmitter glutamate playing a key role. Glutamate interacts with its ionotropic and metabotropic receptors to promote both tumor progression and excitotoxicity. In this review, based on its physiological functions, our current understanding of glutamate receptors and glutamatergic signaling will be discussed in detail. Furthermore, preclinical models to study glutamatergic interactions between glioma cells and the tumor-surrounding microenvironment will be presented. Finally, current studies addressing glutamate receptors in glioma and tumor-related epilepsy will be highlighted and future approaches to interfere with the glutamatergic network are discussed. Full article

Seizures are common in patients with high-grade gliomas (30–60%) and approximately 15–30% of glioblastoma (GB) patients develop drug-resistant epilepsy. Reliable animal models are needed to develop adequate treatments for glioma-related epilepsy. Therefore, fifteen rats were inoculated with F98 GB cells (GB group) and four rats with vehicle only (control group) in the right entorhinal cortex. MRI was performed to visualize tumor presence. A subset of seven GB and two control rats were implanted with recording electrodes to determine the occurrence of epileptic seizures with video-EEG recording over multiple days. In a subset of rats, tumor size and expression of tumor markers were investigated with histology or mRNA in situ hybridization. Tumors were visible on MRI six days post-inoculation. Time-dependent changes in tumor morphology and size were visible on MRI. Epileptic seizures were detected in all GB rats monitored with video-EEG. Twenty-one days after inoculation, rats were euthanized based on signs of discomfort and pain. This study describes, for the first time, reproducible tumor growth and spontaneous seizures upon inoculation of F98 cells in the rat entorhinal cortex. The development of this new model of GB-related epilepsy may be valuable to design new therapies against tumor growth and associated epileptic seizures. Full article

The importance of the extent of resection (EOR) has been widely demonstrated as the main predictor for survival, nevertheless its effect on tumor related epilepsy is less investigated. A total of 155 patients were enrolled after a first-line surgery for supratentorial Diffuse Low Grade Gliomas (DLGGs). Postoperative seizure outcome was analyzed stratifying the results by tumor volumetric data and molecular markers according to 2016 WHO classification. Receiver operating characteristic (ROC) curves were computed to asses EOR, residual tumor volume, and ΔT2T1 MRI index (expressing the tumor growing pattern) corresponding to optimal seizure outcome. A total of 70.97% of patients were seizure-free 18 months after surgery. Better seizure outcome was observed in IDH1/2 mutated and 1p/19q codeleted subgroup. At multivariate analysis, age (p = 0.014), EOR (p = 0.030), ΔT2T1 MRI index (p = 0.016) resulted as independent predictors of postoperative seizure control. Optimal parameters to improve postoperative seizure outcome were EOR ≥ 85%, ΔT2T1 MRI index ≤ 18 cm³, residual tumor volume ≤ 15 cm³. This study confirms the role of EOR and tumor growing pattern on postoperative seizure outcome independently from the molecular class. Higher ΔT2T1 MRI index, representing the infiltrative component of the tumor, is associated with worse seizure outcome and strengthens the evidence of common pathogenic mechanisms underlying tumor growth and postoperative seizure outcome. Full article

Perampanel (PER) is a selective blocker of AMPA receptors showing efficacy in treating various epileptic disorders including brain tumor-related epilepsy and also potential in treating motor neuron disease. However, besides its inhibition of AMPA-induced currents, whether PER has any other direct ionic effects in different types of neurons remains largely unknown. We investigated the effects of PER and related compounds on ionic currents in different types of cells, including hippocampal mHippoE-14 neurons, motor neuron-like NSC-34 cells and U87 glioma cells. We found that PER differentially and effectively suppressed the amplitude of voltage-gated Na⁺ currents (I_Na) in mHippoE-14 cells. The IC₅₀ values required to inhibit peak and late I_Na were 4.12 and 0.78 μM, respectively. PER attenuated tefluthrin-induced increases in both amplitude and deactivating time constant of I_Na. Importantly, PER also inhibited the amplitude of M-type K⁺ currents (I_K(M)) with an IC₅₀ value of 0.92 μM. The suppression of I_K(M) was attenuated by the addition of flupirtine or ZnCl₂ but not by L-quisqualic acid or sorafenib. Meanwhile, in cell-attached configuration, PER (3 μM) decreased the activity of M-type K⁺ channels with no change in single-channel conductance but shifting the activation curve along the voltage axis in a rightward direction. Supportively, PER suppressed I_K(M) in NSC-34 cells and I_Na in U87 glioma cells. The inhibitory effects of PER on both I_Na and I_K(M), independent of its antagonistic effect on AMPA receptors, may be responsible for its wide-spectrum of effects observed in neurological clinical practice. Full article

The detection of neuronal surface protein autoantibody-related disorders has contributed to several changes in our understanding of central nervous system autoimmunity. The clinical presentation of these disorders may be associated (or not) with tumors, and often patients develop an inexplicable onset of epilepsy, catatonic or autistic features, or memory and cognitive dysfunctions. The autoantigens in such cases have critical roles in synaptic transmission and plasticity, memory function, and process learning. For months, patients with such antibodies may be comatose or encephalopathic and yet completely recover with palliative care and immunotherapies. This paper reviews several targets of neuronal antibodies as biomarkers in seizure disorders, focusing mainly on autoantibodies, which target the extracellular domains of membrane proteins, namely leucine-rich glioma-inactivated-1 (LGI1), contactin-associated protein-like 2 (CASPR2), the N-methyl-D-aspartate receptor (NMDAR), γ-aminobutyric acid receptor-B (GABA_BR), the glycine receptor (GlyR), and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). In order to restore health status, limit hospitalization, and optimize results, testing these antibodies should be done locally, using internationally certified procedures for a precise and rapid diagnosis, with the possibility of initiating therapy as soon as possible. Full article

The dysfunction of astrocytic inwardly rectifying potassium (Kir) 4.1 channels, which mediate the spatial potassium-buffering function of astrocytes, is known to be involved in the development of epilepsy. Here, we analyzed the Kir4.1 expressional changes in Leucine-Rich Glioma-Inactivated 1 (Lgi1) mutant rats, which is a model of autosomal dominant lateral temporal lobe epilepsy in humans, to clarify the role of astrocytic Kir4.1 channels in Lgi1-related epileptogenesis. Priming acoustic stimulation (at postnatal day 16) conferred seizure susceptibility on Lgi1 mutant rats, which evoked audiogenic seizures with test stimulation at eight weeks. In the seizure-susceptible Lgi1 mutant rats (before test stimulation), astrocytic Kir4.1 expression was down-regulated region-specifically in the cerebral cortex, hippocampus, and amygdala. In addition, prophylactic treatments of Lgi1 mutant rats with valproic acid (VPA, 30 mg/kg and 200 mg/kg) for two weeks prevented both the development of seizure susceptibility and the down-regulation of Kir4.1 expression in astrocytes. The present study demonstrated for the first time that the astrocytic Kir4.1 expression was reduced in the Lgi1-related seizure model, suggesting that the down-regulation of Kir4.1 channels in astrocytes is involved in audiogenic epileptogenesis caused by Lgi1 mutation. In addition, VPA seemed to have a prophylactic effect on Lgi1-related seizures. Full article