Since a DLGG is a space-occupying lesion, which also permeates the surrounding functional brain with infiltrating and migrating glioma cells, it may contribute to produce epileptic activities by mechanical effects [2]. Mass effect and edema may induce microcirculation impairments by reducing cerebral perfusion responsible for focal ischaemic changes in the surrounding neocortex [35]. DLGGs that grow slowly and invade the surrounding brain may isolate and deafferentate cortico-subcortical local and distant networks, leading to epileptogenicity [33, 36]. Contrarily, high-grade gliomas that grow rapidly and induce neoangiogenesis, may provoke acute tissue damages such a haemorrhage or necrosis that may participate in epileptogenesis [36]. However in DLGG, the lack of significant correlations between seizures and tumor volume, mass effect, edema, necrosis, histopathological and molecular findings and the existence of a positive correlation between seizures, cortex involvement and tumor location argue for the implication of interactions between tumor and neocortex rather than intrinsic tumor properties alone in epileptogenicity [1, 2, 33, 35].

Structural reorganization and functional deafferentation with neuronal and glial losses, neurogenesis, reactive astrogliosis, neuronal, axonal and synaptic plasticity within the peritumoral neocortex have been described, resulting mainly in a reduction of inhibitory pathways and in an increase of excitatory ones [33, 35, 36]. Accordingly, magnetoencephalography has shown that gliomas interfere with normal brain function by disrupting functional connectivity of brain networks within peritumoral and distant brain areas [33]. Taken together, these findings suggest that such changes may induce alterations in local neuronal networks, leading to imbalance between excitation and inhibition and, eventually to epileptogenicity.

Glioma cells impact the surrounding environment by recruiting non-glioma cells (astrocytes, microglia, stromal cells) that provide resources and growth advantage to facilitate tumor progression by the mean of secreted factors (cytokines, growth factors, chemokines) and of extracellular communication. Glioma cells activate and attract the neighboring microglia that, in turn, can modulate glioma biology: activated microglia enhance glioma cells migration abilities by inducing the secretion of matrix metalloproteinases and glioma cells proliferation through the EGF/Pi3K/Akt pathway.

Although rarely observed in DLGG, the pathological disruption of the blood brain barrier exposes the brain to blood serum components, such as glutamate, fibrinogen and albumin, together with the release of vascular endothelial growth factor [37]. The vascular endothelial growth factor can induce edema and its subsequent mass effect and can alter the gap-junctions permeability [37]. The extravased glutamate participate to the sustained increase of its extracellular concentration. The perivascular astrocytes may uptake albumin, whom intracellular accumulation induces a downregulation of inward—rectifying K⁺ (Kir 4.1) channels in astrocytes, resulting in reduced buffering of extracellular K⁺. Further, fibrinogen and albumin can induce a reactive astrogliosis with an impaired clearance for extracellular K⁺ and glutamate, leading to an increase neuronal hyperexcitability in the surrounding neuronal network. Finally, immunoglobulins themselves may be incorporated in neurons and affect their behavior.

Glutamate homeostasis is impaired in the peritumoral neocortex. Glioma cells lack sodium-dependant excitatory amino acid transporters 1 and 2, leading to a decrease in glutamate uptake [33, 38], and highly express the system Xc- cystine glutamate transporter, leading to a increase in glutamate release [38–41], both resulting in a poor regulation of glutamate homeostasis with highly elevated and sustained extracellular glutamate concentrations, up to 100 μm and up to tenfold higher than normal. In addition, non tumoral astrocytes and activated microglia of the peritumoral neocortex display impaired glutamate clearance abilities with reduced extracellular glutamate upload and with increased glutamate release [37]. In parallel, mutations of the isocitrate dehydrogenase genes are frequent in DLGG and they lead to conversion of isocitrate to D-2-hydroxyglutarate rather than to α-ketoglutarate [42]. Consequently, D-2-hydroxyglutarate accumulates in glioma cells and the extracellular space, where it is thought to act as a glutamate receptor agonist owing to its steric analogy to glutamate [28, 43]. In clinical practice, IDH mutations in DLGG are possibly associated with a high prevalence of epilepsy [1, 22]. Last, the glutamate extravased from blood due to blood-brain-barrier disruption participated to an increase in extracellular glutamate concentrations. Glioma epileptogenicity is thus related, in part, to an excessive glutamatergic excitatory neurotransmission. The excessive extracellular glutamate may induce seizures through the facilitation of pathological pyramidal cells synchronization [39] and experimentations on glioma-bearing mice confirmed that peritumoral neuronal hyperexcitability was attributable to glutamate release by glioma cells via the system Xc- cystine glutamate transporter [31]. In accordance, increased glutamate concentration and altered glutamate transporter expression have been shown to be associated with the presence of tumor-related seizures in patients harboring a glioma [40]. Gliomas utilize the glutamate as an “autocrine tumor growth factor” to gain a growth advantage as the released glutamate enhances glioma cells proliferation and invasion with neurotoxic, pro-invasive and proliferative effects [41]. These effects are increased by glioma cell overexpression of glutamate receptors, including metabotropic glutamate receptor (mGluR) types 2 and 3, N-Methyl-d-Aspartate (NMDA) receptors and Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [28]. Glutamate NMDA receptors on glioma cells increase motility of these cells [41]. NMDA receptor activation, which induces Ca²⁺ inflow, increases glioma cell proliferation, and AMPA receptors that predominantly lack GluR2 subunit expression, allowing a Ca²⁺ influx and overexpress GlutR1 subunit, resulting in an increase in glioma cells adhesion to extracellular matrix components, which have been shown to promote cell motility and invasion [39]. They also result in an activation of the glioma cell proliferation through the EGF/Pi3K/Akt pathway [44] and mitogen-activated protein kinase pathways [28]. The excessive extracellular glutamate can cause peritumoral neuronal excitotoxicity through the activation of NMDA receptors on neurons adjacent to the glioma, contributing to a glutamatergic-mediated cell death [31, 38, 39, 41], thus giving glioma cells the free space required for tumor expansion where neurons die.

GABAergic signaling is also involved both in glioma growth and epilepsy. GABA levels are higher in tissue around gliomas than in the tumor core [45]. Glioma cells express GABA_A receptors that contribute to the cell volume changes required for glioma cells proliferation and migration [46]. The released extracellular glutamate downregulates neuronal and nontumoral astrocytes GABA_A receptors [33, 37] and the peritumoral neocortex presents reduced GABAergic inhibitory pathways with a loss of GABAergic interneurons [32] and a reduction of inhibitory synapses within pyramidal cells [47]. These alterations result in a weakening of the GABAergic inhibitory functioning within the peritumoral neocortex [31, 33, 37, 45]. Regulation of intracellular Cl⁻ influences neuronal responses to GABA. In healthy mature neurons, intracellular Cl⁻ is maintained at low levels by activation of K⁺-Cl⁻ transporter 2 (KCC2), which cotransports Cl⁻ with K⁺ out of cells, and repression of Na⁺-K⁺-Cl⁻ transporter (NKCC1), which cotransports Cl⁻, Na⁺ and K⁺ into immature neurons [28]. In this context, activation of GABA receptors causes Cl⁻ influx that hyperpolarizes cells and inhibits neuronal activity. As in other non-glioma human focal epilepsies [48] where pathological changes in Cl⁻ homeostasis can switch GABAergic signaling from hyperpolarizing to depolarizing, aberrant expression of KCC2 and/or NKCC1 is associated with gliomas and epileptic activity, and leads to accumulation of intracellular Cl⁻, which contributes both to glioma proliferation and migration and epileptic activity [28, 34, 46]. The intracellular Cl⁻ accumulation of glioma cells, up to ~100 mM and tenfold higher than normal, is actively maintained by the NKCC1 cotransporter [49], which is expressed in glioma cells at higher ranges in peritumoral cortex of gliomas than in controls through phosphorylation mediated by WNK3, which is controlled by the EGF/Pi3K/Akt pathway [34, 50, 51]. Both glioma cell division and migration require a fast volume cell reduction, which is operated by the efflux of Cl⁻ from Cl⁻ channels [46, 52] coupled to K⁺ efflux from K⁺ big-conductance channels, and draw water out of the cell through aquaporines [46]. All Cl⁻, K⁺ and water channels are abnormally and highly expressed in the cytoplasmic membrane of glioma cells and are spatially restricted to the leading edge of the cell and to the invadipodia. Neurons within peritumoral cortex are affected by such Cl⁻ dysregulation were Cl⁻ homeostasis is disrupted in about 60% of pyramidal cells [34, 53]. This disruption is caused by upregulated expression of NKCC1 and downregulated expression of KCC2 in these neurons [34, 50, 53, 54]. Such Cl⁻ defects are responsible for depolarizing GABAergic effects that are observed ex vivo in the cortex surrounding human gliomas and that may favor epileptogenesis in this tissues [34]. Changes in the expression of Cl⁻ cotransporters can be triggered by brain-derived neurotrophic factor (BDNF) that is released by glioma cells and activated microglia : BDNF increases expression of NKCC1 and reduces expression of KCC2 [2, 55]. In addition, a NMDA-mediated glutamate signaling also suppresses KCC2 expression, so aberrant extracellular glutamate in gliomas could exacerbate dysregulation of Cl⁻ levels [37].

Astrocytes are also involved in K⁺ homeostasis by extracellular K⁺ buffering through Kir4.1 channels [56]. K⁺ buffering is impaired in gliomas by a loss of expression of Kir4.1 channels in the plasma membrane of glioma cells that is required for cell proliferation [56]. The resulting high extracellular K⁺ concentration together with other local perturbations, such as the alkalization of the peritumoral neocortex [35] and the alterations of the gap-junctions functioning [33, 35] may increase the excitability of the pyramidal cells. The mTOR signalling pathways, which can be dysregulated in gliomas, result from upregulation of Pi3K/Akt signalling, and mutations in PTEN [28]. Hyperactivation of the mTOR pathway affects neuronal differentiation and migration, axonal and dendritic growth, neuronal excitability, upregulation of immature forms of the glutamatergic NMDA receptor GluN2C, and impairment of Cl⁻ regulation [28].

Several studies have supported the beneficial role of oncological treatments (surgery, radiotherapy, chemotherapy) in seizure control of DLGG-related epilepsy. The impact of oncological treatments on seizure control are illustrated in Figs. 12.2 and 12.3.