Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma

Abstract

Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures.

Understanding the Brain-Heart Connection Through a Case of Angry Glioma Syndrome

“…Understanding the pathophysiology of wounded glioma syndrome requires knowledge of the peritumoral neocortex. The “peri-tumoral border,” or the area where the tumor and the normal brain meet, is a highly epileptogenic area since network organization happens particularly within its supragranular cortical layers, thus, making it possible for patients with no previous history of epilepsy secondary to a brain tumor, to develop new-onset seizures post-resection [ 2 ]. Microscopically, there is a breakdown in glutamate homeostasis particularly the upregulation of cystine/glutamate antiporter system which increases glutamate production [ 6 ].…”

“…Wounded glioma syndrome is a rare complication observed after incomplete tumor resection, resulting in edema or hemorrhage within the tumoral bed arising from the disruption of the tumor’s richly vascularized tissue [ 1 ]. The resulting peritumoral border, known to be a highly epileptogenic area, also predisposes patients into having new-onset seizures after tumor resection [ 2 ]. Depending on its location within the cerebral cortex, these complications may affect the brain’s ability to modulate cardiac activity through its influence to the autonomic nervous system and neurocardiac reflexes that influence autonomic outflow [ 3 ].…”

Epileptogenesis and Tumorigenesis in Glioblastoma: Which Relationship?

“…Current evidence suggests that the major site of epileptiform discharge development is represented by peritumoral tissue, and an increasingly important role is attributed to the interaction between glioma cells and peritumoral neurons [ 7 , 11 ]. From a structural point of view, it results in neuronal and glial loss, altered blood-brain barrier permeability, and recruitment of astrocytes, microglial cells, and circulating macrophages, as well as increased concentrations of cytokines, such as interleukins (ILs) IL-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, chemokines, and extracellular matrix remodeling enzymes, including matrix metalloproteinase (MMP)-2 and MMP-9, that promote both tumor proliferation and invasiveness as well as increase seizure susceptibility [ 10 , 11 ]. Moreover, distortion and deafferentation of cortico-subcortical networks are observed even far from the neoplastic lesion, and this may partially explain seizure persistence and recurrence after gross total resection of the tumor [ 10 , 11 ].…”

“…From a structural point of view, it results in neuronal and glial loss, altered blood-brain barrier permeability, and recruitment of astrocytes, microglial cells, and circulating macrophages, as well as increased concentrations of cytokines, such as interleukins (ILs) IL-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, chemokines, and extracellular matrix remodeling enzymes, including matrix metalloproteinase (MMP)-2 and MMP-9, that promote both tumor proliferation and invasiveness as well as increase seizure susceptibility [ 10 , 11 ]. Moreover, distortion and deafferentation of cortico-subcortical networks are observed even far from the neoplastic lesion, and this may partially explain seizure persistence and recurrence after gross total resection of the tumor [ 10 , 11 ]. Changes in the peritumoral cortex also affect the homeostasis of excitatory and inhibitory neurotransmitters, as well as ionic channel expression.…”

“…Some evidence suggests that the presence of seizures at the onset of GBM could be a possible independent favorable prognostic factor in patients [ 8 , 9 ]. However, the relationship between seizures and prognosis has been investigated by studies carrying some limitations (e.g., the lack of distinction between IDH-mutant vs. IDH-wildtype tumors) [ 10 ]. It remains unclear how the same mechanisms that control tumor behavior may regulate epileptogenesis and how epileptogenesis and tumorigenesis may influence each other.…”