Gliomas and seizures

Abstract

Glial neoplasms account for nearly 50% of all adult primary brain tumors. They originate from glial cells in the brain and/or spinal cord and include low-grade diffuse astrocytomas, anaplastic-astrocytomas, and glioblastomas. Of all brain tumors, glioblastoma multiforme (GBM) is the most aggressive and is characterized by rapid glial cell growth, resistance to radio- and chemo- therapies, and relentless infiltration and spreading throughout the central nervous system (CNS). In glioblastomas, primary tumor growth and CNS invasion are associated with the activation of complex structural molecular and metabolic changes within the tumor tissue, which profoundly affect the surrounding neuronal networks and may in part explain induction of epilepsy. In fact, epileptic seizures are very common among patients with glial tumors, reaching nearly 50% in glioblastoma patients and almost 90% in low-grade astrocytomas. The overall hypothesis presented here discusses the possibility that the aberrant tumor cell metabolism may act directly on neuronal network, and this leads to seizure susceptibility. Further invasion and growth of the malignant glial cells exacerbate this initial pathologic state which promotes recurrent seizures (epileptogenesis).

Fig. 1

Hypothesis for the influence of GBM-produced factors on epileptogenesis. Tumor expression of receptor tyrosine kinases and extracellular matrix protein integrins activates focal adhesion kinase and Src family kinases directly and indirectly, respectively. SKF’s activation promotes survival, proliferation and invasion. These molecular tumoregenic processes lead to accumulation of glutamate and miRNAs in the peritumoral area. Glutamate accumulation is exacerbated by malfunctioning of glial cells in the peritumoral area due to downregulation of glutamate synthetase. In addition, miRNAs and glutamate induce increase of connexins in the neighboring interneuronal network. The aberrant expression of connexins, N-methyl-d-aspartate and miRNAs in principal neurons strengthens the neuronal circuit synchronization of abnormal neuronal activity leading to seizures.