Tumors generate excitement: the role of glutamate in tumor-related epilepsy.

Commentary One of the biggest fears that immediately arises in people presenting with their first seizure is the worry that they have a brain tumor. While fortunately the majority of patients with epilepsy do not have brain tumors, about 4% of all patients with epilepsy have seizures caused by brain tumors. Conversely , approximately 30% of patients with brain tumors have epilepsy (1). The risk of developing seizures depends on the type of tumor, with low-grade tumors typically having the highest incidence of epilepsy. For example, low-grade astrocy-tomas, gangliogliomas, and dysembryoplastic neuroepithelial tumors have a seizure incidence of about 75 percent, 80 to 90 percent, and 100 percent, respectively (1). Furthermore, while seizure medications are standard treatment for tumor-related epilepsy, these tumors represent common causes of medically refractory epilepsy (2–4). Although surgical resection of the tumor has a relatively high success rate in eliminating seizures, a substantial proportion of patients continue to have seizures or suffer a seizure relapse despite tumor resection (3, 4). Furthermore , some tumors cannot be completely resected, and risk of tumor recurrence is high. Thus, tumor-induced epilepsy significantly increases morbidity in patients, adding to the direct detrimental effects of brain tumors themselves. Developing more effective therapies for tumor-related epilepsy depends on understanding the underlying mechanisms of epileptogenesis. However, while a number of mechanistic hypotheses exist about tumor-related epilepsy, the specific cellular and molecular mechanisms involved in epileptogenesis related to brain tumors are incompletely understood. One important issue is whether seizures originate within the tumors themselves or from the areas surrounding the tumors. Most studies indicate that tumors are electrically relatively quiescent, and seizures are more likely triggered in the peritumoral region surrounding the tumor (5, 6). Regardless of where seizures are generated, an important related issue is whether tumors directly cause seizures via intrinsic physical or biochemical properties of the tumors themselves or whether tumors induce secondary changes in the surrounding tissue, which then mediate epileptogenesis. Abnormalities observed within tumors or in the peritumoral region that have been hypothesized to promote epilepsy include inflammation, hypoxic-ischemic injury, metabolic changes, blood-brain barrier disruption, and alterations of neurotransmit-ter receptor systems (7). A leading mechanistic hypothesis about tumor-mediated epileptogenesis involves abnormal glutamate homeostasis. In other types of epilepsy, glutamate levels are elevated in epileptic brains and may directly trigger seizures by increasing neuronal excitability or promote epileptogenesis by inducing neuronal death (8). Glutamate concentrations have also been found to …