Abstracts

Rationale: Epilepsy is a common clinical manifestation of primary brain tumors, and low-grade tumors are more often associated with seizures than high-grade tumors. This higher prevalence of epilepsy with low grade tumors might be due to modulators released from these tumors that stimulate epileptogenesis. One possible mechanism for epileptogenesis associated with tumors is the production of neurotoxic tryptophan metabolites via the kynurenine pathway. The aim of this study was to examine whether there were differences in tryptophan metabolism in patients with low grade compared to high grade tumors associated with seizures. Tryptophan metabolism was measured in vivo using positron emission tomography (PET) with α-[11C]methyl-L-tryptophan (AMT). In addition, indoleamine 2,3-dioxygenase (IDO), the rate limiting enzyme for tryptophan metabolism by the kynurenine pathway, was measured in vitro using immunocytochemistry in brain tumor tissues from patients who had undergone resective surgery.Methods: Brain tumor patients presenting clinically with epilepsy (N=14, mean age ± SD = 28 ± 18 years) with different types of brain tumors (oligodendroglioma = 2; mixed glioma = 4; astrocytoma = 1; dysembryoplastic neuroepithelial tumor [DNET] = 4; glioblastoma = 2; ependymoma = 1) were included in the study. Patients underwent tumor resection after AMT PET scanning. In vivo accumulation of AMT (and its metabolites) was quantified by calculating a metabolic rate constant (k3) from PET-derived tumor tissue time-activity curves and blood input function. Using immunohistochemistry, the expression of IDO in various cell types and neuropil of tumor samples was measured using a semi-quantitative rating scale.Results: Low-grade tumors showed higher metabolic rate (k3) for AMT as compared to high-grade tumors (0.023 ± 0.002 vs. 0.013 ± 0.003, p < 0.001). Glial cells in perivascular tissue stained consistently for IDO, except in glioblastomas, which showed no perivascular IDO expression. IDO was also expressed in the neuropil across all types of tumors. IDO was positive more consistently in low-grade tumors (6 of 7 cases, 86%), including all DNET, while only 1 of 7 (14%) high-grade tumors showed IDO staining in tumor cells (Fisher’s exact test, p = 0.029). IDO was also positive in the neuropil and perivascular tissue more frequently in low-grade tumors than high-grade tumors, although this result was not statistically significant (57% vs. 29%, for neuropil, and 57% vs. 14% for perivascular tissue; Fisher’s test: p = 0.59 and p = 0.27, respectively).Conclusions: Increased IDO expression in brain tumors, especially in low-grade tumors, may account for increased AMT accumulation on PET. The higher tryptophan metabolism via the kynurenine pathway associated with low-grade tumors, might contribute to epileptogenicity of these tumors. Therapeutic approaches aimed at the kynurenine pathway may aid in the treatment of tumor-associated seizures. (Parts of the study was funded by a grant from the Children's Research Center of Michigan)