Mutating Our Understanding of Brain Tumors and Seizures: Entrez IDH

Commentary

Mutant IDH1 and Seizures in Patients With Glioma.

Chen H, Judkins J, Thomas C, Wu M, Khoury L, Benjamin CG, Pacione D, Golfinos JG, Kumthekar P, Ghamsari F, Chen L, Lein P, Chetkovich DM, Snuderl M, Horbinski C. Neurology 2017;8819:1805–1813.

OBJECTIVE: Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1^mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1^mutincreases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons. METHODS: Three WHO grade II–IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1^mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5. RESULTS: Preoperative seizures were observed in 18%–34% of IDH1 wild-type (IDH1^wt) patients and in 59%–74% of IDH1^mut patients (p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1^mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6–3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5. CONCLUSIONS: The D2HG product of IDH1^mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1^mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1^mut inhibitors may improve antiepileptic therapy in patients with IDH1^mut gliomas.

Seizures in patients with brain tumors are common and debilitating. Of the approximately 200,000 patients diagnosed with brain tumors in the United States each year, 20 to 40 percent of patients experience seizures by the time their tumors are diagnosed, and an additional 20 to 45 percent of patients who do not initially present with seizures eventually develop them. Seizures substantially contribute to morbidity and cause a marked decrease in the quality of life in patients with brain tumors; a higher seizure burden is associated with more severe deterioration of cognitive function in brain tumor patients. As advances in brain tumor treatments increase life expectancy, morbidity from tumor-associated seizures is becoming increasingly burdensome to the patient.

The relatively recent discovery of the IDH1/2 mutation (collectively, IDH mutation as their functional characteristics are analogous) in brain tumors is now well known. This was initially found in 12% of patients with glioblastomas and was associated with a strong survival benefit (1). The mutation was subsequently found in more than 70% of patients with low-grade gliomas (2). The IDH mutations confer neomorphic enzyme activity that catalyzes an enormous overproduction of the on-co-metabolite D-2-hydroxyglutarate (D2HG), to the degree that it can actually be detected even through serum measurements or magnetic resonance spectroscopy. It is now believed that all glioblastomas with an IDH mutation were transformed from lower grade gliomas. Additionally, histologically low-grade gliomas without an IDH mutation had mutation patterns more similar to glioblastomas (3), thus underscoring the importance of molecular diagnostics in addition to histopathology.

Subsequent to the discovery of this mutation, several (though not all) studies have reported finding that patients with IDH mutations were also more likely to present with seizures in low-grade gliomas (4). In fact, one recent study reports that different seizure rates within the histological subgroups of gliomas was primarily explained by the different prevalence of IDH mutations (5). Furthermore, presentation with seizures in these patients conferred a survival benefit as well (6), overturning the long-held assumption that this previously observed relationship among tumors heralded by seizures and increased survival was due merely to lead-time bias.

In the current article, the authors study a large cohort (712) WHO grade II–IV gliomas from three institutions where they found that IDH mutant tumors confer risk for preoperative seizures, adjusted for other suspected seizure risk factors (1p/19q codeletion, WHO grade, and temporal lobe location). They found that in IDH mutated gliomas, there was no difference in survival with or without seizures. In IDH wild-type gliomas, there was only a weak suggestion that seizures may provide modest survival benefit. These results are largely confirmatory of results published in several previous studies. They develop an IDH1 mutation prediction model based on age, histology, and seizures, which is probably less relevant, given that IDH mutational status is (or should be) determined either through immunohistochemistry or genotyping in virtually all primary brain tumor patients now. It should be noted that this study has lumped glioblastomas together with lower-grade gliomas, with some justification, given the new molecular understanding of these tumors, detailed above. However, as a result, more than 70% of this paper's population consists of glioblastomas, with the expected marked skewing of the statistics strongly in favor of a relationship between IDH mutation and seizures—thus, this is predominantly a glioblastoma study. It has already been well established that glioblastomas are far less likely to harbor IDH mutations or present with seizures than their lower-grade brethren.

Most importantly, though, this study attempted to examine the mechanism by which IDH mutation confers seizure risk, with the hypothesis that structural similarity between D2HG and glutamate may result in glutaminergic activity. The choice of the model to test this hypothesis was the use of a multi-well multi-electrode array in 14-day-old rat cortical neurons. They found that D2HG increased in vitro electrical activity in this model, resulting in increased synchronized firing in neuronal networks in a dose-dependent manner and that this was blocked by a selective NMDA receptor antagonist. The study provides the first direct mechanistic evidence for IDH mutation-associated seizures. The choice of the model for this critical portion unfortunately makes this quite preliminary at this point, as it is a strictly in vitro (though elegant) system. Thus, this effect will need to be verified through in vivo animal models of epilepsy, and preferably, in brain tumor models.

It is unclear how the current findings integrate with the other major model of seizures in brain tumors. Several previous studies had advanced the glutamate hypothesis, that 1) upregulation of cysteine/glutamate antiporter system xc⁻, responsible for increasing extracellular glutamate (7); and 2) decrease in the excitatory amino acid transporters, responsible for uptake of glutamate from the synaptic cleft (8), were putative mechanisms of tumor associated seizures. One study did find that strong expression of system xc⁻ was inversely correlated to IDH1 immunohistochemistry (9). Whether or not there is an interaction between these two mechanisms, clearly, there are multiple mechanisms of seizures. It is even uncertain to me whether the direct glutaminergic-like effect of 2DHG is the only mechanism of epileptogenicity in IDH mutated tumors causing greater number of seizures. In fact, 18 to 34 percent of the present cohort of IDH wild-type tumors still present with seizures.

Notably, less progress has been made in addressing the more clinically relevant question of postoperative seizures. Although the study of preoperative seizures provides a model for the underlying mechanism of epileptogenicity in tumor-associated seizures, persistent postoperative seizures are a major reason for the extreme difficulty in managing these patients. In the studies that have examined this question, no association was found with IDH mutation and postoperative seizures (5, 10). This may reflect the fact that there are inevitably greater number of factors involved, such as degree of tumor debulking, perioperative injury, effects of chemo/radiotherapy, choice of anticonvulsant regimen, and likely a host of other reasons. Moreover, there are no anticonvulsants that have been specifically designed to treat tumor-associated seizures, although many postmarketing studies have demonstrated effectiveness of several of them. More investigation is definitely needed in this aspect of tumor-associated seizures.

Ultimately, effective treatment of tumors is likely the most important factor in controlling postoperative seizures. A number of IDH inhibitors are in clinical trials for the purpose of tumor control; it remains to be seen whether this treatment confers benefit for seizure control independent of tumor management. It is also notable that the discovery of the system xc⁻ system of tumor-associated seizures has not yet translated into meaningful treatment options, and specifically inhibiting the system xc⁻ pathway through sulfasalazine has caused excessive toxicity in clinical trial patients (11), a fate that we hope does not befall on the targets of the IDH mechanism.