The role of elevated glutamate in patients with glioma related seizures

Abstract

Patients with gliomas commonly present with seizures, which are refractory to standard anticonvulsant medication and associated with significant morbidity. Variable success is seen with standard and electrocorticography guided surgical resection for seizure control. There is a clear need for a marker that will guide resection of the ictogenic areas during surgery, to improve seizure control, limit morbidity and achieve better tumour clearance. Multiple lines of evidence support the notion that increased extracellular glutamate from an over expression of the cystine-glutamate antiporter, system xc- in the peri-tumoural region, leads to a propensity for peri-tumoural cell death, reduced patient survival, and seizure generation. Pre-operative 1D chemical shift imaging (CSI) MRS with an echo time (TE) averaged point-resolved spectroscopy (PRESS) sequence was used to quantify glutamate levels in a peri-tumoural region to be sampled using an intra-operative neuronavigation system (Brainlab). ex vivo human cortical slice electrophysiology from these samples revealed that peri-tumoural regions with elevated glutamate to creatine ratios, are strongly associated with spontaneous interictal discharges (IIDs). The similarity in choline to creatine ratios and N-acetyl-aspartate to creatine ratios implies that this difference does not reflect the degree of tumour infiltration or the health of the neuronal network. Slices with spontaneous IIDs did appear more susceptible to the proconvulsant effects of a modified solution of artificial cerebrospinal fluid but not 4-aminopyridine. Pharmacological experiments in ex vivo slices from peri-tumoural regions in patients with glioma (and control non-glioma tissue) demonstrated that spontaneous IIDs and induced epileptiform events in the form of ictal discharges (IDs) are sensitive to the system xc- antagonist sulfasalazine. Spontaneous IIDs were also sensitive to the GABA receptor antagonist gabazine and the Na-K-Cl co transporter 1 (NKCC1) antagonist bumetanide suggesting that they are in part also a depolarising GABAergic phenomenon driven by intracellular chloride loading. Spontaneous IIDs were also sensitive to the calcium permeable α-amino-3-hydroxl-5-methyl-4-isoxazoleproprionic acid (CP-AMPA) receptor blocker 1-naphthyl-acetyl spermine (NASPM) suggesting that CP-AMPA receptors are also involved in glioma associated seizures. 3 This thesis demonstrates that peri-tumoural regions that harbour spontaneous IIDs, have elevated levels of glutamate compared to peri-tumoural cortex that is electrically quiescent, supporting the proposition that MRS may serve as a non-invasive tool to map the epileptogenic zones around gliomas. Further work should clarify whether glutamate signal on MR spectroscopy is associated with in vivo electrographic markers of epileptogenicity.