Molecular Imaging of Brain Tumor-Associated Epilepsy

Abstract

Epilepsy is a common clinical manifestation and a source of significant morbidity in patients with brain tumors. Neuroimaging has a pivotal role in neuro-oncology practice, including tumor detection, differentiation, grading, treatment guidance, and posttreatment monitoring. In this review, we highlight studies demonstrating that imaging can also provide information about brain tumor-associated epileptogenicity and assist delineation of the peritumoral epileptic cortex to optimize postsurgical seizure outcome. Most studies focused on gliomas and glioneuronal tumors where positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques can detect metabolic and biochemical changes associated with altered amino acid transport and metabolism, neuroinflammation, and neurotransmitter abnormalities in and around epileptogenic tumors. PET imaging of amino acid uptake and metabolism as well as activated microglia can detect interictal or peri-ictal cortical increased uptake (as compared to non-epileptic cortex) associated with tumor-associated epilepsy. Metabolic tumor volumes may predict seizure outcome based on objective treatment response during glioma chemotherapy. Advanced MRI, especially glutamate imaging, can detect neurotransmitter changes around epileptogenic brain tumors. Recently, developed PET radiotracers targeting specific glutamate receptor types may also identify therapeutic targets for pharmacologic seizure control. Further studies with advanced multimodal imaging approaches may facilitate development of precision treatment strategies to control brain tumor-associated epilepsy.

Keywords: amino acid; brain tumors; epilepsy; glioma; glutamate; magnetic resonance imaging; neuroinflammation; peritumoral cortex; positron emission tomography; seizures.

Figure 1

Coronal slices of magnetic resonance imaging (MRI) (a), ¹⁸F-2-fluoro-2-deoxy-D-glucose (FDG) PET (b), and α-[¹¹C]methyl-L-tryptophan (AMT) PET (c) images of a 10-year-old girl with a non-enhancing left inferior temporal dysembryoplastic neuroepithelial tumor (DNT) (arrow). FDG PET showed hypometabolism (FDG uptake tumor/cortex ratio: 0.45), while AMT PET demonstrated markedly increased tryptophan uptake (AMT uptake tumor/cortex ratio: 1.27) in the lesion. The colors on the bar represent a relative scale for the PET images, where the red areas include voxels with the highest and those with deep blue, the lowest radioactivity values within the brain. (Reproduced with permission from Figure 1 of Alkonyi et al. [21]).

Figure 2

Co-registered axial MRI (a), FDG PET (b), and AMT PET (c) images of a 6-year-old boy with a left medial temporal DNT (arrow). FDG PET demonstrated severe glucose hypometabolism of the tumor (FDG uptake tumor/contralateral cortex ratio: 0.29), and AMT PET showed no prominent tryptophan accumulation in the tumor volume (AMT uptake ratio: 0.99). However, an extensive area of ipsilateral cortex (mostly temporal) showed a marked increase of AMT uptake (arrowheads) (ipsilateral/contralateral cortex ratio: 1.21). Note that tracer accumulation seen in the bilateral occipital cortex and in the visualized portions of the basal ganglia, seen on the AMT PET image, is likely physiologic, because these regions (along with the cerebellum) are among the highest uptake regions in the brain in both healthy controls and epilepsy patients (regardless of the location of the presumed epileptic focus) [28]. The colors on the bar represent a relative scale for the PET images, where the red areas include voxels with the highest and those with deep blue the lowest radioactivity values within the brain. (Reproduced with permission from Figure 2 of Alkonyi et al. [21]).

Figure 3

Cortical amino acid uptake in O-(2-¹⁸F-fluoroethyl)-L-tyrosine (FET) PET in the course of a prolonged postictal episode. A 44-year-old man with clinically stable anaplastic astrocytoma WHO III without any evidence of a residual tumor over years presented with tonic-clonic seizures followed by severe and prolonged postictal symptoms (global aphasia, right-sided hemiplegia, and hemineglect) over an 8-week period. (A) MRI (day 1) and FET PET (day 4) showed distinct increased and extended cortical FET uptake of the left hemisphere (LBR_max, 3.95; LBR_mean, 2.08) with frontal and temporal accentuation, corresponding to slight cortical vasogenic and cytotoxic edema (T2/FLAIR, DWI/ADC) without contrast enhancement (T1wCE). EEG monitoring, ¹⁸F-FDG PET (glucose hypometabolism, red arrows), and 99mTc-HMPAO SPECT (showing hypoperfusion), however, revealed no evidence of status epilepticus. (B) For FET PET 11 days after symptom onset and 7 days after the first FET PET, slight regression of cortical FET uptake (LBR_max, 2.34; LBR_mean, 1.45) was observed. (C) The patient slowly recovered within 8 weeks after seizure onset. FET PET and MRI 12 weeks after symptom onset demonstrated complete recovery of cortical FET uptake and brain edema; only residual cortical atrophy in T1 and T2/FLAIR sequences remained. (Reproduced with permission from Figure 3 of Hutterer et al. [30]). LBR: lesion-to-brain ratio.

Figure 4

In a newly diagnosed, isocitrate dehydrogenase (IDH)-wildtype glioblastoma, a moderate spatial overlap was found between the biological tumor volume from TSPO (GE-180) PET (red line) and amino acid (FET) PET (green line). Note that both PET volumes extended way beyond the boundaries of the contrast-enhancing volume (ce-T1), and the high TSPO volume further extended behind the FET PET volume. (Reproduced with permission from Figure 1 of Unterrainer et al. [36]).

Figure 5

GluCEST contrast vs. gadolinium enhancement in a WHO grade II oligodendroglioma. (A) 3T FLAIR images in the axial GluCEST acquisition plane, tumor identified by white arrows. (B) 3T T1-weighted images without gadolinium contrast in the axial GluCEST acquisition plane. (C) 3T T1-weighted images with gadolinium contrast in the axial GluCEST acquisition plane with evidence of nodular, wispy mesial contrast enhancement (red arrows). (D) 3T T1-weighted images with gadolinium coregistered with GluCEST contrast maps. Increased GluCEST contrast in a region overlapping but extending beyond the area of gadolinium enhancement (black arrows). (Reproduced from Figure 2 of Neal et al. [54]).