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Quantitative measurement of peritumoral concentrations of glutamate, N-acetyl aspartate, and lactate on magnetic resonance spectroscopy predicts glioblastoma-related refractory epilepsy

  • Original Article - Brain Tumors
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Abstract

Background

Increased extracellular glutamate is known to cause epileptic seizures in patients with glioblastoma (GBM). However, predicting whether the seizure will be refractory is difficult. The present study investigated whether evaluation of the levels of various metabolites, including glutamate, can predict the occurrence of refractory seizure in GBM by quantitative measurement of metabolite concentrations on magnetic resonance spectroscopy (MRS).

Methods

Forty patients were treated according to the same treatment protocol for primary GBM at Ehime University Hospital between April 2017 and July 2021. Of these patients, 23 underwent MRS to determine concentrations of metabolites, including glutamate, N-acetylaspartate, creatine, and lactate, in the tumor periphery by applying LC-Model. The concentration of each metabolite was expressed as a ratio to creatine concentration. Patients were divided into three groups: Type A, patients with no seizures; Type B, patients with seizures that disappeared after treatment; and Type C, patients with seizures that remained unrelieved or appeared after treatment (refractory seizures). Relationships between concentrations of metabolites and seizure types were investigated.

Results

In 23 GBMs, seizures were confirmed in 11 patients, including Type B in four and Type C in seven. Patients with epilepsy (Type B or C) showed significantly higher glutamate and N-acetylaspartate values than did non-epilepsy patients (Type A) (p < 0.05). No significant differences in glutamate or N-acetylaspartate levels were seen between Types B and C. Conversely, Type C showed significantly higher concentrations of lactate than did Type B (p = 0.001). Cutoff values of lactate-to-creatine, glutamate-to-creatine, and N-acetylaspartate-to-creatine ratios for refractory seizure were > 1.25, > 1.09, and > 0.88, respectively.

Conclusions

Extracellular concentrations of glutamate, N-acetylaspartate, and lactate in the tumor periphery were significantly elevated in patients with GBM with refractory seizures. Measurement of these metabolites on MRS may predict refractory epilepsy in such patients and could be an indicator for continuing the use of antiepileptic drugs.

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Acknowledgements

We are grateful to Taichi Furumochi and Yasuhiro Shiraishi from the Department of Neurology and to Satsuki Myoga from the Department of Pathology at Ehime University Hospital, Japan, for their help in obtaining pathological and radiological imaging findings. We also wish to thank Kohei Miura and Koji Maehara at GE Healthcare Japan for their advice regarding the technical background of MRS sequences and the postprocessing steps during the revision process.

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Authors and Affiliations

  1. Department of Neurosurgery, Ehime University School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan

    Yawara Nakamura, Akihiro Inoue, Masahiro Nishikawa, Yoshihiro Ohtsuka, Saya Ozaki, Kosuke Kusakabe, Satoshi Suehiro, Daisuke Yamashita, Seiji Shigekawa, Hideaki Watanabe & Takeharu Kunieda

  2. Department of Neurosurgery, Washoukai Sadamoto Hospital, 1-6-1 Takehara, Matsuyama, Ehime, 790-0052, Japan

    Takanori Ohnishi

  3. Department of Molecular and Cellular Physiology, Ehime University School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan

    Hajime Yano & Junya Tanaka

  4. Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Osaka, 540-0006, Japan

    Yonehiro Kanemura

  5. Department of Neurosurgery, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Osaka, 540-0006, Japan

    Yonehiro Kanemura

  6. Division of Diagnostic Pathology, Ehime University Hospital, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan

    Riko Kitazawa

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  1. Yawara Nakamura
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Corresponding author

Correspondence to Akihiro Inoue.

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Ethical approval

This study was approved by the Ethics Committee for Clinical Research at Ehime University Hospital (approval No. 2110012) prior to initiation and was performed in accordance with the ethical standards as established in the 1964 Declaration of Helsinki and its later amendments.

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ESM 3

Supplementary Fig. S1 Concentration of Creatine (Cr) in three types of epilepsy in glioblastoma (GBM). Type A: 4.43±0.72, Type B: 4.90±0.47, Type C: 3.51±1.24 (Type A vs Type B, p=0.638, Type A vs Type C, p=0.0985, Type B vs Type C, p=0.0534). There was no significant difference in the Cr concentration among patients showing three types of epileptic seizure. (PNG 299 kb)

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Supplementary Fig. S2 Representative features of three types of epilepsy in GBM. (a) T1-weighted, gadolinium-enhanced imaging, (b) FLAIR, (c) MRS analysis using the LC-Model. Analysis of the concentrations of each metabolite (Glu, NAA, Lac, Cr) on MRS was performed by taking ROIs for target sites at the 11C-methionine uptake area with a TNR of 1.4 on methionine PET outside the gadolinium-contrast enhancing area on MRI (yellow square: target site). (PNG 2318 kb)

High Resolution (TIF 568 kb)

ESM 5

Supplementary Fig. S3 CD44 expression (presented by P/C ratio) in three types of tumor-related epilepsy reclassified by cutoff values of Glu/Cr, NAA/Cr, and Lac/Cr. Type A: Glu/Cr ≤1.09; NAA/Cr ≤0.88; and Lac/Cr ≤1.25. Type B: Glu/Cr >1.09; NAA/Cr >0.88; and Lac/Cr >1.25. Type C: Glu/Cr >1.09; NAA/Cr >0.88; and Lac/Cr >1.25. Values for the P/C ratio of CD44: Type A (n=6), 5.45±5.08; Type B (n=5), 1.06±0.95; and Type C (n=4), 11.86±4.91. Type A vs. Type B, p=0.2259; Type A vs. Type C, p=0.079; and Type B vs. Type C, p=0.0056. *p<0.01; ns, not significant.(PNG 436 kb)

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Nakamura, Y., Inoue, A., Nishikawa, M. et al. Quantitative measurement of peritumoral concentrations of glutamate, N-acetyl aspartate, and lactate on magnetic resonance spectroscopy predicts glioblastoma-related refractory epilepsy. Acta Neurochir 164, 3253–3266 (2022). https://doi.org/10.1007/s00701-022-05363-y

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