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. 2021 Oct 4;3(1):vdab146.
doi: 10.1093/noajnl/vdab146. eCollection 2021 Jan-Dec.

Pharmacoresistant seizures and IDH mutation in low-grade gliomas

Carlos Eduardo Correia  1 , Yoshie Umemura  1 , Jessica R Flynn  2 , Anne S Reiner  2 , Edward K Avila  1
Affiliations

Pharmacoresistant seizures and IDH mutation in low-grade gliomas

Carlos Eduardo Correia et al. Neurooncol Adv. .

Abstract

Background: Many low-grade gliomas (LGG) harbor isocitrate dehydrogenase (IDH) mutations. Although IDH mutation is known to be epileptogenic, the rate of refractory seizures in LGG with IDH mutation vs wild-type had not been previously compared. We therefore compared seizure pharmacoresistance in IDH-mutated and wild-type LGGs.

Methods: Single-institution retrospective study of patients with histologic proven LGG, known IDH mutation status, seizures, and ≥2 neurology clinic encounters. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥2 changes in anti-epileptic drugs were considered pharmacoresistant. Incidence rates of pharmacoresistant seizures were estimated using competing risks methodology.

Results: Of 135 patients, 25 patients (19%) had LGGs classified as IDH wild-type. Of those with IDH mutation, 104 (94.5%) were IDH1 R132H; only 6 were IDH2 R172K. 120 patients (89%) had tumor resection, and 14 (10%) had biopsy. Initial post-surgical management included observation (64%), concurrent chemoradiation (23%), chemotherapy alone (9%), and radiotherapy alone (4%). Seizures became pharmacoresistant in 24 IDH-mutated patients (22%) and in 3 IDH wild-type patients (12%). The 4-year cumulative incidence of intractable seizures was 17.6% (95% CI: 10.6%-25.9%) in IDH-mutated and 11% (95% CI: 1.3%-32.6%) in IDH wild-type LGG (Gray's P-value = .26).

Conclusions: 22% of the IDH-mutated patients developed pharmacoresistant seizures, compared to 12% of the IDH wild-type tumors. The likelihood of developing pharmacoresistant seizures in patients with LGG-related epilepsy is independent to IDH mutation status, however, IDH-mutated tumors were approximately twice as likely to experience LGG-related pharmacoresistant seizures.

Keywords: 2-hydroxyglutarate; IDH mutation; low-grade glioma; medically refractory seizure; pharmacoresistant epilepsy.

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Figures

Figure 1.
Figure 1.
Putative mechanism for epileptogenicity in IDH-mutant tumors. IDH genes encode for isocitrate dehydrogenase (IDH). Mutant IDH reduces α-ketoglutarate in Krebs cycle to 2-hydroxyglutarate (2-HG), which is structurally similar to glutamate, an excitatory neurotransmitter that is both oncogenic and epileptogenic.
Figure 2.
Figure 2.
Consort flow chart for study participants by IDH status. Abbreviations: IDH, isocitrate dehydrogenase; IHC, immunohistochemistry; LGG, low-grade glioma; NGS, next-generation sequencing.
Figure 3.
Figure 3.
Tumor location by IDH mutation status. Out of 110 IDH-mutated LGGs (Mut), tumors were located in frontal (n = 65, 59%), temporal (n = 27, 24%), parietal (n = 15, 14%), and occipital lobes (n = 3, 3%). Tumor location of 25 IDH wild-type (WT) LGGs were temporal (n = 16, 64%), frontal (n = 5, 20%), parietal (n = 1, 4%), and occipital lobes (n = 0). There were 3 (12%) IDH wild-type LGG with gliomatosis pattern. Abbreviations: IDH, isocitrate dehydrogenase; LGGs, low-grade gliomas.
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