Pharmacoresistant seizures and IDH mutation in low-grade gliomas

Abstract

Purpose 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 six 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= 0.26). 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.

Identification of functional immune and neuronal tumour cells in glioma

“…Importantly, SCRAM predicted the existence of these neuronal-like tumor cells as a defining feature of IDH1 mut tumors representing nearly half of tumor cells in our human datasets, which we confirmed experimentally. Notably, IDH1 mut glioma frequently presents with seizures 45 despite a slower disease course, raising the possibility that these neuronal-like cell types may contribute to hyperexcitable phenotypes that present clinically. Future investigations may aim to better define the electrophysiological contributions of these cells to tumor progression and may seek to characterize how modulation of electrophysiological activity originating from tumor cells alters disease outcomes in glioma.…”

“…Importantly, NLTs were the only cells expressing proliferation markers in our Patch-seq dataset, suggesting that NLTs are important contributors to both the neurophysiological and proliferative characteristics of glioma. Clinically, IDH1 mut glioma frequently presents with seizures 58 , raising the possibility that NLTs may contribute to both hyperexcitable and proliferative phenotypes in these tumors.…”

Mutant IDH in Gliomas: Role in Cancer and Treatment Options

“…Patients affected by IDH mutant gliomas present a more frequent epileptic activity compared to IDH wildtype patients [88] [89]. Unfortunately, the seizures showed by IDH mutant patients are frequently resistant to first line epilepsy treatment [90]. Nevertheless, recently it has been reported that a patient affected by IDH1 mutant oligodendroglioma showed reduced tumor-associated epilepsy after treatment with the IDH1 mutant inhibitor AG-120 (ivosidenib) [91].…”

Seizure Management and Prophylaxis Considerations in Patients with Brain Tumors

“…Patients with IDH mutated grade 2 gliomas are much more likely to experience medication-refractory seizures than IDH wt grade 2 patients. Within the group of IDH wt tumors [10], grades 2 and 3 tumors are more likely to present with early seizures, have more seizure days, and require more often polytherapy than IHD wt glioblastomas [11].…”