The IDH1 inhibitor ivosidenib improved seizures in a patient with drug-resistant epilepsy from IDH1 mutant oligodendroglioma

Vo, Anh Huan; Ambady, Prakash; Spencer, David C.

doi:10.1016/j.ebr.2022.100526

Cited by 19 publications

(7 citation statements)

References 19 publications

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“…Thus, we were able to show that IDHmut inhibition could help control TAE, independent of any other antitumor effects that clinical trials might ultimately reveal. This aligns with isolated clinical reports and small case series suggesting that IDHmut inhibitors substantially and rapidly reduce seizures, even when those seizures are resistant to multiple ASMs ( 63 – 65 ). The current data could therefore inform a clinical trial of IDHmut inhibitor with seizure control as a primary endpoint, especially since reducing seizures is becoming a higher priority in glioma clinical trials ( 53 ).…”

Section: Discussionsupporting

confidence: 87%

Postoperative risk of IDH mutant glioma–associated seizures and their potential management with IDH mutant inhibitors

Drumm¹,

Wang²,

Sears³

et al. 2023

Journal of Clinical Investigation

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Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH–wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d -2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma–associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.

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Section: Discussionsupporting

confidence: 87%

Postoperative risk of IDH mutant glioma–associated seizures and their potential management with IDH mutant inhibitors

Drumm¹,

Wang²,

Sears³

et al. 2023

Journal of Clinical Investigation

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“…In a case report, authors reported post-operative drug resident epilepsy in a patient with oligodendroglioma. They treated the patients with ivosidenib, his seizure frequency decreased substantially after starting ivosidenib [18]. The inhibition of D2HG production by drug inhibition of IDH1 shows us the importance of IDH1 mutation in the pathophysiology of epilepsy in adult diffuse gliomas.…”

Section: Discussionmentioning

confidence: 99%

Association of IDH1 Mutations with Epilepsies in Patients with Diffuse Adult Glioma according to the WHO 2021 Classification

Džurlić

Omerhodžić

Rovčanin

et al. 2022

Open Access Maced J Med Sci

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BACKGROUND: Tumors of the central nervous system comprise a wide range of over 100 histological distinct subtypes with different descriptive epidemiology, clinical features, treatments, and outcomes. The presence of isocitrate dehydrogenase gene mutation 1 (IDH1) has become one of the most critical biomarkers for molecular classification and prognosis in adult diffuse gliomas. About 65–90% of patients with adult diffuse gliomas have seizures as their initial symptoms. AIM: The objective of this study was to determine the association between IDH1 mutations in adult diffuse gliomas with an incidence of symptomatic epilepsy. METHODS: The study was conducted as an observational, cross-sectional, and prospective clinically controlled study at the Clinic of Neurosurgery of the Clinical Center of the University of Sarajevo. The research included a total of 100 patients treated at the Clinic of Neurosurgery, with pathohistological confirmation of glioma Grades II–IV who were stratified by groups according to tumor grade. Data were collected on tumor localization and grade, the presence of IDH mutations, and the presence of epileptic seizures as the first symptom of the glioma. RESULTS: Out of a total of 100 patients, 39 had IDH 1 mutations, while 61 patients were without them: Of these, diffuse astrocytoma Grade II 30 cases (30%), Grade III 5 (5%), and Grade IV 7 (7%), and the number of patients with glioblastoma was 58 (58%). In the group of patients with IDH 1 mutations, epileptic seizures were present in 87.2% compared to the group of patients without IDH 1 mutations (wild type) in which epileptic seizures were present in 16.4% of cases. Statistical analysis showed that the positive mutated IDH-type carries an almost 70% increase in the likelihood of epileptic seizures (χ2 = 8.378; p = 0.0001). If we separate the group of diffuse astrocytomas in the IDH 1-positive subgroup, 34 patients (85.81%) had epileptic seizures, while in the IDH 1-negative subgroup, there were no patients with epileptic seizures, which carries a statistically significant difference in frequency in favor of IDH 1-positive tumors (p ≤ 0.001). CONCLUSION: There is a clear connection between the presence of IDH1 mutations and the occurrence of epileptic seizures in the clinical picture of patients with diffuse adult glioma.

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“…For instance, increased functional connectivity (FC) of nodes located in the premotor area and decreased shortest path length of the sensorimotor network are specific alterations in patients with prefrontal glioma and GRE onset. 13 Oligodendroglioma 14,15 and astrocytoma with isocitrate dehydrogenase (IDH) mutation 16,17 were considered to be risk factors for GRE onset. One of the potential mechanisms to induce GRE at the microcosmic level was that the d-2-hydroxyglutarate products of IDH mutations potentially increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor.…”

Section: Introductionmentioning

confidence: 99%

“…Oligodendroglioma 14 , 15 and astrocytoma with isocitrate dehydrogenase (IDH) mutation 16 , 17 were considered to be risk factors for GRE onset. One of the potential mechanisms to induce GRE at the microcosmic level was that the d‐2‐hydroxyglutarate products of IDH mutations potentially increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor.…”

Section: Introductionmentioning

confidence: 99%

Altering patterns of sensorimotor network in patients with different pathological diagnoses and glioma‐related epilepsy under the latest glioma classification of the central nervous system

Sun

Weng

et al. 2023

CNS Neurosci Ther

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Aims:We aimed to clarify the relationship between alterations in functional networks and glioma-related epilepsy (GRE) in patients with different molecular diagnoses. Methods:We enrolled 160 patients with prefrontal gliomas and different histories of GRE. The patients were grouped based on the latest pathological glioma classification and GRE history. Graph theory analysis was applied to reveal alterations in the sensorimotor networks among various subgroups. Binary logistic regression was used to identify risk factors for preoperative GRE onset.Results: Decreasing shortest path length was found in patients with GRE, regardless of the chromosome 1p/19q status. Nodes located in the premotor and supplementary motor areas showed decreased nodal betweenness centrality and vulnerability in patients with GRE and chromosome 1p/19q intact. Additionally, the node on the primary motor area showed decreased nodal vulnerability but the node on the sensory-related thalamus increased in patients with GRE and chromosome 1p/19q codeletion. Decreased shortest path length, grade 2, and decreased nodal betweenness centrality of the premotor area were risk factors for GRE. Conclusion:Decreased shortest path length was a characteristic alteration in GRE and prefrontal glioma. Alterations in global properties were similar, but nodal properties were different in patients with GRE and different chromosome 1p/19q statuses.

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The IDH1 inhibitor ivosidenib improved seizures in a patient with drug-resistant epilepsy from IDH1 mutant oligodendroglioma

Cited by 19 publications

References 19 publications

Postoperative risk of IDH mutant glioma–associated seizures and their potential management with IDH mutant inhibitors

Postoperative risk of IDH mutant glioma–associated seizures and their potential management with IDH mutant inhibitors

Association of IDH1 Mutations with Epilepsies in Patients with Diffuse Adult Glioma according to the WHO 2021 Classification

Altering patterns of sensorimotor network in patients with different pathological diagnoses and glioma‐related epilepsy under the latest glioma classification of the central nervous system

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