Mutant isocitrate dehydrogenase (IDH) 1/2 gene products gain a new ability to produce D-2-hydroxyglutarate (D2HG). IDH1/2 mutations are thought to be associated with seizures owing to the structural similarity between D2HG and glutamate. However, the effects of D2HG on seizures in clinical settings are not fully understood. We sought to investigate the relationship between tissue 2-hydroxyglutarate (2HG) concentration and preoperative seizures using clinical samples.

We included 104 consecutive patients with diffuse glioma who underwent surgery from August 2008 to May 2016 and whose clinical presentation and IDH1/2 status were identified. The presence of preoperative seizures, tumor location, histopathologic diagnosis, IDH1/2 status, and 1p/19q codeletion were assessed from the patient charts. Tissue 2HG concentration was measured using liquid chromatography–tandem mass spectrometry. To evaluate 2HG distribution without artefactual tissue disruption, we applied matrix-assisted laser desorption/ionization high-resolution mass spectrometry imaging (MALDI-MSI) in 12 patients' surgically resected samples. We assessed the correlation of preoperative seizures with tissue 2HG concentration, IDH1/2 status, WHO grade, and 1p/19q codeletion.

Tissue 2HG concentration was higher in IDH1/2 mutant tumors (IDH-Mut, n = 42) than in IDH1/2 wild-type tumors (IDH-WT, n = 62) (median 4,860 ng/mg vs 75 ng/mg) (p < 0.0001). MALDI-MSI could detect 2HG signals in IDH-Mut, but not in IDH-WT. Preoperative seizures were observed in 64.3% of patients with IDH-Mut and 21.0% patients with IDH-WT (p < 0.0001). The optimal cutoff value of tissue 2HG concentration for predicting preoperative seizures was 1,190 ng/mg, as calculated by the receiver operating characteristic curve. Increased preoperative seizure risk was only observed in tumors with 2HG concentration above the cutoff value among IDH-Mut (IDH-Mut with above the cutoff value: 71.4% vs IDH-Mut with below the cutoff value: 28.6%; p = 0.031). Multivariate analysis, including IDH1/2 mutation status, tissue 2HG concentration, WHO grade, and 1p/19q codeletion, revealed that only increased tissue 2HG concentration was associated with preoperative seizures (odds ratio 5.86, 95% confidence interval 1.02–48.5; p = 0.048).

We showed that high tissue 2HG concentration was associated with preoperative seizures, suggesting that excess 2HG increases risk of preoperative seizures in IDH1/2 mutant tumors.

突变异柠檬酸脱氢酶 ( IDH ) 1/2 基因产物获得了产生 D-2-羟基戊二酸 (D2HG) 的新能力。由于 D2HG 和谷氨酸之间的结构相似性， IDH1/2突变被认为与癫痫发作有关。然而，D2HG 在临床环境中对癫痫发作的影响尚不完全清楚。我们试图使用临床样本研究组织 2-羟基戊二酸 (2HG) 浓度与术前癫痫发作之间的关系。

我们纳入了 2008 年 8 月至 2016 年 5 月接受手术的 104 名弥漫性胶质瘤患者，他们的临床表现和IDH1/2状态均已确定。从患者图表中评估了术前癫痫发作、肿瘤位置、组织病理学诊断、IDH1/2状态和 1p/19q 共缺失的存在。使用液相色谱-串联质谱法测量组织 2HG 浓度。为了评估 2HG 分布而不造成人为组织破坏，我们在 12 名患者手术切除的样本中应用了基质辅助激光解吸/电离高分辨率质谱成像 (MALDI-MSI)。我们评估了术前癫痫发作与组织 2HG 浓度IDH1/2的相关性状态、WHO 分级和 1p/19q 共缺失。

IDH1/2突变肿瘤 ( IDH -Mut, n = 42) 中的组织 2HG 浓度高于IDH1/2野生型肿瘤 ( IDH -WT, n = 62)（中位数 4,860 ng/mg vs 75 ng/mg） ( p < 0.0001)。MALDI-MSI 可以在IDH -Mut 中检测到 2HG 信号，但在IDH -WT 中无法检测到。64.3% 的IDH -Mut 患者和 21.0% 的IDH -WT患者观察到术前癫痫发作（p< 0.0001)。根据受试者工作特征曲线计算，预测术前癫痫发作的组织 2HG 浓度的最佳截止值为 1,190 ng/mg。仅在IDH -Mut中 2HG 浓度高于临界值的肿瘤中观察到术前癫痫风险增加（IDH -Mut 高于临界值：71.4% vs IDH -Mut 低于临界值：28.6%；p = 0.031）。多变量分析，包括IDH1/2突变状态、组织 2HG 浓度、WHO 分级和 1p/19q 共缺失，显示只有组织 2HG 浓度增加与术前癫痫发作相关（优势比 5.86，95% 置信区间 1.02-48.5；p = 0.048)。

我们发现高组织 2HG 浓度与术前癫痫发作相关，这表明过量的 2HG 会增加IDH1/2突变肿瘤术前癫痫发作的风险。