Structural brain lesions, including the broad range of malformations of cortical development (MCD) and glioneuronal tumors, are among the most common causes of drug-resistant focal epilepsy. Epilepsy surgery can provide a curative treatment option in respective patients. The currently available pre-surgical multi-modal diagnostic armamentarium includes high- and ultra-high resolution magnetic resonance imaging (MRI) and intracerebral EEG to identify a focal structural brain lesion as epilepsy underlying etiology. However, specificity and accuracy in diagnosing the type of lesion have proven to be limited. Moreover, the diagnostic process does not stop with the decision for surgery. The neuropathological diagnosis remains the gold standard for disease classification and patient stratification, but is particularly complex with high inter-observer variability. Here, the identification of lesion-specific mosaic variants together with epigenetic profiling of lesional brain tissue became new tools to more reliably identify disease entities. In this review, we will discuss how the paradigm shifts from histopathology toward an integrated diagnostic approach in cancer and the more recent development of the DNA methylation-based brain tumor classifier have started to influence epilepsy diagnostics. Some examples will be highlighted showing how the diagnosis and our mechanistic understanding of difficult to classify structural brain lesions associated with focal epilepsy has improved with molecular genetic data being considered in decision making.

中文翻译：

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耐药局灶性癫痫的分子诊断定义了新的疾病实体

结构性脑损伤，包括广泛的皮质发育畸形（MCD）和胶质神经元肿瘤，是耐药局灶性癫痫的最常见原因之一。癫痫手术可以为各个患者提供治愈性治疗选择。目前可用的术前多模式诊断设备包括高分辨率和超高分辨率磁共振成像（MRI）和脑内脑电图，以将局灶性结构性脑病变识别为癫痫的潜在病因。然而，诊断病变类型的特异性和准确性已被证明是有限的。此外，诊断过程并不会随着手术决定而停止。神经病理学诊断仍然是疾病分类和患者分层的金标准，但由于观察者间的高度变异性而特别复杂。在这里，病变特异性嵌合变异的识别以及病变脑组织的表观遗传分析成为更可靠地识别疾病实体的新工具。在这篇综述中，我们将讨论这种范式如何从组织病理学转向癌症综合诊断方法，以及基于 DNA 甲基化的脑肿瘤分类器的最新发展如何开始影响癫痫诊断。将重点介绍一些例子，展示如何通过在决策中考虑分子遗传数据来改善与局灶性癫痫相关的难以分类的结构性脑损伤的诊断和我们对局灶性癫痫相关的结构性脑损伤的机制理解。