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Review
. 2021 Jul;31(4):e12963.
doi: 10.1111/bpa.12963.

Molecular diagnostics in drug-resistant focal epilepsy define new disease entities

Katja Kobow  1 , Stéphanie Baulac  2 , Andreas von Deimling  3   4 , Jeong Ho Lee  5   6
Affiliations
Review

Molecular diagnostics in drug-resistant focal epilepsy define new disease entities

Katja Kobow et al. Brain Pathol. 2021 Jul.

Abstract

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.

Keywords: DNA methylation; focal epilepsy; malformation of cortical development (MCD); somatic mutation; structural brain lesion.

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Figures

FIGURE 1
FIGURE 1
Molecular brain tumor classification. t‐SNE summarizing examples of LEATs and novel tumor entities or variants detected on the grounds of DNA methylation patterns. AG, angiocentric glioma; DNET, dysembryoplastic neuroepithelial tumor; DGONC, diffuse glioneuronal tumor with oligodendroglioma‐like features and nuclear clusters; GG, ganglioglioma; IDG, isomorphic diffuse glioma; HGNET‐BCOR, high‐grade neuroepithelial tumor with BCOR alteration; HGNET‐MN1, high‐grade neuroepithelial tumor with MN1 alteration; PA, pilocytic astrocytoma; PGNT, papillary glioneuronal tumor; PLNTY, Polymorphous low‐grade neuroepithelial tumor of the young; SEGA, Subependymal giant cell astrocytoma; SCS‐DICER1, spindle cell sarcoma DICER1‐mutant; NB‐FOXR2, CNS neuroblastoma FOXR2 activated
FIGURE 2
FIGURE 2
REST‐mediated intrinsic epileptogenicity by BRAF in glioneuronal tumors. Adapted from Dr. Jeong Ho Lee (22) (with permission). When the BRAF V600E variant was introduced into progenitor cells of neuronal lineage, cells were intrinsically epileptogenic. In contrast, tumorigenic properties were attributed to a BRAF V600E variant introduced into glial cells. WT, wild‐type BRAF
See this image and copyright information in PMC

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