Molecular diagnostics reveals novel causal lesions in drug-resistant focal epilepsy

In patients with drug-resistant focal epilepsy, considering genetic data has improved clinical decision-making and has led to the definition of new disease entities, according to a review published in Brain Pathology.

Structural brain lesions such as glioneuronal tumors or malformations of cortical development are often the cause of drug-resistant focal epilepsy. The process of identifying causal lesions includes magnetic resonance imaging and intracerebral electroencephalogram. It has been found that these methods are not specific and accurate in diagnosing the type of causal lesion with high interobserver variability.

Recently a brain tumor classifier was formulated using epigenetic profiling. It uses CpG sites to best differentiate between tumor groups. This method has been used to successfully identify several new tumor entities such as isomorphic diffuse glioma, glionural tumors with oligodendroglioma life features and nuclear clusters, primary mismatch-repair-deficient isocitrate dehydrogenase (IDH) -mutated astrocytoma, and primary intracranial underdevelopmental spindle domarcoma-like features other DICER1 mutant. These lesions tend to be morphologically heterogeneous and would likely not be properly diagnosed without molecular approaches.

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The review authors discussed 14 types of lesions that were associated with specific molecular markers. The lesions are caused by a mixture of somatic and germline variants that often affect the mechanistic target of rapamycin (mTOR) signaling, receptor tyrosine kinase (RTK) / mitogen-activated protein kinase (MAPK) signaling, or glycosylation.

Lesions caused by somatic mutations can be examined by cell-free DNA and may not require a biopsy. Instead, a sample of cerebrospinal fluid obtained through a dural puncture can be used to diagnose some lesions caused by somatic variants. However, the review authors point out that this method requires additional validation.

DNA methylation profiles determined from peripheral blood can also have prognostic value for epilepsy. Although research on methylation in epilepsy is currently in its infancy, there is potential to reduce the variability of diagnosis between observers. Additional samples and studies are needed to evaluate the predictive potential of DNA methylation in drug-resistant focal epilepsy.

The review authors concluded that molecular approaches are changing the diagnostic process for patients with drug-resistant focal epilepsy. These approaches have the potential to formulate more accurate diagnoses of causal lesions based on data collected with less invasive procedures.


Kobow K, Baulac S, from Deimling A, Lee JH. Molecular diagnostics in drug-resistant focal epilepsy defines new disease entities. Brain pathology. 2021; 31: e12963. doi: 10.1111 / bpa.12963

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