For patients with drug-resistant focal epilepsy, taking into account 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 causal for drug-resistant focal epilepsy. The process of identifying causal lesions includes magnetic resonance imaging and intracerebral electroencephalogram. These methods have been found to lack specificity and accuracy in the diagnosis of the type of the causal lesion with high interobserver variability.
Recently, a brain tumor classifier which uses epigenetic profiling has been formulated. It uses CpG sites to best discriminate between tumor groups. This method has been used to successfully identify multiple novel tumor entities such as isomorphic diffuse glioma, glioneuronal tumors with oligodendroglioma-life features and nuclear clusters, primary mismatch repair-deficient isocitrate dehydrogenase (IDH)-mutant astrocytoma, and primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features DICER1-mutant, among others. These lesions tend to be morphologically heterogeneous and would likely not be properly diagnosed without molecular approaches.
The review authors discussed 14 lesion types that have been associated with specific molecular markers. The lesions are caused by a mixture of somatic and germline variants, often affecting the mechanistic target of rapamycin (mTOR) signaling, receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) signaling, or glycosylation.
Lesions caused by somatic mutations have the potential to be assessed through cell-free DNA and may not require biopsy. Instead, a sample of cerebrospinal fluid collected by dural puncture may be used to diagnose some lesions caused by somatic variants. The review authors caution, however, that this method requires additional validation.
DNA methylation profiles, assessed from peripheral blood may also have prognostic value for epilepsy. Although research into methylation in epilepsy is currently in its infancy, there is the potential to reduce the interobserver variation in diagnosis. Additional samples and study 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 allow for more accurate diagnoses of causal lesions to be formulated on the basis of data collected via less invasive procedures.
Kobow K, Baulac S, von Deimling A, Lee JH. Molecular diagnostics in drug-resistant focal epilepsy define new disease entities. Brain Pathology. 2021;31:e12963. doi:10.1111/bpa.12963