Pathological Targets for Treating Temporal Lobe Epilepsy: Discoveries From Microscale to Macroscale

Temporal lobe epilepsy (TLE) is one of the most common and severe types of epilepsy, characterized by intractable, recurrent, and pharmacoresistant seizures. Histopathology of TLE is mostly investigated through observing hippocampal sclerosis (HS) in adults, which provides a robust means to analyze the related histopathological lesions. However, most pathological processes underlying the formation of these lesions remain elusive, as they are difficult to detect and observe. In recent years, significant efforts have been put in elucidating the pathophysiological pathways contributing to TLE epileptogenesis. In this review, we aimed to address the new and unrecognized neuropathological discoveries within the last 5 years, focusing on gene expression (miRNA and DNA methylation), neuronal peptides (neuropeptide Y), cellular metabolism (mitochondria and ion transport), cellular structure (microtubule and extracellular matrix), and tissue-level abnormalities (enlarged amygdala). Herein, we describe a range of biochemical mechanisms and their implication for epileptogenesis. Furthermore, we discuss their potential role as a target for TLE prevention and treatment. This review article summarizes the latest neuropathological discoveries at the molecular, cellular, and tissue levels involving both animal and patient studies, aiming to explore epileptogenesis and highlight new potential targets in the diagnosis and treatment of TLE.

Somatic mutation involving diverse genes leads to a spectrum of focal cortical malformations

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT3-mTOR-signaling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n=16), focal cortical dysplasia type I and related phenotypes (n=48), focal cortical dysplasia type II (n=44), or focal cortical dysplasia type III (n=15) classified using imaging and pathological findings. We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel, and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1, and NIPBL, genes associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a very small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that FCD types I, II, and III, are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.