An introduction to the mini‐symposium on “The Neuropathology of Focal Human Epilepsy”

In May 2012, Brain Pathology published a minisymposium on “etiology of epilepsy,” to update the neuropathology community on common and difficult to diagnose brain lesions associated with earlyonset and drugresistant focal epilepsy and amenable to epilepsy surgery. At this time, epilepsy surgery became widely accepted as a successful treatment option for a carefully selected group of patients and the number of epilepsy surgery centers had been growing continuously. Under the motto “cause matters,” the authors appraised the rejuvenation of neuropathology in the arena of epileptology and its increasing impact for patient selection and postsurgical management. Articles reviewed (i) the concept of lowgrade epilepsyassociated tumors, a terminology still used nowadays in the scientific literature (1); (ii) the 1st international consensus classification system for Focal Cortical Dysplasia (FCD), which was just published in 2011 and became the gold standard for diagnosing FCD in clinical practice and research (2); (iii) anticipating an international classification scheme for Hippocampal Sclerosis, published subsequently in 2013 (3); and (iv) the role of the innate and adaptive immune system in epileptic encephalitis. (4) Over the past 9 years, these topics remained in the center of the scientific interest and fascinating discoveries led to a better understanding of the pathogenesis and potentially druggable targets for pharmacological treatment. We are proud, therefore, to present a followup minisymposium on “Neuropathology and Focal Human Epilepsy” and invited a panel of distinguished and highly recognized authors whom were fundamental to these exciting developments. Five topics were chosen to summarize and discuss most current knowledge in epilepsyassociated brain lesions and the quest for best treatment options in epileptology. The discovery of postzygous brain somatic mosaicism in cortical malformations and their causal role in the pathogenesis of focal brain lesions as well as epileptogenesis, deciphering also their impact at the singlecell level, will be a focus of our minisymposium, therefore. Other topics of interest cover new diagnostic entities, new molecular diagnostic platforms, and the impact of a reliable neuropathology diagnosis for the prediction of successful postsurgical outcome. Drs. Blumcke, Cendes, Miyata, Thom, Aronica, and Najm will start this minisymposium reflecting not only the success of the FCD classification scheme from 2011 (5), but also highlight its gaps and challenges, which will likely result in a timely first update (currently in preparation). They present a series of three case vignettes, each representing a common, although challenging clinical scenario. We will then better understand the need of a comprehensive integration of diagnostic modalities including highpower neuroimaging, advanced EEG recordings, and the neuropathology phenotype– genotype work up to advance clinical patient management to the next level. The discovery of somatic brain mutations in the MTOR or GATOR signaling pathway causing distinct subtypes of cortical malformations represented a hallmark of scientific research during the past 5 years. Drs. Kobow, Baulac, von Deimling, and Lee describe the currently known genetic landscape of epileptogenic brain lesions and also introduce novel entities defined by their clinicopathological and genetic signature (6). Their review will offer an intriguing insight into DNA methylation analysis, which opened the avenue to “Neuropathology 2.0. ” Much was learned from brain tumors and the question remains whether this platform can be translated into the arena of epileptology. In fact, electrical activity transmitted by the epileptic seizures may trigger itself an epigenetically encrypted cellular disease memory and DNA methylation shall be successfully used to differentiate the broad spectrum of cortical malformations in epilepsy. Drs. Khoshkoo, Lal, and Walsh will continue this path to the exciting area of singlecell genomics, which provides a molecular biological basis to better understand the complex issue of epileptogenic neocortical lesions (7). It is the ever challenging question of (i) which gene is mutated, (ii) in which neuroepithelial cell lineage, (iii) in which region, and (iv) at which time point during neocortical development to produce an epileptogenic and anatomopathologically complex lesion. Drs. Coras, Holthausen, and Sarnat address the challenging issue of Focal Cortical Dysplasia ILAE Type 1 (8). They will reflect on the ongoing discussion how to address the clinicopathological and genetic spectrum of this disease category at the clinical and scientific level. Received: 20 April 2021 | Accepted: 27 April 2021