Purpose: Focal cortical dysplasias (FCD) are localized regions of malformed cerebral cortex and are very frequently associated with epilepsy in both children and adults. A broad spectrum of histopathology has been included in the diagnosis of FCD. An ILAE task force proposes an international consensus classification system to better characterize specific clinicopathological FCD entities. Methods: Thirty‐two Task Force members have reevaluated available data on electroclinical presentation, imaging, neuropathological examination of surgical specimens as well as postsurgical outcome. Key Findings: The ILAE Task Force proposes a three‐tiered classification system. FCD Type I refers to isolated lesions, which present either as radial (FCD Type Ia) or tangential (FCD Type Ib) dyslamination of the neocortex, microscopically identified in one or multiple lobes. FCD Type II is an isolated lesion characterized by cortical dyslamination and dysmorphic neurons without (Type IIa) or with balloon cells (Type IIb). Hence, the major change since a prior classification represents the introduction of FCD Type III, which occurs in combination with hippocampal sclerosis (FCD Type IIIa), or with epilepsy‐associated tumors (FCD Type IIIb). FCD Type IIIc is found adjacent to vascular malformations, whereas FCD Type IIId can be diagnosed in association with epileptogenic lesions acquired in early life (i.e., traumatic injury, ischemic injury or encephalitis). Significance: This three‐tiered classification system will be an important basis to evaluate imaging, electroclinical features, and postsurgical seizure control as well as to explore underlying molecular pathomechanisms in FCD.

Summary: Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug‐resistant temporal lobe epilepsy (TLE). Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome. However, no international consensus about definitions and terminology has been achieved. A task force reviewed previous classification schemes and proposes a system based on semiquantitative hippocampal cell loss patterns that can be applied in any histopathology laboratory. Interobserver and intraobserver agreement studies reached consensus to classify three types in anatomically well‐preserved hippocampal specimens:HSInternational League Against Epilepsy (ILAE) type 1 refers always to severe neuronal cell loss and gliosis predominantly inCA1 andCA4 regions, compared toCA1 predominant neuronal cell loss and gliosis (HS ILAEtype 2), orCA4 predominant neuronal cell loss and gliosis (HS ILAEtype 3). Surgical hippocampus specimens obtained from patients withTLEmay also show normal content of neurons with reactive gliosis only (no‐HS).HS ILAEtype 1 is more often associated with a history of initial precipitating injuries before age 5 years, with early seizure onset, and favorable postsurgical seizure control.CA1 predominantHS ILAEtype 2 andCA4 predominantHS ILAEtype 3 have been studied less systematically so far, but some reports point to less favorable outcome, and to differences regarding epilepsy history, including age of seizure onset. The proposed international consensus classification will aid in the characterization of specific clinicopathologic syndromes, and explore variability in imaging and electrophysiology findings, and in postsurgical seizure control.

Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico‐pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular‐genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro‐clinical‐imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico‐pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and “no definite FCD on histopathology” as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi‐layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options.

Summary: The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%‐70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood‐brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K⁺conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post–status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, orHMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles ofmTOR1 pathways,JAK‐STAT3,IL‐1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

Brain tumors represent the second most frequent etiology in patients with focal seizure onset before 18 years of age and submitted to epilepsy surgery. Hence, this category of brain tumors, herein defined as low-grade, developmental, epilepsy-associated brain tumors (LEAT) is different from those frequently encountered in adults as (A): 77% of LEAT occur in the temporal lobe; (B): the vast majority of LEAT are of low malignancy and classified as WHO I°; (C): LEAT are often composed of mixed glial and neuronal cell components and present with variable growth patterns including small cysts or nodules; (D): LEAT do not share common gene driving mutations, such as IDH1 or 1p/19q co-deletions. Characteristic entities comprise the ganglioglioma (GG), the dysembryoplastic neuroepithelial tumor (DNT), the angiocentric glioma (AG), the isomorphic diffuse glioma (IDG) and the papillary glio-neuronal tumor (PGNT), representing 73.2% of 1680 tumors collected in a large German series of 6747 patients submitted to epilepsy surgery. In the realm of exciting discoveries of genetic drivers of brain tumors new genes have been also reported for LEAT. BRAF V600E mutations were linked to GG with CD34 expression, FGFR1 mutations to DNT, MYB alterations to AG and also IDG and PRKCA fusions to PGNT, suggesting the possibility to also develop a genetically driven tumor classification scheme for LEAT. Rare availability of LEAT in a single center is a challenging obstacle, however, to systematically unravel the neurobiological nature and clinical behavior of LEAT. Other challenges in need of clarification include malignant tumor progression of LEAT entities, seizure relapse in patients following bulk tumor resection and the controversial issue of associated focal cortical dysplasia as additional pathomechanism. In order to advance our understanding and promote reliable diagnostic work-up of LEAT, we recommend, therefore, international collaboration to achieve our goals.