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Epilepsia Aug 2022Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An...
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.
Topics: Consensus; Epilepsy; Humans; Magnetic Resonance Imaging; Malformations of Cortical Development; Malformations of Cortical Development, Group I; Neuroimaging; Retrospective Studies
PubMed: 35706131
DOI: 10.1111/epi.17301 -
Neuroradiology Mar 2022Focal cortical dysplasia (FCD) are histopathologically categorized in ILAE type I to III. Mild malformations of cortical development (mMCD) including those with... (Review)
Review
Focal cortical dysplasia (FCD) are histopathologically categorized in ILAE type I to III. Mild malformations of cortical development (mMCD) including those with oligodendroglial hyperplasia (MOGHE) are to be integrated into this classification yet. Only FCD type II have distinctive MRI and molecular genetics alterations so far. Subtle FCD including FCD type II located in the depth of a sulcus are often overlooked requiring the use of dedicated sequences (MP2RAGE, FLAWS, EDGE) and/or voxel (VBM)- or surface-based (SBM) postprocessing. The added value of 7 Tesla MRI has to be proven yet.
Topics: Epilepsy; Humans; Magnetic Resonance Imaging; Malformations of Cortical Development; Malformations of Cortical Development, Group I
PubMed: 34839379
DOI: 10.1007/s00234-021-02865-x -
Indian Journal of Pathology &... May 2022Focal cortical dysplasias (FCDs) represent the third most frequent cause of drug-resistant focal epilepsy in adults (after hippocampal sclerosis and tumours) submitted... (Review)
Review
Focal cortical dysplasias (FCDs) represent the third most frequent cause of drug-resistant focal epilepsy in adults (after hippocampal sclerosis and tumours) submitted to surgery, and the most common in the pediatric age group. The International League Against Epilepsy (ILAE) classification of focal cortical dysplasia is still a reference and consists of a three-tiered system: FCD type I refers to isolated abnormalities in cortical layering; FCD type II refers to cases with abnormalities in cortical architecture and dysmorphic neurons with or without balloon cells; and FCD type III refers to abnormalities in cortical layering associated with other lesions. Recent studies have demonstrated that somatic mutations occurring post-zygotically during embryonal development and leading to mosaicism, underlie most brain malformations. The molecular pathogenesis of FCD type II is associated with activation of the mTOR pathway. Pathogenic variants in this pathway are recognized in up to 63% of cases and may occur both through single activating variants in activators of the mTOR signaling pathway or double-hit inactivating variants in repressors of the signaling pathway. The newly described mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy, has been found to show recurrent pathogenic variants in SLC35A2 with mosaicism. The present review describes the lesions of FCD and discusses the molecular pathogenesis and proposal for a revised classification.
Topics: Adult; Child; Epilepsy; Humans; Malformations of Cortical Development; Mosaicism; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 35562149
DOI: 10.4103/ijpm.ijpm_1226_21 -
Practical Neurology Aug 2023Focal cortical dysplasia (FCD) is a malformation of cortical development characterised by disruption of cortical cytoarchitecture. Classification of FCDs subtypes has... (Review)
Review
Focal cortical dysplasia (FCD) is a malformation of cortical development characterised by disruption of cortical cytoarchitecture. Classification of FCDs subtypes has initially been based on correlation of the histopathology with relevant clinical, electroencephalographic and neuroimaging features. A recently proposed classification update recommends a multilayered, genotype-phenotype approach, integrating findings from histopathology, genetic analysis of resected tissue and presurgical MRI. FCDs are caused either by single somatic activating mutations in MTOR pathway genes or by double-hit inactivating mutations with a constitutional and a somatic loss-of-function mutation in repressors of the signalling pathway. Mild malformation with oligodendroglial hyperplasia in epilepsy is caused by somatic pathogenic mutations. FCDs most often present with drug-resistant focal epilepsy or epileptic encephalopathy. Most patients respond to surgical treatment. The use of mechanistic target of rapamycin inhibitors may complement the surgical approach. Treatment approaches and outcomes have improved with advances in neuroimaging, neurophysiology and genetics, although predictors of treatment response have only been determined in part.
Topics: Humans; Malformations of Cortical Development; Focal Cortical Dysplasia; Neurologists; Epilepsy; Mutation; Drug Resistant Epilepsy
PubMed: 36823117
DOI: 10.1136/pn-2022-003404 -
Expert Review of Neurotherapeutics Nov 2021Focal cortical dysplasias (FCDs) represent the most common etiology in pediatric drug-resistant focal epilepsies undergoing surgical treatment. The localization, extent... (Review)
Review
INTRODUCTION
Focal cortical dysplasias (FCDs) represent the most common etiology in pediatric drug-resistant focal epilepsies undergoing surgical treatment. The localization, extent and histopathological features of FCDs are considerably variable. Somatic mosaic mutations of genes that encode proteins in the PI3K-AKTmTOR pathway, which also includes the tuberous sclerosis associated genes and , have been implicated in FCD type II in a substantial subset of patients. Surgery is the principal therapeutic option for FCD-related epilepsy. Advanced neurophysiological and neuroimaging techniques have improved surgical outcome and reduced the risk of postsurgical deficits. Pharmacological MTOR inhibitors are being tested in clinical trials and might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease, used alone or in combination with surgery.
AREAS COVERED
This review will critically analyze the advances in the diagnosis and treatment of FCDs, with a special focus on the novel therapeutic options prompted by a better understanding of their pathophysiology.
EXPERT OPINION
Focal cortical dysplasia is a main cause of drug-resistant epilepsy, especially in children. Novel, personalized approaches are needed to more effectively treat FCD-related epilepsy and its cognitive consequences.
Topics: Child; Drug Resistant Epilepsy; Epilepsy; Humans; MTOR Inhibitors; Magnetic Resonance Imaging; Malformations of Cortical Development; Tuberous Sclerosis
PubMed: 33834938
DOI: 10.1080/14737175.2021.1915135 -
Seminars in Neurology Jun 2015Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been... (Review)
Review
Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been classified into neuropathological subtypes (type Ia, Ib, IIa, IIb, and III) based on the severity of cytoarchitectural disruption--tangential or radial dispersion, or loss of laminar structure--and the presence of unique cells types such as cytomegalic neurons or balloon cells. Most focal cortical dysplasias can be identified on neuroimaging and many require resective epilepsy surgery to cure refractory seizures. The pathogenesis of focal cortical dysplasias remains to be defined, although there is recent evidence to suggest that focal cortical dysplasias arise from de novo somatic mutations occurring during brain development. Some focal cortical dysplasia subtypes show a link to the mammalian target of rapamycin signaling cascade; this has now extended to other cortical malformations, including hemimegalencephaly.
Topics: Animals; Drug Resistant Epilepsy; Humans; Malformations of Cortical Development; Neuroimaging; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 26060899
DOI: 10.1055/s-0035-1552617 -
Brain Pathology (Zurich, Switzerland) Jul 2021The ILAE classification of Focal Cortical Dysplasia (FCD) from 2011 has quickly gained acceptance in clinical practice and research and is now widely used around the... (Review)
Review
The ILAE classification of Focal Cortical Dysplasia (FCD) from 2011 has quickly gained acceptance in clinical practice and research and is now widely used around the world. This histopathology-based classification scheme proposed three subtypes, that is, FCD Type 1 (with architectural abnormalities of the neocortex), FCD Type 2 (with cytoarchitectural abnormalities of the neocortex) and FCD Type 3 (architectural abnormalities of the neocortex associated with another principle lesion acquired during early life). Valuable knowledge was gathered during the last decade validating the clinical, pathological and genetic classification of FCD Type 2. This is in contrast to FCD subtype 1 and 3 with only few robust or new insights. Herein, we provide an overview about current knowledge about FCD Type 1 and its three subtypes. Available data strengthened, however, FCD Type 1A in particular, whereas a comprehensive clinico-pathological specification for FCD Type 1B and 1C subtypes remain to be shown. The lack of a valid animal model for FCD Type 1 further supports our call and the ongoing need for systematic research studies based on a careful clinico-pathological and genetic stratification of patients and human brain tissues.
Topics: Animals; Disease Models, Animal; Epilepsy; Humans; Magnetic Resonance Imaging; Malformations of Cortical Development; Malformations of Cortical Development, Group I; Neocortex; Retrospective Studies
PubMed: 34196986
DOI: 10.1111/bpa.12964 -
The Lancet. Neurology Nov 2021During the past decade, there have been considerable advances in understanding of the genetic and morphogenic processes underlying cortical malformations and... (Review)
Review
During the past decade, there have been considerable advances in understanding of the genetic and morphogenic processes underlying cortical malformations and developmental brain tumours. Focal malformations are caused by somatic (postzygotic) variants in genes related to cell growth (ie, in the mTOR pathway in focal cortical dysplasia type 2), which are acquired in neuronal progenitors during neurodevelopment. In comparison, developmental brain tumours result from somatic variants in genes related to cell proliferation (eg, in the MAP-kinase pathway in ganglioglioma), which affect proliferating glioneuronal precursors. The timing of the genetic event and the specific gene involved during neurodevelopment will drive the nature and size of the lesion, whether it is a developmental malformation or a brain tumour. There is also emerging evidence that epigenetic processes underlie a molecular memory in epileptogenesis. This knowledge will together facilitate understanding of why and how patients with these lesions have epilepsy, and could form a basis for a move towards precision medicine for this challenging cohort of patients.
Topics: Brain; Brain Neoplasms; Epilepsy; Ganglioglioma; Humans; Malformations of Cortical Development; Neocortex
PubMed: 34687638
DOI: 10.1016/S1474-4422(21)00265-9 -
Pediatric Neurology Aug 2013Focal cortical dysplasias are among the most common causes of intractable epilepsy in children. As the neuropathology of these conditions has been better clarified, the... (Review)
Review
Focal cortical dysplasias are among the most common causes of intractable epilepsy in children. As the neuropathology of these conditions has been better clarified, the nomenclature has undergone numerous revisions. Their recognition has grown with the use of neuroimaging, and recent advances in imaging technology will further improve detection. Clinical, electroencephalographic, and imaging findings are often diagnostic, so it is imperative for the clinician to recognize the characteristic patterns. Treatment for developmental and behavioral disability remains largely symptomatic, and epilepsy medications are often ineffective. Epilepsy surgery, however, can be successful in selected patients. The basic science underlying the development of focal cortical dysplasias may lead to novel therapeutic approaches in the future.
Topics: Humans; Malformations of Cortical Development
PubMed: 23859852
DOI: 10.1016/j.pediatrneurol.2012.12.024 -
International Journal of Molecular... Jan 2022Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the... (Review)
Review
Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the presence of both dysmorphic neurons and balloon cells (FCDIIB). The year 2021 marks the 50th anniversary of the recognition of FCD as a cause of drug resistant epilepsy, and it is now the most common reason for epilepsy surgery. The causes of FCD remained unknown until relatively recently. The study of resected human FCD tissue using novel genomic technologies has led to remarkable advances in understanding the genetic basis of FCD. Mechanistic parallels have emerged between these non-neoplastic lesions and neoplastic disorders of cell growth and differentiation, especially through perturbations of the mammalian target of rapamycin (mTOR) signalling pathway. This narrative review presents the advances through which the aetiology of FCDII has been elucidated in chronological order, from recognition of an association between FCD and the mTOR pathway to the identification of somatic mosaicism within FCD tissue. We discuss the role of a two-hit mechanism, highlight current challenges and future directions in detecting somatic mosaicism in brain and discuss how knowledge of FCD may inform novel precision treatments of these focal epileptogenic malformations of human cortical development.
Topics: Brain; Drug Resistant Epilepsy; Epilepsy; Humans; Malformations of Cortical Development; Malformations of Cortical Development, Group I; Mutation; Neurons; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 35163267
DOI: 10.3390/ijms23031344