Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Blümcke I, Coras R, Busch RM, Morita-Sherman M, Lal D, Prayson R, Cendes F, Lopes-Cendes I, Rogerio F, Almeida VS, Rocha CS, Sim NS, Lee JH, Kim SH, Baulac S, Baldassari S, Adle-Biassette H, Walsh CA, Bizzotto S, Doan RN, Morillo KS, Aronica E, Mühlebner A, Becker A, Cienfuegos J, Garbelli R, Giannini C, Honavar M, Jacques TS, Thom M, Mahadevan A, Miyata H, Niehusmann P, Sarnat HB, Söylemezoglu F, Najm I (2021)

Publication Type: Journal article

Publication year: 2021

Journal

DOI: 10.1111/epi.16899

Abstract

Objective: Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme. Methods: Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients. Results: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa =.65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases. Significance: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype–phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype–phenotype diagnosis in the near future.

Authors with CRIS profile

Involved external institutions

Sorbonne Université France (FR) Assistance Publique-Hôpitaux de Paris (AP-HP) France (FR) Cleveland Clinic United States (USA) (US) University College London (UCL) United Kingdom (GB) Universitätsklinikum Bonn Germany (DE) Hospital Pedro Hispano Portugal (PT) Hacettepe University Turkey (TR) Foundation of the Carlo Besta Neurological Institute (IRCCS) Italy (IT) University of Calgary Canada (CA) University of Oslo Norway (NO) Mayo Clinic United States (USA) (US) National Institute of Mental Health and Neuroscience (NIMHANS) India (IN) Akita Research Institute of Brain and Blood Vessels / 秋田県立脳血管研究センター Japan (JP) Boston Children's Hospital United States (USA) (US) Instituto Brasileiro de Neurociência e Neurotecnologia / Brazilian Institute of Neuroscience and Neurotechnology (BRAINN) Brazil (BR) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Yonsei University Health System (YUHS) Korea, Republic of (KR) Korea Advanced Institute of Science and Technology (KAIST) Korea, Republic of (KR) Universidade Estadual de Campinas (UNICAMP) / University of Campinas Brazil (BR)

How to cite

APA:

Blümcke, I., Coras, R., Busch, R.M., Morita-Sherman, M., Lal, D., Prayson, R.,... Najm, I. (2021). Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial. Epilepsia. https://doi.org/10.1111/epi.16899

MLA:

Blümcke, Ingmar, et al. "Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial." Epilepsia (2021).

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