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

Author(s):Show less -

Bluemcke, Ingmar ^{[1, 2]} ; Coras, Roland ^[1] ; Busch, Robyn M. ^{[2, 3, 4]} ; Morita-Sherman, Marcia ^[2] ; Lal, Dennis ^{[2, 4]} ; Prayson, Richard ^[5] ; Cendes, Fernando ^{[6, 7]} ; Lopes-Cendes, Iscia ^{[8, 7]} ; Rogerio, Fabio ^{[7, 9]} ; Almeida, Vanessa S. ^{[8, 7]} ; Rocha, Cristiane S. ^{[8, 7]} ; Sim, Nam Suk ^[10] ; Lee, Jeong Ho ^{[10, 11]} ; Kim, Se Hoon ^[12] ; Baulac, Stephanie ^[13] ; Baldassari, Sara ^[13] ; Adle-Biassette, Homa ^{[14, 15]} ; Walsh, Christopher A. ^{[16, 17, 18]} ; Bizzotto, Sara ^{[16, 17, 18]} ; Doan, Ryan N. ^{[16, 17, 18]} ; Morillo, Katherine S. ^{[16, 17, 18]} ; Aronica, Eleonora ^{[19, 20]} ; Muhlebner, Angelika ^{[19, 21]} ; Becker, Albert ^[22] ; Cienfuegos, Jesus ^{[23, 24]} ; Garbelli, Rita ^[25] ; Giannini, Caterina ^{[26, 27]} ; Honavar, Mrinalini ^[28] ; Jacques, Thomas S. ^{[29, 30]} ; Thom, Maria ^[31] ; Mahadevan, Anita ^[32] ; Miyata, Hajime ^[33] ; Niehusmann, Pitt ^{[34, 35]} ; Sarnat, Harvey B. ^{[36, 37, 38]} ; Soylemezoglu, Figen ^[39] ; Najm, Imad ^{[2, 3]}

Affiliation:Show less -

^[1] Univ Hosp, Dept Neuropathol, Schwabachanlage 6, D-91054 Erlangen - Germany

^[2] Cleveland Clin, Epilepsy Ctr, Cleveland, OH 44106 - USA

^[3] Cleveland Clin, Dept Neurol, Cleveland, OH 44106 - USA

^[4] Cleveland Clin, Genom Med Inst, Cleveland, OH 44106 - USA

^[5] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44106 - USA

^[6] Univ Estadual Campinas, Dept Neurol, Sao Paulo, SP - Brazil

^[7] Brazilian Inst Neurosci & Neurotechnol, Sao Paulo, SP - Brazil

^[8] Univ Estadual Campinas, Dept Med Genet & Genom Med, Sao Paulo, SP - Brazil

^[9] Univ Estadual Campinas, Dept Pathol, Sao Paulo, SP - Brazil

^[10] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon - South Korea

^[11] SoVarGen Inc, Daejeon - South Korea

^[12] Yonsei Univ, Coll Med, Dept Pathol, Seoul - South Korea

^[13] Sorbonne Univ, CNRS, INSERM, Inst Cerveau Paris Brain Inst ICM, Paris - France

^[14] Publ Hosp Network Paris, Pathol Anat Serv, Paris - France

^[15] Univ Paris, Inserm U1141, NeuroDiderot, Paris - France

^[16] Harvard Med Sch, Dept Pediat, Boston, MA 02115 - USA

^[17] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Gcn, Dept Pediat, Boston, MA - USA

^[18] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA - USA

^[19] Amsterdam UMC, Dept Neuro Pathol, Locat Acad Med Ctr, Amsterdam - Netherlands

^[20] Epilepsy Inst Netherlands Fdn, Heemstede - Netherlands

^[21] Univ Med Ctr Utrecht, Dept Pathol, Utrecht - Netherlands

^[22] Univ Bonn, Dept Neuropathol, Med Ctr, Bonn - Germany

^[23] Humanitas Med Grp Hosp, Int Ctr Epilepsy Surg, Dept Anat Pathol, Mexico City, DF - Mexico

^[24] Angels Mexico Hosp, Dept Anat Pathol, Mexico City, DF - Mexico

^[25] Sci Inst Res & Hlth Care Fdn, Carlo Besta Neurol Inst, Epilepsy Unit, Milan - Italy

^[26] Mayo Clin, Anat Pathol, Rochester, MN - USA

^[27] Univ Bologna, Dept Biomed & Neuromotor Sci, Alma Mater Studiorum, Bologna - Italy

^[28] Pedro Hispano Hosp, Dept Anat Pathol, Matosinhos - Portugal

^[29] UCL, Inst Child Hlth, Dev Biol & Canc Res & Teaching Programme, Great Ormond St, London - England

^[30] Natl Hlth Serv Fdn Trust, Dept Histopathol, Hosp Children, Great Ormond St, London - England

^[31] UCL, Inst Neurol, Dept Neuropathol, London - England

^[32] Natl Inst Mental Hlth & Neurosci, Dept Neuropathol, Bangalore, Karnataka - India

^[33] Akita Cerebrospinal & Cardiovasc Ctr, Res Inst Brain & Blood Vessels, Dept Neuropathol, Akita - Japan

^[34] Univ Oslo, Dept Neuro Pathol, Translat Neurodegenerat Res & Neuropathol Lab, Oslo - Norway

^[35] Oslo Univ Hosp, Oslo - Norway

^[36] Univ Calgary, Alberta Childrens Hosp Res Inst, Dept Paediat, Fac Med, Calgary, AB - Canada

^[37] Univ Calgary, Alberta Childrens Hosp Res Inst, Dept Pathol Neuropathol, Fac Med, Calgary, AB - Canada

^[38] Univ Calgary, Alberta Childrens Hosp Res Inst, Dept Clin Neurosci, Fac Med, Calgary, AB - Canada

^[39] Hacettepe Univ, Fac Med, Dept Pathol, Ankara - Turkey

• Document type: Journal article
• Source: Epilepsia; v. 62, n. 6, p. 1416-1428, JUN 2021.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 13/07559-3 - BRAINN - The Brazilian Institute of Neuroscience and Neurotechnology
• Grantee: Fernando Cendes
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC