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.
| Original language | English |
|---|---|
| Pages (from-to) | 1416-1428 |
| Number of pages | 13 |
| Journal | Epilepsia |
| Volume | 62 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2021 Jun |
Bibliographical note
Funding Information:I.B. is funded by the German Research Council (DFG Bl 421/4‐1). M.M.‐S. is funded by the National Institutes of Health (National Institute of Neurological Disorders and Stroke R01 NS097719). This work was funded by the European Research Council (No. 682345 to S.Bau.), the program "Investments of the Future" (ANR‐10‐IAIHU‐06 and ANR‐18‐RHUS‐0005 to S.Bau.), and the Cleveland Clinic Epilepsy Center. R.G. is funded by the Italian Ministry of Health. E.A. is funded by ZonMw, Programme Translational Research (project number 95105004). S.Bi. was supported by the Manton Center for Orphan Disease Research at Boston Children's Hospital. F.C. and I.L.‐C. are funded by São Paulo Research Foundation (FAPESP) grant No. 2013/07559‐3. T.S.J. is grateful for funding from the Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital (GOSH) Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research (NIHR). All research at GOSH National Health Service Foundation Trust and University College London Great Ormond Street Institute of Child Health is made possible by the NIHR GOSH Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. We cordially thank Lisa Ferguson and Christina O'Connor from the Cleveland Clinic for their assistance with data collection and tissue preparation, respectively. Also, we would like to acknowledge Jennifer Neil Partlow, research coordinator/genetic counselor, for assistance at Boston Children's Hospital.
Funding Information:
I.B. is funded by the German Research Council (DFG Bl 421/4-1). M.M.-S. is funded by the National Institutes of Health (National Institute of Neurological Disorders and Stroke R01 NS097719). This work was funded by the European Research Council (No. 682345 to S.Bau.), the program "Investments of the Future" (ANR-10-IAIHU-06 and ANR-18-RHUS-0005 to S.Bau.), and the Cleveland Clinic Epilepsy Center. R.G. is funded by the Italian Ministry of Health. E.A. is funded by ZonMw, Programme Translational Research (project number 95105004). S.Bi. was supported by the Manton Center for Orphan Disease Research at Boston Children's Hospital. F.C. and I.L.-C. are funded by S?o Paulo Research Foundation (FAPESP) grant No. 2013/07559-3. T.S.J. is grateful for funding from the Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital (GOSH) Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research (NIHR). All research at GOSH National Health Service Foundation Trust and University College London Great Ormond Street Institute of Child Health is made possible by the NIHR GOSH Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. We cordially thank Lisa Ferguson and Christina O'Connor from the Cleveland Clinic for their assistance with data collection and tissue preparation, respectively. Also, we would like to acknowledge Jennifer Neil Partlow, research coordinator/genetic counselor, for assistance at Boston Children's Hospital.
Publisher Copyright:
© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy
All Science Journal Classification (ASJC) codes
- Neurology
- Clinical Neurology