Dominique F Leitner1,2, Declan McGuone3,4, Christopher William2,4,5, Arline Faustin2,6, Manor Askenazi7, Matija Snuderl5, Melissa Guzzetta4,5, Heather S Jarrell4,8, Katherine Maloney4,9, Ross Reichard4,10, Colin Smith4,11, Victor Weedn4,12, Thomas Wisniewski2,4,5,6,13, Laura Gould1,14, Orrin Devinsky1,2. 1. Comprehensive Epilepsy Center, NYU Langone Health and School of Medicine, New York, New York, USA. 2. Department of Neurology, NYU Langone Health and School of Medicine, New York, New York, USA. 3. Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA. 4. SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA. 5. Department of Pathology, NYU Langone Health and School of Medicine, New York, New York, USA. 6. Center for Cognitive Neurology, NYU Langone Health and School of Medicine, New York, New York, USA. 7. Biomedical Hosting LLC, Arlington, Massachusetts, USA. 8. New Mexico Office of the Medical Investigator, Albuquerque, New Mexico, USA. 9. New York Department of Health, Erie County Medical Examiner's Office, Buffalo, New York, USA. 10. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA. 11. Academic Department of Neuropathology, University of Edinburgh, Edinburgh, UK. 12. Maryland Department of Health, Office of the Chief Medical Examiner, Baltimore, Maryland, USA. 13. Department of Psychiatry, NYU Langone Health and School of Medicine, New York, New York, USA. 14. Sudden Unexplained Death in Childhood Foundation, Roseland, New Jersey, USA.
Abstract
AIMS: Hippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls. METHODS: Hippocampal haematoxylin and eosin (H&E) slides (n = 67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by nine blinded reviewers: three board-certified forensic pathologists, three neuropathologists and three dual-certified neuropathologists/forensic pathologists. RESULTS: Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (52.5% SUDC, 53.0% controls), with no difference by cause of death (COD) (p = 0.16) or febrile seizure history (p = 0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' κ = 0.014, p = 0.47). Within reviewer groups, there were no findings more frequent in SUDC compared with controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD (p = 0.41). CONCLUSIONS: The lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal maldevelopment associated with sudden death (HMASD). These findings underscore a need for larger studies to standardise evaluation of hippocampal findings, identifying the range of normal variation and changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.
AIMS: Hippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls. METHODS: Hippocampal haematoxylin and eosin (H&E) slides (n = 67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by nine blinded reviewers: three board-certified forensic pathologists, three neuropathologists and three dual-certified neuropathologists/forensic pathologists. RESULTS: Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (52.5% SUDC, 53.0% controls), with no difference by cause of death (COD) (p = 0.16) or febrile seizure history (p = 0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' κ = 0.014, p = 0.47). Within reviewer groups, there were no findings more frequent in SUDC compared with controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD (p = 0.41). CONCLUSIONS: The lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal maldevelopment associated with sudden death (HMASD). These findings underscore a need for larger studies to standardise evaluation of hippocampal findings, identifying the range of normal variation and changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.
Authors: Meng-Han Tsai; David N Vaughan; Yuliya Perchyonok; Greg J Fitt; Ingrid E Scheffer; Samuel F Berkovic; Graeme D Jackson Journal: Epilepsia Date: 2016-08-26 Impact factor: 5.864
Authors: Marco M Hefti; Hannah C Kinney; Jane B Cryan; Elisabeth A Haas; Amy E Chadwick; Laura A Crandall; Felicia L Trachtenberg; Dawna D Armstrong; Marjorie Grafe; Henry F Krous Journal: Forensic Sci Med Pathol Date: 2016-01-19 Impact factor: 2.007
Authors: Robin L Haynes; Hannah C Kinney; Elisabeth A Haas; Jhodie R Duncan; Molly Riehs; Felicia Trachtenberg; Dawna D Armstrong; Sanda Alexandrescu; Jane B Cryan; Marco M Hefti; Henry F Krous; Richard D Goldstein; Lynn A Sleeper Journal: Front Pediatr Date: 2021-12-21 Impact factor: 3.418