Dominique F. Leitner, Comprehensive Epilepsy Center, NYU Langone Health and School of Medicine, New York, New York, USA; Department of Neurology, NYU Langone Health and School of Medicine, New York, New York, USA
Declan McGuone, Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA; SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA
Christopher William, Department of Neurology, NYU Langone Health and School of Medicine, New York, New York, USA; SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA; Department of Pathology, NYU Langone Health and School of Medicine, New York, New York, USA
Arline Faustin, Department of Neurology, NYU Langone Health and School of Medicine, New York, New York, USA; Center for Cognitive Neurology, NYU Langone Health and School of Medicine, New York, New York, USA
Manor Askenazi, Biomedical Hosting LLC, Arlington, Massachusetts, USA
Matija Snuderl, Department of Pathology, NYU Langone Health and School of Medicine, New York, New York, USA
Melissa Guzzetta, SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA; Department of Pathology, NYU Langone Health and School of Medicine, New York, New York, USA
Heather S. Jarrell, SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA; New Mexico Office of the Medical Investigator, Albuquerque, New Mexico, USA
Katherine Maloney, SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA; New York Department of Health, Erie County Medical Examiner's Office, Buffalo, New York, USA
Ross Reichard, SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
Colin Smith, SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA; Academic Department of Neuropathology, University of Edinburgh, Edinburgh, UK
Victor Weedn, SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA; Maryland Department of Health, Office of the Chief Medical Examiner, Baltimore, Maryland, USA
Thomas Wisniewski, Department of Neurology, NYU Langone Health and School of Medicine, New York, New York, USA; SUDC Registry and Research Collaborative (SUDCRRC) Study Group, Roseland, New Jersey, USA; Department of Pathology, NYU Langone Health and School of Medicine, New York, New York, USA; Center for Cognitive Neurology, NYU Langone Health and School of Medicine, New York, New York, USA; Department of Psychiatry, NYU Langone Health and School of Medicine, New York, New York, USA
Laura Gould, Comprehensive Epilepsy Center, NYU Langone Health and School of Medicine, New York, New York, USA; Sudden Unexplained Death in Childhood Foundation, Roseland, New Jersey, USA
Orrin Devinsky, Comprehensive Epilepsy Center, NYU Langone Health and School of Medicine, New York, New York, USA; Department of Neurology, NYU Langone Health and School of Medicine, New York, New York, USA

Document Type

Article

Publication Date

2-1-2022

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.

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