Sudden unexpected death in early childhood genera

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

Publish Date: 2016/01/19

Volume: 12, Issue: 1, Pages: 4-13

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Abstract

The purpose of this study was to determine the major subcategories and clinicopathologic features of sudden unexpected death in young children in a large retrospective cohort and to confirm the association of sudden unexplained death in children abbreviated by us for unexplained deaths as SUDC with hippocampal pathology and/or febrile seizuresThere were no significant differences between SUDC and explained cases in postnatal gestational or postconceptional age frequency of preterm birth gender race or organ weights In contrast 967  117/121 of the SUDC group were discovered during a sleep period compared to 533  8/15 of the explained group p  0001 and 488  59/121 of the SUDC cases had a personal and/or family history of febrile seizures compared to 67  1/15 of the explained group p  0001 Of the explained deaths 56  9/16 were subclassified as infection 31  5/16 cardiac 6  1/16 accidental and 6  1/16 metabolic Two of the three cases specifically tested for cardiac channelopathies at autopsy based upon clinical indications had genetic variants in cardiac genes one of uncertain significance Bacterial cultures at autopsy typically revealed organisms interpreted as contaminants Two of the four seizurerelated deaths were witnessed with two of the brains from these cases showing generalized malformations Hippocampal anomalies including a specific combination we termed hippocampal maldevelopment associated with sudden death were found in almost 50  40/83 of the SUDC and undetermined cases in which hippocampal sections were availableThis study highlights the key role for the hippocampus febrile seizures and sleep in SUDC pathophysiology It also demonstrates the role of known predisposing conditions such as cardiac channelopathies and infections in causing sudden unexpected death in childhood and the need for improved ancillary testing and protective strategies in these cases even when the cause of death is established at autopsySudden unexplained death in childhood SUDC is the sudden and unexpected death of a child older than 1 postnatal year that remains unexplained after a review of the clinical history and circumstances of death and the performance of a complete autopsy 1 It is a subset of sudden and unexpected death—the subset without explanation While a rare disorder with an incidence of 13/100000 between 1 and 4 years SUDC nevertheless accounts for approximately 10  of all unexpected childhood deaths in populationbased studies although by definition the rate will vary depending on the completeness of the investigation undertaken 2 3 4 5 Our overall hypothesis is that SUDC is comprised of a heterogeneous group of diseases yet to be discovered that share the clinical phenotype of sudden unexpected death in a seemingly healthy child In 1999 the San Diego SUDC Research Project was founded to attempt to discover the causes of these deaths through indepth review of retrospectively accrued cases via national and international referrals to a centralized database 6 7 While such a dataset is limited by its retrospective nonpopulation based design in an initial study we were nevertheless able to identify a subset of SUDC cases with multiple structural abnormalities of the hippocampus with or without a personal and/or family history of febrile series 8 In this study we report the findings of the entire database from 1999 to 2011 which includes an addition of 87 cases of sudden unexpected death including 72 additional unexplained SUDC casesThe main goal of the present study was to determine the major subcategories and clinicopathologic features of sudden unexpected death in young children in the entire complete San Diego cohort of 151 cases the largest such series to date Our second objective was to confirm the association of SUDC with hippocampal pathology and/or febrile seizures found in the initial analysis of the dataset in the expanded cohort Due to the large scope of the findings the neuropathology of the hippocampus and other brain regions in SUDC associated with hippocampal maldevelopment is reported in detail in a separate publicationThe cases of sudden unexpected death in this study were accrued under the auspices of the SUDC Research Project from 1999 to 2011 We have previously described the mission history design and methods of the study in detail 6 7 8 9 The dataset was based mainly upon case referrals from the SUDC Program Hackensack NJ LAC which in turn received referrals from families medical examiners coroners and pathologists nationally and internationally The inclusion criteria were 1 parental consent for research 2 autopsy not restricted to a single organ and 3 death between 1 and 15 years This paper examines data for the major group of children who were 1–6 years 7 years old There were no cases of homicide or suicide in this cohort given that the study was based upon a referral dataset of sudden and unexpected deaths due to natural causes particularly those that were unexplainedFor each case autopsy reports death scene investigations pediatric and obstetrical records ancillary testing eg toxicology metabolic screening and any available glass microscopic slides of the systemic organs and brain were collected for review In a small number of cases it was possible to obtain formalinfixed tissues from which additional slides were prepared and reviewed In addition the majority of parents completed a detailed study questionnaire concerning the child’s medical neurodevelopmental environmental and family histories Indepth telephone conversations were undertaken with the parents or caretakers to verify and/or clarify information in the family surveys HFK LAC The Institutional Review Boards of Rady Children’s Hospital San Diego CA and Boston Children’s Hospital Boston MA

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