title: Sudden unexpected death in early childhood: general observations in a series of 151 cases: Part 1 of the investigations of the San Diego SUDC Research Project.
abstract: OBJECTIVE
  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 seizures.
  
  
  METHODS
  We undertook analysis of a retrospective cohort of 151 cases, of which 80% (121/151) were subclassified as SUDC, 11% (16/151) as explained, 7% (10/151) as undetermined, and 3% (4/151) as seizure-related.
  
  
  RESULTS
  There 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, 96.7% (117/121) of the SUDC group were discovered during a sleep period compared to 53.3% (8/15) of the explained group (p < 0.001), and 48.8% (59/121) of the SUDC cases had a personal and/or family history of febrile seizures compared to 6.7% (1/15) of the explained group (p < 0.001). 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 seizure-related 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 available.
  
  
  CONCLUSIONS
  This 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 autopsy.
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA, USA. marco.hefti@mountsinai.org.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. marco.hefti@mountsinai.org.|Division of Neuropathology, Department of Pathology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA. marco.hefti@mountsinai.org.
authors.forename: Marco M
authors.initials: MM
authors.lastname: Hefti
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Kinney
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA, USA.|Division of Neuropathology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Cryan
authors.affiliation: Department of Pathology, Rady Children's Hospital-San Diego, San Diego, CA, USA.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Haas
authors.affiliation: Department of Pathology, Rady Children's Hospital-San Diego, San Diego, CA, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Chadwick
authors.affiliation: The SUDC Foundation, Hackensack, NJ, USA.|Department of Neurology, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Crandall
authors.affiliation: New England Research Institutes, Watertown, MA, USA.
authors.forename: Felicia L
authors.initials: FL
authors.lastname: Trachtenberg
authors.affiliation: Department of Pathology, Emeritus, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Dawna D
authors.initials: DD
authors.lastname: Armstrong
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Grafe
authors.affiliation: Department of Pathology, Rady Children's Hospital-San Diego, San Diego, CA, USA.|Department of Pediatrics, UCSD School of Medicine, La Jolla, CA, USA.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Krous
mesh_terms: D000059:Accidents / Q000401:mortality; D053447:Channelopathies / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003645:Death, Sudden / Q000209:etiology*; D005260:Female; D005334:Fever / Q000401:mortality; D049429:Forensic Pathology; D006331:Heart Diseases / Q000151:congenital / Q000401:mortality; D006624:Hippocampus / Q000002:abnormalities / Q000473:pathology; D006801:Humans; D007223:Infant; D007239:Infections / Q000401:mortality; D008297:Male; D008659:Metabolic Diseases / Q000401:mortality; D012189:Retrospective Studies; D003294:Seizures, Febrile / Q000401:mortality; D012890:Sleep
keywords: Febrile seizures; Hippocampus; Sudden death; Sudden unexpected death in childhood