Laura Crandall

Sudden Unexpected Death in Childhood:A Report of 50 Cases

Sudden unexplained death in childhood (SUDC) is rare, with a reported incidence in the United States of 1.5 deaths per 100,000 live births compared with 56 deaths per 100,000 live births for sudden infant death syndrome in 2001. The objectives of this study include a proposal for a general definition for SUDC and presentation of 36 cases of SUDC and 14 cases of sudden unexpected death in childhood. Cases were accrued through referrals or unsolicited via our Web page (http://www.sudc.org). Our analyses tentatively suggest a SUDC profile characterized by cases being 1 to 3 years in age, predominantly male, and frequently having a personal and family history of seizures that are often associated with a fever. A history of recent minor head trauma is not uncommon. They are usually born at term as singletons and occasionally have a family history of sudden infant death syndrome or SUDC. Most are found prone, often with their face straight down into the sleep surface. Minor findings are commonly seen at postmortem examination but do not explain their deaths. Comprehensive review of the medical history and circumstances of death and performance of a complete postmortem examination including ancillary studies and extensive histologic sampling of the brain are critical in determining the cause of death in these cases of sudden unexpected childhood death. Legislation enabling research and formation of a multicenter research team is recommended to unravel the mystery of SUDC.

Sudden Death, Febrile Seizures, and Hippocampal and Temporal Lobe Maldevelopment in Toddlers: A New Entity

Recently, we reported hippocampal and temporal lobe abnormalities in 5 toddlers with sudden unexplained death in childhood (SUDC). The association of these anomalies with a high incidence (40%) of individual/family histories of simple febrile seizures in the cases raised concern that febrile seizures can be associated with death. In a series of 64 toddlers with sudden death, we tested the hypothesis that an SUDC subset is characterized by hippocampal and temporal lobe maldevelopment and an individual and/or family history of simple familial seizures. Cases of sudden and unexplained death in children aged 1.0 to 5.9 years (median 1.7 years) were divided into groups based upon a history of febrile or nonfebrile seizures, familial febrile seizures, and autopsy classification of cause of death. Forty-nine of the 64 cases (77%) were classified as SUDC, of which 40% had an individual/family history of febrile seizures. Of the 26 SUDC cases with available hippocampal sections, 62% (16/26) had hippocampal and temporal lobe anomalies, including 82% (9/11) of cases with an individual/family history of febrile seizures. Cases with these anomalies were all found dead during a sleep period, typically in the prone (87%) position. We conclude that a potential new entity may account for the majority of SUDC in toddlers, defined by sleep-related death in the prone position, individual/family history of febrile seizures, and hippocampal and temporal lobe anomalies. The mechanism of death appears analogous to sudden death in (temporal lobe) epilepsy, with a putative unwitnessed seizure during sleep leading to airway occlusion and death. This study mandates further research into the potential link between simple febrile seizures and death.

Sudden Death in Toddlers Associated with Developmental Abnormalities of the Hippocampus: A Report of Five Cases

Sudden unexplained death in childhood (SUDC) is the sudden death of a child older than 1 year of age that remains unexplained after review of the clinical history, circumstances of death, and autopsy with appropriate ancillary testing. We report here 5 cases of SUDC in toddlers that we believe define a new entity associated with hippocampal anomalies at autopsy. All of the toddlers died unexpectedly during the night, apparently during sleep. Within 48 hours before death, 2 toddlers had fever, 3 had a minor upper respiratory tract infection, and 3 experienced minor head trauma. There was a history of febrile seizures in 2 (40%) and a family history of febrile seizures in 2 (40%). Hippocampal findings included external asymmetry and 2 or more microdysgenetic features. The incidence of certain microdysgenetic features was substantially increased in the temporal lobes of these 5 cases compared with the temporal lobes of 39 (control) toddlers with the causes of death established at autopsy (P < 0.01). We propose that these 5 cases define a potential subset of SUDC whose sudden death is caused by an unwitnessed seizure arising during sleep in the anomalous hippocampus and producing cardiopulmonary arrest. Precipitating factors may be fever, infection, and/or minor head trauma. Suggested risk factors are a history of febrile seizures and/or a family history of febrile seizures. Future studies are needed to confirm these initial findings and to define the putative links between sudden death, hippocampal anomalies, and febrile seizures in toddlers.

Sudden unexplained death in childhood: A comparison of cases with and without a febrile seizure history

We considered whether a subset of children with sudden unexplained death in childhood (SUDC) and a history of febrile seizures (FS) may parallel those in sudden unexpected death in epilepsy (SUDEP). The prevalence of a history of FS was examined, and factors that may distinguish SUDC cases with and without FS were described.

Sudden and unexpected death in early life: proceedings of a symposium in honor of Dr. Henry F. Krous.

Reported here are the proceedings of a symposium given in honor of Dr. Henry F. Krous upon his retirement as Clinical Professor of Pathology and Pediatrics at the University of California Schools of Medicine, and as Director of the San Diego SIDS/SUDC Research Project. Dr. Krous’ distinguished 37-year-career was dedicated to research into sudden unexpected death in infancy and childhood, notably the sudden infant death syndrome (SIDS) and sudden unexplained death in childhood (SUDC). The presentations were given at the International Conference on Stillbirth, SIDS, and infant survival on October 5, 2012, in Baltimore, MD, USA. Eight colleagues of Dr. Krous whose own professional careers were touched by his efforts discussed forensic issues related to SIDS, tissue banking, animal models in SIDS, brainstem studies in SIDS, genetic studies in SIDS, establishment of a SUDC registry, neuropathologic research in SUDC, and potential shared mechanisms underlying sudden and unexpected death in early life. The wide scope of the presentations crossed the disciplines of forensic pathology, pediatric pathology, neuropathology, neuroscience, physiology, genetics, and bereavement, and attest to Dr. Krous’ far-reaching influence upon SIDS and SUDC research.

Mosaic mutations in early-onset genetic diseases

Purpose:An emerging approach in medical genetics is to identify de novo mutations in patients with severe early-onset genetic disease that are absent in population controls and in the patient’s parents. This approach, however, frequently misses post-zygotic “mosaic” mutations that are present in only a portion of the healthy parents’ cells and are transmitted to offspring.Methods:We constructed a mosaic transmission screen for variants that have an ~50% alternative allele ratio in the proband but are significantly less than 50% in the transmitting parent. We applied it to two family-based genetic disease cohorts consisting of 9 cases of sudden unexplained death in childhood (SUDC) and 338 previously published cases of epileptic encephalopathy.Results:The screen identified six parental-mosaic transmissions across the two cohorts. The resultant rate of ~0.02 identified transmissions per trio is far lower than that of de novo mutations. Among these transmissions were two likely disease-causing mutations: an SCN1A mutation transmitted to an SUDC proband and her sibling with Dravet syndrome, as well as an SLC6A1 mutation in a proband with epileptic encephalopathy.Conclusion:These results highlight explicit screening for mosaic mutations as an important complement to the established approach of screening for de novo mutations.Genet Med 18 7, 746–749.

Sudden death in toddlers with viral meningitis, massive cerebral edema, and neurogenic pulmonary edema and hemorrhage: report of two cases.

Viral (lymphocytic) meningitis typically does not cause sudden death, especially in the absence of severe inflammation in the brain or other organs. We report 2 toddlers with clinical evidence of a viral infection who died unexpectedly and were found at autopsy to have lymphocytic meningitis associated with severe brain edema, transtentorial herniation, neurogenic pulmonary edema and hemorrhage, and cardiomegaly. Influenza A virus, demonstrated in tracheal epithelium by immunocytochemistry, is the presumed cause of the mild meningitis in 1 case; adenovirus was cultured from swabs of the brain and anus in the 2nd case. Current concepts of neurogenic pulmonary edema and acute cardiac dysfunction associated with intracranial disease are discussed in considering the mechanism of sudden death in these toddlers. These cases emphasize the possibility that mild intracranial viral infections may be a rare cause of sudden death via lethal cardiopulmonary complications. They also underscore the importance of a comprehensive autopsy, including detailed neuropathologic examination and viral testing, in determining of the cause of unexpected death in toddlers.

Inheritance of Febrile Seizures in Sudden Unexplained Death in Toddlers

Sudden unexplained death in toddlers has been associated with febrile seizures, family history of febrile seizures, and hippocampal anomalies. We investigated the mode of inheritance for febrile seizures in these families. A three-generation pedigree was obtained from families enrolled in the San Diego Sudden Unexplained Death in Childhood Research Project, involving toddlers with sudden unexplained death, febrile seizures, and family history of febrile seizures. In our six cases, death was unwitnessed and related to sleep. The interval from last witnessed febrile seizure to death ranged from 3 weeks to 6 months. Hippocampal abnormalities were identified in one of three cases with available autopsy sections. Autosomal dominant inheritance of febrile seizures was observed in three families. A fourth demonstrated autosomal dominant inheritance with incomplete penetrance or variable expressivity. In two families, the maternal and paternal sides manifested febrile seizures. In this series, the major pattern of inheritance in toddlers with sudden unexplained death and febrile seizures was autosomal dominant. Future studies should develop markers (including genetic) to identify which patients with febrile seizures are at risk for sudden unexplained death in childhood, and to provide guidance for families and physicians.

To hold or not to hold.

It is common for hospital personnel, police, and death investigators to allow a family to hold their child and have time with their child before the body is transported for a postmortem evaluation. But this is not universal. Why is this so? The literature is scant on this issue. Police and death investigator training might not address this issue directly. This particular aspect of a death scene may be based on the personal perspective of the police officer or death investigator or the historical policy of their department. What is the rationale for not granting a family’s request to hold and have time with their child before their body is transported? Investigative concerns appear to center on evidence collection, the emotional response of the family that might delay the investigation process, and postmortem alteration of the body that would impact the pathologist’s ability to determine the cause and manner of death.

Experiences with premorbid SUDEP discussion among participants in the North American SUDEP Registry (NASR)

The North American SUDEP Registry (NASR) is a repository of clinical data and biospecimens in cases of sudden unexpected death in epilepsy (SUDEP), a leading cause of epilepsy-related deaths. We assessed whether bereaved families were aware of SUDEP before their family members death and their preferences for SUDEP disclosure. At enrollment, next-of-kin of SUDEP cases completed an intake interview, including questions assessing premorbid SUDEP discussions. Only 18.1% of the 138 next-of-kin recalled a previous discussion of SUDEP with a healthcare provider or support resource. Of the 112 who did not recall such a discussion, 72.3% wished it was discussed, 10.7% were satisfied it was not discussed, and 17% were unsure. A history of status epilepticus predicted SUDEP discussion. Rates of SUDEP discussion were not significantly higher among SUDEPs after 2013 (the approximate study midpoint) compared with those before then. Our study suggests that SUDEP remains infrequently discussed with family members of persons with epilepsy. Nearly three-quarters of family members wished they had known of SUDEP before the death. However, some were indifferent or were satisfied that this discussion had not occurred. We must balance more systematic education of patients and families about SUDEP while respecting individual preferences about having this discussion.