Genes determine the structure and the function of proteins and these proteins ultimately result in traits. Proteomics is the study of proteins. This is the first published study of proteomics in SUDC which studied the brain tissue (cortex and hippocampus) from 19 SUDC and 19 control. Molecular signaling pathways associated with protein differences were identified. Some protein changes correlated to SUDC clinical history. Authors identify need for larger scale analyses, mechanistic studies, and proteomic analysis in other brain regions to improve our understanding of SUDC.
A study of genetic data from 124 separate families with children who died suddenly without explanation, with an average age of 34.2 months, finds that pathogenic rare variants present in the child contributed to 11 deaths, (9% of the cohort), and that these variants are enriched within cardiac and seizure genes; of the seven pathogenic mutations identified in the cohort as present in the child and absent in both parents, six potentially alter heart cell calcium regulation. https://www.pnas.org/content/118/52/e2115140118
Press release from NYU Langone Health
This white paper outlines some of those barriers to strategically advancing medical research in the field of MDI and the efforts U.S. states and jurisdictions can make to address them. This will address sorely needed improvements to access biospecimens and reduce legal barriers to improve public health, justice, and the rights of next of kin. This document is designed for use by U.S. states, other jurisdictions, and medicolegal death investigation systems. https://www.nist.gov/system/files/documents/2021/08/27/OSAC_MDI_Principles%20To%20Promote%20Research_Aug2021.pdf
Researchers at the SUDCRRC utilized hippocampal H&E slides (n=67; 36 SUDC, 31 controls) and evaluated them across 9 blinded reviewers. Results identified a lack of an association of hippocampal findings in SUDC and controls. Inconsistent observations call for larger studies to standardize the evaluation of hippocampal findings and better understand its normal variation.
This literature review provides a current analysis of the shared epidemiological features of SUDC, SUDEP and SUID as they relate to seizures and recognizes the crucial need for improved recognition, surveillance and research to better understand and address these tragedies.
Forensic pathologists blindly reviewed 100 case series of sudden unexpected pediatric deaths enrolled in the SUDC Registry and Research Collaborative 2014-2017. These reviewers were discordant with the original certifier’s cause of death (COD)opinion in 40% of cases, including 28 cases originally considered accident or natural but adjudicated as unexplained by our review. The blinded comprehensive review and adjudication process of the SUDCRRC suggests the SUDC rate by the U.S. Centers for Death Control and Prevention (CDC) may be an underestimation and that there is a low rate of consistency in death certification of sudden unexpected pediatric deaths.
An overview of the relatively limited published literature concerning the neuropathology of SUDC, the knowledge gaps that exist and research needed. https://doi.org/10.3389/fneur.2020.582051
Authors prospectively performed systematic neuropathologic investigation in 20 SUDC cases and found hippocampal alterations were the most common finding on histological review but were also found in possibly explained deaths. They concluded the “significance and specificity of hippocampal findings is unclear as they may result from seizures, contribute to seizure pathogenesis, or be an unrelated phenomenon”.
Neuropathologic Changes in Sudden Unexplained Death in Childhood
A combined effort of a panel of medical examiners, pediatricians, and federal agency representatives, representing the diverse interests of death investigation, autopsy performance, certification, clinical subspecialties (pediatrics, neurology, cardiology, child abuse, injury prevention, infectious diseases, genetics, and metabolic diseases), family needs, prevention, and epidemiology, culminated in this publication. Procedural guidance for investigation, autopsy and ancillary testing, certification and reporting, and key considerations for prevention, research and working with family members and other professional team members are provided.
Authors report two asymptomatic siblings who died unexpectedly at approximately 1 year of age found to have biallelic (compound heterozygous) variants in PPA2. PPA2 encodes a mitochondrially located inorganic pyrophosphatase implicated in progressive and lethal cardiomyopathies. Authors conclude these findings provide further information on clinical and molecular features of PPA2 variants.
Sudden Unexpected Death in Asymptomatic Infants Due to PPA2 Variants
The OSAC’s subcommittee on medicolegal death investigation has created and submitted to a standard development organization that describes the fundamental activities, minimal requirements, procedures, and personnel that are necessary to meet the basic components of a fully competent medicolegal death investigation system.
A case series study of 622 consecutive sudden child death cases aged 1 to 17 years from 2001 to 2017 from 18 countries reported to the SUDC Foundation. 391 families with child deaths aged 1 to 6 years with completed interviews were analyzed. “This analysis of the largest SUDC cohort confirmed an increased FS rate and found significantly increased rates of FS among sudden explained deaths in children. This study suggests that seizures may contribute to some SUDC and SEDC deaths. The risk of sudden death in a sibling was low. To develop and assess preventive strategies, population-based studies are needed to define the epidemiology and spectrum of risk factors and identify biomarkers of patients with FS at high risk of sudden death.”
Potential Role of Febrile Seizures and Other Risk Factors Associated with Sudden Deaths in Children
“This report details the proceedings and conclusions from the 3rd International Congress on Unexplained Deaths in Infants and Children, held November 26-27, 2018 at the Radcliffe Institute at Harvard University. Four categories (International Classification of Diseases (ICD)-11 categories of MH11, MH12, MH14, PB00-PB0Z) were recommended for classification, and explicit definitions and guidance were provided for death certifiers. A distinct category for children over the age of 1 was recommended (MH12). The conclusions will be submitted to the World Health Organization for inclusion in the upcoming ICD-11.”
Inconsistent Classification of Unexplained Sudden Deaths in Infants and Children Hinders Surveillance, Prevention and Research
Authors analyzed neuroimaging (3T MRI imaging scanner) data of the basal forebrain in SUDC cases and authors conclude findings “better define individual variations relevant to functional neurosurgical targeting and validate/complement advanced MR imaging methods”.
Authors analyzed neuroimaging (3T MRI imaging scanner) data from SUDC cases of the brain stem which contains life-sustaining sensorimotor and autonomic structures. “Possible structure-function asymmetries in these pathways will require further study-that is, the cross-sectional area of the left corticospinal tract in the midpons appeared 20% larger (n = 13 brains, P < .10).”
A commentary by Laura Gould Crandall and Dr Devinsky on SUDC as an ignored public health issue.
Sudden Unexplained Death in Children
A review of resources available to the medicolegal death investigation community through the SUDC Foundation and NYU Langone Health’s SUDC Registry and Research Collaborative.
Inexplicable Child Deaths
Authors surveyed bereavement organization and bereaved parents to understand their perceptions of changing practices in regards to shifts in diagnoses of sudden infant death- including the use of SIDS, undetermined and asphyxia. Over 50% (34/67) of the organizations perceived the changing practices as effecting their ability to provide bereavement support and education. Forty percent (22/55) of parent stated they did not understand the final diagnosis of their infant's death. Author recommendations include the integration of collaborative efforts to combat sudden infant death with all stakeholders, in and outside of MDI, to achieve better understanding and eradication of these tragedies, improved public education, and effective care of all bereaved.
The Diagnostic Shift of SIDS to Undetermined
OSAC informs the forensic science community of research needs that are uncovered during standards development activities. The subcommittee on medicolegal death investigation issued a research need regarding pediatric sudden deaths.
The SUDC Scientific Advisory Board’s letter to the editor on the Hefti et al articles Part 1 and Part 2 describing the limitations of the study and the importance of “needing more data” and comprehensive investigations to understand the significance of stated hippocampal findings. The authors noted that such findings could be the cause or result of seizures, or non-related entity.
Authors detail the hippocampal findings in 42 cases from the San Diego SUDC Research Project. Key features described were focal granule cell bilamination of the dentate gyrus, and increased frequencies of other developmental abnormalities. Authors considered these changes a distinct clinicopathologic entity characterized by a likely developmental failure of neuronal migration in the dentate gyrus and that future research was needed to determine a causal role in sudden death.
Data analysis of 151 cases of sudden unexpected childhood death collected retrospectively through the San Diego SUDC Research Project of which 80% (121/151) were subclassified as SUDC. Authors highlight findings in the hippocampus, a history of febrile seizures, relation to sleep and the roles of cardiac channelopathies and infections in causing sudden unexpected death in childhood. They reiterate the need for improved investigations.
National Commission on Forensic Science reports their view that the Attorney General should work to develop a permanent National Office of Medicolegal Death Investigation that would coordinate ongoing support of the nation’s medicolegal death investigation systems to improve quality, consistency, and the meeting of criminal justice and public health needs.
Medicolegal death investigation is a public service, and conveying information in a clear, sensitive, and effective manner to the surviving family members is a critical aspect of the medicolegal death investigation system. It is the view of the National Commission on Forensic Science (NCFS) that: coroners and medical examiners should have policies to support sensitive interactions, to understand what translation and interpretation services are available and that professionals who interact with families should receive culturally competent appropriate training for communicating with the acutely bereaved.
Authors analyzed data of 123 consecutive children with SUDC reported to the SUDC program (4/1/11-3/31/14) by their parents and report that “31.7% of SUDC cases had a history of FS, among which 74.4% had simple FS. Compared to those without a history of FS, a history of FS was associated with a greater median age at death (p = 0.03) and death during the weekdays (p = 0.02). Terminal fever was similar in those with and without FS. The median time from FS to death was 6.0 months (interquartile range [IQR] 3.0-10.0). In all SUDC cases, prone position at death, death during sleep, and unwitnessed deaths predominated. There are parallels among SUDC, sudden infant deaths, and sudden unexpected death in epilepsy (SUDEP) with regard to prone position, unwitnessed deaths mostly during sleep, and male predominance. The greater than expected prevalence of a FS history and the proportion with terminal fever or illness in this cohort suggests that some SUDC deaths may be seizure related and therefore have potential commonalities with SUDEP.”
Authors present an approach assessing frequently missed post-zygotic "mosaic" genetic mutations (those present in only a portion of the healthy parents' cells and are transmitted to offspring). It was applied 9 cases of sudden unexplained death in childhood (SUDC) and found a likely disease-causing mosaic mutation in an SCN1A mutation transmitted to an SUDC proband and her sibling with Dravet syndrome.
This report reviews the reasons for the shortage of forensic pathologists and makes recommendations to increase their supply in the United States.
197 professionals and 156 bereaved parents were surveyed regarding death investigation practices and experiences. Results showed that the majority of professional respondents (96.5%) allow the next of kin (NOK) to view his/her child before transport to the morgue while holding the infant/child was somewhat less commonplace (68.9%). The majority of professional respondents (70.4%) would also permit memorial keepsakes to be made. Furthermore, professional practices and NOK experiences in regard to communicating preliminary and final cause of death information to the NOK were highly variable.
SWGMDI recommends that all primary personnel responsible for investigating deaths, and the consultants and entities providing supportive services, be certified by a qualified accrediting agency.
SWGMDI identified barriers to research in medicolegal death investigation including time constraints, access to appropriate study materials, legal issues, skill, funding, obstacles encountered in writing grants, and lack of interest. They also provide recommendations to address barriers.
SWGMDI provides standards to ensure appropriate interactions to support the donation of organs and tissues. It is the position of SWGMDI that “the procurement of at least some organs and/or tissues for transplantation can occur in almost all cases without a negative impact to the goals of medicolegal death investigation.”
SWGMDI evaluated the perceived need of regional medicolegal death investigation centers to meet the public needs.
In this series, the major pattern of inheritance in toddlers with sudden unexplained death and febrile seizures was autosomal dominant. The authors recommend future studies to develop markers (including genetic) to identify which patients with febrile seizures are at risk for sudden death.
Reported here are the proceedings of a symposium given in honor of Dr. Henry F. Krous upon his retirement of his distinguished 37-year-career dedicated to research into sudden unexpected death in infancy and childhood.
SWGMDI provides the 13 principles for professionals communicating with surviving families members during medicolegal death investigations. The authors explain that “families of individuals who died in situations requiring an investigation experience additional challenges and emotions not faced by families following normal or anticipated deaths. Sudden deaths exacerbate the experience of grief and loss- regardless of the manner of death. How medicolegal professionals communicate with families in the aftermath of a death will have a direct impact on their ability to cope, their view of the medicolegal system, and their willingness to cooperate with the investigation and future proceedings.”
SWGMDI provides guidance on media relations related to medicolegal death investigations, including but not limited to information that MAY be released to the public and information that should NOT be released unless authorized.
SWGMDI analyzed the shortage of forensic pathologists, provided background information on the problem, and offered ten recommendations to increase the supply of forensic pathologists in the United States to meet the needs of the public.
26 SUDC cases with available hippocampal sections, 62% (16/26) had hippocampal and temporal lobe anomalies. Authors conclude potential new entity defined by sleep-related death in prone position, with individual/family history of febrile seizures, and hippocampal and temporal lobe anomalies. This study mandates further research into the potential link between simple febrile seizures and death.
Dr Baker and Ms Crandall write a commentary discussing the pathologist versus family perspectives in death scene investigations. The authors conclude, “in the majority of situations—and certainly whenever possible—the family should be allowed a reasonable amount of time to touch and hold their child, managed in a way that does not hamper the investigation process.”
Case report of 5 cases of SUDC in toddlers that we believe define a new entity associated with hippocampal anomalies at autopsy. Authors suggest risk factors include a case and/or family history of febrile seizures and recommend future studies to confirm and further evaluate findings.
Case report of 2 sudden deaths in toddlers with clinical evidence of a viral infection and found at autopsy to have lymphocytic meningitis. Viral (lymphocytic) meningitis typically does not cause sudden death. Authors recommend the importance of a comprehensive autopsy, including detailed neuropathologic examination and viral testing, in determining of the cause of unexpected death in toddlers.
A case report of a 9-year-old, previously healthy girl who died suddenly and unexpectedly and was found at postmortem examination to have a cardiac rhabdomyoma, megalencephaly, and an involuting adrenal ganglioneuroma. The authors suggest a possible diagnosis of tuberous sclerosis, but confirmatory genetic analysis was not performed.
The first published definition of SUDC describing a profile characterized as male, 1 to 3 years in age, predominantly male, frequently personal and family history of seizures, and being found prone. The authors recommend legislation enabling research and formation of a multicenter research team to unravel the mystery of SUDC.
A case report of a 13-year-old, previously healthy male without a history of seizures, neurologic deficits, or clinical stigmata of neurofibromatosis or family history. The autopsy revealed a brain mass descriptive of meningioangiomatosis (type of mass in/around meninges). The authors speculate his death was the result of a seizure due to meningioangiomatosis.
A review of tumors associated with sudden infant and child death find they are rare but most (84%) affect the heart and brain and require thorough postmortem examination for accurate determination.