Cases Of Sudden Unexpected Death Research Articles

Intracranial meningioma: an unusual silent killer—about two cases report and a literature review

BackgroundMeningiomas are common benign intracranial tumors, accounting for 1/3 of all primary intracranial neoplasms, and hence, are not considered the chief cause of death when encountered incidentally during autopsy. These tumors are usually slow-growing, and the clinical course may be asymptomatic to the point of acute complications. Sudden unexpected deaths due to meningiomas are exceptional and rarely reported in the literature.In the present report, we describe two autopsy cases of sudden unexpected death due to meningiomas and we discuss the mechanism of death.Case presentationTwo apparently healthy men were discovered dead in their home. A judicial autopsy was ordered. At dissection, a pedunculated firm mass, attached to the dura was found in both cases. Tumors were located in the anterior and middle fossa. The remaining organs were congestive without any abnormality. A microscopic examination confirmed the diagnosis of meningiomas. Postmortem toxicology analysis was negative. Forensic pathologists concluded to sudden unexpected death due to intracranial meningioma.ConclusionsThese cases illustrate the possibility of meningioma remaining silent till acute complication and fatal outcome. Therefore, clinicians must bear in mind the possibility, albeit extremely rare, of sudden unexpected death in cases of undiagnosed intracranial meningiomas, as documented in the present report. Thus, we emphasize the value of promptly and thoroughly investigating even seemingly minor neurological symptoms, such as headaches or acute epileptic seizures, in adults. We also stress the importance of the early detection and appropriate management of brain tumors in fatal outcome prevention, and we highlight the role of the post-mortem examination to detect such a fatal complication.

Clinical characteristics and genetic analysis of pediatric patients with sodium channel gene mutation-related childhood epilepsy: a review of 94 patients.

This study aimed to examine the clinical and gene-mutation characteristics of pediatric patients with sodium channel gene mutation-related childhood epilepsy and to provide a basis for precision treatment and genetic counseling. The clinical data from 94 patients with sodium channel gene mutation-related childhood epilepsy who were treated at Hunan Children's Hospital from August 2012 to December 2022 were retrospectively evaluated, and the clinical characteristics, gene variants, treatment, and follow-up status were analyzed and summarized. Our 94 pediatric patients with sodium channel gene variant-related childhood epilepsy comprised 37 girls and 57 boys. The age of disease onset ranged from 1 day to 3 years. We observed seven different sodium channel gene variants, and 55, 14, 9, 6, 6, 2, and 2 patients had SCNlA, SCN2A, SCN8A, SCN9A, SCN1B, SCN11A, and SCN3A variants, respectively. We noted that 52 were reported variants and 42 were novel variants. Among all gene types, SCN1A, SCN2A, and SCN8A variants were associated with an earlier disease onset age. With the exception of the SCN1B, the other six genes were associated with clustering seizures. Except for variants SCN3A and SCN11A, some patients with other variants had status epilepticus (SE). The main diagnosis of children with SCN1A variants was Dravet syndrome (DS) (72.7%), whereas patients with SCN2A and SCN8A variants were mainly diagnosed with various types of epileptic encephalopathy, accounting for 85.7% (12 of 14) and 88.9% (8 of 9) respectively. A total of five cases of sudden unexpected death in epilepsy (SUDEP) occurred in patients with SCN1A, SCN2A, and SCN8A variants. The proportion of benign epilepsy in patients with SCN9A, SCN11A, and SCN1B variants was relatively high, and the epilepsy control rate was higher than the rate of other variant types. Sodium channel gene variants involve different epileptic syndromes, and the treatment responses also vary. We herein reported 42 novel variants, and we are also the first ever to report two patients with SCN11A variants, thereby increasing the gene spectrum and phenotypic profile of sodium channel dysfunction. We provide a basis for precision treatment and prognostic assessment.

Clinical phenotype and genetic characteristics of SZT2 related diseases: A case report and literature review

PurposeSeizure threshold 2 protein homolog gene (SZT2, MIM: 615463) related diseases are extremely rare autosomal recessive disorders with a wide spectrum of clinical phenotypes ranging from mild intellectual impairment to severe developmental epileptic encephalopathy (DEE). Most SZT2 related diseases are accompanied by craniofacial malformation and corpus callosum malformation. This study attempts to analyze and summarize the clinical phenotype and genetic characteristics of SZT2 related diseases, providing a basis for early diagnosis, treatment, and prognosis. MethodWe analyzed the clinical characteristics of a Chinese child with pathogenic variants of SZT2. We also performed whole-exome sequencing (WES) on the patient. In addition, we conducted a literature review of previously reported patients with pathogenic mutations in the SZT2 gene. ResultThe proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drug-controlled focal epilepsy, cluster epilepsy, autism spectrum disorder, craniofacial deformity, hypotonia, focal EEG discharge, corpus callosum malformation, and persistent cavum septum pellucidum. WES revealed that the patient carried the SZT2 gene c.7584dupA and c.6302A>C complex heterozygous variants; the former being Likely Pathogenic (LP) and the latter Uncertain Significance (VUS) according to ACMG classification guidelines. According to our literature review, 43 cases of SZT2 related diseases have been reported so far; these include 15 cases with homozygous variations and 28 cases with complex heterozygous variations. A total of 57 types of variation were found, including 47 genetic variants, 2 de novo variants, and 8 unknown genetic modes. In addition, 2 high-frequency variants were found (c.5949_5951delTGT and c.6553C>T). The main clinical manifestations of the 40 patients were global developmental delay (GDD) of varying degrees (38/40, 95.00%), seizures (36/40, 90.00%), cranial deformity (27/40, 67.50%), facial deformity (22/40, 55.00%), hypotonia (22/40, 55.00%), abnormal interseizure EEG discharge (26/40, 65.00%), slow background activity (20/40, 50.00%), corpus callosum deformity (18/40, 45.00%). There was also one case of sudden unexpected death in epilepsy (SUDEP) and 3 cases of death from infection. In addition, three fetuses with the same variant had hydrocephalus and encephalocele. ConclusionThe compound heterozygous mutation of c.7584dupA and c.6302A>C in the SZT2 gene is the genetic etiology of this patient, expanding the mutation spectrum of SZT2 related diseases. Early genetic testing is the best choice for clear diagnosis, treatment, and prognosis.

Screening for viral pathogens in the gastrointestinal tract from cases of sudden unexpected death in infancy at the Tygerberg Medico-legal Mortuary

Sudden and unexpected death in infancy (SUDI) may be triggered by an external risk or exposure. Intestinal infections with enteric viruses may disrupt the gut and enhance bacterial toxins present in SUDI cases. While diarrhoeal disease deaths have decreased worldwide, approximately half a million deaths still occur in children in Sub- Saharan Africa and South Asia. Furthermore, the role of viral enteropathogens in SUDI cases have not been investigated. The aim of this study was to describe specific viral pathogens in stool samples collected from SUDI cases and age-matched, apparently healthy infants in Cape Town, South Africa. Stool samples were collected from 176 SUDI cases between June 2017 and May 2018. In addition, stool samples were collected from the nappies of 30 age-matched, apparently healthy infants as a control group. Real-time polymerase chain reaction was performed on the stool samples for viral detection. A total of 111 SUDI cases were positive for viruses, with rotavirus (38.6%; 68/176) and norovirus GI and GII (30.0%; 53/176) were prevalent in SUDI cases. Adenovirus Type F was present in only 15.9% (28/176), astrovirus in 9.7% (17/176), and sapovirus in 0.6% (1/176) of cases. In the control samples, norovirus GII was detected most frequently (36.7%; 11/30), followed by rotavirus (33.3%; 10/30), and sapovirus in 6.7% (2/30). While there was no significant association between SUDI cases and enteric viruses, the majority of viruses were significantly associated with the seasons. The study confirms the importance of rotavirus vaccination and describes the significance of norovirus infection in children, post rotavirus vaccine introduction.

Lethal lymphocytic myocarditis-an underestimated diagnosis in infancy and childhood?

In the past, histological diagnosis of (post-)viral myocarditis was based on the so-called Dallas criteria, which have been criticized because of high interobserver variability and sampling error. Immunohistochemical qualification and quantification of interstitial intramyocardial leucocytes was established and standard values concerning adults were published. Fatal casualties due to aviral myocarditis are rare as far as babies and children are concerned (sudden unexpected death in infancy; SUDI). Cases of sudden unexpected death in the first year of life are frequently regarded as sudden infant death syndrome (SIDS). To diagnose myocarditis when there are only single focal lymphocytic infiltrates in the myocardium, the number of samples taken by autopsy is relevant. But even in babies, immunohistochemical qualification and quantification of interstitial lymphocytes and macrophages can lead to standard values allowing diagnosis of myocarditis. Depending on the course of aviral infection, molecular pathological detection of viral genome in the myocardium is possible to support the diagnosis. Using the mentioned methods gradually, there are more cases of suspected SIDS, which are in fact cases of virus-induced myocarditis as cause of death. Primary enteroviruses (coxsackie viruses) and adenoviruses were found but also Epstein-Barr virus and PVB-19.

Autopsy for Medical Diagnostics: Finding the Cause of Sudden Unexpected Death through Investigation of the Cardiac Conduction System by Serial Sections.

Sudden unexpected death (SUD) is a fatal event that occurs in an apparently healthy subject in a way that such an abrupt outcome could have not been predicted. SUD-including sudden intrauterine unexplained death (SIUD), sudden neonatal unexpected death (SNUD), sudden infant death syndrome (SIDS), sudden unexpected death of the young (SUDY), and sudden unexpected death in the adult (SUDA)-occurs as the first manifestation of an unknown underlying disease or within a few hours of the presentation of a disease. SUD is a major unsolved, shocking form of death that occurs frequently and can happen at any time without warning. For each case of SUD, a review of clinical history data and performance of a complete autopsy, particularly focused on the study of the cardiac conduction system, were carried out according to the necropsy protocol devised by the Lino Rossi Research Center, Università degli Studi di Milano, Italy. Research cases collected and selected for this study were represented by 75 SUD victims that were subdivided into 15 SIUD, 15 SNUD, 15 SUDY, and 15 SUDA victims. After a routine autopsy and clinical history analysis, death remained unexplained, and hence a diagnosis of SUD was assigned to 75 subjects, which included 45 females (60%) and 30 (40%) males ranging in age from 27 gestational weeks to 76 years. Serial sections of the cardiac conduction system disclosed frequent congenital alterations of the cardiac conduction system in fetuses and infants. An age-related significant difference in distribution among the five age-related groups was detected for the following anomalies of the conduction system: central fibrous body (CFB) islands of conduction tissue, fetal dispersion, resorptive degeneration, Mahaim fiber, CFB cartilaginous meta-hyperplasia, His bundle septation, sino-atrial node (SAN) artery fibromuscular thickening, atrio-ventricular junction hypoplasia, intramural right bundle branch, and SAN hypoplasia. The results are useful for understanding the cause of death for all SUD cases that were unexpected and would have otherwise remained unexplained, so as to motivate medical examiners and pathologists to perform more in-depth studies.

Assessing retinal hemorrhages with non-invasive post-mortem fundus photographs in sudden unexpected death in infancy

IntroductionIn the case of sudden unexpected death in infancy (SUDI), eye examination is systematic to detect retinal hemorrhages (RH) that are a crucial hallmark for abusive head trauma (AHT). The aim of this study is to assess the ability of non-invasive post-mortem fundus photographs (PMFP) to detect RH in case of SUDI.MethodsBicentric retrospective analysis of consecutive cases of SUDI under 2 years of age were managed by two French SUDI referral centers with PMFP by RetCam (Clarity Medical Systems USA). PMFP were reviewed randomly, twice, by three independent ophthalmologists blinded for clinical data.ResultsThirty cases (60 eyes) were included. Median age was 3.5 months (interquartile [1.6; 6.0]). No child died of AHT. Image quality was sufficient to assert presence or absence of RH in 50 eyes (83%). Sufficient quality rate was significantly higher when the post-mortem interval was inferior to 18 h (91%, 42/46) as opposed to over 18 h (57%, 8/14, p=0.0096). RH were found in six eyes (10%), four children (13%), with excellent inter and intra-raters’ concordance (Cohen’s Kappa from 0.81 [0.56–1.00] to 1.00 [1.00–1.00]).ConclusionPMFP can detect RH in case of SUDI and is a relevant systematic screening test to be carried out as soon as the deceased child arrives in the hospital. It can decrease the need of eye removal for pathological examination, but further studies are needed to define the best decision algorithm.

Postmortem Genetic Testing in Sudden Unexpected Death: A Narrative Review.

Sudden unexpected death (SUD) is one of the challenging situations encountered in forensic medicine. As a rule, a comprehensive forensic assessment is performed to identify the cause of death in such cases; however, the absence of findings suggestive of a cause, i.e., a negative autopsy, warrants further investigation such as a molecular autopsy. In this review, we aim to highlight the genetic causes of SUD, tools used in a molecular autopsy, and the role of screening in surviving relatives. As per several guidelines, the most preferred samples for DNA extraction are whole blood and fresh frozen tissues. Furthermore, Sanger sequencing and next-generation sequencing are the technologies that are used for genetic analysis; the latter overcomes the former's drawbacks in terms of cost-effectiveness, time consumption, and the ability to sequence the whole exome. SUD have diverse etiologies; we can generally classify them into cardiac and non-cardiac causes. Regarding cardiac causes, many conditions having an underlying genetic basis are included, such as channelopathies and cardiomyopathies. Regarding non-cardiac causes of SUD, the main etiologies are epilepsy and metabolic disorders. Nevertheless, it has been proposed that there is a genetic overlap between channelopathies, especially long QT syndromes and epilepsy. Additionally, fatty acid oxidation disorders are major metabolic conditions that are caused by certain genetic mutations that can lead to SUD in infancy. Since many SUD causes have an underlying genetic mutation, it is important to understand the genetic variations not only to recognize the cause of death but also to undertake further preventive measures for surviving relatives. In conclusion, a molecular autopsy has a major role in the forensic examination of cases of SUD.

Morphological Array of Cardiac and Coronary Artery Diseases in Cases of Sudden Death: An Autopsy-Based Histopathological Study in Rural Setup

Cardiovascular diseases are the foremost cause of sudden death in adults. The primary objective of this study is to estimate the prevalence of various cardiac and coronary artery diseases in sudden unexpected death cases in rural setup. Estimation of age and sex-wise frequency of coronary atherosclerotic disease (CAD), and grading of CAD by applying the Modified American Heart Association (AHA) classification are secondary objectives. In this three years prospective cross-sectional study, heart specimens were studied from 136 persons whose death was sudden and unexpected. Gross dissection and histopathological examination of coronary arteries and heart were done. Diagnoses were based on both gross and microscopic findings. CAD with or without other diseases was the most frequent pathology (n-100, 73.5%). Left ventricular hypertrophy in 45 cases (33.09%), myocardial infarction in 30 cases (22.06%), valvular abnormalities in three cases (2.2%), infective endocarditis in two cases (1.47%), aortic dissection in one case (0.74%), right ventricular hypertrophy in one case (0.74%) and cardiac myocyte atrophy in one case (0.74%) were observed. Male-female ratio of CAD was 8.09:1. Advanced CADs (type IV, V, VI) were found in 94 (94%) cases. In males, the maximum number of advanced CAD was observed in the fifth decade (n- 27, 31.76%) and in females in the seventh decade (n- 4, 44.44%). This study reveals the increasing trend of CAD in rural populations. This study adds rare entities like young-age aortic dissection and cardiac myocyte atrophy to the existing literature and emphasises the importance of autopsy in sudden death cases.

Causes of sudden cardiac death according to age and sex in persons aged 1–49 years

Knowledge of causes of sudden cardiac death (SCD) according to age is important in clinical decision making and to lower the risk of SCD in family members of the deceased. The purpose of this study was to report overall and sex-stratified causes of SCD according to age in persons aged 1-49 years. The study population consisted of all persons in Denmark aged 1-35 years in 2000-2009 and 36-49 years in 2007-2009, which equals 27.1 million person-years. Danish death certificates, discharge summaries, autopsy reports, and data from nationwide registries were used to identify all SCD cases. The SCD cases were divided into 5-year age groups. In the 10-year study period, there were 14,294 deaths, of which 1362 (10%) were classified as SCD. Potentially inherited cardiac disease accounted for a high proportion (43%-78%) of autopsied SCD in all age groups. A significant proportion (19%-54%) of SCD was caused by sudden arrhythmic death syndrome in all age groups. Autopsy rates in both sudden unexpected death cases and SCD cases declined significantly with increasing age (74% in the youngest age group vs 35% in the oldest). The proportion of SCD cases that were identified with a potentially inherited cardiac disease postmortem was high in all studied age groups, while autopsy rates in sudden and unexpected death cases declined markedly with increasing age. Our findings indicate that diagnoses of inherited heart disease are likely missed in some SCD cases, along with the opportunity for treatment and prevention in surviving relatives.

Gastric aspiration in sudden unexpected infant death of Prader–Willi syndrome: immunohistochemical detection of feeding components

Prader–Willi syndrome (PWS) in infants is characterized by hypotonia and poor sucking with feeding difficulties. Two autopsy cases of sudden unexpected death during sleep after tube feeding are described herein. For one, gastric aspiration caused by the possible milk regurgitation was suspected. Immunohistochemical examination of lung sections was performed using three antibodies to human α-lactalbumin, human gross cystic disease fluid protein 15, and cow whey β-lactoglobulin. Five cases of sudden unexpected infant death occurring earlier than at 6 months old were selected as controls. Marked immune-staining for infant formula in one PWS subject was evident within terminal bronchioles and alveoli with granular and amorphous features. However, no positive staining was apparent in the other subject, who exhibited contrasting features in milk distribution. Among control cases, one showed mild staining in the bronchiole, but the others did not. The antibody to β-lactoglobulin reacted specifically with formula, with no nonspecific background. Gastric contents in the airway can be a difficult issue because of the consequent terminal gasping. However, because of an episode of antemortem symptoms of potential regurgitation, and from findings at autopsy such as petechiae, we inferred that fatal regurgitation occurred in this PWS infant after tube feeding. Several clinical reports have described milk aspiration, but this pathological report is the first related to aspiration in PWS during tube feeding.

Forensic Analysis of 9 Cases of Sudden Unexpected Death in Epilepsy.

To analyze the case, scene and forensic pathological characteristics of sudden unexpected death in epilepsy (SUDEP), to provide a practical basis for forensic identification. A total of 9 autopsy cases of SUDEP were collected. The basic information of the cases, the scene characteristics, the forensic pathological changes, the common drugs and antiepileptic drug test results, and pericardial fluid biochemical test results were analyzed. All of the 9 cases were male epilepsy patients died during sleep at night, the age of death was (37.1±8.6) years, and the course of epilepsy was (21.3±5.6) years. Six corpses were in prone position and three in left lateral position. The hemorrhage of the sternocleidomastoid muscle, sternal thyroid muscle and sternohyoid muscle were found with 8 cases, 5 cases and 4 cases, respectively, all of them were unilateral. Six cases had bilateral hemorrhage of pectoralis minor muscle. Brain edema, phagocytosis of frontotemporal neurons and gliosis, cardiac fibers bend in wavy patterns and eosinophilic staining enhancement, pulmonary edema, pulmonary congestion, alveolar hemorrhage, pulmonary small bronchiole wall shrinking, tubular proteinuria and pancreatic parenchymal hemorrhage were the common histopathological changes. The biochemical test results of pericardial fluid indicated that there were myocardial ischemic damage. Young male, early onset, long course of disease, sleep in the prone position, poor drug compliance or combination, epileptic seizure may be the risk factors of SUDEP. Cardiac dysfunction and respiratory depression might be the main death mechanism of SUDEP.

Cannabis recent use in sudden unexpected deaths

The aim of this study was to review all sudden unexpected death received in our laboratory over a four years’ period (2018–2021) in order to ascertain the prevalence of recent cannabis consumption. The main cause of death in industrialized countries is ischemic heart disease, and risk factors include smoking, obesity, age, hypercholesterolemia, arterial hypertension, diabetes mellitus and alcohol. The scientific literature now also links cannabis use to cardiovascular accidents. Cannabinoids exert their effects through the activation of two specific membrane receptors, CB1 and CB2 and, at the cardiovascular level, the activation of these receptors is related to increased cardiac output and sinus tachycardia. In total, 7150 cases of sudden unexpected death had been received in our laboratory for toxicological analysis from January 2018 to December 2021, 262 were related to cannabis use and we selected those in which recent cannabis use was demonstrate due to the presence of THC in blood, after having discarded those cases that presented a concomitant consumption of other drugs of abuse, as well as, other psychoactive substances at toxic concentrations. Blood samples were screened for cannabis by CEDIA and Δ9-tetrahydrocannabinol (THC), 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) were confirmed and quantified using solid-phase extraction (SPE) followed by gas chromatography tandem mass spectrometry (GC-MS/MS). The cut-offs applied were 1 ng/mL for THC and 11-OH-THC and 5 ng/mL for THC-COOH. Forty-eight sudden unexpected deaths following recent cannabis use were recorded. THC blood levels have been increasing over the period studied. The mean in 2018 was 1.84 ng/mL, increasing to 8.08 ng/mL in 2021. In terms of sex, 87.5% of cases were male, the age range ranged from 16 to 74 years, with the median being 50 years and the mode 47 years. In 77% of the cases the cause of death was cardiogenic, 6.2% of the cases corresponded to subarachnoid hemorrhage and the rest to other causes. The highest incidence is presented by the population aged between 40–60 years (58.3%), with alcohol and/or tobacco consumption habits in 50% of the cases. In addition, in this group there are cases with different pathological antecedents like arterial hypertension, obesity, epilepsy and congenital heart disease. The lower incidence of sudden unexpected death is in the age group from 16 to 30 years (10.4%). The distribution of the number of deaths was not homogeneous throughout the four years studied. Both, an increase in the number of deaths and in THC blood levels can be seen. This may be directly related to the increase in THC concentrations in the different forms of cannabis presentations in street samples. Despite cannabis being the most consumed drug among young people, the incidence of sudden unexpected death in this age group is lower, which highlights the importance of the existence of previous pathologies. In people with certain pathologies and/or alcohol and tobacco consumption habits cannabis use is a risk factor that can contribute to sudden unexpected death.

Case Report of a Cardiac Arrest during Surgery Revealing an Arnold Chiari Malformation

Arnold Chiari malformation is a common congenital anomaly of the craniocervical junction. It is defined as a descent of the cerebellar tonsils below the foramen magnum, putting pressure on both the brain and spine causing many symptoms. The patients typically experience no symptoms or chronic slowly progressive symptoms. However, recent reports indicate that a subset of patients with AC may present with acute deterioration, cardiorespiratory arrest and sudden unexpected death. We report a case of sudden unexpected death of a 34 years old woman, married with 3 kids, without any medical history, that was admitted for a heterogeneous multinodular goiter in clinical and biological euthyroidism and scheduled for total thyroidectomy. In intraoperative, the patient presented a cardiorespiratory arrest while positioning her head in hyperextension for a good surgical approach, neck released by anesthesia. Para-clinical tests showed later an AC malformation. Cases of sudden cardiorespiratory arrest in children and adults with AC malformation have been documented, leading to death in some cases. However, these patients who died unexpectedly have experienced a recent trauma. This is a unique example of a sudden unexpected death of a woman undiagnosed AC, in absence of any previous trauma, that occurred during a conventional anesthesia for a thyroid surgery.

Towards molecular autopsies: Development of a FFPE tissue DNA extraction workflow

Sudden unexpected death (SUD) is a devastating event and forms a substantial proportion of the cases investigated at forensic mortuaries each year. Despite post-mortem investigations, the cause of death may remain undetermined. There is potential for these unresolved cases to benefit from retrospective molecular autopsies for investigation into genetic mutations which may have contributed towards death. Often, formalin fixed paraffin embedded tissues (FFPET) are the only archival sources of DNA available for retrospective analyses. However, extracting usable DNA from FFPET is challenging as current methods yield poor quality and quantity DNA. Thus, this study aimed to optimise DNA recovery from FFPET by investigating several variables within the DNA extraction workflow, including the selection of tissue type, number and thickness of tissue sections, deparaffinisation method, and DNA extraction kit. The quantity and quality of DNA recovered were assessed using spectrophotometry, real time PCR, digital capillary electrophoresis and DNA profiling. This study was the first to implement a nuclei quantification using microscopy to guide the selection of the best tissue type to use for DNA analysis. The use of a greater number of thinner tissue sections (100 sections, each 1 μm) significantly improved DNA concentration, purity and fragment length. Additionally, the combination of Deparaffinization Solution with the QIAamp® DNA FFPE Tissue Kit proved most favourable with a median DNA yield of 320 ng and 55% of DNA fragments greater than 400 bp. Isolated DNA was of single source, indicating no contamination in the workflow, and FFPET blocks that were stored for up to 3.5 years did not significantly affect DNA degradation (p = 0.1764). These results are especially informative for designing library preparation and sequencing workflows for determining cause of death in unresolved SUD cases.

Abstract 9188: Sex Differences in Cardiovascular Risk and Guideline-Based Preventive Medication Use Among Sudden Death Victims

Introduction: Atherosclerotic cardiovascular disease (ASCVD) is associated with an increased risk of sudden death. Preventive medications are recommended by clinical practice guidelines for those with elevated ASCVD risk. Guidelines are often underutilized and use of preventive medications differs by sex. Methods: Out-of-hospital deaths of adults aged 18-64 were reported by emergency medical services in Wake County, North Carolina from 2013-2015 and underwent adjudication to identify sudden unexpected death cases. A cohort of 1,114 living controls was generated through random sampling from a central electronic health records repository and propensity scores matched to the sudden death victims based on sex and race. A 10-year ASCVD risk was calculated for all subjects with the requisite components and categorized as low (<7.5%), intermediate (7.5%-19.9%), and high (≥20%). Use of preventive medications, specifically aspirin and statin, was assessed. Logistic regression models were fitted to evaluate the association between 10-year ASCVD risk and sudden death both overall and by sex. Odds ratios for males and females were compared in a pairwise fashion using an adjusted Wald test. Results: The average 10-year ASCVD risk was higher among sudden death victims compared to living controls for both males (36.4 ± 22.2 vs. 16.3 ± 16.0, p-value <0.001) and females (20.6 ± 17.9 vs. 7.1 ± 8.4, p-value <0.001). Among intermediate or high 10-year ASCVD risk sudden death victims and controls, aspirin and statin use were low (13-21%). Among those with intermediate or high ASCVD risk, male sudden death victims were less likely than living controls to be prescribed aspirin (p-value 0.007). Comparing sudden death victims to living controls, there was no difference in statin use among males or in aspirin or statin use among females. There was no significant difference in the strength of association between 10-year ASCVD risk categories and sudden death by sex. Conclusions: Although the average 10-year ASCVD risk of sudden death victims is higher than living controls both overall and by sex, the use of aspirin and statin was low and did not differ significantly between victims and controls. Improvements are needed to increase the use of guideline-based preventive medications.

Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis

In sudden unexpected death in infancy cases, postmortem genetic analysis with next-generation sequencing potentially can extract candidate genes associated with sudden death. However, it is difficult to accurately interpret the clinically significant genetic variants. The study aim was to conduct trio analysis of cases of sudden unexpected death in infancy and their parents to more accurately interpret the clinically significant disease-associated gene variants associated with cause of death. From the TruSight One panel targeting 4813 genes we extracted candidate genetic variants of 66 arrhythmia-, 63 inherited metabolic disease-, 81 mitochondrial disease-, and 6 salt-losing tubulopathy-related genes in 7 cases and determined if they were de novo or parental-derived variants. Thirty-four parental-derived variants and no de novo variants were found, but none appeared to be related to the cause of death. Using trio analysis and an in silico algorithm to analyze all 4813 genes, we identified OBSCN of compound heterozygous and HCCS of hemizygous variants as new candidate genetic variants related to cause of death. Genetic analysis of these deceased infants and their living parents can provide more accurate interpretation of the clinically significant genetic variants than previously possible and help confirm the cause of death.

Pulmonary arterial hypertension (PAH) from autopsy study: T-cells, B-cells and mastocytes detection as morphological evidence of immunologically mediated pathogenesis

BackgroundPulmonary arterial hypertension (PAH) is characterized by severe vascular remodelling, resulting in increased pulmonary vascular resistance with cardiac hypertrophy and heart failure. However, the diagnosis of PAH is often inaccurate. Many cases of PAH are incorrectly diagnosed or missed, and they are often associated with death. The aim of this study was to verify the morphological and histological criteria of fatal cases of PAH and evaluate the lymphocytic populations associated to lesions with reactive neo-angiogenesis. MethodsPulmonary lung sections from 10 cases of sudden unexpected death (SUD) in the absence of previously diagnosed diseases and in an apparent state of well-being, with final histological post autopsy diagnosis of PAH were collected. The pathological findings were compared using ten controls from non-pathological lung from deaths from other causes. The autopsies included 4 males (40%) and 6 females (60%) with an average age of 52.1 ± 10.1 years. Sections stained with hematoxylin and eosin (H&E) were revised for a morphological diagnosis. Subsequently, serial sections were performed and stained with immunohistochemistry for anti-CD20 (B-lymphocytes), anti-CD3 (T-lymphocytes), anti-CD4 (T-helper lumphocytes), anti-CD8 (T-cytotoxic lymphocytes) and anti-CD117/C-Kit (mast cells/MCs) to detect inflammatory infiltrate and different ratios of cell-type. Statistical analysis was conducted using a paired t-test looking at 100 cells in 3 different tissue samples representative of vascular lesion and 3 different random normal lung parenchyma fields without lesion (from 10 normal control lungs), to identify specific lymphocyte subpopulations in inflammatory infiltrates. ResultsThere was a significant percentage increase of CD20 (p < 0.001), CD8 (p = 0.002), CD4 (p < 0.001), and CD117/C-Kit positive (C-Kit+; p < 0.001) cells mainly detected around wall vessels; while increased MCs positivity and C-Kit+ were observed especially in alveolar septa. In addition, reactive angiomatosis was observed. ConclusionsThe inflammatory infiltrate should be included for a correct diagnosis of PAH besides the vascular remodelling. The inflammatory infiltrate seems to be implicated as a main factor in the pathogenesis. This finding is important to rule out secondary pulmonary hypertension, to identify SUDs of unknown causes and to add new elements to the literature that can explain the immunologically related pathogenesis of PAH.

Sudden unexpected death in infancy: Severe pulmonary anatomopathological findings in spite of inconsistent clinical features.

Respiratory tract infections play a considerable pathogenetic role in many cases of sudden infant death (SID). Frequently, clinicians encounter difficulties in diagnosing the disease because of its often unspecific clinical and radiological presentation. We report three cases of sudden unexpected death in infancy (SUDI), involving two males and one female admitted to hospital due to mild respiratory distress. In all three cases, complete post-mortem investigations were successful in uncovering interstitial lung disease as the cause of death. These cases highlight the key role of infection-related interstitial lung diseases in the pathogenesis of some currently unexplained SUDI/SIDS and the diagnostic difficulties due to the variable clinical and histological pattern, thereby explaining the importance of performing complete post-mortem investigations whenever an infant dies suddenly and unexpectedly.

Genetic analysis of sudden unexpected death cases: Evaluation of library preparation methods to handle heterogeneous sample material

Over the past years, next-generation sequencing (NGS) technologies revolutionized the possibilities in a broad range of application areas. Also in the field of forensic genetics, NGS continuously gained in importance and attentiveness. A significant number of sudden cardiac deaths (SCD) in the young is due to heritable arrhythmia syndromes emphasizing the need of examining the genetic basis in these cases also with regard to the identification of relatives and/or patients being at risk. As a result, high-throughput methods became of increasing value in molecular autopsy investigations enabling the analysis of a broad spectrum of genes. Most standard protocols are optimized for high-quality samples and frequently not directly applicable to challenging forensic sample material. In the present study, we intended to examine a comprehensive gene panel associated with SCD and inherited arrhythmogenic disorders. We compared three different hybridization-based library preparation technologies in order to implement a suitable NGS workflow for heterogeneous, forensic as well as diagnostic sample material. The results obtained indicated, that the Illumina technologies Nextera DNA Flex and TruSeq were compatible with samples exhibiting varying levels of degradation. In comparison, the TruSight method also resulted in good sequencing data, but seemed to be more dependent on DNA integrity. The preparation protocols evaluated in our study are not restricted to molecular autopsy investigations and might be helpful for and transferrable to further forensic research applications.