The Molecular Autopsy: Should the Evaluation Continue After the Funeral?

Sudden cardiac death (SCD) is one of the most common causes of death in developed countries, with most SCDs involving the elderly, and structural heart disease evident at autopsy. Each year, however, thousands of sudden deaths involving individuals younger than 35 years of age remain unexplained after a comprehensive medicolegal investigation that includes an autopsy. In fact, several epidemiologic studies have estimated that at least 3% and up to 53% of sudden deaths involving previously healthy children, adolescents, and young adults show no morphologic abnormalities identifiable at autopsy. Cardiac channelopathies associated with structurally normal hearts such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) yield no evidence to be found at autopsy, leaving coroners, medical examiners, and forensic pathologists only to speculate that a lethal arrhythmia might lie at the heart of a sudden unexplained death (SUD). In cases of autopsy-negative SUD, continued investigation through either a cardiologic and genetic evaluation of first- or second-degree relatives or a molecular autopsy may elucidate the underlying mechanism contributing to the sudden death and allow for identification of living family members with the pathogenic substrate that renders them vulnerable, with an increased risk for cardiac events including syncope, cardiac arrest, and sudden death.     

Successful parental use of an automated external defibrillator for an infant with long-QT syndrome

Congenital long-QT syndrome with 2:1 atrioventricular block presenting in the perinatal period is rare, has a poor prognosis, and leads to high risk for lethal ventricular arrhythmic events. An implantable cardioverter-defibrillator seems to be the most effective treatment in the prevention of arrhythmic sudden cardiac death in patients with long-QT syndrome. Technical limitations and risks associated with implantable cardioverter-defibrillators in asymptomatic infants is considered too great to justify use for primary prophylaxis against sudden cardiac death. In this case report we describe the first successful parental use of an automated external defibrillator prescribed for primary prophylaxis against sudden cardiac death in an infant with long-QT syndrome.     

Cardiac pathology in sudden unexpected infant death

OBJECTIVES: To determine the spectrum of cardiac pathology and circumstances of death in infants with sudden unexpected death and to define the impact of sudden cardiac deaths to overall sudden infant death.Study design: Retrospective analysis of all autopsies of infants with sudden death 7 days to 2 years of age between January 1987 and December 1999 in the province of Québec (Canada). RESULTS: Eighty-two cases of sudden death with cardiac pathology were found, representing 10% of the total number of sudden infant deaths. A structural malformation was present in the majority of cases (54%); however, cardiac pathology in anatomically normal hearts was also common (46%). Most (64%) anatomic malformations were detected before death compared with 13% of nonstructural heart disease. Although a major proportion of children were found dead during sleep, a significant number were described as being awake at time of death (32%). CONCLUSIONS: Heart disease is present in a significant percentage of autopsies of infants with sudden death. Structural heart malformations predominate, although nonstructural pathologic features of the heart are common and usually unrecognized before an autopsy is performed. Cardiac pathologic features are frequent when the child is witnessed to be awake at the time of sudden death.     

Sudden death in children and adolescents

This article focuses on sudden unexpected cardiac death (SCD) in children and adolescents. The authors discuss the epidemiology of SCD in children and adolescents, its incidence and etiologies, and strategies for prevention. Because most of the episodes of SCD or sudden cardiac arrest in children and adolescents occur in asymptomatic individuals unknown to have an underlying abnormality before their "event," the issues in this article primarily focus on this group of individuals.     

Sudden death in patients with right isomerism (asplenism) after palliation

OBJECTIVE: To define the risk of sudden death in patients with right isomerism (asplenia) after palliation. STUDY DESIGN: A total of 154 patients with right isomerism was identified from 1980 to 1999. Sudden death was defined as acute cardiovascular collapse from which death occurred within 24 hours. RESULTS: A total of 620 patient-years were evaluated. The 1-year and 5-year survival was 72% and 50%, respectively. There were 22 sudden unexpected deaths (14%, 35 events/1000 patient-years). Sudden death tended to occur in infancy or early childhood (12 +/- 9 months; median, 9 months). The mechanisms were classified as sudden tachyarrhythmic in 2 (9%), sudden cardiac but nontachyarrrhythmic (sudden onset severe cyanosis) in 15 (68%), and sudden noncardiac in 5 (23%)(fulminant sepsis with positive blood culture: streptococcus pneumonia (3), Escherichia coli (1), and yeast-like organism (1)). The incidence of sudden death steadily decreased with age until the age of 3 years. CONCLUSION: The incidence of sudden death in patients with right isomerism after initial palliation remained high. Sudden death was related to complex cardiac anomalies, a susceptibility to fulminant infection, and arrhythmia.     

Neonatal long QT syndrome and sudden cardiac death

Neonatal sudden cardiac death most often results from cardiac electrical diseases, cardiomyopathies, or sudden infant death syndrome. In infants without a known premortem diagnosis or abnormalities identified at autopsy, sudden infant death syndrome accounts for the vast majority of sudden deaths. Potential cardiac causes of some sudden infant death syndrome cases may include malignant brady- or tachyarrhythmias and congenital long QT syndrome. The possible mechanisms include abnormal brain stem respiratory control of arousal, dysautonomia and malignant cardiac bradyarrhythmias or tachyarrhythmias. Screening for neonatal sudden cardiac death may not be feasible, but hopefully through careful review of history, physical examination, and family health history, and judicious diagnostic testing, can the risk of cardiac sudden death be reduced. Further comprehension of the genetic basis of inherited arrhythmia disorders may help elucidate the mechanisms of arrhythmogenesis and etiologies of sudden infant death. Prevention and treatment of these disorders may also be improved through more detailed understanding of the molecular basis of cardiac electrical pathophysiology.     

Deadly proposal: a case of catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare adrenergically mediated arrhythmogenic disorder classically induced by exercise or emotional stress and found in structurally normal hearts. It is an important cause of cardiac syncope and sudden death in childhood. Catecholaminergic polymorphic ventricular tachycardia is a genetic cardiac channelopathy with known mutations involving genes affecting intracellular calcium regulation. We present a case of a 14-year-old boy who had cardiopulmonary arrest after an emotionally induced episode of CPVT while attempting to invite a girl to the school dance. Review of his presenting cardiac rhythm, induction of concerning ventricular arrhythmias during an exercise stress test, and genetic testing confirmed the diagnosis of CPVT. He recovered fully and was treated with β-blocker therapy and placement of an implantable cardioverter-defibrillator. In this report, we discuss this rare but important entity, including its molecular foundation, clinical presentation, basics of diagnosis, therapeutic options, and implications of genetic testing for family members. We also compare CPVT to other notable cardiomyopathic and channelopathic causes of sudden death in youth including hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and Brugada syndrome.     

Clinicopathological features of paediatric deaths due to myocarditis: an autopsy series.

INTRODUCTION: Myocarditis is a recognised cause of cardiac failure in childhood but the frequency of myocarditis as a cause of sudden unexpected death across the paediatric age range is uncertain. METHODS: A structured review of the results of all autopsies carried out in a single paediatric centre over a 10-year period, including the results of all investigations performed as part of the centre's policy for the post-mortem investigation of paediatric deaths. RESULTS: During the study period there were 1516 autopsies of children aged 0-18 years. Histologically proven myocarditis was present in 28 cases (1.8%, age range 10 days to 16 years, median age 10 months), of which 16 (57%) presented as sudden death. More than half of all cases (54%) occurred in infants less than 1 year of age, accounting for 2% of infant deaths referred for autopsy, compared with around 5% of childhood deaths over the age of 5 years. In almost 40% of cases there were no macroscopic cardiac abnormalities, the diagnosis being entirely dependent on routine histological examination of the heart, and post-mortem heart weight was normal in the majority of cases. Virus was detected in nine (36%) of the 25 cases in whom virological analyses were performed. The histological features were similar in all cases, with an interstitial inflammatory cell infiltrate, predominantly lymphocytic, with focal myocyte necrosis and interstitial oedema. CONCLUSIONS: Myocarditis is a rare cause of death in infancy and childhood, and the majority of cases present as sudden unexpected deaths, which require routine histological sampling of the heart for its detection.     

Tumors Associated with Sudden Infant and Childhood Death

Tumors are rare causes of sudden death in infancy and early childhood. The goals of this study were to determine the types and frequency of the tumors associated with sudden death occurring in cases between birth and age 3 years. The San Diego Sudden Infant Death Syndrome/sudden unexplained death in childhool (SUDC) Research Project database and the literature were reviewed retrospectively. Sixty-eight cases, with the most (84%) affecting the heart and brain, were identified. Tumors are a rare but significant cause of sudden death in infancy and early childhood, and their diagnosis may have significant genetic implications for planning future pregnancies. The diagnosis of these lesions can be established only after thorough postmortem examination.     

Aborted sudden cardiac death in a child with left ventricular non‐compaction

Left ventricular non‐compaction is a rare form of cardiomyopathy believed to be the result of intrauterine arrest of compaction of the endomyocardial morphogenesis, leading to persistence of the embryonic myocardium. Clinical manifestations are highly variable, ranging from no symptoms to a progressive deterioration in cardiac function that results in congestive heart failure, systemic thromboemboli, arrhythmias, and sudden cardiac death. Presented here is the case of a 4‐year‐old child with a history of aborted sudden cardiac death. Following resuscitation, he was admitted to the intensive care unit with neurologic sequelae that regressed later on. Transthoracic echocardiography and magnetic resonance imaging showed numerous prominent trabeculations and deep intertrabecular recesses at the apical and anterolateral region of the left ventricle. Electrophysiologic study showed polymorphic ventricular tachycardia. An implantable cardioverter–defibrillator (ICD) was implanted following clinical recovery. Five months after implantation, appropriate ICD shock due to ventricular fibrillation was documented.     

Percutaneous Transcatheter Device Closure of an Isolated Congenital LV Diverticulum: First Case Report

A congenital left ventricular diverticulum is a rare cardiac malformation. It is a developmental anomaly that occurs during embryogenesis. Presentations vary from asymptomatic patients to sudden death. To date, the treatment described has been surgical correction. The authors report the first transcatheter closure of an isolated congenital left ventricular diverticulum in a 12-year-old symptomatic girl.     

重视导致危重症及猝死的潜在遗传代谢病及内分泌疾病

不明原因猝死综合征是高收入国家儿童死亡的主要原因。猝死可发生在新生儿期至成人,貌似健康的人在日常活动、睡眠或运动中意外死亡,潜在的遗传病是导致心脏性猝死和脑死亡的病因。1977年美国首先关注到不明原因猝死综合征,美国、英国、泰国、日本等国家通过对猝死者的病因研究,证实多种遗传病导致的心脏病、脑病是猝死的两组主要疾病。其中心脏性猝死占一半以上,猝死或猝死样发作也常常是潜在遗传病的首发表现。已知多种遗传代谢病及内分泌疾病可导致猝死,如：原发性肉碱缺乏症、长QT综合征、心律失常、低镁血症、低钾血症、高钾血症、低钙血症、低血糖、线粒体病等。遗传代谢病及内分泌疾病包括氨基酸、有机酸、糖、脂肪等近千种先天性代谢缺陷,其中许多疾患可导致急性危重症甚至猝死。运用生化、电生理、影像、病理和基因诊断等技术,一些疾病可通过新生儿筛查及高危筛查获得早期诊断,通过饮食及药物干预,有望减少意外死亡,降低残障的发生。     

Sports preparticipation cardiac screening: what about children?

Sudden cardiac death in young athletes is a devastating event. Screening programs have been proposed to prevent sudden cardiac death in young athletes. Mortality rates and causes of death differ among young adults and children. Children have a considerably lower incidence of sudden cardiac death. Data lack to compare athletes and non-athletes in childhood, but 40–50 % of sudden cardiac death in this age group seems to be related to exercise. Screening programs including history and physical exam are not very sensitive or specific and will result in important numbers of false-positives and false-negatives. Especially, interpretation of ECG in children is different from ECG in adults, with less accurate diagnoses as a consequence. Secondary prevention by widespread education of simple resuscitation techniques and use of automatic external defibrillators if available will probably save as many lives as any screening program. Conclusion: Sufficient data are lacking to support general preparticipation screening with history, physical exam, and ECG in competitive children. Nevertheless, the impact of such a program, together with secondary preventive measures, should be evaluated in large prospective studies.     

Abrupt aggravation of atrioventricular block and syncope in hypertrophic cardiomyopathy.

A 10 year old girl with hypertrophic cardiomyopathy (HCM) developed high grade atrioventricular (A-V) block unexpectedly, which instantly led to syncope; she required a permanent pacemaker. High grade A-V block, a rare complication of HCM, relates closely to syncope or sudden death in this disease and if progressive the use of cardiac pacing should be considered without delay.     

Abrupt aggravation of atrioventricular block and syncope in hypertrophic cardiomyopathy

A 10 year old girl with hypertrophic cardiomyopathy (HCM) developed high grade atrioventricular (A-V) block unexpectedly, which instantly led to syncope; she required a permanent pacemaker. High grade A-V block, a rare complication of HCM, relates closely to syncope or sudden death in this disease and if progressive the use of cardiac pacing should be considered without delay.     

Vascular events in patients receiving high-dose infusional 5-fluorouracil-based chemotherapy: the University of Chicago experience

In a retrospective review, 22 of a total of 244 patients (9%) patients with head and neck or gastrointestinal cancer who were treated with infusional 5-fluorouracil (5-FU)-based chemotherapy regimens experienced thrombotic vascular events. These events occurred concurrently with treatment or several months following the completion of therapy and consisted mainly of cardiac arrhythmias, myocardial infarction, sudden death, and thromboembolism. The temporal relationship of these vascular events to the time of treatment suggests that infusional 5-FU may have been the underlying cause.     

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.     

线粒体脂肪酸氧化代谢病与猝死

线粒体脂肪酸β氧化代谢病是一类潜在的致死性疾病。由于编码某种酶的基因致病突变导致酶活性缺乏,引起能量代谢衰竭和多器官损害。患儿临床表现复杂,轻重不同,可急可缓。少数既往无症状的患儿急性发病,在不明原因情况下发生心源性猝死。随着生化分析技术及基因检测技术的发展和应用,通过对猝死患者的代谢尸检及基因分析,明确了线粒体脂肪酸β氧化代谢病是导致猝死的一组遗传病。通过串联质谱法扩展新生儿筛查或高危筛查,患儿可在无症状时期或疾病早期获得诊断,早期干预是减少残障及病死率的关键。     

Sudden unexpected non-violent death between 1 and 19 years in north Spain.

AIMS: To study the epidemiological, clinical, and pathological characteristics of sudden unexpected non-violent deaths between 1 and 19 years. METHODS: Population based observational study of all sudden unexpected non-violent deaths between 1 and 19 years, from 1990 to 1997, in a north Spain county (Bizkaia). In each case, clinical information and circumstances of death were obtained and a complete forensic autopsy was performed. RESULTS: There were 34 sudden unexpected non-violent deaths. The mortality rate was 1.7 per 100 000 persons per year (representing 9% of the mortality rate of all non-violent deaths). In 10 cases the cause of death was cardiac, in 13 cases extracardiac, and 11 cases were unexplained. In 17 cases there were no pathological antecedents and in nine cases death occurred in patients with known disorders. Syncopes prior to death were present in five cases. Exercise related deaths occurred in seven cases (mainly associated with cardiac causes). Eight cases were "death in bed".