Guidelines for autopsy investigation of sudden cardiac death

Although sudden cardiac death is one of the most important mode of death in Western Countries, pathologists and public health physicians have not given this problem the attention it deserves. New methods of preventing potentially fatal arrhythmias have been developed, and the accurate diagnosis of the causes of sudden cardiac death is now of particular importance. Pathologists are responsible for determining the precise cause of sudden death but there is considerable variation in the way in which they approach this increasingly complex task. The Association for European Cardiovascular Pathology developed guidelines, which represent the minimum standard that is required in the routine autopsy practice for the adequate assessment of sudden cardiac death, including not only a protocol for heart examination and histological sampling, but also for toxicology and molecular investigation. Our recommendations apply to university medical centres, regional and district hospitals and all types of forensic medicine institutes. If a uniform method of investigation is adopted throughout the European Union, this will lead to improvements in standards of practice, allow meaningful comparisons between different communities and regions and, most importantly, permit future trends in the patterns of disease causing sudden death to be monitored. *http://anpat.unipd.it/aecvp/     

Sudden unexpected death in patients with malignancy: a clinicopathologic study of 28 autopsy cases

Sudden unexpected death (SUD) in patients with malignancy has not been comprehensively studied. We defined SUD as intrinsic natural death within 24h after initial clinical presentation of the disease responsible for the death. Intra- and postoperative death and cases associated with a myelosuppressive state were excluded. Of 2,216 autopsy cases with malignancy registered at Saitama Cancer Center, Japan, 28 SUD cases (1.3%) were studied clinicopathologically. Fifteen cases (53.6%) died of non-neoplastic cardiovascular events (CVEs), with acute myocardial infarction (AMI) being the most common death (n=13). Ten cases (35.7%) died of neoplasm-related complications (NRCs), and a miscellaneous pathophysiology was apparent, including cardiac involvement by tumor cells (n=3), fistula formation between great vessels and the alimentary canal (n=3), hepatic rupture (n=2), cardiac tamponade (n=1), and neoplastic pulmonary emboli (n=1). An anaphylaxis reaction (AR) was the cause of SUD in three cases (10.7%). Our results imply that the main route for prevention of SUD in patients with malignancy is incorporation of measure against ischemic heart disease. In addition, a variety of mechanisms causing SUD as a complication of malignant neoplasms should be recognized, including AR. Accumulation of SUD cases is necessary to better understand the causes of SUD in patients with malignancy.     

心源性猝死33例尸检临床病理分析

目的 分析心源性猝死的临床特点以及尸检病理学特征.方法 收集与医疗纠纷有关的不明原因死亡的87例尸体解剖资料进行病理组织学检查.结果 心源性猝死33例,其中,冠心病20例(占64%),主动脉夹层动脉瘤破裂4例,心肌炎5例,肥厚性心肌病2例,冠状动脉炎和肺动脉脂肪栓塞各1例.结论 正确、系统地进行尸体解剖,可以明确猝死原因,提高医疗质量,并为医疗纠纷鉴定提供可靠的鉴定依据.     

Sudden cardiac death: an 11-year postmortem analysis in the region of Epirus, Greece

The aim of the study was to determine the rate of sudden cardiac death in people aged between 1 and 80 years, and to investigate its etiology. All autopsies performed during an 11-year period were reviewed. Circumstances of death, individual's information, and post-mortem findings were determined. Among 1254 sudden death autopsies performed during the study period, 688 cases were recognized as sudden cardiac death (79.8% males). The estimated annual frequency of sudden cardiac death in the region of Epirus was 18.6/100,000. The major cause of death was ischemic heart disease (82%), and in 2.6%, death was unexplained. Among our study's total population, 4.1% were <35 years old. The estimated annual rate of sudden cardiac death in the population 1-35 years old was 1.78/100,000. The most common etiology in that age group was atherosclerosis (17.8%), myocarditis (10.7%), and cardiomyopathies (10.7%), whereas 39.3% exhibited structurally normal heart. Although ischemic heart disease accounts for most of sudden cardiac death episodes, many other causes contribute. Most sudden deaths in the young were "unascertained". The likely cause of death in these cases might be a primary arrhythmogenic disorder. Correct identification of such cases at autopsy will enable an appropriate clinical screening of surviving relatives.     

A rapid scoring tool to assess mutation probability in patients with inherited cardiac disorders

Aims

To explore clinical features and relationship with positive mutation ascertainment in inherited heart diseases in order to develop a clinical tool to assist identification of individuals in whom to offer genetic testing. A clinical tool that increases pre test probability of mutation detection would have the benefits of improving patient counselling, prioritising cases for MPS and allowing equity in decision making.

Molecular autopsy and subsequent functional analysis reveal de novo DSG2 mutation as cause of sudden death

Sudden cardiac death (SCD) is a common cause of death in young adults. In up to 80% of cases a genetic cause is suspected. Next-generation sequencing of candidate genes can reveal the cause of SCD, provide prognostic management, and facilitate pre-symptomatic testing and prevention in relatives. Here we present a proband who experienced SCD in his sleep for which molecular autopsy was performed.We performed a post-mortem genetic analysis of a 49-year-old male who died during sleep after competitive kayaking, using a Cardiomyopathy and Primary Arrhythmia next-generation sequencing panel, each containing 51 candidate genes. Autopsy was not performed.Genetic testing of the proband resulted in missense variants in KCNQ1 (c.1449C > A; p.(Asn483Lys)) and DSG2 (c.2979G > T; p.(Gln993His)), both absent from the gnomAD database. Familial segregation analysis showed de novo occurrence of the DSG2 variant and presence of the KCNQ1 variant in the proband's mother and daughter. KCNQ1 p.(Asn483Lys) was predicted to be pathogenic by MutationTaster. However, none of the KCNQ1 variant carrying family members showed long QTc on ECG or Holter. We further functionally analysed this variant using patch-clamp in a heterologous expression system (Chinese Hamster Ovary (CHO) cells) expressing the KCNQ1 mutant in combination with KCNE1 wild type protein and showed no significant changes in electrophysiological function of Kv7.1.Based on the above evidence, we concluded that the DSG2 p.(Gln993His) variant is the most likely cause of SCD in the presented case, and that there is insufficient evidence that the identified KCNQ1 p.(Asn483Lys) variant would confer risk for SCD in his mother and daughter. Fortunately, the DSG2 variant was not inherited by the proband's two children. This case report indicates the added value of molecular autopsy and the importance of subsequent functional study of variants to inform patients and family members about the risk of variants they might carry.     

Thalamic nuclear abnormalities as a contributory factor in sudden cardiac deaths among patients with schizophrenia

Patients with schizophrenia have a two- to three-fold increased risk of premature death as compared to patients without this disease. It has been established that patients with schizophrenia are at a high risk of developing cardiovascular disease. Moreover, an important issue that has not yet been explored is a possible existence of a “cerebral” focus that could trigger sudden cardiac death in patients with schizophrenia. Along these lines, several structural and functional alterations in the thalamic complex are evident in patients with schizophrenia and have been correlated with the symptoms manifested by these patients. With regard to abnormalities on the cellular and molecular level, previous studies have shown that schizophrenic patients have fewer neuronal projections from the thalamus to the prefrontal cortex as well as a reduced number of neurons, a reduced volume of either the entire thalamus or its subnuclei, and abnormal glutamate signaling. According to the glutamate hypothesis of schizophrenia, hypofunctional corticostriatal and striatothalamic projections are directly involved in the pathophysiology of the disease. Animal and post-mortem studies have provided a large amount of evidence that links the sudden unexpected death in epilepsy (SUDEP) that occurs in patients with schizophrenia and epilepsy to thalamic changes. Based on the results of these prior studies, it is clear that further research regarding the relationship between the thalamus and sudden cardiac death is of vital importance.     

Sudden death: ethical and legal problems of post‐mortem forensic genetic testing for hereditary cardiac diseases

Elger BS, Michaud K, Fellmann F, Mangin P. Sudden death: ethical and legal problems of post‐mortem forensic genetic testing for hereditary cardiac diseases. Hereditary non‐structural diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT, and the Brugada syndrome as well as structural disease such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cause a significant percentage of sudden cardiac deaths in the young. In these cases, genetic testing can be useful and does not require proxy consent if it is carried out at the request of judicial authorities as part of a forensic death investigation. Mutations in several genes are implicated in arrhythmic syndromes, including SCN5A, KCNQ1, KCNH2, RyR2, and genes causing HCM. If the victim's test is positive, this information is important for relatives who might be themselves at risk of carrying the disease‐causing mutation. There is no consensus about how professionals should proceed in this context. This article discusses the ethical and legal arguments in favour of and against three options: genetic testing of the deceased victim only; counselling of relatives before testing the victim; counselling restricted to relatives of victims who tested positive for mutations of serious and preventable diseases. Legal cases are mentioned that pertain to the duty of geneticists and other physicians to warn relatives. Although the claim for a legal duty is tenuous, recent publications and guidelines suggest that geneticists and others involved in the multidisciplinary approach of sudden death (SD) cases may, nevertheless, have an ethical duty to inform relatives of SD victims. Several practical problems remain pertaining to the costs of testing, the counselling and to the need to obtain permission of judicial authorities.     

Sudden death in a 21-year-old man caused by thrombosed coronary aneurysm: Late sequelae or a very late onset of Kawasaki disease?

Kawasaki disease (KD; mucocutaneous lymph node syndrome) is an infantile febrile illness of unknown origin that occurs in worldwide epidemics. The main clinical features of the disease, such as fever, mucositis, cervical lymphoadenopathy and skin rash, associated with coronary aneurysms or arteritis are diagnostic. Late sequelae of coronary arteritis are very rare in the second decade of life; we describe the case of a 21-year-old male who died suddenly. The autopsy revealed a large thrombotic coronary aneurysm, coronary arteritis and myocarditis, supporting the diagnosis of a late fatal sequela of KD. The hypothesis of a very late onset of the disease is also considered and discussed.     

Sudden death in a 15-year-old with diffuse cardiac rhabdomyomatosis: an autopsy case report

A 15-year-old African–American female with a 4-month history of sporadic rapid heartbeat and fatigue was found pulseless and apneic in her residence. At autopsy, patchy scarring was diffuse throughout the circumference of the left ventricle of the heart. Microscopically, the myocardium had diffuse infiltration of rhabdomyoma-like cells with significant associated fibrosis. Unlike cardiac rhabdomyoma, there was no discrete tumor mass. Differential diagnoses considered were congenital cardiac rhabdomyoma with partial regression, cardiac fibroma, histiocytoid cardiomyopathy, glycogen storage diseases, and drug-induced vacuolar cardiomyopathy. However, the findings are most consistent with cardiac rhabdomyomatosis, an entity not well described in the literature.     

The spectrum of inheritable cardiac disease in sudden cardiac death: investigation and pathology

Sudden cardiac death in young adults is rarely related to ischaemic or hypertensive heart disease but has increasingly been associated with a number of inheritable conditions including cardiomyopathies, channelopathies and storage disorders. Once other potential causes of death have been excluded, a careful consideration must be given to inheritable cardiac conditions through careful macroscopic and microscopic examination of the heart and where necessary supported by investigation of the potential underlying genetic abnormality. A pragmatic approach to the examination of the heart is given together with the potential inheritable causes to be considered. When appropriate, support should be sought from a special interest cardiac pathologist through the UK Cardiac Pathology Network (UKCPN).     

Pleomorphic rhabdomyosarcoma in adults: immunohistochemistry as a tool for its diagnosis

Pleomorphic rhabdomyosarcoma in adults over 30 years of age was a diagnosis frequently made in the 1960s and 1970s. Since the general acceptance of malignant fibrous histiocytoma (MFH) as a tumor entity at the end of the 1970s, however, it has become a very rare tumor in adults. Therefore, 21 cases originally diagnosed on the basis of histology and clinical data as pleomorphic rhabdomyosarcoma in the 1960s and 1970s were reexamined immunohistochemically. Other types of pleomorphic sarcomas involved in the differential diagnosis were also studied. Specific antibodies against vimentin, desmin, creatine kinase subunit M, skeletal muscle actin and myosin, and myoglobin, and the avidin-biotin-peroxidase complex technique were used. The immunohistochemical findings indicate that rhabdomyosarcoma occurs only rarely in adults over 30 years of age and that the majority of the tumors have to be reclassified as MFH or leiomyosarcoma. On the other hand, several pleomorphic sarcomas were found to be diagnosed incorrectly as MFH or liposarcoma by routine histologic stains and electron microscopy. The revised diagnosis was pleomorphic rhabdomyosarcoma for one case and pleomorphic leiomyosarcoma for the other cases. Thus, this study clearly shows the usefulness of immunohistochemistry as a technique in the diagnosis of pleomorphic sarcomas in adults.     

Causes of death in a hospitalized geriatric population: An autopsy study of 3000 patients

Macroscopic and histological studies of 3000 consecutive autopsies (43.9% of the registered deaths) were performed by the same pathologist in a geriatric institution over a period of 20 years. Bronchopneumonia (42.9%), malignant neoplasms — mainly of the gastrointestinal tract and its annexae and the lungs (28.1%) — pulmonary thrombo-embolism (21.2%) and acute myocardial infarction (19.6%), were the most prevalent fatal conditions observed. Next, in decreasing order were: urinary tract infection (12.3%), acute cerebrovascular disease (6.5%), internal haemorrhage (5.5%), and congestive cardiac failure (3.3%). Some rare causes of death noted included trauma, metabolic disease, acute asphyxia from foreign body obstruction of the upper respiratory tract and degenerative neurological diseases. Some potentially treatable disorders which led to death were unsuspected clinically: for example, acute pyelonephritis (87%), pulmonary thrombo-embolism (74%), acute myocardial infarction (74%) and active pulmonary tuberculosis (61%). With advancing age there is an increased frequency of multiple pathological processes in a given subject and interactions play an important role in morbidity and mortality. We observed that two or more co-existing conditions often determine the fatal event. We also emphasize the relevance of post-mortem examination to prevention of disease and to therapeutic medicine in a hospitalized geriatric setting.     

Retrospective review of Japanese sudden unexpected death in infancy: the importance of metabolic autopsy and expanded newborn screening

Sudden unexpected death in infancy is defined as sudden unexpected death occurring before 12 months of age. The common causes of sudden unexpected death in infancy are infection, cardiovascular anomaly, child abuse, and metabolic disorders. However, the many potential inherited metabolic disorders are difficult to diagnose at autopsy and may therefore be underdiagnosed as a cause of sudden unexpected death in infancy. In the present study we retrospectively reviewed 30 Japanese sudden unexpected death in infancy cases encountered between 2006 and 2009 at our institute. With postmortem blood acylcarnitine analysis and histological examination of the liver, we found two cases of long-chain fatty acid oxidation defects. Molecular analysis revealed that the one patient had a compound heterozygote for a novel mutation (p.L644S) and a disease-causing mutation (p.F383Y) in the carnitine palmitoyltransferase 2 gene. Furthermore, retrospective acylcarnitine analysis of the newborn screening card of this patient was consistent with carnitine palmitoyltransferase II deficiency. Metabolic autopsy and expanded newborn screening would be helpful for forensic scientists and pediatricians to diagnose fatty acid oxidation disorders and prevent sudden unexpected death in infancy.     

Cardiovascular protective effect of melatonin in sudden unexpected death in epilepsy: a hypothesis

Epilepsy is the most common neurological disorder, approximately 1% of the population worldwide have epilepsy. Moreover, sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning risk factors for SUDEP is conflicting, but potential risk factors include: age, early onset of epilepsy, duration of epilepsy, uncontrolled seizures, seizure frequency, AED number and winter temperatures. Additionally, the cause of SUDEP is still unknown; however, the most commonly suggested mechanisms are cardiac abnormalities during and between seizures. Furthermore, the evidence from the last 10 years suggests that melatonin has an important role in the epileptogenesis process and influences the cardiovascular system as well. The positive effect of melatonin has been demonstrated against different convulsive stimuli in several rodents, including seizures induced by pentylenetetrazole kainate, glutamate, maximal electrical shock and electrically kindled stimulation of amygdala. Clinical studies have also demonstrated a positive role of melatonin on the seizure frequency in children and reduced spiking activity and seizure frequency in patients with intractable epilepsy. In the rat hearts, studies in vivo and in vitro using pharmacological concentrations of melatonin confirmed an anti-arrhythmic effect of this hormone and studies in humans have been shown that chronic heart disease patients have significantly lower melatonin levels in their blood stream than do normal individuals. Thus, caution should be taken in generalization of these findings to epileptic population. Moreover, it is important to note that when dealing with intractable epilepsy that do not respond to any conventional treatment, the additional of melatonin may be evaluated. Taken together, in this paper we suggested a possible relationship between cardiac abnormalities, melatonin and SUDEP.     

Sudden arrhythmic death and cardiomyopathies in the young: a molecular and pathology overview

Cardiovascular disease is a significant cause of sudden death (SD) requiring autopsy investigation. Non-ischaemic causes of SD are more prevalent in young people (<35 years of age) and conditions such as cardiomyopathies and channelopathies account for about one half of cases.The pathologist's task is to provide the correct diagnosis and, when dealing with a genetic disease, to initiate pre-symptomatic cardiologic and genetic cascade screening of first-degree family members. Early identification is important because SD can be the first and last clinical presentation of the underlying disease and the only medical examination undertaken is the autopsy. A standardized and detailed post-mortem procedure on the SD victims, in combination with molecular testing (“molecular autopsy”), will provide vital information for the family in preventing a further tragedy. Therefore proper sampling to allow post-mortem DNA analysis as well as accurate morphological evaluation, are mandatory, as recommended in the guidelines for autopsy investigation of SD from the Association for European Cardiovascular Pathology.     

Interleukin-2 as a neuromodulator possibly implicated in the physiopathology of sudden infant death syndrome

Dysfunction in vital brainstem centers, including those controlling cardiorespiratory- and sleep/arousal pathophysiology, is reported in sudden infant death syndrome (SIDS). Biological mechanisms underlying SIDS, however, remain unclear. Cytokines are inter-cellular signaling chemicals. They can interact with neurotransmitters and might thus modify neural and neuroimmune functions. Cytokines could therefore act as neuromodulators. Interleukin (IL)-2 is a major immune-related cytokine. It has not been previously depicted in vital brainstem centers. We detected intense neuronal IL-2 immune-reactivity in the SIDS brainstem, namely in vital neural centers. This IL-2 overexpression might interfere with neurotransmitters in those critical brainstem centers, causing disturbed homeostatic control of cardiorespiratory and arousal responses, possibly leading to SIDS.     

Human anatomy: A foundation for education about death and dying in medicine

In most medical schools, little curricular time is devoted to the art of medicine, and this is particularly evident with respect to death education. We make a case for including education on death and dying in medical schools, specifically its early introduction in the anatomy course. Studies indicate that whereas dissection of cadavers is an exciting discovery for most students, for many it is traumatic and if not addressed, students may use depersonalization and denial as their approach to suffering. The dissecting experiences in two different medical schools are described. The University of Massachusetts program developed in a traditional curriculum and explores humanistic issues with lectures and group discussions. Parallels are drawn between dissection and patient care, and coping styles are discussed openly. In the problem-based curriculum at Dalhousie Medical School, death and grief are discussed in the first week of medical school, and students are given information about the body donor program and support systems for students. This program is part of a longitudinal curriculum on death and dying. In both schools, students tour the dissecting rooms before the course begins and organize memorial events for body donors at the end of the academic year. These examples illustrate how death education can begin early in the medical curriculum and contribute to the development of practitioners who are sensitive to broader issues of human mortality. Clin. Anat. 10:118–122, 1997 © 1997 Wiley-Liss, Inc.     

Coxsackie B3 myocarditis in 4 cases of suspected sudden infant death syndrome: diagnosis by immunohistochemical and molecular-pathologic investigations

Immunohistochemical and molecular-pathologic techniques have improved the diagnosis of myocarditis as compared with conventional histologic staining methods done according to the Dallas criteria. Most investigations were carried out on adults, and only a few authors investigating childhood deaths applied these modern methods, used for diagnosing myocarditis. We report on four children under one year of age, who suddenly died without prodromal symptoms. Their deaths were attributed to SIDS (sudden infant death syndrome). Immunohistochemical (LCA, CD68, CD45R0, MHC-class-II-molecules, VP1-capsid-protein of enteroviruses) and molecular-pathologic (RT-PCR) investigations, however, suggested that death was caused by a coxsackie-B3-myocarditis. In the future, these methods should be used for investigating cases with suspicion of SIDS.