The autopsy in sudden unexpected adult death: Epilepsy

There are up to 500 epilepsy-related deaths annually in the UK, many of which are unwitnessed. Likely mechanisms for sudden and unexpected death in epilepsy (SUDEP) are cerebrogenic cardiac arrhythmias, or central respiratory depression occurring during the peri-ictal period. Pathologists should be informed of the circumstances of the death, severity of seizures, seizure control and the certainty of the clinical diagnosis of epilepsy; this allows accurate clinicopathological correlation. SUDEP autopsies include neuropathological assessment, histological examination of other organs and toxicology, and require the elimination of other causes of sudden death. Macroscopic (non-fatal) abnormalities described in SUDEP include evidence of previous cerebral injury, hippocampal sclerosis and cerebellar atrophy. Histological examination may reveal neuronal loss and gliosis consistent with seizure-related brain injury. Hippocampal sclerosis shows subfield-specific patterns of neuronal loss, granule cell dispersion and mossy fibre sprouting. Rarely, acute neuronal injury is seen as evidence of a more recent cerebral event. This article discusses the pathological findings and possible mechanisms in SUDEP, and future directions for pathology-based research.     

Malignant neoplasms: discordance between clinical diagnoses and autopsy findings in 3,118 cases

BACKGROUND: During the past few decades, hospital autopsy rates have steadily declined throughout the Western world. This decline is mainly attributed to the introduction of advanced diagnostic techniques. Despite technological developments, discrepancy rates between clinical diagnoses and autopsy findings remain high. Few studies have addressed discrepancy rates exclusively with regard to malignant neoplasms. In the present study, we reviewed the records of 3,118 autopsies performed at Mayo Clinic during a 6-year period (1994-1999) and identified clinically undiagnosed malignancies found at autopsy and clinically diagnosed cancers not confirmed at postmortem examination. MATERIALS AND METHODS: Autopsy protocols, provisional and final anatomic diagnoses, and data from the Mayo Autopsy Pathology Quality Assurance program were reviewed in an attempt to identify discrepancies between clinical diagnoses and autopsy findings regarding malignant neoplasms. RESULTS: In 3,118 autopsies performed at Mayo Clinic between 1994 and 1999, a malignant tumor was identified in 768 cases (25%). In 128 of 3,118 cases (4.1%), the malignancy was not diagnosed clinically. In 14 of 3,118 cases (0.45%), autopsy failed to confirm a clinically diagnosed cancer. A review of the literature is presented. CONCLUSIONS: Autopsy remains an effective tool for the confirmation and refutation of clinical diagnostic findings regarding malignant neoplasms.     

The autopsy in cases of unascertained sudden death

After a properly conducted autopsy, a small proportion of cases will not reveal a cause of death. This is probably of the order of 2–5%. However, before the death is recorded as unascertained, it is important that appropriate ancillary investigations have been conducted. These tests include toxicology, microbiology and genetic testing where appropriate. The history and scene examination findings must be known, and the possibility of a hidden homicide reasonably excluded. However, even with a full and thorough investigation, some natural disease processes such as cardiac conduction abnormalities and sudden death in epilepsy will result in a negative autopsy. If investigated properly, a cause of death may still be identified for decomposed bodies.     

Pathological findings in coronary arteries associated with sudden death in Austria

Summary 50 witnessed sudden cardiac deaths in the age group between 20–50 years have been studied at autopsy. The most remarkable findings were a high percentage of stenosis and arterioisclerosis of the descending branch of the left coronary artery and a large amount of three vessel disease. It is clear that severe stenosis and sclerosis of the coronary arteries are not essentially related to sudden cardiac death, but a high number of vessels with moderate stenoses and sclerosis has been found.The severity of vessel disease has been evaluated by a coronary score, which takes the haemodynamic effects of the injured coronary arteries on the myocardium into account. We also noted that patients below 35 years of age who died of sudden cardiac death showed a very low coronary score.     

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.     

尸检组织环氧合酶2、妊娠相关血浆蛋白A在冠状动脉的表达与急性冠状动脉综合征发生的关系

目的 检测急性冠状动脉综合征(ACS)发生时尸检标本中环氧合酶2(COX-2)与妊娠相关血浆蛋白A(PAPP-A)在冠状动脉局部的表达情况及两者相关性.方法 从2002-2007年尸检例中筛选出有ACS发生的21例标本作为ACS组,选择未发生ACS的标本21例作为对照组,分别取其左、右冠状动脉.以CD68标记巨噬细胞、α-肌动蛋白标记平滑肌细胞,通过对这两种细胞的标记定位PAPP-A、COX-2的阳性部位.结果 (1)COX-2及PAPP-A的阳性部位均为内皮细胞胞质、巨噬细胞胞质、平滑肌细胞胞质.COX-2在ACS组平滑肌细胞胞质的表达阳性率为28.60%,在对照组平滑肌细胞胞质阳性率为4.76%,结果表明ACS组COX-2表达明显高于对照组(x2=14.13,P<0.05).(2)在ACS发生时,COX-2与PAPP-A在冠状动脉中膜平滑肌的表达有明显的相关性(r=0.88,P<0.05).(3)非斑块处平滑肌表达PAPP-A强度明显强于斑块底部平滑肌(x2=10.36,P<0.05).结论 COX-2、PAPP-A可通过在冠状动脉局部发挥作用来参与ACS的发生.     

Pathological evaluation of coronary lesions in cases of cardiac rupture during acute myocardial infarction: An autopsy study of 148 out-of-hospital sudden death cases

We pathologically evaluated coronary artery lesions of left ventricular ruptures during acute myocardial infarctions (148 sudden out-of-hospital death cases; 93 men and 55 women; age range 42–94 years; mean age 68.9 years; 143 atherosclerotic and 5 non-atherosclerotic lesions). Among the 143 hearts with atherosclerotic coronary lesions, three-vessel disease was most frequent, and plaque rupture or erosion and occlusive thrombus were identified in most cases. Ages of the main component of the occlusive thrombus in the culprit coronary artery corresponded histopathologically to those of myocardial infarction. One of the most outstanding features in this pathological study is that acute thrombus in the culprit coronary artery was identified morphologically in most of the cases with advanced myocardial infarction (3 or more days). On the other hand, in cases of fresh myocardial infarction, a preceding mural non-occlusive organizing thrombus was observed mostly underneath the main component of the thrombus. It is suggested that, in most cases, cardiac rupture during acute myocardial infarction occurs at the time of a new ischemic event caused by a new thrombotic coronary lesion.     

An Autopsy Case of Kawasaki Disease with Reference to Occurrence of Acute Coronary Thrombosis in the Convalescent Stage

A one-year, four month-old boy who had suffered from Kawasaki disease died suddenly during convalescence despite intensive gamma-globulin treatment. Autopsy revealed a) sausage-like aneurysms of the left and right coronary arteries and fresh thrombosis in the right coronary aneurysm, b) fresh transmural myocardial necrosis in the whole wall of the left ventricle and the anterior part of the wall of the right ventricle, and c) swelling of the cervical lymph nodes and thymus (60 g). Histologically, fibrocellular thickening of the intima and destruction of the media and internal elastic lamina were conspicuous in the area of the aneurysm, but those of the intima and media in the areas adjacent to the aneurysm were mild. Abrupt narrowing of the lumen at the border between the aneurysm and periphery of the right coronary artery was detected, and this may have been responsible for formation of the thrombus in the right coronary aneurysm. In the systemic arteries, perivascular fibrosis was very noticeable despite less severe injury to the intima and media. These findings suggest that severe inflammation of the periarterial regions was present in the acute phase. The lymph system still showed inflammation, supporting the infectious or toxic nature of Kawasaki disease. Acta Pathol Jpn 42: 604–613, 1992.     

The necessary role of the autopsy in cardiovascular epidemiology

The autopsy rate in the United States today is remarkably low, with proportionally fewer autopsies for natural causes of death. Consequently, most cardiovascular epidemiology studies do not use autopsy data and rely on death certificates, medical records, questionnaires, and family interviews as sources of mortality information. These practices introduce a high degree of variability and uncertainty regarding cause of death. This review illustrates the necessity for increased use of autopsies in cardiovascular epidemiology by critically evaluating other measures of cardiovascular disease (CVD) incidence. We evaluated the literature regarding CVD as cause of death and conducted discussions with cardiologists, pathologists, and epidemiologists. No attempt was made for meta-analysis. This review shows the limited reliability of death certificates, medical records, and interviews as sources of mortality statistics. In addition, the autopsy's role in clearly indicating the presence of CVD is illustrated. The autopsy used in conjunction with medical records is the only reliable means for establishing cause of death from CVD. There is an urgent need to reassess the current dependence of statistical mortality data on death certificates and other inadequate sources of CVD incidence. Death certificates, in general, are inadequately monitored for quality control and appropriate administrative oversight. With an increase in the number of hospitals performing no autopsies to investigate cause of death, a uniform national autopsy database is needed.     

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.     

Metabolic autopsy with postmortem cultured fibroblasts in sudden unexpected death in infancy: diagnosis of mitochondrial respiratory chain disorders

Mitochondrial respiratory chain disorders are the most common disorders among inherited metabolic disorders. However, there are few published reports regarding the relationship between mitochondrial respiratory chain disorders and sudden unexpected death in infancy. In the present study, we performed metabolic autopsy in 13 Japanese cases of sudden unexpected death in infancy. We performed fat staining of liver and postmortem acylcarnitine analysis. In addition, we analyzed mitochondrial respiratory chain enzyme activity in frozen organs as well as in postmortem cultured fibroblasts. In heart, 11 cases of complex I activity met the major criteria and one case of complex I activity met the minor criteria. In liver, three cases of complex I activity met the major criteria and four cases of complex I activity met the minor criteria. However, these specimens are susceptible to postmortem changes and, therefore, correct enzyme analysis is hard to be performed. In cultured fibroblasts, only one case of complex I activity met the major criteria and one case of complex I activity met the minor criteria. Cultured fibroblasts are not affected by postmortem changes and, therefore, reflect premortem information more accurately. These cases might not have been identified without postmortem cultured fibroblasts. In conclusion, we detected one probable case and one possible case of mitochondrial respiratory chain disorders among 13 Japanese cases of sudden unexpected death in infancy. Mitochondrial respiratory chain disorders are one of the important inherited metabolic disorders causing sudden unexpected death in infancy. We advocate metabolic autopsy with postmortem cultured fibroblasts in sudden unexpected death in infancy cases.     

Genetics of sudden cardiac death in the young

Sudden cardiac death (SCD) has an enormous impact on those who are left behind, evoking strong feelings of anxiety and incomprehension because such a dramatic event was not anticipated. Moreover, over the last decade a prominent genetic contribution to the pathogenesis of SCD has been unveiled. As many inherited cardiac diseases show an autosomal dominant pattern of inheritance, the risk of carrying the same inherited predisposition is a real concern for the relatives. In this article, we discuss the major causes of primary electrical disorders, cardiomyopathies and thoracic aortic dissection and address issues in genotype–phenotype correlation, personalized management and cardiogenetic counselling.     

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.     

心源性猝死心肌细胞凋亡与c-jun基因蛋白的表达

目的 探讨心肌细胞凋亡和c-jun基因蛋白在心源性猝死(SCD)中的表达及其法医学意义. 方法 50例法医尸检案例,其中冠心病猝死组16例,病毒性心肌炎猝死组14例,扩张型心肌病猝死组10例及对照组(非SCD猝死病例)10例.通过TUNEL法和免疫组织化学法对各组心肌细胞凋亡指数、c-jan基因蛋白表达情况的吸光度进行半定量检测,并分析各组之间的差异. 结果 冠心病猝死组、病毒性心肌炎猝死组、扩张型心肌病猝死组的凋亡指数均显著高于对照组(P<0.01).病毒性心肌炎猝死组和扩张型心肌病猝死组的凋亡指数均高于冠心病猝死组(P<0.01),前两者之间差异无统计学意义(P>0.05).冠心病猝死组、病毒性心肌炎猝死组、扩张型心肌病猝死组的c-jan基因蛋白吸光度值均显著高于对照组(P<0.01).3组之间的吸光度值差异无统计学意义(P>0.05). 结论 应用TUNEL法检测心肌细胞凋亡和免疫组织化学法检测心肌细胞内c-jun基因蛋白的表达,可作为法医鉴定SCD的重要指标.     

Endocardial tears and rupture tracts of left ventricular ruptures during acute myocardial infarction: an autopsy study of 50 out-of-hospital sudden death cases

We pathologically evaluated endocardial tears and rupture tracts of left ventricular ruptures during acute myocardial infarctions (50 sudden out-of-hospital death cases; 28 men and 22 women; age range 42–88 years; mean age 68.4 years). Endocardial tears were frequently seen at or near the base of the papillary muscles (54%) or in the area where the septum meets the free wall (42%). The endocardial tear was longer in the adjacent septum (mean 2.1±1.0 cm) than at the papillary muscle base (mean 1.0±0.8 cm). Accessory tears were observed near the main endocardial tear in about half of the cases (44%). The rupture tract was located well within the infarcted area in 88% and at the border of the infarcted and normal myocardium in 12%. Mature fresh thrombus was found on most main endocardial tears. In most rupture tracts, the thrombus was more mature in the subendocardial than in the subepicardial zone. Morphologically, this study confirmed that most cardiac ruptures start with an endocardial tear at or near the base of the papillary muscles or in the area where the septum meets the free wall, and rapidly progress independent of the histopathologic age of the infarction.     

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.     

Fibromuscular hyperplasia of the pulmonary artery in sudden infant and perinatal unexpected death

IntroductionThe purpose of this study was to describe cases presenting with fibromuscular hyperplasia of the pulmonary arteries that could belong to the group of sudden infant death syndrome (SIDS) and sudden unexpected perinatal death “gray zone” or borderline cases.MethodsIn a total of 12 cases, eight females and four males, ranging in age from 39 gestational weeks to 93 postnatal days, dying suddenly and unexpectedly, a fibromuscular hyperplasia of the pulmonary artery was detected. Postmortem examinations were requested with a clinical SIDS or sudden unexpected perinatal death. A complete autopsy was performed, including close examination of the brainstem and cardiac conduction system.ResultsHistological examination showed the presence of various degrees of fibromuscular hyperplasia with fibrosis of the right (six cases), left (five cases) or both (one case) pulmonary arteries.ConclusionsIn our cases, fibromuscular hyperplasia of the pulmonary artery alone might or might not have accounted for the sudden deaths, if it had not been for the concomitant presence of hypoplasia of the arcuate nucleus in the brainstem and/or cardiac conduction system abnormalities. Therefore, they were classified as SIDS/sudden unexpected perinatal death gray zone or borderline cases. Necropsy studies of sudden infant and perinatal death should always include an accurate gross and histological examination of the pulmonary arteries, as well as of the brainstem and cardiac conduction system.