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Bundock EA, Corey TS, Andrew TA, et al., editors. Unexplained Pediatric Deaths: Investigation, Certification, and Family Needs [Internet]. San Diego (CA): Academic Forensic Pathology International; 2019.
ADELINE
“Adeline was 14 months old and my first and only child at the time of her death. When Adeline smiled, she did it not only with her mouth, but with her big, chocolate brown eyes. She was our world. When Adeline died, her pediatrician drove to the hospital as soon as she heard. She offered what seemed like a very odd suggestion at the time – to take pictures of us with Adeline in the hospital, despite the fact she was already gone. I didn’t understand how much I’d learn to love those pictures. Adeline just looked asleep, and they give me comfort that she left this world in no pain, peacefully.”
– Adeline’s Mom
OUTLINE.
Cardiovascular diseases are important causes of sudden unexpected death in pediatrics (1, 2). Complete and thorough autopsies must be performed to recognize and diagnose cardiovascular etiologies. In infants and young children, undiagnosed congenital heart disease (CHD) along with potentially heritable cardiomyopathies and channelopathies can lead to sudden unexpected death (3). Therefore, dissection techniques should be modified to ensure that identifiable congenital malformations are not missed. In many instances of undiagnosed congenital heart disease, there will be some indication in the investigative report that the child was symptomatic. And, usually, the heart will appear abnormal during the initial examination of the organs at autopsy.
Any type of congenital heart disease can present for the first time at autopsy, including both simple (isolated atrial or ventricular septal defects, valvular abnormalities, patent ductus arteriosus, and coarctation of the aorta) and complex (tetralogy of Fallot, atrioventricular septal defects, complex lesions involving the great vessels, single ventricle heart disease, double inlet/outlet) lesions, depending on the age of the child at death (3–8). Additionally, undiagnosed coronary artery abnormalities, such as anomalous origins of the coronary arteries and coronary aneurysms (Kawasaki disease) can lead to sudden unexpected death in pediatrics (9–19).
An enlarged or dilated heart in a child should always make the examiner consider cardiomyopathy. However, the presence of a normal heart size and shape does not rule out the presence of a cardiomyopathy; many types of cardiomyopathy may still be present (20). Other clues that may point to a cardiomyopathy are hypertrophy of the interventricular septum or chamber walls or chamber dilatation. Cardiomyopathies that can cause sudden unexpected death in pediatrics include hypertrophic cardiomyopathy (21–23), restrictive/infiltrative cardiomyopathies (24–26), dilated cardiomyopathies (27, 28), and arrhythmogenic cardiomyopathy (29–35). There is debate regarding whether left ventricular noncompaction and primary endocardial fibroelastosis are true cardiomyopathies or whether they represent changes associated with other cardiomyopathies (36–41).
Some of the most challenging cases are those in which no gross or microscopic cause of death is found after a complete autopsy (autopsy-negative cases). In these situations, additional dissections and more extensive histological sampling may reveal subtle causes of sudden unexpected death in pediatrics. Hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, histiocytoid cardiomyopathy, and other forms of cardiomyopathy may have subtle findings that only manifest microscopically in children (42).
Pericardial, myocardial, or endocardial inflammation can result in sudden unexpected death in pediatrics and may not be apparent at the time of autopsy (43–47). Myocarditis can present at autopsy as a dilated or grossly normal-appearing heart. Myocarditis is defined as inflammation with associated cardiac myocyte necrosis, and borderline myocarditis is defined as significantly increased interstitial inflammation without definitive cardiac myocyte necrosis (47). The types of myocarditis (lymphocytic, eosinophilic, neutrophilic, giant cell) can be diagnosed with adequate histological sectioning at autopsy (47, 48).
In children over one year of age, if no definitive cause of death is found after microscopic examination, then examination of the cardiac conduction system – including the sinoatrial (SA) node, atrioventricular (AV) node, penetrating AV bundle of His, and proximal bundle branches – may be warranted (49–53). Inflammation and tumors (cystic AV nodal tumor) are known to cause sudden death, if they involve components of the cardiac conduction system. However, the significance of other lesions – such as fibrointimal hyperplasia of the SA or AV nodal arteries, increased fibrosis or adipose tissue in the nodes or AV bundles, persistent fetal dispersion of the AV node, cartilaginous metaplasia or fragmentation of the AV bundle – is unclear in the setting of sudden unexpected death in pediatrics (54).
In any case of sudden unexpected death in pediatrics, the pathologist should consider the possibility of a genetic disease, such as a heritable cardiomyopathy or a cardiac channelopathy (55–60). An appropriate specimen for subsequent DNA extraction and possible postmortem genetic testing (blood in EDTA or frozen heart) should be procured and saved. The family may be referred for cardiovascular screening and possible genetic counseling by clinicians specially trained in this area (61).
There are significant gaps in our knowledge of the onset, natural history, and clinical and pathological manifestations of many of the cardiovascular diseases that result in sudden unexpected death in pediatrics. Additionally, there are gaps in our understanding of when certain anatomical and pathological changes – such as alterations in coronary artery anatomy, increased heart size, fibrosis, and inflammation – become significant enough to be invoked as the cause and manner of death (62, 63).
Many variants of the normal cardiac anatomy have been identified, some more benign than others (9, 64). An anomalous origin of a coronary artery can cause sudden death (9, 64–66). Usually, the coronary ostia are situated within the sinuses of Valsalva, but they may occur in coronary ostia situated above the sinuses at the level of the sinotubular junction, or higher in the ascending aorta (9). There is thought to be an increased risk of sudden death if the coronary ostia are situated high enough in the aorta, so that there is an acute angle of take-off of the coronary arteries relative to the aorta. However, the angle of take-off is difficult to measure in the postmortem setting and it is unclear at what point a high coronary artery take-off increases the risk of sudden death. Another anatomic variant of unknown clinical significance is myocardial bridging or tunneling (67–70). In adults, it is not uncommon for the left anterior descending coronary artery to dive into the myocardium for a short distance, and this is considered a normal anatomic variant with no pathological significance. If the coronary artery is too deep within the myocardium and travels over a long distance, then there may be transient ischemia during systole (67). However, the features that differentiate pathologic myocardial bridging from a normal variant is unknown.
An enlarged heart (cardiomegaly) can be one of the first indications of a cardiomyopathy. However, determining the normal heart weight or weight range can be problematic in children (and adults). There is a direct correlation between heart weight and body weight. However, we do not have a clear understanding of what constitutes a pathologically enlarged heart in children. There are tables of normal, average, heart weights (with confidence intervals) for children with different body weights (71). However, there is neither any single, standard source for normal child heart weights nor any accepted, uniform method for determining a child’s heart weight at autopsy. The situation is even more complicated in obese children, in whom an increased heart weight is expected due to increased body weight. But in these cases, is the enlarged heart “normal” or is it pathologically enlarged? There is currently no answer to this question. Some consider enlarged hearts, whether the enlargement is expected based on body weight or pathological, to be more vulnerable to arrhythmias, while others consider an enlarged heart appropriate for increased body weight to be normal.
In grossly and microscopically normal hearts, channelopathies and cardiomyopathies should be considered as possible causes of death in children with no obvious cause of death following autopsy (2, 57, 72, 73). Most channelopathies will not have any histopathological signs, unless there is remodeling of the myocardium, producing fibrosis (58). In contrast, cardiomyopathies will often display histological changes, even if they are very subtle (42, 72). Little is known regarding the histopathological progression of cardiomyopathies in children. The microscopic changes most frequently seen in cardiomyopathy (fibrosis and inflammation) are often nonspecific (48, 62, 74), as are some of the other pathological changes that may be seen – left ventricular hypertrophy in the absence of fibrosis or cardiac myocyte disarray, fatty infiltration of the right ventricle in the absence of fibrosis, mild ventricular dilatation, isolated floppy mitral valve, and scattered foci of interstitial lymphocytes without cardiac myocyte necrosis (62, 74).
Increased interstitial fibrosis can be an early indication of a cardiomyopathy (62). However, assessing the degree and significance of interstitial fibrosis in the heart can be difficult. In certain parts of the heart, like the SA and AV nodes and cardiac conduction system, fibrosis is necessary for normal electrophysiology (75). However, abnormal fibrosis can cause disturbances in electrical conductance, leading to arrhythmias (50, 75–77). Performing special stains to highlight fibrosis, such as a Masson’s trichrome stain, can be helpful, but interpreting the significance of the fibrosis can be challenging (62). When accompanied by fibrosis, cardiac myocyte enlargement and disarray are histologic signs of hypertrophic cardiomyopathy (20, 23, 78–80). However, focal cardiac myocyte disarray can be seen in normal hearts, especially in areas of architectural distortion, such as around blood vessels and in the posterior interventricular septum (62). These focal changes can be misinterpreted as hypertrophic cardiomyopathy (62).
Arrhythmogenic cardiomyopathy can be used as clinical term to cover a diverse group of arrhythmogenic etiologies not explained by ischemic, hypertensive, or valvular heart disease (81). More commonly, the term is used to refer to the pathologic subtypes of arrhythmogenic right ventricular cardiomyopathy and arrhythmogenic left ventricular cardiomyopathy, which are rare genetic conditions that typically manifests later in life than other genetic cardiomyopathies (30, 32). The pathologic diagnosis of arrhythmogenic cardiomyopathy is made when there is fatty replacement with fibrosis in the right and/or left ventricular myocardium, and mutations in genes affecting cardiac myocyte junctions are present (30, 32, 35, 82, 83). Arrhythmogenic cardiomyopathy can present in children, but the gross and histological changes are not as well-understood as in adults and focal fatty replacement (without fibrosis) of the right ventricular wall (a normal finding) can be misinterpreted as arrhythmogenic cardiomyopathy (20, 62, 74).
Focal interstitial chronic inflammation can also be challenging to interpret (48, 62, 63). It is unclear how many chronic inflammatory cells are normally found in the hearts of children of various ages. The distinction between an increased number of interstitial lymphocytes and borderline lymphocytic myocarditis (without cardiac myocyte necrosis) is not well-defined (63). Some consider myocarditis to be overdiagnosed and there is a great deal of disagreement between pathologists over what constitutes a diagnosis of myocarditis, with or without obvious cardiac myocyte necrosis (63). Some pathologists diagnose myocarditis when there is an increase in lymphocytes, while others require definitive cardiac myocyte necrosis. While transient systemic immune responses in children may result in increased interstitial lymphocytes in the heart, this may also be a sign of a developing cardiomyopathy (20).
Another area of uncertainty in an apparently autopsy-negative case is when to examine the cardiac conduction system and what to assess. Forensic pathologists are taught to dissect and examine this system in sudden unexplained deaths of older children and adults with no significant autopsy findings (49–51). This is a labor-intensive technique that takes practice and experience. Understanding the normal gross and histologic anatomy of the cardiac conduction system is challenging. The challenge is amplified by the existence of normal anatomic variants that must be differentiated from pathological changes. Several studies have focused on examining the cardiac conduction system in infants, children, and young adults ((52, 54, 84, 85). However, it is still not entirely clear which conduction system changes constitute significant pathology, pathology that could result in sudden death. Some changes involving the conduction system are considered pathological and may result in sudden death. These include inflammation in the conduction system (as may be seen in myocarditis and pericarditis) and tumors, such as cystic AV nodal tumors (86). Cardiac conduction system changes of unknown significance include fibrointimal hyperplasia or fibromuscular dysplasia of the SA and AV nodal arteries, increased fibrosis in the SA node leading to sick sinus syndrome, persistent fetal dispersion of the AV node in the central fibrous body, cartilaginous metaplasia of the central fibrous body, fragmentation of the atrioventricular bundle (of His), and increased adipose tissue or inflammatory cells within various components of the cardiac conduction system (51, 54).
While postmortem imaging is routinely practiced in some offices, there is currently very little data regarding the benefit of various modalities, such as postmortem computed tomography, postmortem computed tomography with angiography, postmortem magnetic resonance imaging, and ultrasound in determining cause of death in children (87–98). Postmortem imaging has been used successfully to diagnose congenital anomalies prior to or in place of autopsy (87). Because the coronary and cerebral vasculature are difficult to assess at autopsy, it is possible that pre-autopsy use of postmortem computed tomography with angiography could have a role in the diagnosis of vascular anomalies in the brain and/or heart (89, 95).
Prior to starting the postmortem examination in a case of sudden unexpected death in pediatrics, it is important to have information regarding the circumstances surrounding death and any pertinent medical and family history. This initial investigative information can be very helpful in guiding the postmortem examination (99).
In all cases of sudden unexpected death in pediatrics, postmortem imaging should be performed. At a minimum, plain radiographs should be obtained, which will show the relative size of the heart, position of the heart, and pulmonary changes that might be associated with heart disease, as well as other salient features, such as occult fractures, discussed elsewhere in this publication. If available, newer imaging modalities, such as postmortem computed tomography and postmortem magnetic resonance imaging can be considered. These may provide additional detail of any congenital anomalies or other disease processes that are present. Additionally, postmortem computed tomography with angiography is being investigated as a tool for assessing vascular anomalies in the great vessels, heart, brain, and lungs, anomalies that may cause sudden death.
There are various methods for proper examination of the heart and great vessels at autopsy, including examining the heart in situ or as a heart-lung block, either fresh or after formalin fixation (74, 99–101). The goal is to be able to adequately assess the anatomy of the heart, lungs, and associated great vessels, so that any structural abnormalities can be diagnosed. The approach used may depend on the age of the child or any known prior history (42, 74, 100, 102, 103).
Examination of the heart should start with assessment of the epicardial surface for evidence of pericarditis, fibrofatty replacement, and any discoloration of the myocardium. Next, the epicardial coronary anatomy should be examined to assess for potential anomalies, including aneurysms or hemorrhage. To ensure that there is no anomalous origin of a coronary artery, the ascending aorta can be trimmed so that the coronary ostia can be observed by looking down into the aorta. If coronary artery abnormalities are observed, these should be investigated prior to opening the heart. Pre-autopsy, postmortem computed tomography with angiography could be helpful in showing the anatomy of the coronary arteries, especially if there are anatomic variations.
Before removing the heart from the lungs, the pathologist must assess for normal connections of the great vessels to the heart, a normal, left-sided aortic arch, absence of vascular rings around the trachea or esophagus, absence of coarctation of the aorta (assessing the entire thoracic aorta), and closure or patency of the ductus arteriosus. If any congenital vascular anomalies are observed, it is best to leave the heart attached to the lungs and thoracic aorta, so that the anatomy is not disturbed and can be studied in detail after en block removal.
Dissection of the heart can be performed using several methods (42, 99–101). In infants without congenital heart disease, the preferred method is to open the heart along lines of blood flow (inflow-outflow method). This allows for adequate assessment of chamber anatomy and possible defects. In older children without apparent congenital heart disease, the combination of apical cross-sections and inflow-outflow dissection of the base can be performed, as in an adult heart. Other methods of dissection, such as four-chamber and left ventricular outflow dissection methods, utilized in other types of cases, are not recommended in cases of sudden unexpected death in pediatrics.
Once the heart is opened and all postmortem blood and postmortem thrombi are removed, the heart should be weighed. Measurements of wall thicknesses (left and right ventricle walls and interventricular septum) and valve circumferences (tricuspid, pulmonic, mitral, and aortic) may be recorded (Image 7.1) and compared to reference values (104–107). The heart should be examined for any endocardial or myocardial lesions or discolorations. Cardiac valve anatomy should be assessed, as well as any abnormalities involving the valve leaflets and papillary muscles. Photographs of any abnormalities should be taken.
Measurement of valve circumference.
Histological sections should be taken in every case of sudden unexpected death in pediatrics that remains unexplained after autopsy (42, 99, 100). Sections from the left ventricle, right ventricle, interventricular septum, atria, and any grossly apparent lesions must be examined (Image 7.2). Ventricular sections should be taken at multiple levels (apex, middle, base). Atrial sections may include the right and left atrioventricular (AV) grooves to include the coronary arteries and interatrial septum (99). Consider taking sections from the cardiac conduction system, including the SA and AV nodal regions (Images 7.3 and 7.4), or sending relevant areas to a cardiac pathologist for evaluation.
Method for sampling heart for microscopic examination. Boxes indicate areas to be sampled.
Dissection of the right atrium to sample the SA node. Oval indicates location of superior vena cava. Box indicates portion of right atrium to be fixed and sampled.
Dissection of the right atrium to sample the SA node. The right atrium is serially sectioned (at lines), yielding fragments to be embedded (see Image 7.3C).
Dissection of the right atrium to sample the SA node.
Microscopic examination of sections should include assessment for inflammation, infection, fibrosis, elastosis, and hamartomatous or neoplasia. When minor abnormalities are observed or suspected based on routine hematoxylin and eosin staining, special stains that highlight fibrosis (trichrome or pentachrome), elastosis (elastin), amyloid (Congo red), or infectious organisms (Gram, silver, periodic acid Schiff, acid-fast) may be of benefit. Because the myocardium of infants can be very cellular, immunohistochemical stains – such as CD3 (for T-cells), CD20 (for B-cells), and CD68 (for macrophages) – may be helpful.
In children, blood in EDTA and frozen heart tissue are the preferred samples for genetic testing. Blood on a filter paper card should always be retained and may be considered acceptable for DNA isolation by some laboratories (61). A small amount of myocardium can be frozen in liquid nitrogen or at ultra-low temperature for electron microscopy or molecular testing. In cases of possible or suspected metabolic disorders, oil red-O staining can be performed on frozen sections of fresh, frozen, or formalin-fixed tissue to assess for intracellular lipid accumulation. Finally, in certain cases, electron microscopy may be of benefit in diagnosing cardiomyopathies or storage disorders.
It should be recognized that there are diagnostic “gray zones” in which findings of uncertain significance exist on a continuum between normal and definite pathologic changes (42). Enlargement of the heart, heart chambers, chamber walls, or valves should raise the possibility of an underlying cardiomyopathy, with or without histological changes. Moreover, focal or mild histologic changes, such as inflammation or fibrosis, that are not diagnostic of a particular entity, may be suggestive of a developing cardiomyopathy. Finally, we should remember that some infants and children, just like adults, may die with conditions, rather than of conditions. In the end, historical information, scene findings, and autopsy findings should be interpreted together when formulating a reasonable and defensible opinion regarding cause and manner of death.
For questionable, unusual, or rare cardiac findings, one should consider consulting a pathologist with special expertise in cardiovascular pathology (74).
Forensic pathologists need to gain experience and be comfortable examining hearts from children of all ages so that they can recognize and diagnose various forms of cardiovascular disease and congenital heart disease and recognize more subtle abnormalities that may result in sudden unexpected death in pediatrics. The National Institutes of Health (NIH) hosts the 3D Print Exchange Heart Library, a collection of 3D printed hearts, focused on congenital heart disease (108), which may serve as a resource for forensic pathologists wishing to become more familiar with congenital heart defects.
In conclusion, thorough gross and histologic examination of the heart is important in determining the cause of sudden unexpected death in pediatrics (see recommendations in Table 7.1). There may be subtle findings, such as increased heart weight, inflammation, or fibrosis that may indicate underlying cardiac pathology. Additionally, the heart may show no pathological changes in “autopsy-negative” cases in which a channelopathy or cardiomyopathy may still be responsible for death.
Procedural Guidance and Key Considerations for Evaluation of the Heart.
The views expressed in this manuscript are those of the authors and do not reflect official positions of the National Institutes of Health.
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