Case 2 -

Active Lymphocytic Myocarditis Barbara Sampson Office of the Chief Medical Examiner New York, NY

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Clinical History This previously healthy 30 year old obese woman presented to the emergency room with shortness of breath and weakness. She also had nausea, vomiting, diarrhea, right subscalpular pain, and flank pain. She was febrile and tachycardic. Her oxygen saturation on room air was 99%. Lab results revealed a white blood cell count of 22,000, and urine analysis was positive for leucocyte esterase and many white blood cells. She was diagnosed with pyelonephritis and discharged with PO antibiotics. The next day she presented to the emergency room again with worsening shortness of breath. She was hypotensive and tachypnic. Her oxygen saturation was 90% on room air. A chest x-ray was normal. EKG showed ST elevations. Labs revealed a troponin of 119 and CPK of 960. She developed ventricular tachycardia and ventricular fibrillation, and could not be resuscitated. The case was reported to and accepted by the Office of Chief Medical Examiner of the City of New York based on the sudden and unexpected nature of this woman's death. Case 2 - Figure 1 - H&E stained section of myocardium shows the diffuse nature of the interstitial inflammatory infiltrate. Case 2 - Figure 2 - H&E stained section of myocardium shows the mainly mononuclear interstitial inflammatory infiltrate and associated myocyte damage. Case 2 - Figure 3 - H&E stained section of myocardium , shows that the inflammatory infiltrate is mainly composed of lymphocytes with scattered plasma cells, and the occasional neutrophil, with associated myocyte destruction. Case 2 - Figure 4 - H&E stained section of myocardium, high power, shows that the inflammatory infiltrate is mainly composed of lymphocytes with scattered plasma cells, and the occasional neutrophil, with associated myocyte destruction. Autopsy Findings External Examination The body is that of a well-developed, 5'6", 239 lb white woman whose appearance is consistent with the given age of 30 years. There is no skin rash. Cardiovascular System The slightly soft heart weighs 450 gm and has a normal distribution of right predominant coronary arteries without atherosclerotic stenosis of the epicardial vessels. The epicardial surface is unremarkable. The myocardium is homogenous, dark red, and firm without pallor, hemorrhage, or fibrosis. The left ventricle wall is 1.2 cm, and the right is 0.3 cm thick. The foramen ovale is closed. The endocardial surfaces and cardiac valves are unremarkable. There are no congenital anomalies. The other organ systems are unremarkable. There is no evidence of pyelonephritis. Microscopic Multiple sections of myocardium reveal a dense lymphocytic infiltrate with few plasma cells, macrophages, and neutrophils throughout the heart. Occasional eosinophils are present. The inflammation is associated with extensive myocyte necrosis of individual and groups of myocytes. Focal interstitial edema is present. Histology of the other major organs is unremarkable. In particular, multiple sections of kidney and bladder reveal no inflamation. Final Diagnosis Active Lymphocytic Myocarditis Comment Myocarditis is a disease of the myocardium characterized by an inflammatory infiltrate associated with myocyte destruction [1, 2, 3] . Etiologies include infectious, hypersensitivity, and immune-related injury. The incidence of myocarditis is difficult to estimate as the clinical spectrum is wide, ranging from subclinical, to congestive heart failure, to sudden death. It is estimated that myocarditis is responsible for approximately 5% of sudden deaths when marked atherosclerotic cardiovascular disease is excluded [4]. Grossly in the active phase of myocarditis, the heart may appear normal or show focal or diffuse areas of mottling and softening. Mottling refers to areas of pallor alternating with areas of hemorrhage. The heart may be normal size or enlarged with cardiac chamber dilatation [4]. In those surviving the active phase, healed myocarditis may result in a normal appearing heart, or there may be areas of fibrosis. These are usually patchy and in no apparent vascular distribution, unlike a healed ischemic infarct. Dilated cardiomyopathy may also result from a healed myocarditis. The Dallas criteria were developed to establish uniform, reproducible criteria for the endomyocardial biopsy diagnosis of myocarditis. They define idiopathic myocarditis as "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischemic damage associated with coronary artery disease" [1, 5] . Histologically, active myocarditis is characterized by an interstitial mononuclear (predominantly lymphocytic) inflammatory infiltrate with associated myocyte damage. Myocyte damage includes myocytolysis, irregular myocyte contours, and necrosis/apoptosis. There may be interstitial edema. Giant cell myocarditis is marked by a fulminant clinical course and the histologic presence of multinucleated giant cells [6]. The mechanism by which myocarditis produces myocyte damage is unclear. The role of the immune system, be it through T-cell dependent mechanisms or soluble mediators, is thought to be important, as are host and viral genetics [7, 8] . Direct viral cytotoxicity is thought to be less important. The major causes of myocarditis are listed in the table below: From: Winters, G.L, McManus, B.M. Myocarditis. In: Silver, M.D., Gottlieb, A.I., Schoen, F.J. (eds.), Cardiovascular Pathology. Churchill Livingstone, 2001. 257. They include infectious agents, (particularly viruses such as enteroviruses), immune-mediated damage (including hypersensitivity), and toxic reactions. Documentation of a viral etiology is often difficult but can be attempted by immunohistochemistry, in situ hybridization, or polymerase chain reaction. Myocarditis has also been associated with human immunodeficiency virus [9], parasitic infections and systemic diseases such as rheumatoid arthritis and collagen vascular diseases. Hypersensitivity myocarditis is the result of a drug exposure and is characterized by a predominance of eosinophils in the inflammatory infiltrate and less myocyte necrosis. Fibrosis is absent [10]. The differential diagnosis of myocarditis is wide and highly dependent on the composition of the inflammatory infiltrate. From: Winters, G.L, McManus, B.M. Myocarditis. In: Silver, M.D., Gottlieb, A.I., Schoen, F.J. (eds.), Cardiovascular Pathology. Churchill Livingstone, 2001. 258. Distinguishing myocarditis from ischemic damage can be difficult. As a rule, in myocarditis, the degree of inflammation is greater than the associated myocyte damage. The presence of many neutrophils should raise the suspicion of ischemic damage, which is far more common than myocarditis. Myocarditis can be a very focal disease. Therefore, it is essential that the myocardium be widely sampled to rule out this diagnosis. As routine autopsy practice, we sample at least 10 sections of myocardium in this setting. The complete investigation of a sudden death must include a complete autopsy with toxicology and appropriate histology, as well as a scene investigation and interviews with family and physicians. Cases of witnessed, instantaneous death without structurally demonstrable cause at autopsy lead to the compelling conclusion that the decedent had a lethal cardiac arrhythmia. Occasionally the only finding in such a case with be a small focus of inflammation associated with myocyte destruction. Although such foci can be found incidentally in traumatic deaths, one must evaluate this finding in the context of the particular case. Since myocarditis is known to be a focal disease, it is possible that other, more significant foci are present but unsampled. The significance of such a small focus in and of itself is unknown. Caution is advisable with its interpretation, but it should be considered a plausible cause of death in the appropriate setting. References Aretz, H.T. Myocarditis: The Dallas criteria. Human Pathology. 1987. 18:619-624. Olinde, K.D., O=Connell, J.B. Inflammatory heart disease: Pathogenesis, clinical manifestations, and treatment of myocarditis. Ann Rev Med 1994. 45:481-490. Winters, G.L, McManus, B.M. Myocarditis. In: Silver, M.D., Gottlieb, A.I., Schoen, F.J. (eds.), Cardiovascular Pathology. Churchill Livingstone, 2001. 256-284. Virmani, R. Burke, AP, Farb, A., Smialek, J. Problems in forensic cardiovascular pathology. In: Schoen, F.J., Gimbrone, M.A., Jr. (eds.), Cardiovascular Pathology: Clinicopathologic correlations and pathogenetic mechanisms. Williams and Wilkins, 1995. 173-193. Aretz, H.T. Billingham, M.E., Edwards, W.D., et al. Myocarditis: A histopathologic definition and classification. American J. Cardiovasc. Pathol. 1987. 1:3-14. Cooper, L.T., Berry, G.J., Shabetai, R. Idiopathic giant cell myocarditis- natural history and treatment. N Engl J. Med. 1997. 336:1860-1866. Barry, W.H. Mechanisms of immune-mediated myocyte injury. Circulation. 1994. 89:2421-2432. Maisch, B. Ristic, A.D., Hufnagel, G., Pankuweit, S. Pathophysiology of viral myocarditis: the role of humoral immune response. Cardiovascular Pathology. 2002. 11(2}:112-122. Klatt, E.C. Cardiovascular Pathology in AIDS. Adv. Cardiol. 2003. 40:23-48. Burke, A.P., Saenger, J., Mullick, F., Virmani, R. Hypersensitivity myocarditis. Arch. Pathol. Lab Med. 1991. 115:764-769.