Sudden, Unexpected Death Related to Viral Myocarditis

A Survey of Histological, Immunohistochemical, and Molecularpathological Methods for the Postmortem Diagnosis
  • Reinhard Dettmeyer
  • Burkhard Madea
Part of the Forensic Pathology Reviews book series (FPR, volume 2)


Sudden, unexpected deaths of previously healthy individuals without establishment of a definitive acute lethal event at autopsy represent a substantial proportion of forensic autopsy cases. It is well established that viral myocarditis can be associated with sudden, unexpected manifestation of death. Nevertheless, this diagnosis may present difficulties when there are no relevant histological findings using conventional histological stains. When applying a comprehensive combination of molecularpathological and immunohistochemical techniques, obviously a higher prevalence of viral myocarditis can be detected with regard to forensic pathological autopsy cases. Immunohistochemical methods include qualification and quantification of interstitial leukocytes including macrophages, T-lymphocytes, and the expression of adhesion molecules and cytokines as well as major histocompatibility complex class I and II molecules. Conventional histology may provide, when supplemented by immunohistochemistry, important clues regarding the underlying etiology of myocarditis. The actual demonstration of microorganisms in the myocardium or the elucidation of a previous administration of drugs or exposure to toxic substances are the only reliable means of establishing an etiological diagnosis of myocarditis. Molecularpathological techniques should be employed particularly for the detection of viral genome in the myocardium by reverse transcriptase polymerase chain reaction (rt-PCR) as already established regarding the investigation of endomyocardial biopsies. In combination with histological, immunohistochemical, and in situ hybridization, these techniques will enable the forensic pathologist or medical examiner, respectively, to clarify the cause of death in a higher number of cases of sudden, unexpected death that present otherwise without any relevant morphological findings.

Key Words

Sudden death myocarditis immunohistochemistry molecularpathology polymerase chain reaction (PCR) forensic pathology 


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  1. 1.
    Feldmann AM, McNamara D. Myocarditis. N Engl J Med 2000;343:1388–1398.CrossRefGoogle Scholar
  2. 2.
    Pankuweit S, Pratig I, Eckhardt H, Crombach M, Hufnagel G, Maisch B. Prevalence of viral genome in endomyocardial biopsies from patients with inflammatory heart muscle disease. Herz 2000;25:221–226.PubMedCrossRefGoogle Scholar
  3. 3.
    Droroy TY, Hiss Y. Sudden unexpected death in persons less than 40 years of age. Am J Cardiol 1991; 68:1388–1392.CrossRefGoogle Scholar
  4. 4.
    Neuspiel DR, Kuller LH. Sudden unexpected natural death in childhood and adolescence. JAMA 1985;254: 1321–1325.PubMedCrossRefGoogle Scholar
  5. 5.
    McCaffrey FM, Braden DS, Strong WB. Sudden cardiac death in young athletes. Am J Dis Child 1991; 145:177–183.PubMedGoogle Scholar
  6. 6.
    Huber SA, Gauntt CJ, Sakkinen P. Enteroviruses and myocarditis: viral pathogenesis through replication, cytokine induction, and immunopathogenicity. Adv Vir Res 1999;51:35.CrossRefGoogle Scholar
  7. 7.
    Bowles NE. Detection of coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet 1986;1:1120–1123.PubMedCrossRefGoogle Scholar
  8. 8.
    Muir P. Enteroviruses and heart disease. Br J Biomed Sci 1993;50:258–271.PubMedGoogle Scholar
  9. 9.
    Phillips CA, Aronson MD, Tomkow J, Phillips ME. Enteroviruses in Vermont, 1969–1978: an important cause of illness throughout the year. J Infect Dis 1980;141:162–164.PubMedGoogle Scholar
  10. 10.
    Mounts AW, Amr S, Jamshidi R, et al. A cluster of fulminant myocarditis cases in children, Baltimore, Maryland, 1997. Pediatr Cardiol 2001;22:34–39.PubMedCrossRefGoogle Scholar
  11. 11.
    Kawai C, Matsumori A, Fujiwara H. Myocarditis and dilated cardiomyopathy. Ann Rev Med 1987;38: 221–239.PubMedCrossRefGoogle Scholar
  12. 12.
    Haddad J, Gut J, Wendling M, et al. Enterovirus infections in neonates. A retrospective study of 21 cases. Eur J Med 1993;2:209–214.PubMedGoogle Scholar
  13. 13.
    Dettmeyer R, Baasner A, Winkelmann S, Graebe M, Madea B. Myocarditis and sudden death in infancy—immunohistochemical and molecularpathological investigations. J Perinat Med 2001;29(Suppl 2):25.Google Scholar
  14. 14.
    Dettmeyer R, Baasner A, Schlamann M, Haag C, Madea B. Coxsackie B3 myocarditis in 4 cases of suspected sudden infant death syndrome: diagnosis by immunohistochemical and molecular-pathologic investigations. Pathol Res Pract 2002;198:689–696.PubMedCrossRefGoogle Scholar
  15. 15.
    Dettmeyer R, Kandolf R, Schmidt P, Schlamann M, Madea B. Lympho-monocytic enteroviral myocarditis: traditional, immunohistological and molecularpathological methods for diagnosis in a case of suspected sudden infant death syndrome (SIDS). Forensic Sci Int 2001;119:141–144.PubMedCrossRefGoogle Scholar
  16. 16.
    Rambaud C, Cieuta C, Canioni D, et al. Cot death and myocarditis. Cardiol Young 1992;2:266–271.Google Scholar
  17. 17.
    Bajanowski T, Ortmann C, Teige K, et al. Pathological changes of the heart in sudden infant death. Int J Legal Med 2003;117:193–203.PubMedCrossRefGoogle Scholar
  18. 18.
    Gold E, Carver DH, Heineberg H, Adelson L, Robbins FC. Viral infection. A possible cause of sudden unexpected death in infants. New Engl J Med 1961;264:53–60.PubMedCrossRefGoogle Scholar
  19. 19.
    Jin O, Sole M, Butany JW, et al. Detection of enterovirus RNA in myocardial biopsies from patients with myocarditis and cardiomyopathy using gene amplification by polymerase chain reaction. Circulation 1990;82: 8–16.PubMedGoogle Scholar
  20. 20.
    Lozinski GM, Davis GG, Krous HF, Billman GF, Shimizu H, Burns JC. Adenovirus myocarditis: retrospective diagnosis by gene amplification from formalin-fixed, paraffin-embedded tissues. Hum Pathol 1994;25: 831–834.PubMedCrossRefGoogle Scholar
  21. 21.
    Hebert MM, Yu C, Towbin JA, Rogers BB. Fatal Epstein-Barr virus myocarditis in a child with repetitive myocarditis. Ped Pathol Lab Med 1995;15:805–812.Google Scholar
  22. 22.
    Bajanowski T, Rolf B, Jorch G, Brinkmann B. Detection of RNA viruses in sudden infant death (SID). Int J Legal Med 2003;117:237–240.PubMedCrossRefGoogle Scholar
  23. 23.
    Maisch B, Schönian U, Crombach M, et al. Cytomegalovirus associated inflammatory heart muscle disease. Scand J Infect 1993;88(Suppl):135–148.Google Scholar
  24. 24.
    Murry CE, Jerome KR, Reichenbach DD. Fatal parvovirus myocarditis in a 5-yearold girl. Hum Pathol 2001;32:342–345.PubMedCrossRefGoogle Scholar
  25. 25.
    Bültmann BD KK, Sotlar K, Bock TH, Baba HA, Sauter M, Kandolf R. Fatal parvovirus B19-associated myocarditis clinically mimicking ischemic heart disease: an endothelial cell-mediated disease. Hum Pathol 2003; 34:92–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Aretz HT. Myocarditis: the Dallas criteria. Hum Pathol 1987;18:619–624.PubMedCrossRefGoogle Scholar
  27. 27.
    Dettmeyer R, Schlamann M, Madea B. Immunohistochemical techniques improve the diagnosis of myocarditits in cases of suspected sudden infant death syndrome (SIDS). Forensic Sci Int 1999;105:83–94.PubMedCrossRefGoogle Scholar
  28. 28.
    Cioc AM, Nuovo GJ. Histologic and in situ viral findings in the myocardium in cases of sudden, unexpected death. Mod Pathol 2002;15:914–922.PubMedCrossRefGoogle Scholar
  29. 29.
    Drescher J ZP, Verhagen W, Flik J, Milbradt H. Recent influenza virus A infections in forensic cases of sudden unexplained death. Arch Virol 1987;92:63–76.PubMedCrossRefGoogle Scholar
  30. 30.
    Morens DM. Enteroviral disease in infancy. J Pediatr 1978;92:374–377.PubMedCrossRefGoogle Scholar
  31. 31.
    Friman G, Fohlman J. The epidemiology of viral heart disease. Scand J Infect Dis 1993;88(Suppl): 7–10.Google Scholar
  32. 32.
    Fairley CK, Ryan M, Wall PG, Weinberg J. The organisms reported to cause infective myocarditis and pericarditis in England and Wales. J Infect 1996;32:223–225.PubMedCrossRefGoogle Scholar
  33. 33.
    Martino TA, Liu P, Sole MJ. Viral infection and the pathogenesis of dilated cardiomyopathy. Circ Res 1994;74:182–188.PubMedGoogle Scholar
  34. 34.
    Kawai C. From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death. Circulation 1999;99:1091–1100.PubMedGoogle Scholar
  35. 35.
    Aretz HT, Billingham ME, Edwards W, et al. Myocarditis: a histopathologic definition and classification. Am J Cardiovasc Pathol 1987;1:5–14.Google Scholar
  36. 36.
    Shanes JG, Ghali J, Billingham ME, et al. Interobserver variability in the pathologic interpretation of endomyocardial biopsy results. Circulation 1987;75:401–405.PubMedGoogle Scholar
  37. 37.
    Strauer B, Kandolf R, Mall G, et al. Myokarditis-Kardiomyopathie. Update 2001. Med Klin 2001;96: 608–625.Google Scholar
  38. 38.
    Kandolf R, Klingel K, Zell R, et al. Molecular mechanisms in the pathogenesis of enteroviral heart disease: acute and persistent infections. Clin Immunol Immunopathol 1993;68:153–158.PubMedCrossRefGoogle Scholar
  39. 39.
    Heusch A, Kühl U, Rammos S, Krogmann ON, Schultheiss HP, Bourgeois M. Complete AV-block in two children with immunohistological proven myocarditis. Eur J Pediatr 1996;155:633–636.PubMedCrossRefGoogle Scholar
  40. 40.
    Wojnicz R, Nowalany-Kozielska E, Wodniecki J. Immunohistological diagnosis of myocarditis. Eur Heart J 1998;19:1564–1572.PubMedCrossRefGoogle Scholar
  41. 41.
    Schnitt SJ, Ciano PS, Schoen FJ. Quantification of lymphocytes in endomyocardial biopsies. Hum Pathol 1987;18:796–800.PubMedCrossRefGoogle Scholar
  42. 42.
    Chow LH, Ye Y, Linder J, McManus BM. Phenotypic analysis of infiltrating cells in human myocarditis. Arch Pathol Lab Med 1989;113:1357–1362.PubMedGoogle Scholar
  43. 43.
    Steenbergen C, Kolbeck PC, Wolfe JA, Anthony RM, Sanfilippo FP, Jennings RB. Detection of lymphocytes in endomyocardium using immunohistochemical techniques. Relevance to evaluation of endomyocardial biopsies in suspected cases of lymphocytic myocarditis. J Appl Cardiol 1986;1:63–73.Google Scholar
  44. 44.
    Southern J, Kaynor B, Howard CA, Bain KM, Palcios IF, Fallon JT. Is immunoperoxidase staining of endomyocardial biopsies for interstitial inflammatory cells helpful in the diagnosis of myocarditis? Eur Heart J 1987;8:195–197.Google Scholar
  45. 45.
    Forcada P, Beigelman J, Milei J. Inapparent myocarditis and sudden death in pediatrics. Diagnosis by immunohistochemical staining. Int J Cardiol 1996;56:93–97.PubMedCrossRefGoogle Scholar
  46. 46.
    Hufnagel G, Maisch B. Expression of MHC class I and II antigens and the IL-2 receptor in rejection, myocarditis and dilated cardiomyopathy. Eur Heart J 1991;12(Suppl D):137–140.PubMedGoogle Scholar
  47. 47.
    Daar AS, Fuggle SV, Fabre JW, Ting A, Morris PJ. The detailed distribution of MHC class II antigens in normal human organs. Transplantation 1984;38:293–298.PubMedCrossRefGoogle Scholar
  48. 48.
    Daar AS, Fuggle SV, Fabre JW, Ting A, Morris J. The detailed distribution of HLA-A, B, C antigens in normal human organs. Transplantation 1984;38:287–292.PubMedGoogle Scholar
  49. 49.
    Thorsby E. Structure and function of HLA molecules. Transplant Proceed 1987;19:29–35.Google Scholar
  50. 50.
    Henke A, Nain M, Stelzner A, Gemsa D. Induction of cytokine release from human monocytes by coxsackievirus infection. Eur Heart J 1991;12(Suppl D):134–136.PubMedGoogle Scholar
  51. 51.
    Ino T, Kishiro M, Okubo M, et al. Late, persistent expressions of ICAM-1 and VCAM-1 on myocardial tissue in children with lymphocytic myocarditis. Cardiovasc Res 1997;34:323–328.PubMedCrossRefGoogle Scholar
  52. 52.
    Noutsias M, Seeberg B, Schultheiss HP, Kühl U. Expression of cell adhesion molecules in dilated cardiomyopathy. Evidence for endothelial activation in inflammatory cardiomyopathy. Circulation 1999;99: 2124–2131.PubMedGoogle Scholar
  53. 53.
    Seko Y, Takahashi N, Ishiyama S, et al. Expression of costimulatory molecules B7-1, B7-2, and CD40 in the heart of patients with acute myocarditis and dilated cardiomyopathy. Circulation 1998;97:637–639.PubMedGoogle Scholar
  54. 54.
    Li Y, Bourlet T, Andreoletti L, Mosnier JF, Peng T, Yang Y, et al. Enteroviral capsid protein is present in myocardial tissues from some patients with myocarditis or dilated cardiomyopathy. Circulation 2000;101: 231–234.PubMedGoogle Scholar
  55. 55.
    Yousef GE, Mann GF, Brown IN, Mowbray JF. Clinical and research application of an enterovirus group-reactive monoclonal antibody. Intervirology 1987;28:199–205.PubMedGoogle Scholar
  56. 56.
    Edwards WD, Holmes DR, Reeder GS. Diagnosis of active lymphocytic myocarditis by endomyocardial biopsy. Quantitative criteria for light microscopy. Mayo Clin Proc 1982;57:419–425.PubMedGoogle Scholar
  57. 57.
    Linder J, Cassling RS, Rogler WC, et al. Immunohistochemical characterization of lymphocytes in uninflamed ventricular myocardium. Arch Pathol Lab Med 1985;109:917–920.PubMedGoogle Scholar
  58. 58.
    Cassling RS, Linder J, Sears TD, et al. Quantitative evaluation of inflammation in biopsy specimen from idiopathically failing or irritable hearts: experience in 80 pediatric and adult patients. Am Heart J 1985; 110:713–720.PubMedCrossRefGoogle Scholar
  59. 59.
    Martin AB, Webber S, Fricker FJ, et al. Acute myocarditits: rapid diagnosis by PCR in children. Circulation 1994;90:330–339.PubMedGoogle Scholar
  60. 60.
    Severini GM, Mestroni L, Falaschi A, Camerini F, Giacca M. Nested polymerase chain reaction for high-sensitivity detection of enteroviral RNA in biological samples. J Clin Microbiol 1993;31:1345–1349.PubMedGoogle Scholar
  61. 61.
    Bendig JWA, O’Brien PS, Muir P, Porter HJ, Caul EO. Enterovirus sequences resembling coxsackievirus A2 detected in stool and spleen from a girl with fatal myocarditis. J Med Virol 2001;64:482–486.PubMedCrossRefGoogle Scholar
  62. 62.
    Druyts-Voets E, van Renterghem L, Gerniers S. Coxsackie B virus epidemiology and neonatal infection in Belgium. J Infect 1993;27:311–316.PubMedCrossRefGoogle Scholar
  63. 63.
    Singer DB. Infections of fetuses and neonates. In: Wigglesworth JS, Singer DB, eds. Textbook of Fetal and Perinatal Pathology. Blackwell Scientific Publications, Boston, 1991, pp. 554,555.Google Scholar
  64. 64.
    Leipner C, Grün K, Borchers M, Stelzner A. The outcome of coxsackievirus B3-(CVB3-) induced myocarditis is influenced by the cellular immune status. Herz 2000;25:245–248.PubMedCrossRefGoogle Scholar
  65. 65.
    Shimizu H, Rambaud C, Cheron G, et al. Molecular identification of viruses in sudden infant death associated with myocarditis and pericarditis. Ped Infect Dis J 1995;14:584–588.CrossRefGoogle Scholar
  66. 66.
    Bergelson JM, Cunningham JA, Droguett G, et al. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science 1997;275:1320–1323.PubMedCrossRefGoogle Scholar
  67. 67.
    Schwimmbeck PL, Rohn G, Wrusch A, et al. Enteroviral and immune mediated myocarditis in SCID mice. Herz 2000;25:240–244.PubMedCrossRefGoogle Scholar
  68. 68.
    Klingel K, Selinka HC, Huber M, Sauer M, Leube M, Kandolf R. Molecular pathology and structural features of enteroviral replication. Toward understanding the pathogenesis of viral heart disease. Heart 2000;25: 216–220.Google Scholar
  69. 69.
    McManus BM, Chow LH, Wilson JE, et al. Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditits. Clin Immunol Immunopathol 1993;68:159–169.PubMedCrossRefGoogle Scholar
  70. 70.
    Badorff C, Berkely N, Mehrotra S, Talhouk JW, Rhoads RE, Knowlton KU. Enteroviral protease 2A directly cleaves dystrophin and is inhibited by a dystrophinbased substrate analogue. J Biol Chem 2000;275: 1191–1197.CrossRefGoogle Scholar
  71. 71.
    Badorff C, Lee GH, Knowlton KU. Enteroviral cardiomypathy: bad news for the dystrophin-glycoprotein-complex. Herz 2000;25:227–232.PubMedCrossRefGoogle Scholar
  72. 72.
    Dettmeyer R, Kandolf R, Baasner A, Banaschak S, Eis-Hübinger AM, Madea B. Fatal parvovirus B19 myocarditis in an 8-year-old boy. J Forensic Sci 2003;48:183–186.PubMedGoogle Scholar
  73. 73.
    Arola A, Jokinen E, Ruuskanen O, et al. Epidemiology of idiopathic cardiomyopathies in children and adolescents. A nationwide study in Finland. Am J Epidemiol 1997;146:385–393.PubMedGoogle Scholar
  74. 74.
    Pauschinger M, Meissner G, Preis S, et al. Detection of enteroviral RNA by polymerase chain reaction in patients with myocarditis and dilated cardiomyopathy. JACC 1994;1994:880.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Reinhard Dettmeyer
    • 1
  • Burkhard Madea
    • 1
  1. 1.Institute of Forensic MedicineRheinische Friedrich-Wilhelms-University BonnBonnGermany

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