Current Neurology and Neuroscience Reports

, Volume 6, Issue 6, pp 460–468


  • Thiravat Hemachudha
  • Supaporn Wacharapluesadee
  • Jiraporn Laothamatas
  • Henry Wilde


Despite increases in our understanding of rabies pathogenesis, it remains an inevitably fatal disease. Lack of awareness, low level of political commitment to rabies control, and failure to recognize and correlate clinical, laboratory, and neuroimaging features contribute to continuing deaths. Clinical symptomatology, once believed to be unique, may be variable, even in patients associated with lyssaviruses of the same genotype. This article discusses virus transport, the role of virus and host response mechanisms in relation to protean clinical manifestations, and mechanisms responsible for relative intactness of consciousness in human rabies. Differential involvement of the anterior horn cell in furious rabies and the peripheral nerve in paralytic rabies is summarized. Escape mechanisms from host defenses explain why a fatal outcome is unavoidable regardless of therapy. Neuroprotective treatment, using a coma-induction regimen, proves not to be beneficial. Survival of patients with excellent recovery relies on early innate and adaptive immunity plus adequate intensive care support.


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References and Recommended Reading

  1. 1.
    WHO: WHO Expert Consultation on Rabies. WHO technical report series 931. 2005. This is a synopsis of rabies in humans and animals. It contains the most current information on rabies prevention and control including guidelines for pre- and postexposure prophylaxis.Google Scholar
  2. 2.
    Zhang YZ, Xiong CL, Xiao DL, et al.: Human rabies in China. Emerg Infect Dis 2005, 11:1983–1984.PubMedGoogle Scholar
  3. 3.
    Denduangboripant J, Wacharapluesadee S, Lumlertdacha B, et al.: Transmission dynamics of rabies virus in Thailand: implications for disease control. BMC Infect Dis 2005, 5:52. This article presents the theory of compartmentalization and provides evidence for the spread of canine rabies by human-facilitated translocation. The presence of more than one virus group in a region might indicate continuous gene flow, reflecting an active trafficking of the canine vector.PubMedCrossRefGoogle Scholar
  4. 4.
    Jackson AC, Wunner WH: Rabies. Amsterdam: Academic Presss; 2002.Google Scholar
  5. 5.
    Messenger SL, Smith JS, Orciari LA, et al.: Emerging pattern of rabies deaths and increased viral infectivity. Emerg Infect Dis 2003, 9:151–154.PubMedGoogle Scholar
  6. 6.
    Davis PL, Bourhy H, Holmes EC: The evolutionary history and dynamics of bat rabies virus. Infect Genet Evol 2006, In press.Google Scholar
  7. 7.
    Johnson N, Brookes SM, Fooks AR, Ross RS: Review of human rabies cases in the UK and in Germany. Vet Rec 2005, 157:715.PubMedGoogle Scholar
  8. 8.
    Burton EC, Burns DK, Opatowsky MJ, et al.: Rabies encephalomyelitis: clinical, neuroradiological, and pathological findings in 4 transplant recipients. Arch Neurol 2005, 62:873–882. This article reviews the pitfalls in diagnosing rabies and details uncharacteristic neuroimaging features in rabies-transplanted individuals compared with naturally infected cases.PubMedCrossRefGoogle Scholar
  9. 9.
    Srinivasan A, Burton EC, Kuehnert MJ, et al.: Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med 2005, 352:1103–1111. This article documents the transmission of rabies through solid organ transplantation and vascular graft.PubMedCrossRefGoogle Scholar
  10. 10.
    Rupprecht CE, Hemachudha T: Rabies. In Infections of the Central Nervous System, edn 3. Edited by Scheld M, Whitley RJ, Marra C. Philadelphia: Lippincott, Williams & Wilkins; 2004:243–259.Google Scholar
  11. 11.
    Belotto A, Leanes LF, Schneider MC, et al.: Overview of rabies in the Americas. Virus Res 2005, 111:5–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Dietzschold B, Schnell M, Koprowski H: Pathogenesis of rabies. Curr Top Microbiol Immunol 2005, 292:45–56.PubMedCrossRefGoogle Scholar
  13. 13.
    Schnell MJ, Tan GS, Dietzschold B: The application of reverse genetics technology in the study of rabies virus (RV) pathogenesis and for the development of novel RV vaccines. J Neurovirol 2005, 11:76–81.PubMedCrossRefGoogle Scholar
  14. 14.
    Finke S, Conzelmann KK: Replication strategies of rabies virus. Virus Res 2005, 111:120–131.PubMedCrossRefGoogle Scholar
  15. 15.
    Faber M, Pulmanausahakul R, Nagao K, et al.: Identification of viral genomic elements responsible for rabies virus neuroinvasiveness. Proc Natl Acad Sci U S A 2004, 101:16328–16332.PubMedCrossRefGoogle Scholar
  16. 16.
    Lafon M: Subversive neuroinvasive strategy of rabies virus. Arch Virol Suppl 2004, 18:149–159.PubMedGoogle Scholar
  17. 17.
    Juntrakul S, Ruangvejvorachai P, Shuangshoti S, et al.: Mechanisms of escape phenomenon of spinal cord and brainstem in human rabies. BMC Infect Dis 2005, 5:104. Article provides an explanation of the mechanism responsible for the relative intactness of brainstem and spinal cord despite abundance of virus antigen.PubMedCrossRefGoogle Scholar
  18. 18.
    Hemachudha T, Rupprecht C: Rabies. In Principle of Neurological Infectious Diseases. Edited by Roos K. New York: McGraw Hill; 2004:151–174.Google Scholar
  19. 19.
    Hemachudha T, Laothamatas J, Rupprecht CE: Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol 2002, 1:101–109.PubMedCrossRefGoogle Scholar
  20. 20.
    Hemachudha T, Wacharapluesadee S, Mitrabhakdi E, et al.: Pathophysiology of human paralytic rabies. J Neurovirol 2005, 11:93–100.PubMedCrossRefGoogle Scholar
  21. 21.
    Laothamatas J, Hemachudha T, Mitrabhakdi E, et al.: MR imaging in human rabies. Am J Neuroradiol 2003, 24:1102–1109. This article presents MRI details in furious and paralytic human rabies at different clinical stages.PubMedGoogle Scholar
  22. 22.
    Hemachudha T, Sunsaneewitayakul B, Mitrabhakdi E, et al.: Paralytic complications following intravenous rabies immune globulin treatment in a patient with furious rabies. Int J Infect Dis 2003, 7:76–77.PubMedCrossRefGoogle Scholar
  23. 23.
    Hemachudha T, Wacharapluesadee S: Antemortem diagnosis of human rabies. Clin Infect Dis 2004, 39:1085–1086.PubMedCrossRefGoogle Scholar
  24. 24.
    Jackson AC: Rabies: new insights into pathogenesis and treatment. Curr Opin Neurol 2006, 19:267–270.PubMedCrossRefGoogle Scholar
  25. 25.
    Lodmell DL, Dimcheff DE, Ewalt LC: Viral RNA in the bloodstream suggests viremia occurs in clinically ill rabies-infected mice. Virus Res 2006, 116:114–118.PubMedCrossRefGoogle Scholar
  26. 26.
    Sitprija V, Sriaroon C, Lumlertdaecha B, et al.: Does contact with urine and blood from a rabid dog represent a rabies risk? Clin Infect Dis 2003, 37:1399–1400.PubMedCrossRefGoogle Scholar
  27. 27.
    Hemachudha T, Wacharapluesadee S, Lumlertdaecha B, et al.: Sequence analysis of rabies virus in humans exhibiting encephalitic or paralytic rabies. J Infect Dis 2003, 188:960–966.PubMedCrossRefGoogle Scholar
  28. 28.
    Khawplod P, Shoji Y, Ubol S, et al.: Genetic analysis of dog rabies viruses circulating in Bangkok. Infect Genet Evol 2006, 6:235–240.PubMedGoogle Scholar
  29. 29.
    Hooper DC: The role of immune responses in the pathogenesis of rabies. J Neurovirol 2005, 11:88–92.PubMedCrossRefGoogle Scholar
  30. 30.
    Mitrabhakdi E, Shuangshoti S, Wannakrairot P, et al.: Difference in neuropathogenetic mechanisms in human furious and paralytic rabies. J Neurol Sci 2005, 238:3–10. This article documents differential involvement of peripheral nerves and anterior horn cells in human paralytic and furious rabies and shows that dorsal sensory ganglionopathy as responsible for local prodrome.PubMedCrossRefGoogle Scholar
  31. 31.
    Lafon M: Rabies virus receptors. J Neurovirol 2005, 11:82–87.PubMedCrossRefGoogle Scholar
  32. 32.
    Kelly RM, Strick PL: Rabies as a transneuronal tracer of circuits in the central nervous system. J Neurosci Methods 2000, 103:63–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Sheikh KA, Ramos-Alvarez M, Jackson AC, et al.: Overlap of pathology in paralytic rabies and axonal Guillain-Barre syndrome. Ann Neurol 2005, 57:768–772.PubMedCrossRefGoogle Scholar
  34. 34.
    Prehaud C, Lay S, Dietzschold B, Lafon M: Glycoprotein of nonpathogenic rabies viruses is a key determinant of human cell apoptosis. J Virol 2003, 77:10537–10547.PubMedCrossRefGoogle Scholar
  35. 35.
    Thoulouze MI, Lafage M, Yuste VJ, et al.: Apoptosis inversely correlates with rabies virus neurotropism. Ann N Y Acad Sci 2003, 1010:598–603.PubMedCrossRefGoogle Scholar
  36. 36.
    Kassis R, Larrous F, Estaquier J, Bourhy H: Lyssavirus matrix protein induces apoptosis by a TRAIL-dependent mechanism involving caspase-8 activation. J Virol 2004, 78:6543–6555.PubMedCrossRefGoogle Scholar
  37. 37.
    Griffin DE: Neuronal cell death in alphavirus encephalomyelitis. Curr Top Microbiol Immunol 2005, 289:57–77.PubMedGoogle Scholar
  38. 38.
    Guigoni C, Coulon P: Rabies virus is not cytolytic for rat spinal motoneurons in vitro. J Neurovirol 2002, 8:306–317.PubMedCrossRefGoogle Scholar
  39. 39.
    Kerschensteiner M, Stadelmann C, Dechant G, et al.: Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases. Ann Neurol 2003, 53:292–304.PubMedCrossRefGoogle Scholar
  40. 40.
    Castellanos JE, Martinez-Gutierrez M, Hurtado H, et al.: Studying neurotrophin antiviral effect on rabies-infected dorsal root ganglia cultures. J Neurovirol 2005, 11:403–410.PubMedCrossRefGoogle Scholar
  41. 41.
    Wang ZW, Sarmento L, Wang Y, et al.: Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. J Virol 2005, 79:12554–12565.PubMedCrossRefGoogle Scholar
  42. 42.
    Nakamichi K, Saiki M, Sawada M, et al.: Rabies virusinduced activation of mitogen-activated protein kinase and NF-kappaB signaling pathways regulates expression of CXC and CC chemokine ligands in microglia. J Virol 2005, 79:11801–11812.PubMedCrossRefGoogle Scholar
  43. 43.
    McKimmie CS, Johnson N, Fooks AR, Fazakerley JK: Viruses selectively upregulate Toll-like receptors in the central nervous system. Biochem Biophys Res Commun 2005, 336:925–933.PubMedCrossRefGoogle Scholar
  44. 44.
    Prehaud C, Megret F, Lafage M, Lafon M: Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon. J Virol 2005, 79:12893–12904.PubMedCrossRefGoogle Scholar
  45. 45.
    Chelbi-Alix MK, Vidy A, Bougrini JE, Blondel D: Rabies viral mechanisms to escape the IFN system: the viral protein P interferes with IRF-3, Stat1, and PML nuclear bodies. J Interferon Cytokine Res 2006, 26:271–280.PubMedCrossRefGoogle Scholar
  46. 46.
    Lafon M, Prehaud C, Megret F, et al.: Modulation of HLA-G expression in human neural cells after neurotropic viral infections. J Virol 2005, 79:15226–15237.PubMedCrossRefGoogle Scholar
  47. 47.
    Baloul L, Camelo S, Lafon M: Up-regulation of Fas ligand (FasL) in the central nervous system: a mechanism of immune evasion by rabies virus. J Neurovirol 2004, 10:372–382.PubMedGoogle Scholar
  48. 48.
    Willoughby RE Jr, Tieves KS, Hoffman GM, et al.: Survival after treatment of rabies with induction of coma. N Engl J Med 2005, 352:2508–2514. There have been only two survivors of rabies with near full recovery. Both were associated with bat exposures and had early native immune response. It is doubtful whether successful outcome relies on coma-induction treatment, which aims to reduce brain excitotoxicity.PubMedCrossRefGoogle Scholar
  49. 49.
    Hemachudha T, Wilde H: Survival after treatment of rabies. N Engl J Med 2005, 353:1068–1069; author reply 1068–1069.PubMedCrossRefGoogle Scholar
  50. 50.
    Goudsmit J, Marissen WE, Weldon WC, et al.: Comparison of an anti-rabies human monoclonal antibody combination with human polyclonal anti-rabies immune globulin. J Infect Dis 2006, 193:796–801.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2006

Authors and Affiliations

  • Thiravat Hemachudha
    • 1
  • Supaporn Wacharapluesadee
  • Jiraporn Laothamatas
  • Henry Wilde
  1. 1.Neurology Division, Department of MedicineChulalongkorn University HospitalBangkokThailand

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