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  • Review Article
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Herpesvirus infections of the nervous system

Nature Clinical Practice Neurology volume 3, pages 82–94 (2007)Cite this article

Abstract

There are eight human herpesviruses (HHVs). Primary infection by any of the eight viruses, usually occurring in childhood, is either asymptomatic or produces fever and rash of skin or mucous membranes; other organs might be involved on rare occasions. After primary infection, the virus becomes latent in ganglia or lymphoid tissue. With the exception of HHV-8, which causes Kaposi's sarcoma in patients with AIDS, reactivation of HHVs can produce one or more of the following complications: meningitis, encephalitis, myelitis, vasculopathy, ganglioneuritis, retinal necrosis and optic neuritis. Disease can be monophasic, recurrent or chronic. Infection with each herpesvirus produces distinctive clinical features and imaging abnormalities. This Review highlights the patterns of neurological symptoms and signs, along with the typical imaging abnormalities, produced by each of the HHVs. Optimal virological studies of blood, cerebrospinal fluid and affected tissue for confirmation of diagnosis are discussed; this is particularly important because some HHV infections of the nervous system can be treated successfully with antiviral agents.

Key Points

  • Herpes simplex virus 1 (HSV-1) encephalitis predominantly involves the orbital surface of the frontal lobes and medial surface of the temporal lobes, resulting in areas of increased T2 signal on MRI

  • Herpes simplex virus 2 (HSV-2) is the primary cause of recurrent meningitis

  • After varicella, the varicella zoster virus (VZV) becomes latent in ganglia along the entire neuraxis; its reactivation can lead to herpes zoster, vasculopathy, myelitis, necrotizing retinitis or zoster sine herpete

  • The neurological complications of Epstein–Barr virus are diverse, and include meningitis, encephalitis, myelitis, radiculoneuropathy, and even autonomic neuropathy

  • The most common neurological complication of cytomegalovirus (CMV) is poly-radiculoneuropathy in immunocompromised individuals

  • Virological confirmation of neurological disease relies on the detection of herpesvirus-specific DNA in bodily fluids or tissues, herpesvirus-specific IgM in blood, or herpesvirus-specific IgM or IgG antibody in cerebrospinal fluid

  • HSV-1, HSV-2, VZV and CMV are the most treatable herpesviruses

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Figure 1: Typical changes seen on CT and MRI in patients with herpesvirus infections.

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References

  1. Lakeman FD and Whitley RJ (1995) Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 171: 857–863

    Article  CAS  PubMed  Google Scholar 

  2. Weil AA et al. (2002) Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis 34: 1154–1157

    Article  PubMed  Google Scholar 

  3. Westmoreland BF (1987) The EEG in cerebral inflammatory processes. In Electroencephalography: Basic Principles, Clinical Applications, and Related Fields, edn 2, 259–273 (Eds Niedermeyer E and Lopes da Silva FH) Baltimore–Munich: Urban and Schwarzenberg

    Google Scholar 

  4. Smith JB et al. (1975) A distinctive clinical EEG profile in herpes simplex encephalitis. Mayo Clin Proc 50: 469–474

    CAS  PubMed  Google Scholar 

  5. Zimmerman RD et al. (1980) CT in the early diagnosis of herpes simplex encephalitis. Am J Radiol 134: 61–66

    CAS  Google Scholar 

  6. Schroth G et al. (1987) Early diagnosis of herpes simplex encephalitis by MRI. Neurology 37: 179–183

    Article  CAS  PubMed  Google Scholar 

  7. Bastian FO et al. (1972) Herpesvirus hominis: isolation from human trigeminal ganglion. Science 178: 306–307

    Article  CAS  PubMed  Google Scholar 

  8. Baringer JR and Swoveland P (1973) Recovery of herpes simplex virus from human trigeminal ganglions. N Engl J Med 288: 648–650

    Article  CAS  PubMed  Google Scholar 

  9. Warren KG et al. (1978) Herpes simplex virus latency in patients with multiple sclerosis, lymphoma and normal humans. IARC Sci Publ 765–768

  10. Bustos DE and Atherton SS (2002) Detection of herpes simplex virus type 1 in human ciliary ganglia. Invest Ophthalmol Vis Sci 43: 2244–2249

    PubMed  Google Scholar 

  11. Mahalingam R et al. (1992) Localization of herpes simplex virus and varicella zoster virus DNA in human ganglia. Ann Neurol 31: 444–448

    Article  CAS  PubMed  Google Scholar 

  12. Fraser NW et al. (1981) Herpes simplex type 1 DNA in human brain tissue. Proc Natl Acad Sci USA 78: 6461–6465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sawtell NM (1997) Comprehensive quantification of herpes simplex virus latency at the single-cell level. J Virol 71: 5423–5431

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Cohrs RJ et al. (2000) Analysis of individual human trigeminal ganglia for latent herpes simplex virus type 1 and varicella-zoster virus nucleic acids using real-time PCR. J Virol 74: 11464–11471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vrabec JT and Alford RL (2004) Quantitative analysis of herpes simplex virus in cranial nerve ganglia. J Neurovirol 10: 216–222

    Article  CAS  PubMed  Google Scholar 

  16. Rock DL and Fraser NW (1985) Latent herpes simplex virus type 1 DNA contains two copies of the virion DNA joint region. J Virol 55: 849–852

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Stevens JG et al. (1987) RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science 235: 1056–1059

    Article  CAS  PubMed  Google Scholar 

  18. Kang W et al. (2003) Establishment and maintenance of HSV latent infection is mediated through correct splicing of the LAT primary transcript. Virology 312: 233–244

    Article  CAS  PubMed  Google Scholar 

  19. Izumi KM et al. (1989) Molecular and biological characterization of a type 1 herpes simplex virus (HSV-1) specifically deleted for expression of the latency-associated transcript (LAT). Microb Pathog 7: 121–134

    Article  CAS  PubMed  Google Scholar 

  20. Perng GC et al. (2000) Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript. Science 287: 1500–1503

    Article  CAS  PubMed  Google Scholar 

  21. Gupta A et al. (2006) Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript. Nature 442: 82–85

    Article  CAS  PubMed  Google Scholar 

  22. Bourne N et al. (2003) Herpes simplex virus (HSV) type 2 glycoprotein D subunit vaccines and protection against genital HSV-1 or HSV-2 disease in guinea pigs. J Infect Dis 197: 542–549

    Article  Google Scholar 

  23. Murakami S et al. (1996) Bell palsy and herpes simplex virus: identification of viral DNA in endoneurial fluid and muscle. Ann Intern Med 124: 27–30

    Article  CAS  PubMed  Google Scholar 

  24. Furuta Y et al. (1992) Latent herpes simplex virus type 1 in human geniculate ganglia. Acta Neuropathol (Berl) 84: 39–44

    Article  CAS  Google Scholar 

  25. Gonzales N et al. (2003) Recurrent dermatomal vesicular skin lesions: a clue to diagnosis of herpes simplex virus 2 meningitis. Arch Neurol 60: 868–869

    Article  PubMed  Google Scholar 

  26. Tedder DG et al. (1994) Herpes simplex virus infection as a cause of benign recurrent lymphocytic meningitis. Ann Intern Med 121: 334–338

    Article  CAS  PubMed  Google Scholar 

  27. Yamamoto LJ et al. (1991) Herpes simplex virus type 1 DNA in cerebrospinal fluid of a patient with Mollaret's meningitis. N Engl J Med 325: 1082–1085

    Article  CAS  PubMed  Google Scholar 

  28. Baringer JR (1974) Recovery of herpes simplex virus from human sacral ganglions. New Engl J Med 291: 828–830

    Article  CAS  PubMed  Google Scholar 

  29. Krohel GB et al. (1976) Herpes simplex neuropathy. Neurology 26: 596–597

    Article  CAS  PubMed  Google Scholar 

  30. Morris HH and Peters BH (1974) Recurrent sciatica associated with herpes simplex: case report. J Neurosurg 41: 97–99

    Article  PubMed  Google Scholar 

  31. Miller AE (1980) Selective decline in cellular immune response to varicella-zoster in the elderly. Neurology 30: 582–587

    Article  CAS  PubMed  Google Scholar 

  32. Oxman MN et al. (2005) A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352: 2271–2284

    Article  CAS  PubMed  Google Scholar 

  33. Gilden DH et al. (2005) VZV vasculopathy and postherpetic neuralgia: progress and perspective on antiviral therapy. Neurology 65: 21–25

    Article  Google Scholar 

  34. Gilden DH et al. (1996) Varicella zoster virus, a cause of waxing and waning vasculitis: the New England Journal of Medicine case 5-1995 revisited. Neurology 47: 1441–1446

    Article  CAS  PubMed  Google Scholar 

  35. Gilden DH et al. (2002) Two patients with unusual forms of varicella-zoster virus vasculopathy. N Eng J Med 347: 1500–1503

    Article  Google Scholar 

  36. Gilden DH et al. (1998) The value of cerebrospinal fluid antiviral antibody in the diagnosis of neurologic disease produced by varicella zoster virus. J Neurol Sci 159: 140–144

    Article  CAS  PubMed  Google Scholar 

  37. Sato M et al. (1979) Herpes zoster of the maxillary branch of the trigeminus nerve: virological and serological studies. Int J Oral Surg 8: 149–154

    Article  CAS  PubMed  Google Scholar 

  38. Vonsover A et al. (1987) Detection of varicella-zoster virus in lymphocytes of DNA hybridization. J Med Virol 21: 57–66

    Article  CAS  PubMed  Google Scholar 

  39. Gilden DH et al. (1988) Persistence of varicella-zoster virus DNA in blood mononuclear cells of patients with varicella or zoster. Virus Genes 2: 299–305

    Article  Google Scholar 

  40. Mahalingam R et al. (1995) Persistence of varicella-zoster virus DNA in elderly patients with postherpetic neuralgia. J Neurovirol 1: 130–133

    Article  CAS  PubMed  Google Scholar 

  41. Schott GC (1998) Triggering of delayed-onset postherpetic neuralgia. Lancet 351: 419–420

    Article  CAS  PubMed  Google Scholar 

  42. Vafai A et al. (1988) Expression of varicella-zoster virus blood mononuclear cells of patients with postherpetic neuralgia. Proc Natl Acad Sci 85: 2767–2770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gilden DH et al. (1994) Zoster sine herpete, a clinical variant. Ann Neurol 34: 530–533

    Article  Google Scholar 

  44. Terada K et al. (1998) Detection of varicella-zoster virus DNA in peripheral mononuclear cells from patients with Ramsay Hunt syndrome or zoster sine herpete. J Med Virol 56: 359–363

    Article  CAS  PubMed  Google Scholar 

  45. Yamada S et al. (2003) Ipsilateral truncal sensory deficit in a patient with ophthalmic zoster sine herpete. Neurology 60: 1049–1050

    Article  CAS  PubMed  Google Scholar 

  46. Hevner RF et al. (2003) An unusual cause of trigeminal distribution pain and tumour. Lancet Neurol 2: 567–571

    Article  PubMed  Google Scholar 

  47. Gilden DH et al. (2003) Chronic varicella zoster virus ganglionitis—a possible cause of postherpetic neuralgia. J Neurovirol 9: 404–407

    Article  CAS  PubMed  Google Scholar 

  48. Quan D et al. (2006) Improvement of postherpetic neuralgia after treatment with intravenous acyclovir followed by oral valacyclovir. Arch Neurol 63: 940–952

    Article  PubMed  Google Scholar 

  49. Devlin ME et al. (1992) Peripheral blood mononuclear cells of the elderly contain varicella-zoster virus DNA. J Infect Dis 165: 619–622

    Article  CAS  PubMed  Google Scholar 

  50. Gilden DH et al. (1983) Varicella-zoster virus DNA in human sensory ganglia. Nature 306: 478–480

    Article  CAS  PubMed  Google Scholar 

  51. Hyman RW et al. (1983) Varicella-zoster virus RNA in human trigeminal ganglia. Lancet 322: 814–816

    Article  Google Scholar 

  52. Gilden DH et al. (1987) Detection of varicella-zoster virus nucleic acid in neurons of normal human thoracic ganglia. Ann Neurol 22: 377–380

    Article  CAS  PubMed  Google Scholar 

  53. Clarke P et al. (1995) Configuration of latent varicella-zoster virus DNA. J Virol 69: 8151–8154

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Wood MJ et al. (1994) A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 330: 896–900

    Article  CAS  PubMed  Google Scholar 

  55. Whitley RJ et al. (1996) Acyclovir with and without prednisone for the treatment of herpes zoster: a randomized, placebo-controlled trial. Ann Intern Med 125: 376–383

    Article  CAS  PubMed  Google Scholar 

  56. Bennett JL et al. (1996) Epstein–Barr virus-associated acute autonomic neuropathy. Ann Neurol 40: 453–455

    Article  CAS  PubMed  Google Scholar 

  57. Majid A et al. (2002) Epstein–Barr virus myeloradiculitis and encephalomyeloradiculitis. Brain 125: 159–165

    Article  PubMed  Google Scholar 

  58. Imai S et al. (1993) Epstein–Barr virus genomic sequences and specific antibodies in cerebrospinal fluid in children with neurologic complications of acute and reactivated EBV infections. J Med Virol 40: 278–284

    Article  CAS  PubMed  Google Scholar 

  59. Lehrnbecher T et al. (1996) Activated T lymphocytes in the cerebrospinal fluid of a patient with Epstein-Barr virus-associated meningoencephalitis. Pediatr Infect Dis J 15: 631–633

    Article  CAS  PubMed  Google Scholar 

  60. Baumgarten E et al. (1994) Life-threatening infectious mononucleosis: is it correlated with virus-induced T cell proliferation? Clin Infect Dis 19: 152–156

    Article  CAS  PubMed  Google Scholar 

  61. MacMahon EM et al. (1991) Epstein–Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338: 969–973

    Article  CAS  PubMed  Google Scholar 

  62. Comoli P et al. (2005) Treatment of EBV-related post-renal transplant lymphoproliferative disease with a tailored regimen including EBV-specific T cells. Am J Transplant 5: 1415–1422

    Article  PubMed  Google Scholar 

  63. Cohen JI (2000) Epstein–Barr virus infection. N Engl J Med 343: 481–492

    Article  CAS  PubMed  Google Scholar 

  64. Rickinson A and Kieff E (2001) Epstein-Barr virus. In Virology, edn 4, 2573–2627 (Eds Knipe D et al.) Philadelphia: Lippincott Williams and Wilkins

    Google Scholar 

  65. Duchowny M et al. (1979) Cytomegalovirus infection of the adult nervous system. Ann Neurol 5: 458–461

    Article  CAS  PubMed  Google Scholar 

  66. Schneck SA (1965) Neuropathological features of human organ transplantation. I: probable cytomegalovirus infection. J Neuropathol Exp Neurol 24: 415–429

    Article  Google Scholar 

  67. Eidelberg D et al. (1986) Progressive polyradiculopathy in acquired immune deficiency syndrome. Neurology 36: 912–916

    Article  CAS  PubMed  Google Scholar 

  68. Mocarski ES Jr and Courcelle CT (2001) Cytomegaloviruses and their replication. In Virology, edn 4, 2629–2673 (Eds Knipe D et al.) Philadelphia: Lippincott Williams and Wilkins

    Google Scholar 

  69. Rasmussen L et al. (2003) Inter- and intragenic variations complicate the molecular epidemiology of human cytomegalovirus. J Infect Dis 187: 809–819

    Article  PubMed  Google Scholar 

  70. Stinski MF et al. (1979) DNA of human cytomegalovirus: size heterogeneity and defectiveness resulting from serial undiluted passage. J Virol 31: 231–239

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Hummel M and Abecassis MM (2002) A model for reactivation of CMV from latency. J Clin Virol 25 (Suppl 2): S123–S136

    Article  PubMed  Google Scholar 

  72. Froberg MK (2004) CMV escapes! Ann Clin Lab Sci 34: 123–130

    CAS  PubMed  Google Scholar 

  73. Whitley RJ et al. (1998) Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy. Arch Intern Med 158: 957–969

    Article  CAS  PubMed  Google Scholar 

  74. Dewhurst S (2004) Human herpesvirus type 6 and human herpesvirus type 7 infections of the central nervous system. Herpes 11 (Suppl 2): S105A–S111A

    Google Scholar 

  75. Asano Y et al. (1990) Fatal fulminant hepatitis in an infant with human herpesvirus-6 infection. Lancet 335: 862–863

    Article  CAS  PubMed  Google Scholar 

  76. Portolani M et al. (2005) Post-mortem diagnosis of encephalitis in a 75-year-old man associated with human herpesvirus-6 variant A. J Med Virol 77: 244–248

    Article  PubMed  Google Scholar 

  77. Zerr DM et al. (2001) Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients. Clin Infect Dis 33: 763–771

    Article  CAS  PubMed  Google Scholar 

  78. Wainwright MS et al. (2001) Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol 50: 612–619

    Article  CAS  PubMed  Google Scholar 

  79. Kondo K et al. (1991) Latent human herpesvirus 6 infection of human monocytes/macrophages. J Gen Virol 72: 1401–1408

    Article  CAS  PubMed  Google Scholar 

  80. Kong H et al. (2003) Human herpesvirus type 6 indirectly enhances oligodendrocyte cell death. J Neurovirol 9: 539–550

    Article  CAS  PubMed  Google Scholar 

  81. Dietrich J et al. (2004) Infection with an endemic human herpesvirus disrupts critical glial precursor cell properties. J Neurosci 24: 4875–4883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zerr DM et al. (2002) Effect of antivirals on human herpesvirus 6 replication in hematopoietic stem cell transplant recipients. Clin Infect Dis 34: 309–317

    Article  CAS  PubMed  Google Scholar 

  83. Frenkel N et al. (1990) Isolation of a new herpesvirus from human CD4+ T cells. Proc Natl Acad Sci USA 87: 748–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ward KN et al. (2002) Neuroinvasion during delayed primary HHV-7 infection in an immunocompetent adult with encephalitis and flaccid paralysis. J Med Virol 67: 538–541

    Article  CAS  PubMed  Google Scholar 

  85. Yoshikawa T et al. (2003) Human herpesvirus 7-associated meningitis and optic neuritis in a patient after allogeneic stem cell transplantation. J Med Virol 70: 440–443

    Article  PubMed  Google Scholar 

  86. Yoshikawa T et al. (2000) Invasion by human herpesvirus 6 and human herpesvirus 7 of the central nervous system in patients with neurological signs and symptoms. Arch Dis Child 83: 170–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chang Y et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869

    Article  CAS  PubMed  Google Scholar 

  88. Montaner S et al. (2006) The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor as a therapeutic target for the treatment of Kaposi's sarcoma. Cancer Res 66: 168–174

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by Public Health Service grants NS32623 and AG06127 from the National Institutes of Health. We thank Marina Hoffman for editorial assistance and Cathy Allen for manuscript preparation.

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Authors and Affiliations

  1. DH Gilden is the Louise Baum Professor and Chairman of the Department of Neurology, and Professor of Microbiology; and KL Tyler is the Reuler-Lewin Family Professor of Neurology and Professor of Medicine, Microbiology and Immunology; all are at the University of Colorado Health Sciences Center, Denver, CO, USA.,

    Donald H Gilden, Ravi Mahalingam, Randall J Cohrs & Kenneth L Tyler

  2. R Mahalingam is a Research Professor in the Department of Neurology,

    Donald H Gilden, Ravi Mahalingam, Randall J Cohrs & Kenneth L Tyler

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  1. Donald H Gilden
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Correspondence to Donald H Gilden.

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Gilden, D., Mahalingam, R., Cohrs, R. et al. Herpesvirus infections of the nervous system. Nat Rev Neurol 3, 82–94 (2007). https://doi.org/10.1038/ncpneuro0401

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