Herpes Simplex and Varicella Zoster Virus

  • Karen C. BlochEmail author


Herpes simplex virus (HSV) and varicella zoster virus (VZV) are DNA viruses in the family Herpesviridae, subfamily Alphaherpesvirinae. These viruses are common causes of human mucocutaneous infections and, although central nervous system (CNS) infection occurs in only a minority of cases, are among the most common causes of meningoencephalitis in the United States [1]. The spectrum of CNS disease for both HSV and VZV ranges from a mild, self-limited meningitis to fulminant and sometimes fatal encephalitis. While these viruses share many commonalities, the epidemiology, clinical presentation, and, to some extent, treatment are distinct; therefore HSV and VZV CNS infections will be discussed separately in this chapter.


Herpes simplex virus (HSV) Varicella zoster virus (VZV) Meningitis Encephalitis 


  1. 1.
    Hasbun R, Rosenthal N, Balada-Llasat JM, Chung J, Duff S, Bozzette S, et al. Epidemiology of meningitis and encephalitis in the United States from 2011–2014. Clin Infect Dis. 2017;65(3):359–63. Scholar
  2. 2.
    Delaney S, Gardella C, Saracino M, Magaret A, Wald A. Seroprevalence of herpes simplex virus type 1 and 2 among pregnant women, 1989–2010. JAMA. 2014;312:746–8. Scholar
  3. 3.
    Bradley H, Markowitz LE, Gibson T, McQuillan GM. Seroprevalence of herpes simplex virus types 1 and 2—United States, 1999–2010. J Infect Dis. 2014;209(3):325–33. Scholar
  4. 4.
    Looker KJ, Magaret AS, May MT, Turner KM, Vickerman P, Gottlieb SL, et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLoS One. 2015;10:e0140765. Scholar
  5. 5.
    Vora NM, Holman RC, Mehal JM, Steiner CA, Blanton J, Sejvar J. Burden of encephalitis-associated hospitalizations in the United States, 1998–2010. Neurology. 2014;82:443–51. Scholar
  6. 6.
    George BP, Schneider EB, Venkatesan A. Encephalitis hospitalization rates and inpatient mortality in the United States, 2000–2010. PLoS One. 2014;9:e104169. Scholar
  7. 7.
    Jarrin I, Sellier P, Lopes A, Morgand M, Makovec T, Delcey V, et al. Etiologies and management of aseptic meningitis in patients admitted to an internal medicine department. Medicine (Baltimore). 2016;95:e2372. Scholar
  8. 8.
    Shukla B, Aguilera EA, Salazar L, Wootton SH, Kaewpoowat Q, Hasbun R. Aseptic meningitis in adults and children: diagnostic and management challenges. J Clin Virol. 2017;94:110–4. Scholar
  9. 9.
    Nahmias AJ, Whitley RJ, Visintine AN, Takei Y, Alford CA Jr. Herpes simplex virus encephalitis: laboratory evaluations and their diagnostic significance. J Infect Dis. 1982;145(6):829–36.CrossRefPubMedGoogle Scholar
  10. 10.
    Bradshaw MJ, Venkatesan A. Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics. 2016;13:493–508. Scholar
  11. 11.
    Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med. 1983;98:958–72.CrossRefPubMedGoogle Scholar
  12. 12.
    Li JZ, Sax PE. HSV-1 encephalitis complicated by cerebral hemorrhage in an HIV-positive person. AIDS Read. 2009;19:153–5.PubMedGoogle Scholar
  13. 13.
    Grover D, Newsholme W, Brink N, Manji H, Miller R. Herpes simplex virus infection of the central nervous system in human immunodeficiency virus-type 1-infected patients. Int J STD AIDS. 2004;15:597–600.CrossRefPubMedGoogle Scholar
  14. 14.
    Crusio RH, Singson SV, Haroun F, Mehta HH, Parenti DM. Herpes simplex virus encephalitis during treatment with etanercept. Scand J Infect Dis. 2014;46:152–4. Scholar
  15. 15.
    Bradford RD, Pettit AC, Wright PW, Mulligan MJ, Moreland LW, McLain DA, et al. Herpes simplex encephalitis during treatment with tumor necrosis factor-alpha inhibitors. Clin Infect Dis. 2009;49:924–7. Scholar
  16. 16.
    Sermer DJ, Woodley JL, Thomas CA, Hedlund JA. Herpes simplex encephalitis as a complication of whole-brain radiotherapy: a case report and review of the literature. Case Rep Oncol. 2014;7:774–9. Scholar
  17. 17.
    Berzero G, Di Stefano AL, Dehais C, Sanson M, Gaviani P, Silvani A, et al. Herpes simplex encephalitis in glioma patients: a challenging diagnosis. J Neurol Neurosurg Psychiatry. 2015;86:374–7. Scholar
  18. 18.
    Graber JJ, Rosenblum MK, DeAngelis LM. Herpes simplex encephalitis in patients with cancer. J Neurooncol. 2011;105:415–21. Scholar
  19. 19.
    Koudriavtseva T, Onesti E, Tonachella R, Pelagalli L, Vidiri A, Jandolo B. Fatal herpetic encephalitis during brain radiotherapy in a cerebral metastasized breast cancer patient. J Neurooncol. 2010;100:137–40. Scholar
  20. 20.
    Jaques DA, Bagetakou S, L’Huillier AG, Bartoli A, Vargas MI, Fluss J, et al. Herpes simplex encephalitis as a complication of neurosurgical procedures: report of 3 cases and review of the literature. Virol J. 2016;13:83. Scholar
  21. 21.
    Zhang SY, Abel L, Casanova JL. Mendelian predisposition to herpes simplex encephalitis. Handb Clin Neurol. 2013;112:1091–7. Scholar
  22. 22.
    Lim HK, Seppänen M, Hautala T, Ciancanelli MJ, Itan Y, Lafaille FG, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83:1888–97. Scholar
  23. 23.
    Sironi M, Peri AM, Cagliani R, Forni D, Riva S, Biasin M, et al. TLR3 mutations in adult patients with herpes simplex virus and varicella-zostervirus encephalitis. J Infect Dis. 2017;215:1430–4. Scholar
  24. 24.
    Mørk N, Kofod-Olsen E, Sørensen KB, Bach E, Ørntoft TF, Østergaard L, et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015;16:552–66. Scholar
  25. 25.
    Aurelius E, Johansson B, Sköldenberg B, Forsgren M. Encephalitis in immunocompetent patients due to herpes simplex virus type 1 or 2 as determined by type-specific polymerase chain reaction and antibody assays of cerebrospinal fluid. J Med Virol. 1993;39:179–86.CrossRefPubMedGoogle Scholar
  26. 26.
    Moon SM, Kim T, Lee EM, Kang JK, Lee SA, Choi SH. Comparison of clinical manifestations, outcomes and cerebrospinal fluid findings between herpes simplex type 1 and type 2 central nervous system infections in adults. J Med Virol. 2014;86:1766–71. Scholar
  27. 27.
    Gnann JW Jr, Whitley RJ. Herpes simplex encephalitis: an update. Curr Infect Dis Rep. 2017;19:13. Scholar
  28. 28.
    Chow FC, Glaser CA, Sheriff H, Xia D, Messenger S, Whitley R, et al. Use of clinical and neuroimaging characteristics to distinguish temporal lobe herpes simplex encephalitis from its mimics. Clin Infect Dis. 2015;60:1377–83. Scholar
  29. 29.
    Renard D, Nerrant E, Lechiche C. DWI and FLAIR imaging in herpes simplex encephalitis: a comparative and topographical analysis. J Neurol. 2015;262:2101–5. Scholar
  30. 30.
    Tan IL, McArthur JC, Venkatesan A, Nath A. Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised. Neurology. 2012;79:2125–32. Scholar
  31. 31.
    Miller S, Mateen FJ, Aksamit AJ Jr. Herpes simplex virus 2 meningitis: a retrospective cohort study. J Neurovirol. 2013;19:166–71. Scholar
  32. 32.
    Kaewpoowat Q, Salazar L, Aguilera E, Wootton SH, Hasbun R. Herpes simplex and varicella zoster CNS infections: clinical presentations, treatments and outcomes. Infection. 2016;44:337–45. Scholar
  33. 33.
    Aurelius E, Forsgren M, Gille E, Sköldenberg B. Neurologic morbidity after herpes simplex virus type 2 meningitis: a retrospective study of 40 patients. Scand J Infect Dis. 2002;34:278–83.CrossRefPubMedGoogle Scholar
  34. 34.
    Lakeman FD, Whitley RJ. 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. 1995;171:857–63.CrossRefPubMedGoogle Scholar
  35. 35.
    Weil AA, Glaser CA, Amad Z, Forghani B. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis. 2002;34:1154–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Buerger KJ, Zerr K, Salazar R. An unusual presentation of herpes simplex encephalitis with negative PCR. BMJ Case Rep. 2015;2015.
  37. 37.
    Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Infectious Diseases Society of America, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47:303–27. Scholar
  38. 38.
    Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, International Encephalitis Consortium, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013;57(8):1114–28. Scholar
  39. 39.
    Sauerbrei A, Wutzler P. Laboratory diagnosis of central nervous system infections caused by herpesviruses. J Clin Virol. 2002;25:S45–51.CrossRefPubMedGoogle Scholar
  40. 40.
    Stahl JP, Azouvi P, Bruneel F, De Broucker T, Duval X, Fantin B, et al. Guidelines on the management of infectious encephalitis in adults. Med Mal Infect. 2017;47:179–94. Scholar
  41. 41.
    Britton PN, Eastwood K, Paterson B, Durrheim DN, Dale RC, Cheng AC, Australasian Society of Infectious Diseases (ASID); Australasian College of Emergency Medicine (ACEM); Australian and New Zealand Association of Neurologists (ANZAN); Public Health Association of Australia (PHAA), et al. Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand. Intern Med J. 2015;45:563–76. Scholar
  42. 42.
    Solomon T, Michael BD, Smith PE, Sanderson F, Davies NW, Hart IJ, National Encephalitis Guidelines Development and Stakeholder Groups, et al. Management of suspected viral encephalitis in adults—Association of British Neurologists and British Infection Association National Guidelines. J Infect. 2012;64:347–73. Scholar
  43. 43.
    Stahl JP, Mailles A, De Broucker T, Steering Committee and Investigators Group. Herpes simplex encephalitis and management of acyclovir in encephalitis patients in France. Epidemiol Infect. 2012;140:372–81. Scholar
  44. 44.
    Gateley A, Gander RM, Johnson PC, Kit S, Otsuka H, Kohl S. Herpes simplex virus type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS. J Infect Dis. 1990;161:711–5.CrossRefPubMedGoogle Scholar
  45. 45.
    Schepers K, Hernandez A, Andrei G, Gillemot S, Fiten P, Opdenakker G, et al. Acyclovir-resistant herpes simplex encephalitis in a patient treated with anti-tumor necrosis factor-α monoclonal antibodies. J Clin Virol. 2014;59:67–70. Scholar
  46. 46.
    Schulte EC, Sauerbrei A, Hoffmann D, Zimmer C, Hemmer B, Mühlau M. Acyclovir resistance in herpes simplex encephalitis. Ann Neurol. 2010;67:830–3. Scholar
  47. 47.
    Gnann JW Jr, Sköldenberg B, Hart J, Aurelius E, Schliamser S, Studahl M, National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group, et al. Herpes simplex encephalitis: lack of clinical benefit of long-term valacyclovir therapy. Clin Infect Dis. 2015;61:683–91. Scholar
  48. 48.
    Kamei S, Sekizawa T, Shiota H, Mizutani T, Itoyama Y, Takasu T, et al. Evaluation of combination therapy using acyclovir and corticosteroid in adult patients with herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatry. 2005;76:1544–9.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Martinez-Torres F, Menon S, Pritsch M, Victor N, Jenetzky E, Jensen K, GACHE Investigators, et al. Protocol for German trial of acyclovir and corticosteroids in herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933]. BMC Neurol. 2008;8:40. Scholar
  50. 50.
    Tyler KL. Editorial commentary: failure of adjunctive Valacyclovir to improve outcomes in herpes simplex encephalitis. Clin Infect Dis. 2015;61:692–4. Scholar
  51. 51.
    Noska A, Kyrillos R, Hansen G, Hirigoyen D, Williams DN. The role of antiviral therapy in immunocompromised patients with herpes simplex virus meningitis. Clin Infect Dis. 2015;60:237–42. Scholar
  52. 52.
    Prüss H, Finke C, Höltje M, Hofmann J, Klingbeil C, Probst C, et al. N-methyl-d-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol. 2012;72:902–11. Scholar
  53. 53.
    Armangue T, Moris G, Cantarín-Extremera V, Conde CE, Rostasy K, Erro ME, et al. Spanish prospective multicentric study of autoimmunity in herpes simplex encephalitis. Autoimmune post-herpes simplex encephalitis of adults and teenagers. Neurology. 2015;85:1736–43. Scholar
  54. 54.
    Nosadini M, Mohammad SS, Corazza F, Ruga EM, Kothur K, Perilongo G, et al. Herpes simplex virus-induced anti-N-methyl-d-aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases. Dev Med Child Neurol. 2017;59:796–805. Scholar
  55. 55.
    Westman G, Studahl M, Ahlm C, Eriksson BM, Persson B, Rönnelid J, et al. N-methyl-d-aspartate receptor autoimmunity affects cognitive performance in herpes simplex encephalitis. Clin Microbiol Infect. 2016;22:934–40. Scholar
  56. 56.
    Whitley RJ, Soong SJ, Dolin R, Galasso GJ, Ch’ien LT, Alford CA. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study. N Engl J Med. 1977;297:289–94.CrossRefPubMedGoogle Scholar
  57. 57.
    Whitley RJ, Alford CA, Hirsch MS, Schooley RT, Luby JP, Aoki FY, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med. 1986;314:144–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Erdem H, Cag Y, Ozturk-Engin D, Defres S, Kaya S, Larsen L, et al. Results of a multinational study suggest the need for rapid diagnosis and early antiviral treatment at the onset of herpetic meningoencephalitis. Antimicrob Agents Chemother. 2015;59:3084–9. Scholar
  59. 59.
    Aurelius E, Franzen-Röhl E, Glimåker M, Akre O, Grillner L, Jorup-Rönström C, HSV-2 Meningitis Study Group, et al. Long-term valacyclovir suppressive treatment after herpes simplex virus type 2 meningitis: a double-blind, randomized controlled trial. Clin Infect Dis. 2012;54:1304–13. Scholar
  60. 60.
    Science M, MacGregor D, Richardson SE, Mahant S, Tran D, Bitnun A. Central nervous system complications of varicella-zoster virus. J Pediatr. 2014;165:779–85. Scholar
  61. 61.
    Nagel MA, Gilden D. Developments in varicella zoster virus vasculopathy. Curr Neurol Neurosci Rep. 2016;16:12. Scholar
  62. 62.
    Pahud BA, Glaser CA, Dekker CL, Arvin AM, Schmid DS. Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine. J Infect Dis. 2011;203:316–23. Scholar
  63. 63.
    Levin MJ, DeBiasi RL, Bostik V, Schmid DS. Herpes zoster with skin lesions and meningitis caused by 2 different genotypes of the Oka varicella-zoster virus vaccine. J Infect Dis. 2008;198:1444–7. Scholar
  64. 64.
    Goulleret N, Mauvisseau E, Essevaz-Roulet M, Quinlivan M, Breuer J. Safety profile of live varicella virus vaccine (Oka/Merck): five-year results of the European Varicella Zoster Virus Identification Program (EU VZVIP). Vaccine. 2010;28:5878–82. Scholar
  65. 65.
    Nagel MA, Gilden D. Neurological complications of varicella zoster virus reactivation. Curr Opin Neurol. 2014;27:356–60. Scholar
  66. 66.
    De Broucker T, Mailles A, Chabrier S, Morand P, Stahl JP. Steering committee and investigators group. Acute varicella zoster encephalitis without evidence of primary vasculopathy in a case-series of 20 patients. Clin Microbiol Infect. 2012;18:808–19. Scholar
  67. 67.
    Gilden D, Nagel MA, Cohrs RJ, Mahalingam R. The variegate neurological manifestations of varicella zoster virus infection. Curr Neurol Neurosci Rep. 2013;13:374. Scholar
  68. 68.
    Pollak L, Dovrat S, Book M, Mendelson E, Weinberger M. Varicella zoster vs. herpes simplex meningoencephalitis in the PCR era. A single center study. J Neurol Sci. 2012;314:29–36. Scholar
  69. 69.
    van der Maas NA, Bondt PE, de Melker H, Kemmeren JM. Acute cerebellar ataxia in the Netherlands: a study on the association with vaccinations and varicella zoster infection. Vaccine. 2009;27:1970–3. Scholar
  70. 70.
    Kim SH, Choi SM, Kim BC, Choi KH, Nam TS, Kim JT, et al. Risk factors for aseptic meningitis in herpes zoster patients. Ann Dermatol. 2017;29:283–7. Scholar
  71. 71.
    Persson A, Bergström T, Lindh M, Namvar L, Studahl M. Varicella-zoster virus CNS disease--viral load, clinical manifestations and sequels. J Clin Virol. 2009;46:249–53. Scholar
  72. 72.
    Choi R, Kim GM, Jo IJ, Sim MS, Song KJ, Kim BJ, et al. Incidence and clinical features of herpes simplex viruses (1 and 2) and varicella-zoster virus infections in an adult Korean population with aseptic meningitis or encephalitis. J Med Virol. 2014;86:957–62. Scholar
  73. 73.
    Gilden D, Grose C, White T, Nagae L, Hendricks RL, Cohrs RJ, et al. Successful antiviral treatment after 6 years of chronic progressive neurological disease attributed to VZV brain infection. J Neurol Sci. 2016;368:240–2. Scholar
  74. 74.
    Silver B, Nagel MA, Mahalingam R, Cohrs R, Schmid DS, Gilden D. Varicella zoster virus vasculopathy: a treatable form of rapidly progressive multi-infarct dementia after 2 years’ duration. J Neurol Sci. 2012;323:245–7. Scholar
  75. 75.
    Nagel MA, Cohrs RJ, Mahalingam R, Wellish MC, Forghani B, Schiller A, et al. The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features. Neurology. 2008;70:853–60. Scholar
  76. 76.
    Nagel MA, Jones D, Wyborny A. Varicella zoster virus vasculopathy: the expanding clinical spectrum and pathogenesis. J Neuroimmunol. 2017;308:112–7. Scholar
  77. 77.
    Aberle SW, Aberle JH, Steininger C, Puchhammer-Stöckl E. Quantitative real time PCR detection of varicella-zoster virus DNA in cerebrospinal fluid in patients with neurological disease. Med Microbiol Immunol. 2005;194:7–12.CrossRefPubMedGoogle Scholar
  78. 78.
    Nagel MA, Forghani B, Mahalingam R, Wellish MC, Cohrs RJ, Russman AN, et al. The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology. 2007;68:1069–73.CrossRefPubMedGoogle Scholar
  79. 79.
    Kennedy PG. Issues in the treatment of neurological conditions caused by reactivation of varicella zoster virus (VZV). Neurotherapeutics. 2016;13:509–13. Scholar
  80. 80.
    Schäbitz WR, Rogalewski A, Hagemeister C, Bien CG. VZV brainstem encephalitis triggers NMDA receptor immunoreaction. Neurology. 2014;83:2309–11. Scholar
  81. 81.
    Solís N, Salazar L, Hasbun R. Anti-NMDA receptor antibody encephalitis with concomitant detection of varicella zoster virus. J Clin Virol. 2016;83:26–8. Scholar
  82. 82.
    Pollak L, Dovrat S, Book M, Mendelson E, Weinberger M. Varicella zoster vs.herpes simplex meningoencephalitis in the PCR era. A single center study. J Neurol Sci. 2012;314(1–2):29–36. Scholar

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Authors and Affiliations

  1. 1.Vanderbilt University Medical Center, Department of Infectious DiseasesNashvilleUSA

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