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Herpes simplex virus type 1 encephalitis

Robyn S Klein, MD, PhD
Section Editor
Martin S Hirsch, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Herpes simplex virus type 1 (HSV-1) encephalitis is the most common cause of sporadic fatal encephalitis worldwide. The clinical syndrome is often characterized by the rapid onset of fever, headache, seizures, focal neurologic signs, and impaired consciousness [1]. HSV-1 encephalitis is a devastating disease with significant morbidity and mortality, despite available antiviral therapy.

The pathogenesis, clinical manifestations, diagnosis, and treatment of HSV-1 encephalitis will be reviewed here. Neonatal encephalitis and other manifestations of HSV-1 infection are discussed separately. (See "Clinical manifestations and diagnosis of herpes simplex virus type 1 infection".)


HSV-1 encephalitis is the most common cause of fatal sporadic encephalitis in the United States, accounting for approximately 10 to 20 percent of the 20,000 annual viral encephalitis cases [2,3]. The infection arises in all age groups, with one-third of all cases occurring in children and adolescents [4]. HSV is also the most commonly identified pathogen among hospitalized patients diagnosed with encephalitis in Australia [5]. In a nationwide retrospective study of the incidence of HSV-1 encephalitis in Sweden over a 12-year period (1990 to 2001), the incidence of confirmed cases was 2.2 per million population per year [6].


In nearly all cases of herpes encephalitis beyond the neonatal period, the etiologic agent is herpes simplex virus type 1 (HSV-1). In neonates, herpes encephalitis may be caused by either HSV-1 or HSV-2.

HSV-2 produces a more global encephalitis with significant neurologic impairment. In one series of 24 infants with HSV encephalitis and a mean follow-up of 19 months, only 4 of 14 (28 percent) survivors with HSV-2 encephalitis were neurologically normal compared to nine of nine infants with HSV-1 [7].

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Literature review current through: Nov 2017. | This topic last updated: Mar 21, 2017.
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  1. Hanley DF, Johnson RT, Whitley RJ. Yes, brain biopsy should be a prerequisite for herpes simplex encephalitis treatment. Arch Neurol 1987; 44:1289.
  2. Levitz RE. Herpes simplex encephalitis: a review. Heart Lung 1998; 27:209.
  3. Whitley RJ. Viral encephalitis. N Engl J Med 1990; 323:242.
  4. Whitley RJ, Kimberlin DW. Herpes simplex encephalitis: children and adolescents. Semin Pediatr Infect Dis 2005; 16:17.
  5. Huppatz C, Durrheim DN, Levi C, et al. Etiology of encephalitis in Australia, 1990-2007. Emerg Infect Dis 2009; 15:1359.
  6. Hjalmarsson A, Blomqvist P, Sköldenberg B. Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality. Clin Infect Dis 2007; 45:875.
  7. Corey L, Whitley RJ, Stone EF, Mohan K. Difference between herpes simplex virus type 1 and type 2 neonatal encephalitis in neurological outcome. Lancet 1988; 1:1.
  8. Hudson SJ, Dix RD, Streilein JW. Induction of encephalitis in SJL mice by intranasal infection with herpes simplex virus type 1: a possible model of herpes simplex encephalitis in humans. J Infect Dis 1991; 163:720.
  9. Barnett EM, Jacobsen G, Evans G, et al. Herpes simplex encephalitis in the temporal cortex and limbic system after trigeminal nerve inoculation. J Infect Dis 1994; 169:782.
  10. Stanberry LR, Floyd-Reising SA, Connelly BL, et al. Herpes simplex viremia: report of eight pediatric cases and review of the literature. Clin Infect Dis 1994; 18:401.
  11. Harel L, Smetana Z, Prais D, et al. Presence of viremia in patients with primary herpetic gingivostomatitis. Clin Infect Dis 2004; 39:636.
  12. Stroop WG, Schaefer DC. Production of encephalitis restricted to the temporal lobes by experimental reactivation of herpes simplex virus. J Infect Dis 1986; 153:721.
  13. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. Clin Infect Dis 2013; 57:849.
  14. Bradford RD, Pettit AC, Wright PW, et al. Herpes simplex encephalitis during treatment with tumor necrosis factor-alpha inhibitors. Clin Infect Dis 2009; 49:924.
  15. Pepose JS, Hilborne LH, Cancilla PA, Foos RY. Concurrent herpes simplex and cytomegalovirus retinitis and encephalitis in the acquired immune deficiency syndrome (AIDS). Ophthalmology 1984; 91:1669.
  16. Wildemann B, Ehrhart K, Storch-Hagenlocher B, et al. Quantitation of herpes simplex virus type 1 DNA in cells of cerebrospinal fluid of patients with herpes simplex virus encephalitis. Neurology 1997; 48:1341.
  17. Hudson SJ, Streilein JW. Functional cytotoxic T cells are associated with focal lesions in the brains of SJL mice with experimental herpes simplex encephalitis. J Immunol 1994; 152:5540.
  18. Koprowski H, Zheng YM, Heber-Katz E, et al. In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases. Proc Natl Acad Sci U S A 1993; 90:3024.
  19. Ikemoto K, Pollard RB, Fukumoto T, et al. Small amounts of exogenous IL-4 increase the severity of encephalitis induced in mice by the intranasal infection of herpes simplex virus type 1. J Immunol 1995; 155:1326.
  20. Hayashi K, Yanagi K, Takagi S. Detection of herpes simplex virus type 1-IgM immune complexes in the brain of a patient with prolonged herpes encephalitis. J Infect Dis 1986; 153:56.
  21. Prüss H, Finke C, Höltje M, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol 2012; 72:902.
  22. Whitley RJ, Cobbs CG, Alford CA Jr, et al. Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group. JAMA 1989; 262:234.
  23. Tyler KL, Tedder DG, Yamamoto LJ, et al. Recurrent brainstem encephalitis associated with herpes simplex virus type 1 DNA in cerebrospinal fluid. Neurology 1995; 45:2246.
  24. Hart RP, Kwentus JA, Frazier RB, Hormel TL. Natural history of Klüver-Bucy syndrome after treated herpes encephalitis. South Med J 1986; 79:1376.
  25. Fisher CM. Hypomanic symptoms caused by herpes simplex encephalitis. Neurology 1996; 47:1374.
  26. Nahmias AJ, Whitley RJ, Visintine AN, et al. Herpes simplex virus encephalitis: laboratory evaluations and their diagnostic significance. J Infect Dis 1982; 145:829.
  27. Razavi B, Razavi M. Herpes simplex encephalitis--an atypical case. Infection 2001; 29:357.
  28. Wasay M, Mekan SF, Khelaeni B, et al. Extra temporal involvement in herpes simplex encephalitis. Eur J Neurol 2005; 12:475.
  29. 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.
  30. Domingues RB, Fink MC, Tsanaclis AM, et al. Diagnosis of herpes simplex encephalitis by magnetic resonance imaging and polymerase chain reaction assay of cerebrospinal fluid. J Neurol Sci 1998; 157:148.
  31. McCabe K, Tyler K, Tanabe J. Diffusion-weighted MRI abnormalities as a clue to the diagnosis of herpes simplex encephalitis. Neurology 2003; 61:1015.
  32. Hatipoglu HG, Sakman B, Yuksel E. Magnetic resonance and diffusion-weighted imaging findings of herpes simplex encephalitis. Herpes 2008; 15:13.
  33. Heiner L, Demaerel P. Diffusion-weighted MR imaging findings in a patient with herpes simplex encephalitis. Eur J Radiol 2003; 45:195.
  34. Küker W, Nägele T, Schmidt F, et al. Diffusion-weighted MRI in herpes simplex encephalitis: a report of three cases. Neuroradiology 2004; 46:122.
  35. Launes J, Nikkinen P, Lindroth L, et al. Diagnosis of acute herpes simplex encephalitis by brain perfusion single photon emission computed tomography. Lancet 1988; 1:1188.
  36. Kataoka H, Inoue M, Shinkai T, Ueno S. Early dynamic SPECT imaging in acute viral encephalitis. J Neuroimaging 2007; 17:304.
  37. Rose JW, Stroop WG, Matsuo F, Henkel J. Atypical herpes simplex encephalitis: clinical, virologic, and neuropathologic evaluation. Neurology 1992; 42:1809.
  38. VanLandingham KE, Marsteller HB, Ross GW, Hayden FG. Relapse of herpes simplex encephalitis after conventional acyclovir therapy. JAMA 1988; 259:1051.
  39. Rowley AH, Whitley RJ, Lakeman FD, Wolinsky SM. Rapid detection of herpes-simplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet 1990; 335:440.
  40. Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet 2002; 359:507.
  41. Marano E, Briganti F, Tortora F, et al. Neurosyphilis with complex partial status epilepticus and mesiotemporal MRI abnormalities mimicking herpes simplex encephalitis. J Neurol Neurosurg Psychiatry 2004; 75:833.
  42. Szilak I, Marty F, Helft J, Soeiro R. Neurosyphilis presenting as herpes simplex encephalitis. Clin Infect Dis 2001; 32:1108.
  43. Giglio P, Bakshi R, Block S, et al. Primary central nervous system lymphoma masquerading as herpes encephalitis: clinical, magnetic resonance imaging, and pathologic findings. Am J Med Sci 2002; 323:59.
  44. Hasegawa T, Kanno S, Kato M, et al. Neuro-Behçet's disease presenting initially as mesiotemporal lesions mimicking herpes simplex encephalitis. Eur J Neurol 2005; 12:661.
  45. Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. Herpes 2004; 11 Suppl 2:57A.
  46. Boivin G. Diagnosis of herpesvirus infections of the central nervous system. Herpes 2004; 11 Suppl 2:48A.
  47. DeBiasi RL, Kleinschmidt-DeMasters BK, Weinberg A, Tyler KL. Use of PCR for the diagnosis of herpesvirus infections of the central nervous system. J Clin Virol 2002; 25 Suppl 1:S5.
  48. Soong SJ, Watson NE, Caddell GR, et al. Use of brain biopsy for diagnostic evaluation of patients with suspected herpes simplex encephalitis: a statistical model and its clinical implications. NIAID Collaborative Antiviral Study Group. J Infect Dis 1991; 163:17.
  49. Burns J, Redfern DR, Esiri MM, McGee JO. Human and viral gene detection in routine paraffin embedded tissue by in situ hybridisation with biotinylated probes: viral localisation in herpes encephalitis. J Clin Pathol 1986; 39:1066.
  50. Kahlon J, Chatterjee S, Lakeman FD, et al. Detection of antibodies to herpes simplex virus in the cerebrospinal fluid of patients with herpes simplex encephalitis. J Infect Dis 1987; 155:38.
  51. Lakeman FD, Koga J, Whitley RJ. Detection of antigen to herpes simplex virus in cerebrospinal fluid from patients with herpes simplex encephalitis. J Infect Dis 1987; 155:1172.
  52. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986; 314:144.
  53. Jeffries DJ. Clinical use of acyclovir. Br Med J (Clin Res Ed) 1985; 290:177.
  54. Sköldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients. Lancet 1984; 2:707.
  55. Gordon B, Selnes OA, Hart J Jr, et al. Long-term cognitive sequelae of acyclovir-treated herpes simplex encephalitis. Arch Neurol 1990; 47:646.
  56. Valencia I, Miles DK, Melvin J, et al. Relapse of herpes encephalitis after acyclovir therapy: report of two new cases and review of the literature. Neuropediatrics 2004; 35:371.
  57. De Tiège X, Rozenberg F, Des Portes V, et al. Herpes simplex encephalitis relapses in children: differentiation of two neurologic entities. Neurology 2003; 61:241.
  58. Pouplin T, Pouplin JN, Van Toi P, et al. Valacyclovir for herpes simplex encephalitis. Antimicrob Agents Chemother 2011; 55:3624.
  59. Arciniegas DB, Anderson CA. Viral encephalitis: neuropsychiatric and neurobehavioral aspects. Curr Psychiatry Rep 2004; 6:372.
  60. Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002; 35:254.
  61. Grydeland H, Walhovd KB, Westlye LT, et al. Amnesia following herpes simplex encephalitis: diffusion-tensor imaging uncovers reduced integrity of normal-appearing white matter. Radiology 2010; 257:774.
  62. Morris NA, Kaplan TB, Linnoila J, Cho T. HSV encephalitis-induced anti-NMDAR encephalitis in a 67-year-old woman: report of a case and review of the literature. J Neurovirol 2016; 22:33.
  63. Ellul MA, Griffiths MJ, Iyer A, et al. Anti-N-Methyl-D-Aspartate Receptor Encephalitis In A Young Child With Histological Evidence On Brain Biopsy Of Coexistent Herpes Simplex Virus Type 1 Infection. Pediatr Infect Dis J 2016; 35:347.
  64. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7:1091.