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Herpes simplex encephalitis


Herpes simplex encephalitis (HSE) is an inflammation of the brain parenchyma, typically in the medial temporal lobe, that is caused by either herpes simplex virus 1 (HSV-1) or herpes simplex virus 2 (HSV-2). It is the most common cause of fatal sporadic encephalitis in the US. HSE has a bimodal distribution, commonly affecting patients younger than 20 years of age and older than 50 years of age. Patients with HSE typically present with a prodrome of headaches and fever, followed by sudden focal neurological deficits, altered mental status, and possible seizures. Characteristic clinical findings and brain imaging showing temporal lesions should raise suspicion for HSE. Lumbar puncture often reveals lymphocytic pleocytosis. The diagnosis is best confirmed with polymerase chain reaction (PCR) testing of cerebrospinal fluid. Because HSE has a rapidly progressive and potentially fatal course, treatment with acyclovir should begin as soon as the disease is suspected. The mortality rate is as high as 70% if left untreated, and relapse is possible but uncommon.


  • Bimodal distribution: < 20 years and > 50 years of age
  • Most common cause of fatal sporadic encephalitis in the US


Epidemiological data refers to the US, unless otherwise specified.




  • HSV infection may lead to encephalitis in both immunocompetent and immunocompromised patients.
  • Mechanism of brain infection
    • Primary infection
    • Reactivation


Clinical features

Prodromal phase

Acute or subacute encephalopathy

HSE may resemble bacterial meningitis, but the combination of altered mental status, seizures, and focal neurological deficits is more common for HSE!



Approach [7][8]

  • Strongly suspected HSE: Start immediate treatment prior to investigations (see “Antimicrobial treatment of herpes simplex encephalitis”).
  • All patients require:
  • Initial negative PCR with high clinical and/or radiological probability: Continue empiric treatment and repeat HSV PCR after 3–7 days. [9]
  • Further testing (e.g., brain biopsy) is not routinely required; consider if there are contraindications for LP or uncertain diagnosis in treatment-refractory patients.

Empiric treatment should be initiated while awaiting the definitive diagnosis, as the progression of HSE is very rapid. [7][10]

Laboratory studies [7][11]

Blood studies

  • Prior to LP [7][11][12]
  • Simultaneous to LP: serum glucose
  • Additional testing
    • Consider serum HSV PCR and HSV antibodies. [8]
    • Blood and throat cultures

CSF studies [8][7]

CSF analysis in herpes simplex encephalitis [7][10]
CSF parameters Findings
Cell count and differential
Opening pressure
  • Normal or ↑
  • Variable, normal to mild
  • Mild ↑
  • Normal (or similar to serum glucose)

Neuroimaging [7]

Always consider HSE when imaging suggests potential meningoencephalitis and temporal lobe involvement; bilateral temporal lobe abnormality is a pathognomic sign of HSE. [7]

Electroencephalography (EEG) [7]

  • Indication: all patients with suspected HSE encephalitis
  • Findings
    • Abnormal in > 80% of patients [10]
    • Characteristic finding: periodic lateralized epileptiform discharges from the affected temporal lobe


  • Macroscopic: typical temporal lobe distribution with visible necrosis
  • Microscopic:
    • Hemorrhagic-necrotizing inflammation
    • Eosinophilic nuclear inclusions (Cowdry bodies)

References: [14]

Differential diagnoses

The differential diagnoses listed here are not exhaustive.


Antimicrobial treatment for herpes simplex encephalitis [7][9][10]

All patients should be hospitalized and a neurology consult is highly recommended; intensive care must be readily available. [13]

Monitor for nephrotoxicity during treatment with acyclovir. Manage with adequate hydration and adjust dosages for renal function. [8][10]

Management of complications

Acute management checklist for herpes simplex encephalitis


  • Fatal in up to 70% of cases if left untreated [2]
  • In patients receiving treatment, the mortality rate is still as a high as 20–30%. [3]
  • Relapse may occur
  • Residual deficits may remain in some cases (e.g., paresis, cognitive deficits, psychopathological symptoms)
  • 1. Anderson WE. Herpes Simplex Encephalitis. In: Singh NN. Herpes Simplex Encephalitis. New York, NY: WebMD. http://emedicine.medscape.com/article/1165183-overview#a5. Updated June 15, 2016. Accessed November 6, 2016.
  • 2. Shorvon SD, Andermann F, Guerrini R. The Causes of Epilepsy: Common and Uncommon Causes in Adults and Children. Cambridge University Press; 2011: p. 468.
  • 3. Klein RS. Herpes simplex virus type 1 encephalitis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/herpes-simplex-virus-type-1-encephalitis?source=search_result&search=herpes%20encephalitis&selectedTitle=1~41. Last updated August 15, 2014. Accessed November 6, 2016.
  • 4. Anderson WE. Herpes Simplex Encephalitis. In: Singh NN. Herpes Simplex Encephalitis. New York, NY: WebMD. http://emedicine.medscape.com/article/1165183-overview#a3. Updated June 15, 2016. Accessed November 2, 2016.
  • 5. Anderson WE. Herpes Simplex Encephalitis Clinical Presentation. In: Singh NN. Herpes Simplex Encephalitis Clinical Presentation. New York, NY: WebMD. http://emedicine.medscape.com/article/1165183-clinical#showall. Updated June 15, 2016. Accessed November 6, 2016.
  • 6. Anderson WE. Herpes Simplex Encephalitis. In: Singh NN. Herpes Simplex Encephalitis. New York, NY: WebMD. http://emedicine.medscape.com/article/1165183-overview#showall. Updated June 15, 2016. Accessed November 6, 2016.
  • 7. Tunkel AR, Glaser CA, Bloch KC, et al. The Management of Encephalitis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2008; 47(3): pp. 303–327. doi: 10.1086/589747.
  • 8. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical; 2018.
  • 9. Stahl JP, Mailles A. Herpes simplex virus encephalitis update. Current Opinion in Infectious Diseases. 2019; 32(3): pp. 239–243. doi: 10.1097/qco.0000000000000554.
  • 10. Gnann JW, Whitley RJ. Herpes Simplex Encephalitis: an Update. Current Infectious Diseases Reports. 2017; 19(3). doi: 10.1007/s11908-017-0568-7.
  • 11. Walls R, Hockberger R, Gausche-Hill M. Rosen's Emergency Medicine. Philadelphia, PA: Elsevier Health Sciences; 2018.
  • 12. Chaudhuri A, Kennedy PGE. Diagnosis and treatment of viral encephalitis. Postgraduate Medical Journal. 2002; 78(924): pp. 575–583. doi: 10.1136/pmj.78.924.575.
  • 13. Steiner I, Budka H, Chaudhuri A, et al. Viral encephalitis: a review of diagnostic methods and guidelines for management. European Journal of Neurology. 2005; 12(5): pp. 331–343. doi: 10.1111/j.1468-1331.2005.01126.x.
  • 14. Patel MR. Imaging in Herpes Encephalitis. In: Smirniotopoulos JG. Imaging in Herpes Encephalitis. New York, NY: WebMD. http://emedicine.medscape.com/article/341142-overview. Updated July 14, 2015. Accessed November 6, 2016.
  • 15. Gilbert, DN; Chambers, HF. Sanford Guide to Antimicrobial Therapy 2020. Antimicrobial Therapy, Inc; 2020.
  • 16. Bergmann M, Beer R, Kofler M, Helbok R, Pfausler B, Schmutzhard E. Acyclovir resistance in herpes simplex virus type I encephalitis: a case report. Journal of Neurovirology. 2016; 23(2): pp. 335–337. doi: 10.1007/s13365-016-0489-5.
  • 17. Schulte EC, Sauerbrei A, Hoffmann D, Zimmer C, Hemmer B, Mühlau M. Acyclovir resistance in herpes simplex encephalitis. Annals of Neurology. 2010; 67(6): pp. 830–833. doi: 10.1002/ana.21979.
  • 18. Pandey S, Rathore C, Michael BD. Antiepileptic drugs for the primary and secondary prevention of seizures in viral encephalitis. Cochrane Database of Systematic Reviews. 2016. doi: 10.1002/14651858.cd010247.pub3.
  • Venkatesan A, Geocadin RG. Diagnosis and management of acute encephalitis: A practical approach. Neurology: Clinical Practice. 2014; 4(3): pp. 206–215. doi: 10.1212/cpj.0000000000000036.
  • Anderson WE. Herpes Simplex Encephalitis. In: Singh NN. Herpes Simplex Encephalitis. New York, NY: WebMD. http://emedicine.medscape.com/article/1165183-overview#a6. Updated June 15, 2016. Accessed November 6, 2016.
last updated 11/10/2020
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