eMedicine Specialties > Emergency Medicine > Neurology

Herpes Simplex Encephalitis

Author: Todd Pritz, MD, Intensivist, St Anthony's Medical Center and St John's Mercy Medical Center, St Louis, Missouri
Contributor Information and Disclosures

Updated: Oct 11, 2007

Introduction

Background

Despite advances in antiviral therapy over the past 2 decades, herpes simplex encephalitis (HSE) remains a serious illness with significant risks of morbidity and death.1,2,3 HSE occurs as 2 distinct entities.

  • In children older than 3 months and in adults, HSE is usually localized to the temporal and frontal lobes and is caused by herpes simplex virus type 1 (HSV-1).
  • In neonates, however, brain involvement is generalized, and the usual cause is herpes simplex virus type 2 (HSV-2), which is acquired at the time of delivery.

Unless noted otherwise, this article describes HSE as it occurs in older children and adults. (See Special Concerns for a discussion of neonatal HSE.) HSE must be distinguished from herpes simplex meningitis, which is more commonly caused by HSV-2 than by HSV-1, and which often occurs in association with a concurrent herpetic genital infection. Like other forms of viral meningitis, herpes simplex meningitis usually has a benign course and is not discussed in this article.

Pathophysiology

The pathogenesis of HSE is poorly understood. Neurons are quickly overwhelmed by a lytic and hemorrhagic process distributed in an asymmetric fashion throughout the medial temporal and inferior frontal lobes. Involvement of the basal ganglia, cerebellum, and brainstem is uncommon. The exact mechanism of cellular damage is unclear, but it may involve both direct virus-mediated and indirect immune-mediated processes. The ability of HSV-1 to induce apoptosis (programmed cell death, or "cellular suicide") in neuronal cells, a property not shared by HSV-2, might explain why the former causes virtually all cases of HSE in immunocompetent older children and adults.4,5

A vivid description of the temporal course of tissue destruction is given in an immunohistological autopsy study of patients succumbing to HSE over periods of days to weeks in the era prior to acyclovir:

The impression gained is of a rapidly spreading wave of viral infection within limbic structures, probably starting on one side of the brain and spreading within it and to the other side, lasting about 3 weeks and leaving in its wake a trail of devastatingly severe necrosis and inflammation in infected parts of the brain.6

Brain infection is thought to occur by means of direct neuronal transmission of the virus from a peripheral site to the brain via the trigeminal or olfactory nerve. Factors that precipitate HSE are unknown. The prevalence of HSE is not increased in immunocompromised hosts, but the presentation may be subacute or atypical in these patients.  HSV-2 may cause HSE in patients with HIV-AIDS.7,8,9

HSE represents a primary herpes simplex virus (HSV) infection in about one third of cases. The remaining cases occur in patients with serologic evidence of preexisting HSV infection and are due to reactivation of a latent peripheral infection in the olfactory bulb or trigeminal ganglion, or reactivation of a latent infection in the brain itself. A substantial number of neurologically asymptomatic individuals may have latent HSV present in the brain. In a postmortem study, HSV was present in the brains of 35% of patients with no evidence of neurological disease at the time of death.10

Frequency

United States

HSE is the most common cause of sporadic lethal encephalitis, occurring in about 1 person per 250,000-500,000 population per year.

Mortality/Morbidity

The mortality rate in untreated patients is 70%. Among treated patients, the mortality rate is 19%, and more than 50% of survivors are left with moderate or severe neurological deficits.

Race

No predilection for race exists.

Sex

The male-to-female ratio is 1:1.

Age

HSE has a bimodal distribution by age, with the first peak occurring in those younger than 20 years and a second occurring in those older than 50 years. HSE in younger patients usually represents primary infection, whereas reactivation of latent infection occurs in older persons.

Clinical

History

HSE is an acute or subacute illness, causing both general and focal signs of cerebral dysfunction. It is sporadic and occurs without a seasonal pattern. Although the presence of fever, headache, behavioral changes, confusion, focal neurological findings, and abnormal CSF findings are suggestive of HSE, no pathognomonic clinical findings reliably distinguish HSE from other neurological disorders with similar presentations (eg, non-HSV encephalitis, brain abscess, tumor).11 Confirmation of the diagnosis depends on the identification of HSV in the CSF by means of a polymerase chain reaction (PCR) or on the identification of HSV in brain tissue by means of brain biopsy (see Workup).

Typical symptoms include the following:12

  • Fever (90%)
  • Headache (81%)
  • Psychiatric symptoms (71%)
  • Seizures (67%)
  • Vomiting (46%)
  • Focal weakness (33%)
  • Memory loss (24%)

Physical

The most frequent findings on physical examination are fever and mental status abnormalities. Meningismus is uncommon.

Typical findings on presentation include the following:12

  • Alteration of consciousness (97%)
  • Fever (92%)
  • Dysphasia (76%)
  • Ataxia (40%)
  • Seizures (38%)
    • Focal (28%)
    • Generalized (10%)
  • Hemiparesis (38%)
  • Cranial nerve defects (32%)
  • Visual field loss (14%)
  • Papilledema (14%)

A causal or temporal relationship between peripheral lesions (eg, herpes labialis) and HSE does not exist. Also, many febrile diseases may precipitate herpes labialis. Therefore, the presence or absence of such lesions neither confirms nor excludes the diagnosis.

Causes

  • In children older than 3 months and in adults, HSV-1 is responsible for virtually all cases.
  • HSV-2 causes a small number of cases, particularly in the immunocompromised host.

More on Herpes Simplex Encephalitis

Overview: Herpes Simplex Encephalitis
Differential Diagnoses & Workup: Herpes Simplex Encephalitis
Treatment & Medication: Herpes Simplex Encephalitis
Follow-up: Herpes Simplex Encephalitis
References
[ CLOSE WINDOW ]

References

  1. Whitley RJ. Herpes simplex encephalitis: adolescents and adults. Antiviral Res. Sep 2006;71(2-3):141-8. [Medline].

  2. Whitley RJ, Kimberlin DW. Herpes simplex: encephalitis children and adolescents. Semin Pediatr Infect Dis. Jan 2005;16(1):17-23. [Medline].

  3. Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. Herpes. Jun 2004;11 Suppl 2:57A-64A. [Medline].

  4. Aurelian L. HSV-induced apoptosis in herpes encephalitis. Curr Top Microbiol Immunol. 2005;289:79-111. [Medline].

  5. DeBiasi RL, Kleinschmidt-DeMasters BK, Richardson-Burns S, Tyler KL. Central nervous system apoptosis in human herpes simplex virus and cytomegalovirus encephalitis. J Infect Dis. Dec 1 2002;186(11):1547-57. [Medline].

  6. Esiri MM. Herpes simplex encephalitis. An immunohistological study of the distribution of viral antigen within the brain. J Neurol Sci. May 1982;54(2):209-26. [Medline].

  7. Cinque P, Vago L, Marenzi R, Giudici B, Weber T, Corradini R. Herpes simplex virus infections of the central nervous system in human immunodeficiency virus-infected patients: clinical management by polymerase chain reaction assay of cerebrospinal fluid. Clin Infect Dis. Aug 1998;27(2):303-9. [Medline].

  8. Fodor PA, Levin MJ, Weinberg A, Sandberg E, Sylman J, Tyler KL. Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology. Aug 1998;51(2):554-9. [Medline].

  9. Osih RB, Brazie M, Kanno M. Multifocal herpes simplex virus type 2 encephalitis in a patient with AIDS. AIDS Read. Feb 2007;17(2):67-70. [Medline].

  10. Baringer JR, Pisani P. Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Ann Neurol. Dec 1994;36(6):823-9. [Medline].

  11. Whitley RJ, Cobbs CG, Alford CA Jr, Soong SJ, Hirsch MS, Connor JD, et al. Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group. JAMA. Jul 14 1989;262(2):234-9. [Medline].

  12. Whitley RJ, Soong SJ, Linneman C Jr, Liu C, Pazin G, Alford CA. Herpes simplex encephalitis. Clinical Assessment. JAMA. Jan 15 1982;247(3):317-20. [Medline].

  13. 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 Gr. J Infect Dis. Apr 1995;171(4):857-63. [Medline].

  14. Cinque P, Cleator GM, Weber T, Monteyne P, Sindic CJ, van Loon AM. The role of laboratory investigation in the diagnosis and management of patients with suspected herpessimplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis. J Neurol Neurosurg Psychiatry. Oct 1996;61(4):339-45. [Medline].

  15. Domingues RB, Lakeman FD, Mayo MS, Whitley RJ. Application of competitive PCR to cerebrospinal fluid samples from patients with herpes simplex encephalitis. J Clin Microbiol. Aug 1998;36(8):2229-34. [Medline].

  16. Wildemann B, Ehrhart K, Storch-Hagenlocher B, Meyding-Lamadé U, Steinvorth S, Hacke W, et al. Quantitation of herpes simplex virus type 1 DNA in cells of cerebrospinal fluid of patients with herpes simplex virus encephalitis. Neurology. May 1997;48(5):1341-6. [Medline].

  17. 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. Apr 15 2002;34(8):1154-7. [Medline].

  18. Rathmann K, Scott SA. Acyclovir. In: Drug Evaluation Monographs. Micromedex:2005.

  19. Stone KM, Reiff-Eldridge R, White AD, Cordero JF, Brown Z, Alexander ER. Pregnancy outcomes following systemic prenatal acyclovir exposure: Conclusions from the international acyclovir pregnancy registry, 1984-1999. Birth Defects Res A Clin Mol Teratol. Apr 2004;70(4):201-7. [Medline].

  20. National Institute of Allergy and Infectious Diseases. A Phase III Double-Blind, Placebo-Controlled Trial of Long Term Therapy of Herpes Simplex Encephalitis (HSE): An Evaluation of Valacyclovir (CASG-204). ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct/show/NCT00031486?order=1. Accessed August 8, 2007.

  21. Sergerie Y, Boivin G, Gosselin D, Rivest S. Delayed but not early glucocorticoid treatment protects the host during experimental herpes simplex virus encephalitis in mice. J Infect Dis. Mar 15 2007;195(6):817-25. [Medline].

  22. Thompson KA, Blessing WW, Wesselingh SL. Herpes simplex replication and dissemination is not increased by corticosteroid treatment in a rat model of focal Herpes encephalitis. J Neurovirol. Feb 2000;6(1):25-32. [Medline].

  23. Kamei S, Sekizawa T, Shiota H, Mizutani T, Itoyama Y, Takasu T, et al. Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatry. Nov 2005;76(11):1544-9. [Medline].

  24. Sköldenberg B, Aurelius E, Hjalmarsson A, Sabri F, Forsgren M, Andersson B, et al. Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults. J Neurol. Feb 2006;253(2):163-70. [Medline].

  25. Benson PC, Swadron SP. Empiric acyclovir is infrequently initiated in the emergency department to patients ultimately diagnosed with encephalitis. Ann Emerg Med. Jan 2006;47(1):100-5. [Medline].

  26. Kohl S. Herpes Simplex Virus. In: Behrman RE, Kliegman RM, Jenson HB. Behrman: Nelson Textbook of Pediatrics. 17th ed. Philadelphia: Saunders; 2004.

  27. Kimberlin D. Herpes simplex virus, meningitis and encephalitis in neonates. Herpes. Jun 2004;11 Suppl 2:65A-76A. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

herpes simplex encephalitis, HSE, herpes encephalitis, herpes simplex virus, HSV, herpes simplex virus type 1, HSV-1, herpes simplex virus type 2, HSV-2, sporadic fatal encephalitis, sporadic lethal encephalitis, viral encephalitis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Todd Pritz, MD, Intensivist, St Anthony's Medical Center and St John's Mercy Medical Center, St Louis, Missouri
Todd Pritz, MD is a member of the following medical societies: Massachusetts Medical Society and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Medical Editor

Robin R Hemphill, MD, MPH, Associate Professor, Director, Disaster Preparedness, Department of Emergency Medicine, Vanderbilt University Medical Center
Robin R Hemphill, MD, MPH is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

J Stephen Huff, MD, Associate Professor, Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center
J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: WebMD Salary Employment

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.