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

Other herpes viruses may cause encephalitis but much less frequently than herpes simplex. However cytomegalovirus (CMV) encephalitis should be considered in those with immunodeficiency.

Epidemiology

• Herpes simplex encephalitis (HSE) is the most common non-epidemic encephalitis.
• The incidence is about 1 case per million population per year.²
• About 30% of all infections occur in children, either acquired through maternal genital infection at birth or sporadic encephalitis in later childhood.³
• A second peak in age distribution occurs in those older than 50 years, mainly as a result of reactivation of latent infection.

Presentation

Clinical diagnosis is suggested by encephalopathy, with fever and focal neurological signs. However, numerous other infections in the central nervous system can mimic herpes simplex encephalitis (HSE).⁴

• Prodrome of malaise, fever, headache, nausea and vomiting.
• This is followed by acute or subacute onset of:
  • Altered consciousness
  • Focal and generalised seizures
  • Features of raised intracranial pressure, including papilloedema
  • Focal neurological signs, including hemiparesis and cranial nerve lesions
  • Psychiatric symptoms, behavioural abnormalities, confusion and delirium
  • Hallucinations of taste and smell, anosmia, amnesia, dysphasia and visual field loss
• Herpetic lesions are rarely seen on skin or mucosa, except for genital transmission of HSV-2

Differential diagnosis

• Meningitis
• Other infective causes of encephalitis, e.g. togavirus, Rocky Mountain spotted fever
• Postinfectious encephalomyelitis, e.g. subacute sclerosing panencephalitis
• Intracranial abscess (bacterial, fungal, parasitic)
• Cerebrovascular disease, intracranial haemorrhage
• Intracranial tumours
• Toxic and metabolic encephalopathies

Investigations

• Full blood count and blood film, renal function, electrolytes, blood cultures.
• CT scan or MRI scan, may show a temporal mass-like lesion: MRI is more sensitive than CT scan and is now the imaging study of choice.⁵
• EEG: shows abnormalities in about 80% of cases of herpes simplex encephalitis (HSE). These include focal temporal changes, diffuse slowing, periodic complexes and periodic lateralising epileptiform discharges.
• Lumbar puncture:
  • Only after a mass-effect lesion has been excluded by imaging.
  • Mildly elevated protein, normal or slightly low glucose, and a moderate pleocytosis (mostly mononuclear cells). Red blood cells and xanthochromia may be seen.
  • Herpes infection can usually be confirmed by identification of virus in CSF by a polymerase chain reaction (PCR), which is the diagnostic test of choice to detect herpes simplex virus (HSV) DNA. PCR is highly specific and it remains positive for up to 5 days after initiation of treatment.⁵ PCR is therefore an excellent test but false negatives can occur early after disease onset.⁴
• Brain biopsy: allows identification of HSV in brain tissue but is rarely indicated because of effective methods of diagnosis and relatively nontoxic and effective antiviral medications.

Management

• The patient may require immediate resuscitation.
• Start intravenous aciclovir as soon as herpes simplex encephalitis (HSE) is suspected and do not wait for confirmation.
• Intravenous aciclovir is usually given for at least 10 days and in some cases for up to 21 days.
• The role of steroids in the treatment of HSE remains uncertain.¹
• General nutritional and fluid support, with careful attention to fluid balance. Close monitoring of vital signs and signs of raised intracranial pressure.
• Increased intracranial pressure:
  • See separate article Rising Intracranial Pressure.
  • Surgical decompression is indicated for impending uncal herniation or intolerable increased intracranial pressure.⁶
• Control of seizures.

Complications

• Common sequelae among survivors include mental retardation, motor deficits, memory loss, ataxia, dysphasia, seizures and cranial nerve lesions.
• Cognitive and memory deficits are common. Anterograde memory is often impaired, even after successful treatment. Retrograde memory and language ability may also be impaired.⁷
• If treatment of herpes simplex encephalitis (HSE) is delayed, permanent neurological deficits may occur in survivors. Even in treated cases of HSE, complications and sequelae are not uncommon.

Prognosis

• Untreated herpes simplex encephalitis (HSE) is progressive and often fatal within 7-14 days. There is a 70% mortality rate in untreated patients and more than half of the untreated survivors have severe neurological deficits.⁸
• Among treated patients, the mortality rate is 19%.¹
• Even with early administration of therapy, nearly two thirds of survivors will have significant residual neurological deficits.⁴
• Patients who have a shorter delay between presentation and treatment have a better cognitive outcome.⁶
• Relapses following HSE may happen, with most relapses occurring within the first 3 months after completion of treatment.¹

Document references

1. Pritz T; Herpes Simplex Encephalitis, eMedicine, Jan 2010
2. Kennedy PG, Chaudhuri A; Herpes simplex encephalitis. J Neurol Neurosurg Psychiatry. 2002 Sep;73(3):237-8.
3. Lahat E, Barr J, Barkai G, et al; Long term neurological outcome of herpes encephalitis. Arch Dis Child. 1999 Jan;80(1):69-71. [abstract]
4. Whitley RJ, Kimberlin DW; Herpes simplex encephalitis: children and adolescents. Semin Pediatr Infect Dis. 2005 Jan;16(1):17-23. [abstract]
5. Chaudhuri A, Kennedy PG; Diagnosis and treatment of viral encephalitis.; Postgrad Med J. 2002 Oct;78(924):575-83. [abstract]
6. Yan HJ; Herpes simplex encephalitis: the role of surgical decompression. Surg Neurol. 2002 Jan;57(1):20-4. [abstract]
7. Tookey P, Peckham CS; Neonatal herpes simplex virus infection in the British Isles. Paediatr Perinat Epidemiol. 1996 Oct;10(4):432-42. [abstract]
8. Whitley RJ, Soong SJ, Dolin R, et al; Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study. N Engl J Med. 1977 Aug 11;297(6):289-94. [abstract]
9. Utley TF, Ogden JA, Gibb A, et al; The long-term neuropsychological outcome of herpes simplex encephalitis in a series of unselected survivors. Neuropsychiatry Neuropsychol Behav Neurol. 1997 Jul;10(3):180-9. [abstract]
10. Jones CA, Walker KS, Badawi N; Antiviral agents for treatment of herpes simplex virus infection in neonates. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD004206. [abstract]
11. Hollier LM, Wendel GD; Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD004946. [abstract]

Internet and further reading

• Encephalitis Information Resource

Acknowledgements