• Clinical science

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 type-1 (HSV-1) or type-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 and altered mental status. Characteristic clinical findings and brain imaging showing temporal lesions should raise suspicion of 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. Relapse of HSE is possible. The mortality rate is as high as 70% in the absence of appropriate treatment.


  • 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!




When imaging points to potential meningoencephalitis and temporal lobe involvement, HSE should always be considered.

Lumbar puncture

  • PCR (gold standard): : direct, early detection of the pathogen [3]
  • Cells
  • Other parameters
    • Opening pressure: normal or elevated
    • Protein levels: slightly elevated, cerebrospinal fluid (CSF)/serum albumin ratio
    • Glucose levels: normal
    • Lactate: varies, mainly normal to slightly elevated

Electroencephalography (EEG)

  • Unilateral or bilateral lobe discharge


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

References: [7]

Differential diagnoses

The differential diagnoses listed here are not exhaustive.


Treatment should be initiated while awaiting definitive diagnosis of the condition, as the progression of HSE is very rapid! [8]

Be cautious of acyclovir nephrotoxicity! Manage with adequate hydration and dose tapering; do not switch to foscarnet, which is even more nephrotoxic!


  • 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)