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.
- Pathogen: herpes simplex virus
- Transmission: See “ .”
- Infectivity: highly contagious
- HSV infection may lead to encephalitis in both immunocompetent and immunocompromised patients.
- Mechanism of brain infection
- Primary infection
Acute or subacute encephalopathy
- Focal neurological deficits (primarily affects the medial temporal lobe) 
- Seizures (focal or generalized)
- Altered mental status (e.g., confusion, disorientation, lowered level of consciousness)
- Behavioral changes (e.g., hypersexuality, hypomania, agitation)
- Meningeal signs (e.g., nuchal rigidity, photophobia) may occur.
- 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. 
- 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. 
Laboratory studies 
- Prior to LP 
- Simultaneous to LP: serum glucose
- Additional testing
CSF studies 
CSF PCR for HSV-1 and HSV-2: Gold standard test
- Allows for early detection of the pathogen 
- High sensitivity and specificity
- CSF analysis
|CSF analysis in herpes simplex encephalitis |
|Cell count and differential|
|Opening pressure|| |
MRI head: most sensitive and specific imaging modality 
- Indication: all patients with suspected HSE
CT head with and without intravenous contrast 
- Suspected raised intracranial pressure (see “Criteria for imaging prior to LP in suspected meningitis” for further information)
- Exclusion of differential diagnoses
- Patients with contraindications to MRI
Electroencephalography (EEG) 
- Macroscopic: typical temporal lobe distribution with visible necrosis
- Hemorrhagic-necrotizing inflammation
- Eosinophilic nuclear inclusions (Cowdry bodies)
- Other causes of encephalitis, for example:
- Migraine headache
The differential diagnoses listed here are not exhaustive.
Antimicrobial treatment for herpes simplex encephalitis 
All patients should be hospitalized and a neurology consult is highly recommended; intensive care must be readily available. 
- Antiviral treatment
- Add further antimicrobial treatment if indicated, e.g., for bacterial meningitis, until a definitive diagnosis is made (see “Empiric antibiotic therapy for bacterial meningitis”).
- Corticosteroids may be considered under specialist consultation.
Management of complications
- Elevated intracranial pressure: See “ICP management”.
- Seizure control
- Relapse: uncommon 
Acute management checklist for herpes simplex encephalitis
- Perform a thorough neurological examination.
- Obtain IV access and draw routine laboratory studies (e.g., CBC, BMP, liver chemistries).
- Check for rapidly reversible causes of altered mental status (e.g., point of care glucose).
- Identify and treat any life-threatening complications (e.g., airway compromise, ↑ ICP, status epilepticus).
- Order monitoring (e.g., cardiac monitoring, frequent neurological checks).
- Consider CT head if suspected ↑ ICP, intracranial hemorrhage, or intracranial abscess.
- Perform lumbar puncture if no and send CSF analysis including HSV PCR.
- Start empiric IV acyclovir prior to LP if strong clinical suspicion.
- Consider corticosteroids. and
- Order MRI head and EEG for stable patients.
- Consult neurology.
- Consult ICU for , refractory seizure control, or advanced .
- Consult infectious disease for immunocompromised patients or acyclovir resistance.
- Fatal in up to 70% of cases if left untreated 
- In patients receiving treatment, the mortality rate is still as a high as 20–30%. 
- Relapse may occur
- Residual deficits may remain in some cases (e.g., paresis, cognitive deficits, psychopathological symptoms)