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

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen: herpes simplex virus
  • Neonates: both HSV-1 and HSV-2
  • Adult: usually HSV-1
• Transmission: See “Herpes simplex virus infections.”
• Infectivity: highly contagious

References:^[2]

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

References:^[2][3][4]

Prodromal phase

• Duration: a few hours to days
• Nonspecific symptoms
  • Fever
  • Headache
  • Nausea and vomiting
  • Malaise

Acute or subacute encephalopathy

• Focal neurological deficits (primarily affects the medial temporal lobe) ^[5]
  • Altered sense of smell and loss of vision
  • Aphasia
  • Memory loss
  • Hemiparesis
  • Ataxia
  • Hyperreflexia
• 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.
• Coma

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

References:^[6]

Approach ^[7][8]

• Strongly suspected HSE: Start immediate treatment prior to investigations (see “Antimicrobial treatment of herpes simplex encephalitis”).
• All patients require:
  • Lumbar puncture (LP) with CSF analysis and HSV PCR; Do not delay empiric treatment if LP is delayed.
  • MRI head
  • EEG
• 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]
  • CBC
  • Liver chemistries
  • BMP
  • Coagulation parameters
• Simultaneous to LP: serum glucose
• Additional testing
  • Consider serum HSV PCR and HSV antibodies. ^[8]
  • Blood and throat cultures

CSF studies ^[7][8]

• CSF PCR for HSV-1 and HSV-2: Gold standard test
  • Allows for early detection of the pathogen ^[10]
  • High sensitivity and specificity
• CSF analysis
  • May be normal in immunocompromised patients
  • For a comparison to other CNS infections see “CSF analysis in meningitis.”

• Additional testing
  • CSF antibody detection
  • CSF cultures ^[10]

Neuroimaging ^[7]

• MRI head: most sensitive and specific imaging modality ^[10]
  • Indication: all patients with suspected HSE
  • Findings
    • Characteristic features include signs of unilateral or bilateral temporal lobe edema and/or hemorrhage.
      • T1 sequence: hypointense temporal lobe areas
      • T2/FLAIR sequence: hyperintense temporal lobe lesions and signal abnormalities ^[8]
    • The frontal lobe or insular cortex may also be affected.
• CT head with and without intravenous contrast ^[11]
  • Indications
    • 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
  • Findings
    • Early stages : often no detectable abnormalities ^[12][13]
    • Later stages: unilateral or bilateral hypodense zones in the temporal lobe

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
• 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]

• Other causes of encephalitis, for example:
  • CMV encephalitis in immunocompromised patients (see also HIV-associated CNS lesions)
  • Autoimmune encephalitis (e.g., anti-NMDA encephalitis)
  • Paraneoplastic encephalomyelitis
  • Rabies
  • Creutzfeldt-Jakob disease
  • Cryptococcal meningoencephalitis
• Meningitis
• Stroke
• Epilepsy
• Migraine headache

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]

• Antiviral treatment
  • Start immediate treatment with intravenous acyclovir without waiting for diagnostic confirmation.
  • Duration of treatment: 14–21 days ^[15]
  • Patients with acyclovir resistance and immunocompromised patients: Consult infectious diseases. ^[16][17]
• Additional 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.

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

Management of complications

• Elevated intracranial pressure: See “ICP management”.
• Seizure control
  • Prophylactic anticonvulsant therapy is not recommended. ^[18]
  • For actively seizing patients, administer standard anticonvulsant therapy (see “Status epilepticus”).
• Relapse: uncommon ^[10]
  • Symptoms of relapse may be caused by autoimmune encephalitis (triggered by initial HSV infection).
  • Specialist consultation is recommended for advanced treatment (e.g., immunotherapy).

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 LP contraindications and send CSF analysis including HSV PCR.
• Start empiric IV acyclovir prior to LP if strong clinical suspicion.
• Consider empiric antibiotics for bacterial meningitis and corticosteroids.
• Order MRI head and EEG for stable patients.
• Consult neurology.
• Consult ICU for ICP management, refractory seizure control, or advanced airway management.
• Consult infectious disease for immunocompromised patients or acyclovir resistance.

• Fatal in up to 70% of cases if left untreated ^[2]
• In patients receiving treatment, the mortality rate is still as high as 20–30%. ^[3]
• Relapse may occur.
• Residual deficits may remain in some cases (e.g., paresis, cognitive deficits, psychopathological symptoms)

• There are no known effective strategies for preventing herpes simplex encephalitis in older children (beyond the neonatal period) or adults. ^[19]
• Although the herpes simplex virus itself is highly contagious, person-to-person transmission of HSV encephalitis has not been described, and neither isolation nor chemoprophylaxis for close contacts is necessary.