• Clinical science

Herpes simplex encephalitis (HSV encephalitis)

Abstract

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.

Epidemiology

  • 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.

Etiology

References:[2]

Pathophysiology

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

References:[3][2][4]

Clinical features

Prodromal phase

  • Duration: few hours to days
  • Nonspecific symptoms

Acute or subacute encephalopathy

  • Focal neurological deficits (primarily affects the medial temporal lobe)[5]
  • 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]

Diagnostics

Imaging

  • Magnetic resonance imaging
    • Most sensitive and specific imaging modality, especially in the early stages
    • T2 and FLAIR (fluid attenuation and inversion recovery) sequence: Hyperintense temporal lobe lesions and signal abnormalities (usually in the hippocampus)
  • Computed tomography
    • Often normal during the early stages
    • A unilateral hypodense zone can be observed in the insular cortex, which may become bitemporal with disease progression.

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
  • Focal lesions
    • Constant rhythmic deceleration of the EEG (particularly temporal and orbitofrontal localization, rarely generalized)
    • Epileptiform potential → increased potential for seizures

Pathology

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

References: [7]

Differential diagnoses

Differential diagnoses of meningitis and encephalitis
Condition Etiology Epidemiology Clinical features Diagnostics
Herpes simplex encephalitis
  • Herpes simplex virus
  • Prodrome with nonspecific symptoms (e.g., headache, fever)
  • Altered mental status
  • Focal neurological signs
  • Behavioural changes
CMV encephalitis
Creutzfeldt-Jakob disease
  • Infectious prions
  • Mean age of onset: ∼ 60 years of age
  • Rapidly progressing dementia
  • Cerebellar disorders (e.g., gait)
  • Myoclonus
  • Triphasic periodic sharp‑wave complexes on EEG
  • 14-3-3 protein in CSF
Rabies
  • Any age group
  • Possible history of bite injury from rabid animal
  • Skin: biopsy of back of neck
  • Saliva: RT-PCR
  • Negri bodies in postmortem brain tissue

Cryptococcal meningoencephalitis

  • Subacute or chronic presentation
  • Headache
  • Altered mental status
  • Nausea, vomiting
  • Cryptococcal culture and antigen test on blood and CSF

The differential diagnoses listed here are not exhaustive.

Treatment

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!

Prognosis

  • 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, especially:
    • In children
    • With inadequate treatment
    • During the first 3 months following completion of adequate treatment[6]
  • Residual deficits may remain in some cases (e.g., paresis, cognitive deficits, psychopathological symptoms)
    • Moderate deficits in 9% of cases
    • Severe deficits in 53% of cases[12]