Herpes Simplex Encephalitis

Definition

Clinical Features

• Distinctive focal, necrotizing, and hemorrhagic encephalitis
• Annual prevalence 2–4/1,000,000
• Leads list of potentially fatal, nonepidemic cerebral infections of viral etiology1
• Any age
• Often fulminant in its evolution
• Characterized by:
  • fever
  • disordered affect
  • dysphasia
  • seizure activity
  • deterioration of consciousness

Pathogenesis

• Caused principally by herpes simplex virus type 1 (HSV-1)
• Has been documented with primary brain tumors:2,3
  • raises question whether neoplasm or its surgical or adjuvant management might trigger activation of latent CNS HSV infection
• ‘Limbic’ distribution:
  • reflects transolfactory spread to CNS
  • suggests that some cases follow activation of latent virus in cerebral tissues

Gross Pathology

• Remarkably stereotypic predilection for:
  • anteromedial temporal lobes
  • orbitofrontal cortex
  • insulae
  • cingulate gyri4,5

Histopathology

• Appearances vary considerably with duration4,5
• Earliest changes include:
  • neuronal shrinkage
  • eosinophilia
  • vascular congestion
  • spongy cortical rarefaction
  • pallor
• Eosinophilic intranuclear inclusion bodies:
  • typical but inconstant
  • most likely seen during early symptomatic disease (Fig. 1
    

    Fig. 1: HSE. As shown here, herpes simplex encephalitis may masquerade as a noninfectious, ischemic process (particularly if biopsied early in its clinical evolution). Note the noninflammatory appearance, neuronal shrinkage, pyknosis, and dissolution. The nucleus of an astrocyte in the center of this field contains a well-defined inclusion body.

    )
  • identified in nuclei of:
    • cortical astrocytes
    • satellite oligodendroglia
    • neurons
• Pronounced inflammatory reaction:
  • characteristic of fully developed HSE
  • usually in evidence by second week of clinical disease
  • lymphocytes and plasma cells:
    • colonize meninges
    • cuff penetrating blood vessels
    • migrate into devastated cortex
  • mononuclear cells:
    • may converge on infected neurons to form neuronophagic or so-called microglial nodules
  • accompanied by:
    • hemorrhage:
      • common
    • thrombosis
      • sometimes
    • fibrinoid necrosis of cerebral vasculature:
      • sometimes
• foamy macrophages:
  • eventually dominate invading cellular elements
    • ultimately clear necrotic debris:
      • only cavitated and gliotic remnants persist at sites of previous infection
  • Electron microscopy:
    • more laborious and less sensitive than immunocytochemistry:
      • similar appearances shared by other encephalitogenic herpes viruses
    • direct visualization of mature HSV particle in infected cells:
      • assembled in nucleus
      • an icosahedral nucleocapsid averaging 100–120nm in diameter
      • contains central density representing genomic DNA (Fig. 2
        

        Fig. 2: HSE. This transmission electron photomicrograph reveals enveloped nucleocapsids with an average diameter of 100nm in the cytoplasm of an infected cell. (× 62,000).

        )
      • typically acquire lipid envelope derived from host nuclear membrane on transport into cytoplasm

Special Stains and Immunohistochemistry

• Commercially available antibodies to HSV routinely employed
• Immunohistochemistry strongly recommended if clinically suspected, regardless of whether histology reveals an inflammatory process (Fig. 3
  

  Fig. 3: HSE. In this immunoperoxidase preparation, the cytoplasm of neurons and inclusion bodies within the nuclei of satellite glia are labeled by antibodies to herpes simplex type 1.

  ):
  • HSV antigen detection:
    • most likely to succeed during first week of encephalitic symptoms4
    • declines through second and third weeks coincident with mounting inflammatory reaction
    • usually not demonstrable thereafter but may be if:
      • immunocompromised, including due to cancer
      • HIV-type 1 infection3
        • appears to be arrested at noninflammatory, pseudoischemic phase characteristic of early HSE in otherwise normal individuals

Diagnosis

• Diagnostic method of choice:
  • PCR-based amplification of HSV DNA
• Electron microscopy and immunocytochemistry:
  • may provide evidence of HSV infection in biopsy showing little alteration at light microscopic level6

Other investigations

Differential Diagnosis

• Early histological changes:
  • closely mimic hypoxic-ischemic brain injury
  • may be misdiagnosed as acute cerebral infarction:
    • close scrutiny of degenerating neurons often reveals ground-glass alteration of nucleoplasm suggesting viral cytopathic effect