Periocular Herpes simplex virus (HSV)

Herpes simplex virus can involve any layer of the eye, including the eyelids (blepharitis), conjunctiva (conjunctivitis), cornea (keratitis, corneal endotheliitis), anterior uvea (iritis), posterior uvea (choroiditis), retina (retinitis), retinal vessels (retinal vasculitis), optic disk (optic disc papillitis) or some combination of these entities (ie. belpharoconjunctivitis). This review will focus primarily on periocular manifestations of HSV infection.

Etiology

• Infection with the Herpes simplex virus.
  • A double stranded DNA virus.
  • Two subtypes: Herpes simplex virus 1 and 2 (HSV-1, HSV-2).
    • HSV-1 typically causes periocular and ocular infection.
    • Infection persists for life.
  • Virulence is thought to be mediated by viral production of the US11 protein, which prevents the host’s immune system from antagonizing viral protein translation.
• Primary infection generally occurs in childhood.
  • May or may not be symptomatic.
  • Typically acquired from direct contact with lesions or infected secretions.
• Once the virus enters host cells, it undergoes retrograde transport to sensory neuronal ganglia.
  • Disease is harbored in the trigeminal ganglion in nearly 100% of individuals who experience periocular and ocular HSV (Valerio, 2019).
• In the sensory ganglia, DNA is epigenetically modified and the virus becomes latent.
• Recurrent infection occurs during periods of cellular stress.
  • The virus spreads in an anterograde direction from nerves to mucocutaneous sites.
  • Viral replication at these sites leads to lesion development.
  • This mechanism of viral movement is known as zosteriform spread.
• While primary herpetic eye disease often involves the periocular region, typically manifesting as blepharitis or blepharoconjunctivitis, recurrent disease almost always affects the cornea, causing keratitis.

Epidemiology

• • There are up to 50,000 cases of new or recurrent periocular and ocular HSV in the United States each year (Wilhelmus, 1998).
  • Incidence of herpes simplex virus keratitis and other ocular disease: global review and estimates
    • Over 1.8 million people may have herpetic eye disease annually.
  • Disease is often acquired early in life.
    • 50-80% of individuals have HSV-1 autoantibodies by 30 years of age (Barker, 2008).
  • Risk factors for recurrent disease (typically keratitis) in individuals who have experienced at least one episode of periocular or ocular HSV include (Herpetic Eye Disease Study Group, 2000):
    • Fever
    • UV light
    • Ocular surgery
    • Immunosuppression
      • The use of high dose inhaled corticosteroids for chronic obstructive pulmonary disease (COPD) has been reported to precipitate reactivation of ocular HSV, manifesting as blepharitis with keratoconjunctivitis (Garcia-Medina, 2011).
    • The Herpetic Eye Disease Study Group found no significant association between high psychological stress levels or systemic infection and recurrence of HSV eye disease.
    • Notably, recurrent disease almost always manifests as keratitis.

History

• Individuals may experience a prodrome of pain and/or paresthesias in the periocular region.

Clinical features

• Eruption of clustered vesicles on an erythematous base.
  • HSV blepharitis and blepharoconjunctivitis typically cause lesions on the periocular skin and eyelids with erythema and edema (Figure 1).
  • Disease is typically unilateral in adults, but more likely to be bilateral in children.
• Other features:
  • Bursting of vesicles with periocular crusting
  • Pain and tenderness
  • Photophobia
  • Lymphadenopathy

Other diagnostic studies

• Periocular HSV is a clinical diagnosis.
• HSV polymerase chain reaction (PCR) and viral culture of epithelial scrapings can only be used to confirm diagnosis in entities with active replication of virus (i.e. epithelial keratitis, endotheliitis, retinitis).

• Eczema herpeticum
• Herpes zoster ophthalmicus
• Preseptal cellulitis
• Allergic blepharoconjunctivitis
• Toxin exposure (i.e. poison ivy)

• Medical therapy for blepharitis and blepharoconjunctivitis:
• Topical antibiotic ointment to prevent bacterial superinfection of ruptured vesicles.
• Oral acyclovir is required if systemic symptoms are present (rare).
• Oral antiviral prophylaxis in adults reduces ocular and periocular recurrence by approximately 50% (Wilhelmus, 1998).
• Prophylaxis is controversial in children as it has not been adequately studied.
• Glucocorticoids, although essential for HSV keratitis, should be used with caution in HSV blepharitis and blepharoconjunctivitis as they are implicated in further invasion of disease.
• They should not be initiated if the virus is actively replicating on the cornea as in epithelial keratitis.
• Surgical therapy is sometimes required if disease spreads and causes severe corneal damage.
• Some surgical interventions that may be required for significant corneal thinning or perforation include:
• Tarsorrhaphy
• Conjunctival flap
• Tectonic keratoplasty
• Prognosis: dependent on the extent of disease
• HSV isolated to the eyelid is typically self-limiting and non-scarring.
• Disease can spread into the eye causing a variety of complications (see below).
• Recurrence (typically manifesting as keratitis) occurs at rates as high as 50% in 5 years (Barker, 2008).

• Primarily due to spread of disease into the eye. This may result in permanent vision impairment, with HSV being the number one cause of monocular corneal blindness worldwide (Barker, 2008).
• Corneal ulceration
• Corneal scarring
• Corneal thinning and perforation
• Corneal neovascularization  
• Chronic keratitis
• Neurotrophic keratitis (i.e. viral-induced degradation of corneal nerves)
• Scleritis
• Iris atrophy
• Cataract
• Secondary glaucoma
• Cystoid macular edema
• Retinal necrosis
• Retinal detachment
• Optic neuritis

Photograph courtesy of Roman Shinder, MD.
Figure 1. Herpes simplex blepharitis in a child with crusted vesicles, erythema and edema of the upper and lower eyelids.

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