Herpes Simplex Keratitis (HSK)

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Contents

Aetiology

The Herpes simplex virus (HSV) is a common cause of viral infections of the eye. The infection can manifest as blepharoconjunctivitis, keratitis, anterior uveitis or acute retinal necrosis. 

The prevalence of HSV-1 infection varies with age, time and geographic setting, with European seroprevalence estimates ranging from 50–80%. HSV infections can be categorised into primary and recurrent disease. Infections are most commonly caused by the HSV-1 subtype, which primarily infects mucous membranes of the body ‘above the waist’, including the lips, face and eyes. HSV-2 generally infects ‘below the waist’ and is usually sexually acquired but may rarely cause keratitis, most often in neonates acquired through the birth canal. 

Herpes Simplex keratitis (HSK) is the most common ocular manifestation of HSV ocular infections (incidence 24 per 100,000 population) and is a leading cause of corneal blindness in developed countries. 

HSK is classified depending on the layer of the cornea affected (epithelial, stromal and endothelial). The most common form is epithelial keratitis, accounting for 50% to 80% of cases.

Predisposing factors

Poor general health, immunodeficiency, fatigue
Systemic or topical steroids, or other immunosuppressive drugs
Possible aggravating factors

  • sunlight (UV), fever, extreme heat or cold, infection (systemic or ocular), trauma (ocular)

History of previous attacks of ocular herpes simplex infection (key diagnostic feature)
Severe atopic disease

Symptoms of herpes simplex keratitis

Usually affects one eye; may be bilateral, especially in severely atopic patients
Severity of symptoms can be very variable and may include: pain, burning, irritation, photophobia, blurred vision, redness

Signs of herpes simplex keratitis

HSK has a highly variable and unpredictable course
Can be considered as a spectrum of four distinct disease entities (with differing management strategies):

Epithelial 
Initially punctate lesions, coalescing into dendriform pattern

  • dendritic ulcer, single or multiple opaque cells arranged in a stellate pattern progressing to a linear branching ulcer; terminal bulbs may be visible
  • dendritic lesions stain with fluorescein, edges of lesion, containing dead cells, stain with lissamine green
  • associated with reduced corneal sensitivity
  • continued enlargement may result in an ‘amoebic’ or ‘geographic’ ulcer (especially following inappropriate use of topical steroids)

Stromal
Stromal infiltrates, vascularisation, oedema and opacification, leading to scarring and vision impairment. Stromal HSK can be either necrotising or non-necrotising. In non-necrotising stromal HSK, the oedema is localised, and mostly self-limiting. In necrotising keratitis, the stromal inflammation is widespread and the infection progresses to ulceration, necrosis and possible perforation

Endothelial (Disciform) keratitis
Central or eccentric zone of epithelial oedema overlying an area of stromal thickening, folds in Descemet’s membrane, raised IOP, uveitis and keratic precipitates

Metaherpetic ulcer (trophic keratitis) 
Metaherpetic keratitis is the most severe form of HSV corneal infection. Recurrent attacks of HSV, bullous keratopathy, stromal involvement, endotheliitis, neovascularisation and anterior uveitis characterise the metaherpetic phase of the disease

Differential diagnosis

Herpes zoster keratitis
Bacterial, fungal or amoebic keratitis (NB Dendritic keratitis in a contact lens wearer should raise the index of suspicion of an Acanthamoeba infection)
Healing corneal epithelial defect (e.g. abrasion): may have stellate or dendritic profile
Anti-glaucoma agents-induced corneal toxicity may be misdiagnosed as HSK

Management by optometrist

Practitioners should recognise their limitations and where necessary seek further advice or refer the patient elsewhere

Non pharmacological

Exclude viral retinitis following pupil dilatation (especially in immunocompromised patients) as this would warrant emergency (same day) referral. Signs of viral retinitis include:

  • peripheral infiltrates
  • vasculitis
  • intra-retinal haemorrhages
  • vitreous inflammation

Pharmacological

Acute Herpes Simplex: in non-contact lens wearing adults and where HSK is confined to the epithelium with classic dendritic appearance, commence antiviral therapy with one of the following: 

  • oc. aciclovir 3% (the treatment should continue for at least 3 days after healing is complete)
  • ganciclovir 0.15% ophthalmic gel (treatment should continue for 7 days after the healing is complete).

NB: HSK is a potentially blinding disease and optometrists should consistently apply a low threshold for referral for this condition
(GRADE*: Level of evidence=moderate, Strength of recommendation=strong)

Recurrent Herpes Simplex: where there is:

  • a clear history of previous attacks
  • no doubt about the diagnosis and
  • only epithelial involvement
    • commence antiviral therapy (as above)

(GRADE*: Level of evidence=moderate, Strength of recommendation=strong)
 

Management category

B2 (modified) (acute or recurrent epithelial HSK with no stromal involvement): alleviation or palliation; monitor closely within first 72 hours to evaluate healing, but refer urgently (within one week) to ophthalmologist if epithelium has not healed after seven days
A1 (if stroma involved, or in children or contact lens wearers, or in bilateral cases): emergency (same day) referral to ophthalmologist

Possible management by ophthalmologist

Isolation and characterisation of virus from corneal swab or biopsy
PCR identification of HSV DNA or viral culture
Antivirals (topical and/or systemic antivirals such as aciclovir or famciclovir). Oral antivirals decrease the recurrence of stromal HSK by 50% when used prophylactically at low dose. There is no indication for prophylactic use for epithelial HSK, apart from for those patients with multiple recurrences.
Topical steroid
Anti-glaucoma agents for raised IOP
Epithelial débridement
Penetrating keratoplasty in some quiescent cases with scarring

Evidence base

*GRADE: Grading of Recommendations Assessment, Development and Evaluation (see www.gradeworkinggroup.org)

Sources of evidence

Arshad S, Petsoglou C, Lee T, Al-Tamimi A, Carnt NA. 20 years since the Herpetic Eye Disease Study: Lessons, developments and applications to clinical practice. Clin Exp Optom. 2021;104(3):396-405.

Chang HL, Kuo BI, Wu JH, Huang WL, Su CC, Chen WL. Anti-glaucoma agents-induced pseudodendritic keratitis presumed to be herpetic simplex keratitis: a clinical case series. Sci Rep. 2021;11(1):21443.

Rowe AM, St Leger AJ, Jeon S, Dhaliwal DK, Knickelbein JE, Hendricks RL. Herpes keratitis. Prog Retin Eye Res. 2013;32:88-101

Roozbahani M, Hammersmith KM. Management of herpes simplex virus
epithelial keratitis. Curr Opin Ophthalmol. 2018;29:360-4

Sibley D, Larkin DFP. Eye (Lond). Update on Herpes simplex keratitis management. 2020;34(12):2219-2226

Tsatsos M, MacGregor C, Athanasiadis I, Moschos MM, Hossain P, Anderson D. Herpes simplex virus keratitis: an update of the pathogenesis and current treatment with oral and topical antiviral agents. Clin Exp Ophthalmol. 2016;44(9):824-837

White ML, Chodosh J. Herpes Simplex Virus Keratitis: A Treatment Guideline 2014. 

Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst Rev. 2015;1:CD002898

Summary

What is Herpes Simplex Keratitis?

Up to 90% of people in the UK have an inactive nerve infection caused by herpes simplex virus type 1. This infection is usually acquired in childhood by contact with an adult. The viruses penetrate the skin and travel along the nerves of sensation to the central part of the nervous system (brain or spinal cord) where they become ‘latent’ and produce no symptoms. The infection cannot be eliminated and there is no protective vaccine. Another variety, herpes simplex type 2, is usually sexually transmitted, but can also affect the eye.

The infection remains inactive until some factor such as poor health, disturbance of the body’s immune system or certain drugs allow the virus to become active and then travel back down the nerves to the surface of the body. If this happens in the trigeminal nerve (the nerve that gives sensation to the head and neck), an infection of the skin such as a cold sore on the lip, or an infection of the eye surface, can occur. If the cornea (the clear window at the front of the eye) is involved, the condition is known as Herpes Simplex Keratitis. Usually only one eye is affected.

Several different forms of corneal infection are possible, ranging from slight to severe. One of them, affecting the surface skin of the cornea, produces ulcers with a characteristic branching outline and this is known as a dendritic ulcer. The infection can recur and if this happens scarring may result, which can cause blurring of vision.

How is Herpes Simplex Keratitis managed?

A new case, with involvement of the surface skin of the cornea only, will usually be treated by the optometrist with anti-viral eye ointment. In children, contact lens wearers and where the condition affects both eyes, same-day referral to the ophthalmologist is recommended. This is a condition which tends to recur from time to time. Recurrences involving only the surface skin of the cornea can often be managed by the optometrist, who will usually prescribe anti-viral eye ointment, but if this is not effective after a week, urgent referral to the ophthalmologist is recommended. If the vision has become badly affected by scarring of the cornea, a patient may be offered a corneal transplant.

Herpes Simplex Keratitis (HSK)
Version 16
Date of search 04.05.23
Date of revision 29.06.23
Date of publication 01.09.23
Date for review 03.05.25
© College of Optometrists