Herpes simplex eye infections

Overview¹

There are two types of herpes simplex virus (HSV) which are capable of causing an acute viral infection characterised by clusters of vesicles.

• HSV-1 mainly causes infection above the waist (characteristically the face, lips and eyes) and is spread by saliva.

• HSV-2 generally gives rise to sexually transmitted infection (genital herpes) and is spread by direct genital contact via infected secretions. Occasionally, the latter can give rise to ocular infection either venereally or at birth (ophthalmia neonatorum) during a vaginal delivery.

Primary herpes simplex eye infections usually occur in childhood (rarely before 6 months old) and adolescence. It may manifest itself as a vesicular ulcerative blepharitis or a follicular conjunctivitis but up to 99% of cases are subclinical.

The most common site of this infection is the skin and mucous membranes supplied by the trigeminal nerve (95% of cases). After the acute infection, the virus will remain in the cell body of the trigeminal nerve until a trigger factor reactivates it, so giving rise to secondary infection.

Herpes simplex eye infections¹

Herpes simplex can infect the eye at one or more levels:

• Lids and surrounding skin - seen as blepharitis and dermatitis respectively.

• Conjunctiva - characterised by conjunctivitis.

• Cornea - keratitis. This is inflammation of one or more of the three corneal layers:

  • Epithelial keratitis is the most common ocular manifestation, occurring in up to 80% of cases. It is characterised by dendritic ulcers.

  • The stroma and endothelium can also be affected. Stromal infection may be non-necrotising (disciform keratitis) or, more rarely, necrotising (and may be associated with severe complications, including perforation). Keratitis can lead to scarring and visual disturbance or, in severe cases, visual loss. Indeed, it is the most common infective cause of blindness due to corneal disease in high-income countries.

• Uveal tract - uveitis: patients have usually had severe corneal disease.

• Retina - retinitis: this is rare and may be seen in neonates with severe systemic disease.

How common are herpes simplex eye infections?(Epidemiology)¹

• Ocular herpes simplex infections have an incidence of 5-15 new cases per 100,000 people per year.

• The overall prevalence in developed countries is 149 cases per 100,000 population.

• Men and women are affected equally.

• Up to 12% of people with ocular herpes simplex have bilateral infection, most often younger age groups.

Herpes simplex eye infection symptoms¹

Primary HSV infection

Ubiquitous disease with no apparent risk factors other than contact with an infected individual or an infected mother in the case of ophthalmia neonatorum.

• Usually occurs in children aged 6 months to 5 years. Over 90% are subclinical.

• May have generalised symptoms of a viral illness (upper respiratory tract infection, mild fever, malaise).

• May experience photophobia.

• In immunocompromised individuals and neonates: may become generalised and life-threatening. Neonatal infection is rare but has a high mortality rate.²

Examination

• Unilateral clear skin vesicles on erythematous base (lids, periorbital area), which eventually crust over.

• Acute unilateral follicular conjunctivitis.

• There may be associated punctate keratitis.

• Preauricular lymphadenopathy.

• May have secondary nasolacrimal duct obstruction.

Secondary (recurrent) HSV

Trigger factors
These may include:

• Stress (emotional or physical).

• Sunlight (or any ultraviolet (UV) light).

• Fever or illness.

• Trauma (including surgical).

• Menstruation.

• Cold wind.

• Use of contact lenses.³

• Immunosuppression.

• Trigeminal nerve manipulation.

• Topical latanoprost treatment (for glaucoma).⁴

Symptoms

• Unilateral in about 88% of cases. (Immunosuppression: more likely to be bilateral.)

• Red eye.

• Pain.

• Photophobia.

• Epiphora (tearing).

• History of previous episodes.

• May complain of blurred vision.

Examination

• Assess visual acuity.

• Examine lids and conjunctiva for evidence of inflammation. Involvement here is less common in secondary infection although conjunctival injection (red eye) is almost universal. There may be erosions around the lid margin with the presence of small vesicles or pustules.

• Observe cornea: any opacities or haziness? This may suggest stromal involvement.

• Test corneal sensation (twist the corner of a clean, dry tissue paper to a point and gently touch the corneal surface: this should elicit brisk blepharospasm and some sort of negative comment from the patient) - this can be reduced in epithelial disease.

• Stain the cornea and look for evidence of ulcers by staining with fluorescein. Corneal ulcers in HSV infection:

  • Dendritic - most common: linear branching lesions with terminal bulbs.

  • Geographic - as with dendritic but the linear component widens, giving rise to amoeboid appearance.

  • Marginal - ulcer at the edge of cornea: stromal involvement more likely.

  • Corneal vesicles - only apparent on slit-lamp examination: epithelial vesicles corresponding to skin lesions (eventually coalesce to give rise to the above ulcers).

• There may be associated uveitis which is characterised by limbal injection (redness around the rim of the cornea) and there may be an irregularly shaped pupil owing to posterior synechiae.

• Assess for evidence of tender preauricular lymphadenopathy, systemic illness and, in infants with confirmed ophthalmia neonatorum, assessment of the mother (± sexual partners) for evidence of HSV-2 infection is necessary.

Neonatal ocular HSV

This serious condition usually results in conjunctivitis, epithelial or stromal keratitis, cataracts, iridocyclitis, chorioretinitis and optic neuritis. Referral is mandatory for a full assessment and for further management.

Differential diagnosis

• Herpes zoster ophthalmicus (think of this in the elderly patient).

• Conditions causing epithelial defects (notably abrasions, recurrent corneal erosion, acanthamoeba keratitis, and keratitis of other aetiology).

• Contact lens-related problems.

• Other corneal conditions such as corneal graft rejection, or toxic keratopathies secondary to topical medication.

• Conditions causing conjunctivitis.

• Other conditions causing red eye.

• Orbital cellulitis.

Investigations¹

Most cases will be confirmed clinically and do not require further investigation following ophthalmological review. However, if there is doubt over the diagnosis, corneal or skin scrapings can be taken and a viral swab may be performed (after de-roofing the corneal vesicles). Polymerase chain reaction (PCR) can identify minute quantities of herpes simplex viral DNA in tissue samples and tears. Real-time PCR may be a useful technique for rapid diagnosis of ocular HSV infection, particularly in the identification of aciclovir-resistant keratitis.⁵

High-resolution optical coherence tomography (OCT) may be a useful imaging tool in the future diagnosis of HSV keratitis.

Herpes simplex eye infection treatment^{1 6}

General principles

Misdiagnosis or inappropriate treatment can lead to serious (sometimes sight-threatening) sequelae. Have a high index of suspicion - and refer if in doubt! Steroid therapy should never be initiated in the primary care setting. Treatment should only be initiated in primary care in exceptional circumstances - eg, in recurrent herpes simplex infection as part of a shared care arrangement with a specialist.

Specialist diagnosis of ocular herpes simplex may be made by:

• Slit-lamp examination which may show corneal vesicles.

• Corneal or skin scrapings, or a viral swab, which can be analysed by viral culture and/or polymerase chain reaction (PCR), to detect herpes simplex virus (HSV) DNA.

Recommend avoid touching the lesions where possible, and wash hands with soap and water immediately if needed. Advise not to use contact lenses until 24 hours after all symptoms have resolved.

Specialist management of ocular herpes simplex may include:

• Warm compresses for uncomplicated blepharoconjunctivitis.

• Topical and/or oral antiviral drug treatment for epithelial keratitis.

• Antiviral combination treatment with topical corticosteroids for stromal keratitis.

• Additional specialist treatments which may include cycloplegics, topical antibiotics, and drugs for glaucoma.

• Long-term oral antiviral drug prophylaxis for people with recurrent epithelial or stromal keratitis.

• Surgical treatment such as penetrating keratoplasty (corneal transplantation) in some cases of stromal keratitis after the acute infection has resolved, where a sight-threatening scar remains.

• Corneal opacification being treated by replacement of the scarred cornea with a full-thickness clear donor cornea. Herpes stromal keratitis can recur within the transplanted cornea, which may result in corneal scarring and increase the risk of graft rejection and subsequent graft failure.

Regarding antiviral treatment of ocular herpes simplex infections, a Cochrane review found that:⁷

• Trifluridine and acyclovir are more effective than idoxuridine or vidarabine and similar in therapeutic effectiveness.

• Brivudine and foscarnet do not substantially differ in effectiveness from trifluridine or acyclovir.

• Ganciclovir is at least as effective as acyclovir.

Complications¹

• Corneal scarring and visual impairment this may be progressive and irreversible after recurrent ocular herpes simplex infections. It occurs in 18–28% of cases of stromal keratitis.

• Herpes simplex keratitis is the leading cause of corneal blindness in developed countries.

• Ocular herpes simplex infection is the most common cause of unilateral corneal blindness worldwide.

• Corneal perforation may be a complication of necrotizing stromal keratitis.

• Secondary infection with bacteria or fungi.

• Secondary glaucoma following stromal keratitis.

• Systemic infection, eg aseptic meningitis, encephalitis, or hepatitis. This is rare but there is a greater risk for people with immunodeficiency.

Prognosis^{1 6}

• Blepharoconjunctivitis tends to resolve within two weeks, and epithelial keratitis tends to resolve in 1-2 weeks. Epithelial keratitis may resolve spontaneously without the need for drug treatment.

• About 25% of people with epithelial keratitis will develop stromal keratitis or iritis.

• Stromal keratitis has a variable and unpredictable course, and is more likely to lead to complications such as corneal scarring and visual impairment.

• Recurrent ocular herpes simplex infection:

  • Is common (20% by two years, 40% by five years, 67% by seven years).

  • The risk increases after each subsequent episode.

  • 40% experience 2-5 relapses in a lifetime; 11% experience 6-15 relapses.

  • Stromal keratitis (recurrence rate is about 10% per year) is associated with a higher risk of recurrence than epithelial keratitis.

  • People with immunosuppression or atopy are also more at risk of recurrent episodes.

• Overall, 90% of affected eyes maintain a visual acuity of driving level acuity or better, and only 3% develop vision worse than 20/100 or 6/30.

Prophylaxis

Patients with multiple episodes of epithelial or stromal disease may be considered for prophylactic oral antivirals (such as aciclovir 400 mg twice daily for a year).⁶ This has been shown to reduce incidence of recurrence of the disease during this time if this is not their first episode of HSV activation. There is also some limited evidence suggesting that oral aciclovir may help reduce the recurrence rate (and graft rejection rate) in corneal transplant patients.