Herpes infections of the eye

Herpes infections of the eye include keratitis, corneal dendrites, corneal scarring, uveitis, acute retinitis, chronic conjunctivitis and neurotrophic keratopathy. The principal challenge for clinicians is tailoring the management to the type of damage.

Ophthalmic herpes

Ophthalmic herpes is a broad description, and can include disease such as acute herpetic keratitis, corneal dendrites, corneal scarring, uveitis, acute retinitis, chronic conjunctivitis, neurotrophic keratopathy. The difficulty lies not so much in the management of herpetic disease, but rather the diagnosis of the end organ damage and tailoring the management to the type of end organ damage. Management will therefore be described in broad terms related to the (presumed) underlying disease process. Tailoring of treatment to specifically address the end organ damage should be left to the treating corneal specialist.

Ophthalmic herpes infections typically includes herpes simplex virus (usually HSV-1) and herpes zoster virus, although Epstein Barr virus and cytomegalovirus infections also occur. The herpes virus is a dsDNA virus which has a nucleocapsid envelope surrounding the nuclear genome, and the entire virus surrounded by a capsule. For the purpose of this guideline, management of ophthalmic herpes infections will be limited to addressing herpes simplex and herpes zoster viruses.

Principles of treatment

The principles of treatment of ophthalmic herpetic disease can be summarised as follows:

• Clinical diagnosis
• Virological confirmation of clinical diagnosis
• Debridement of active disease
• Antiviral treatment
• Ocular comfort (lubricants, lid cleaning, cycloplegia)
• Anti-inflammatory treatment (non steroidals, steroidals)
• Protective treatment (tarsorraphy, contact lenses)

Treatment modlities

Available treatment arms for ophthalmic herpetic disease include:

1. Antivirals (topical, systemic)
2. Cycloplegic agents
3. Anti-inflammatory agents
4. Pain relief
5. Nerve stabilising agents
6. Lubricants
7. Topical antibiotics

With both HSV and VZV, there are two broad groups of clinical manifestations of ophthalmic herpetic disease:

1. due to active viral replication
2. due to post-infectious trophic and immunological damage.

HSV keratitis

Figure 1: Herpetic disciform keratitis immune ring:
This image shows a typical pattern of inflammation of the cornea during active immune corneal herpes simplex keratitis

HSV keratitis is the most frequent cause of corneal blindness in the United States of America. Cell mediated immunity is crucial in control of HSV infections, hence issues arise in immunocompromised patients. Primary infection is bimodal, occurring in the 0-5 age group, and again in late teens. Primary infection after age 30 is rare. There is a high prevalence of the virus in the population, therefore serology is not particularly useful. By adulthood, 90% of adults will have antibodies to HSV-1.

The development of ophthalmic HSV infection may be triggered by precipitants including fever, sunlight, stress, menstruation, trauma and prostaglandin analogues used for glaucoma treatment (e.g. xalatan etc). ophthalmic herpetic disease presents as epithelial disease, or trophic disease such as stromal or neurotrophic disease. Clinical presentation of epithelial disease is usually associated with active viral replication and includes symptoms such as ocular irritation, redness and slight blurring of vision. At initial presentation, patients typically present with a slightly red eye and normal vision. Instillation of topical fluorescein reveals a corneal ulcer, described typically as a dendritic ulcer with club shaped dendrites. The ulcer is usually single, but may be multiple in immunocompromised patients. The clinical presentation of stromal disease is postinfectious trophic and immunological damage. Patients often present with blurred vision, conjunctival injection, irritation, and vision loss. There may also be persistent corneal ulceration, and the development of secondary corneal infection.

Figure 2: Herpetic corneal scarring:
This image shows burnt out herpes simplex keratitis with corneal scarring and an irregular surface. This causes permanent reduction in vision due to irregular astigmatism.

Investigations

A swab is taken from the cornea using a calcium alginate swab, or pre-prepared viral and PCR swab. This may be sent for viral culture, Immunohistochemistry for viral antigens or viral PCR. Cytology with Giemsa stain shows multinucleated giant cells and a Papanicolou stain shows intranuclear eosinophilic inclusion bodies.

Treatment of epithelial disease

Debridement of the corneal dendrite will reduce the viral load. Commencement of topical treatment with topical aciclovir (ACV) 3% 5x/day.

Alternative topical treatment includes trifluorothymidine 1% (trifluridine) 9x/day, Possible 0.2% cidofovir; ganciclovir gel 0.15% (Virgan). Older: vidarabine 3% 5x/day (= vira a, or adenosine arabinoside) Vidarabine, trifluridine and acilclovir show no difference in healing rates for herpetic epithelial keratitis. Supportive treatment includes topical lubrication with Refresh Tears Plus, and cycloplegia in acute phases with homatropine 2% qid.

If no response to ACV after 5-7 days, it is unlikely that the lesion will respond to IV ACV or related drugs (valciclovir or famciclovir). Consider topical TFT qds for 10 days, or IV foscarnet (40 mg / kg tds or 60 mg / kg bd) for 10 days or until resolved. If this fails, then consider cidofovir IV or topically (1 or 3%). Viral susceptibility to ACV should be ordered if possible.

Treatment of stromal disease (interstitial keratitis or IK)

Exclude active epithelial disease: stain the cornea to exclude the presence of a dendrite. Commence topical Predneferin Forte 1% qid, with cycloplegia - homatropine 2% qid. Observe closely. If corneal ulceration is present, referral to an ophthalmologist is mandatory.

Clinical pearls

• If a patient develops IK on the same side as a prior episode of either HSV or HZV and there is no indication of other disease in the patient’s history, then no further diagnostic evaluation is necessary. In this case, it can safely be assumed that the cause of the immune stromal disease is herpetic.
• Historically, IK has been associated with syphilis as the main causative agent. Today, however, syphilis is the main cause only in cases of bilateral, inactive interstitial keratitis. By far, the main identifiable cause of active cases of interstitial keratitis is herpes simplex virus.
• In cases of active epithelial herpetic keratitis, topical and oral antiviral medications have been exceedingly disappointing therapeutically. The only use for either oral or topical antiviral medications in herpetic interstitial keratitis is prophylactically to prevent epithelial ulceration when topical corticosteroids are used and to suppress future recurrences.
• Stromal inflammatory infiltration in herpetic interstitial keratitis (IK) can be difficult to differentiate from both bacterial and fungal keratitis. However, IK will have a more intact epithelium whereas the other entities will have ulceration. Further, IK runs a less aggressive course, whereas infectious keratitis is much more aggressive.
• As in other herpetic manifestations, corneal sensitivity is reduced on the affected side.
• Suspect Cogan’s syndrome in patients presenting with ocular inflammation who develop hearing loss, vertigo, ataxia, tinnitus, vasculitis, or aortic insufficiency.

Varicella zoster virus

Varicella zoster virus (VZV) presents as chickenpoxin the young, and the virus lies dormant to later reactivate as herpes zoster (shingles) in adults. Around 75-90% of chickenpox cases occur in children under 10 years of age. It is estimated that 1 in 5 adults will develop shingles in their lifetime. Shingles is most common after 50 years of age. The onset of shingles is often precipitated by factors which compromise the immune status of the host such as illness or infection.

Whereas HSV tends to be focal in immunocompetent patients, VZV is usually more diffuse, involving the distribution along a dermatome. In the head and neck, shingles is twice as likely to occur in V1 than V2. Involvement of V1 may be associated with ophthalmic involvement, typically occurring if the nasociliary nerve is involved. Any distribution of the ophthalmic division of the trigeminal nerve may be involved, typically manifesting as a skin rash involving the unilateral forehead, with lesser involvement of the upper lid, and extending down to the tip of the nose.

Figure 3: Maxillary zoster:
This is a classic presenting picture of zoster involving the maxillary division of the trigeminal nerve.

The typical picture of the acute presentation of herpes zoster ophthalmicus includes a prodrome of malaise and fever which is often missed or initially ignored. Soon after, the patient develops the cutaneous presentation of shingles with vesicular eruption along a dermatome. There is usually associated ocular injection and blurred vision. At the slit lamp, mucous plaques may develop along the corneal surface, and these may be mistaken for the dendrites of HSV. These dendrites usually do not contain viral particles, and patients are often mistakenly commenced on topical antivirals.

The most significant sight threatening conditions usually develop two weeks after onset, and vision loss typically occurs with chronic disease. Although conjunctivitis develops with initial disease, it is usually non-sight threatening. The chronic presentation involves redness, loss of vision and chronic conjunctivitis

A detailed list of differing manifestations of the wide variety of clinical presentation of herpes zoster ophthalmicus is detailed in Table 2.

Figure 4: Corneal dendrites:
This image shows multiple classical corneal dendrites in active epithelial disease of herpes simplex keratitis.

Treatment of VZV involves administration of systemic antivirals in high doses, as the MIC for viral activity of VZV is much higher than HSV. For VZV, MIC in vitro is >8 times that of HSV. Therefore, valaciclovir dose for zoster requires 1gm tid for 7 days for acute cases (vs HSV of 500mg tds). Typically, aciclovir 800mg orally 5x/day is prescribed for 10 days. Ocular lubrication and cleansing is needed, and if ulceration exists, topical antibacterial treatment with chloromycetin qds is recommended. Supportive measures for the skin are also recommended, including appropriate skin hygiene in cases of severe cutaneous eruption In the longer term, supportive measures are required for neurotrophic corneal disease and chronic inflammation. Treatment options include topical steroids, topical lubrication and lateral tarsorraphy of the eyelids. The indications for these specific treatments are shown in Table 1, and the clinical decision to proceed with this treatment is best made by an ophthalmologist.