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Professor Anthony Maloof

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.

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)

Available treatment arms for Ophthalmic Herpetic disease include:

Antivirals (topical, systemic)
Cycloplegic agents
Anti-inflammatory agents
Pain relief
Nerve stabilising agents
Lubricants
Topical antibiotics

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

that due to active viral replication
disease due to postinfectious 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 a 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.

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 Papanicolaou 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 3% 5x/day.

Alternative topical treatment includes trifluorothymidine 1% (TFT, 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 aciclovir 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.

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.

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 interstitial keratitis (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 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

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

Varicella Zoster Virus (VZV) presents as chickenpox in 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.

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.

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, valciclovir 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 qid is recommended. Supportive measures for the skin are also recommended, including appropriate skin hygiene in cases of severe cutaneous eruption.

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

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.

Table 1: Recommended Treatment of Varicella Zoster Virus Infections

Infection	Treatment
Shingles	Aciclovir (Zovirax), 800 mg orally ﬁve times daily for seven to 10 days
Skin	Palliative with cool compresses, mechanical cleansing
Blepharitis/conjunctivitis	Palliative, with cool compresses and topical lubrication. Topical broad-spectrum antibiotic indicated for secondary bacterial infection (usually Staphylococcus aureus)
Epithelial keratitis	Debridement or none
Stromal keratitis	Topical steroids
Neurotrophic keratitis	Topical lubrication Topical antibiotics for secondary infections Tissue adhesives and protective contact lenses to prevent corneal perforation Topical steroids Oral steroids Oral aciclovir
Scleritis/episcleritis	Topical nonsteroidal anti-inﬂammatory agents and/or steroids
Acute retinal necrosis/ progressive outer retinal necrosis	Intravenous aciclovir (1,500 mg per m² per day divided into three doses) for seven to 10 days, followed by oral aciclovir (800 mg orally ﬁve times daily) for 14 weeks Laser/surgical intervention

Table 2: Ocular Involvement in Herpes Zoster Ophthalmicus

Location	Condition
Anterior chamber, angle, ciliary processes	Trabeculitis Glaucoma, secondary to trabeculitis or attendant steroids
Vitreous	Retinitis or neuroretinitis Thrombophlebitis Retinal detachment, exudative or rhegmatogenous Acute retinal necrosis Perivasculitis and arteritis Macular oedema
Lid and adnexa	Blepharitis—secondary infection with Staphylococcus aureus Lid oedema Vesicular lip eruption Phthisis bulbi Cicatricial entropion with or without trichiasis Cicatricial ectropion Chronic permanent scarring Canaliculitis Ptosis Dacryoadenitis
Conjunctiva	Hyperaemic follicular conjunctivitis (rare) Papillary conjunctivitis Petechial haemorrhagic conjunctivitis Vesicular conjunctivitis Conjunctival oedema Cicatricial conjunctival changes
Cornea	Acute epithelial keratitis Coarse punctate keratitis “Pseudodendritic” keratitis (“zoster dendrites”) Mucous plaques Nummular anterior stromal keratitis Interstitial keratitis Fascicular vascularizing keratitis Serpiginous ulceration Disciform keratitis Corneal hypaesthesia or anaesthesia Neurotrophic keratitis, with or without melting and perforation Corneal scars Calciﬁc band keratopathy Lipid keratopathy Corneal oedema Peripheral corneal ulceration Epithelial inclusion cysts
Optic nerve	Optic neuritis Retrobulbar neuritis Optic atrophy Papillitis and papilloedema Neuroretinitis (papilloedema and macular oedema)
Extraocular muscles	Extraocular muscle palsies, myositis Ptosis Diplopia Exophthalmos Proptosis
Orbit	Orbital apex syndrome
Sclera and episclera	Scleritis Episcleritis
Brain	Cephalalgia Hypaesthesia Anaesthesia dolorosa Post herpetic neuralgia Contralateral hemiplegia Zosteriform temporal arteritis and angiitis Facial palsy Cerebrovascular accidents Guillain-Barré syndrome
Pupil	Adie’s tonic pupil Horner’s syndrome
Iris and uvea	Iritis Sectoral iris atrophy Iridocyclitis, occasionally “plastic” with hypopyon Anterior segment necrosis Choroiditis
Lens	Cataract, secondary to inﬂammation or attendant steroids

Disclaimer

The AHMF have made considerable efforts to ensure the information upon which this guideline is based reproduces the evidence as accurately as possible. Users of this guideline are strongly recommended to conﬁrm that the information contained within it, especially drug indications, is correct by way of independent sources, as this guideline does not indicate an exclusive course of action or serve as a standard of medical care. The AHMF accepts no responsibility for any inaccuracies, information perceived as misleading, or success of any treatment regime detailed in this guideline.

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Created:
July 2006
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