Residency · Residency · Ophthalmology

Herpes Simplex and Herpes Zoster Keratitis

Herpes Simplex Virus (HSV) Keratitis

Virology and Pathogenesis

HSV-1 is responsible for the vast majority of ocular herpes infections, while HSV-2 is primarily implicated in neonatal disease. The primary infection is usually subclinical or manifests as a mild blepharoconjunctivitis during childhood. After the initial infection, the virus establishes lifelong latency in the trigeminal ganglion. Reactivation can be triggered by a variety of stimuli including ultraviolet light exposure, physical or emotional stress, fever, immunosuppression, ocular trauma, and menstruation. It is the recurrent disease, rather than the primary infection, that causes the majority of clinical morbidity, through a combination of direct viral cytopathic damage and immune-mediated inflammatory destruction of corneal tissue.

Clinical Forms

Epithelial Keratitis (Infectious)

The classic presentation is the dendritic ulcer, a branching linear epithelial defect with characteristic terminal bulbs at the ends of each branch. The ulcer base stains with fluorescein, while the swollen infected cells at the borders stain with rose bengal or lissamine green. A geographic ulcer is a larger, amoeboid variant of the dendritic pattern that often develops when epithelial disease is inadvertently treated with topical corticosteroids. Since the pathology here is active viral replication within epithelial cells, treatment is antiviral therapy: topical ganciclovir 0.15% gel, trifluridine 1%, or systemic valacyclovir or acyclovir. Corticosteroids are strictly contraindicated in epithelial disease, as they will promote viral replication and worsen the ulcer.

Stromal Keratitis -- Immune Stromal (Interstitial)

Immune stromal keratitis represents an immune-mediated inflammatory response directed against viral antigens deposited in the corneal stroma. The epithelium remains intact, while the underlying stroma develops haze, edema, neovascularization, and potentially lipid keratopathy. The non-necrotizing form is more common. Treatment requires topical corticosteroids (typically prednisolone acetate 1%) to control the immune response, but these must always be administered with concurrent antiviral cover -- oral valacyclovir 500 mg two to three times daily or acyclovir 400 mg five times daily -- to prevent viral reactivation. The HEDS trial demonstrated that topical steroids significantly reduced the persistence and progression of stromal inflammation.

Stromal Keratitis -- Necrotizing

Necrotizing stromal keratitis is less common but considerably more severe, involving active viral replication within the stroma itself. It presents with a dense, cheesy white necrotic stromal infiltrate accompanied by an overlying epithelial defect and an intense anterior chamber reaction. Treatment requires aggressive antiviral therapy (both oral and topical) with cautious, carefully monitored topical corticosteroid use.

Endotheliitis (Disciform Keratitis)

Endotheliitis involves either immune-mediated inflammation or direct viral infection of the corneal endothelium. The characteristic findings are disc-shaped stromal edema with underlying keratic precipitates (KPs) and Descemet membrane folds. There may be a mild anterior chamber reaction and elevated intraocular pressure. The overlying epithelium is typically intact. Treatment consists of topical corticosteroids with oral antiviral coverage.

Neurotrophic Keratopathy (Metaherpetic Disease)

Neurotrophic keratopathy is not an active infection but rather the consequence of corneal nerve damage from prior HSV disease. Loss of corneal sensation impairs the normal trophic support that nerves provide to the epithelium, resulting in epithelial breakdown. The hallmark is a persistent epithelial defect with smooth, rolled edges and no dendrites visible. Treatment focuses on promoting healing rather than fighting infection: options include aggressive lubrication, bandage contact lenses, tarsorrhaphy, amniotic membrane transplantation, and cenegermin (recombinant nerve growth factor). Antivirals are not indicated since there is no active viral replication.

HSV Keratitis Forms Summary

HEDS Trials (Herpetic Eye Disease Study)

The Herpetic Eye Disease Study was a series of landmark randomized controlled trials that established the evidence base for HSV keratitis management. HEDS I found that oral acyclovir did not improve outcomes in epithelial keratitis but significantly reduced the recurrence of stromal keratitis and uveitis. The HEDS II Acyclovir Prevention Trial demonstrated that oral acyclovir 400 mg twice daily reduced the recurrence of any form of HSV ocular disease by approximately 50% over 12 months. The trials also confirmed that topical corticosteroids accelerate the resolution of immune stromal keratitis, and that oral acyclovir as an adjunct to topical steroids for stromal disease reduced the rate of treatment failure.

Prophylaxis Controversy

The HEDS trials established the benefit of oral acyclovir 400 mg twice daily for preventing recurrences of HSV eye disease, but the optimal duration of prophylaxis remains debated. Many experts recommend long-term suppression, potentially for years or even lifelong, particularly after an episode of stromal keratitis, because the risk of recurrence increases once prophylaxis is discontinued. In clinical practice, valacyclovir 500 mg once daily is commonly used as a more convenient alternative to acyclovir.

Herpes Zoster Ophthalmicus (HZO)

Pathogenesis

Herpes zoster ophthalmicus results from reactivation of varicella-zoster virus (VZV) from latency in the trigeminal ganglion, specifically within the ophthalmic (V1) division. It is more common in elderly and immunocompromised individuals. The Hutchinson sign -- vesicles on the tip of the nose indicating nasociliary nerve involvement -- is a clinically important predictor of a higher risk of ocular complications.

Clinical Manifestations

Dermatologic

The characteristic presentation is a painful, unilateral, dermatomal vesicular rash that strictly respects the midline. In V1 distribution, this involves the forehead, upper eyelid, and nose. Post-herpetic neuralgia (PHN), a chronic neuropathic pain syndrome, can persist for months to years after the acute rash has resolved and represents one of the most debilitating complications.

Ocular Involvement (50-72% of V1 HZO)

Ocular involvement occurs in 50-72% of patients with V1 HZO and can affect virtually any structure of the eye. The spectrum includes conjunctivitis, episcleritis, and scleritis. Corneal involvement may manifest as epithelial pseudodendrites (mucous plaques that are elevated and lack terminal bulbs, unlike true HSV dendrites), nummular keratitis (coin-shaped subepithelial infiltrates), or interstitial stromal keratitis. Endotheliitis with corneal edema may develop. Anterior uveitis is common and frequently accompanied by elevated intraocular pressure due to trabeculitis. Rarely, retinal involvement in the form of acute retinal necrosis (ARN) can occur, which is a sight-threatening emergency. Cranial nerve palsies affecting CN III, IV, or VI are additional potential complications.

HZO Pseudodendrites vs. HSV Dendrites

Distinguishing between HSV dendrites and HZO pseudodendrites is clinically critical. True HSV dendrites are branching ulcers with terminal bulbs that stain with fluorescein at the ulcer base and with rose bengal at the swollen cell borders. HZO pseudodendrites, by contrast, are elevated mucous plaques that are broader, lack terminal bulbs, stain with rose bengal but not with fluorescein at the base. This distinction directly influences treatment decisions.

Treatment of HZO

Oral antiviral therapy should be initiated within 72 hours of rash onset. Options include valacyclovir 1000 mg three times daily, acyclovir 800 mg five times daily, or famciclovir 500 mg three times daily, all given for 7-10 days. Topical corticosteroids are used to manage stromal keratitis and uveitis, always with concurrent antiviral coverage. A cycloplegic agent provides comfort and prevents posterior synechiae formation. Elevated intraocular pressure should be managed with aqueous suppressants, avoiding prostaglandin analogs during active uveitis. Post-herpetic neuralgia may require management with gabapentin, pregabalin, tricyclic antidepressants, or capsaicin cream.

Prevention

The Shingrix vaccine (recombinant, adjuvanted) is recommended for all adults aged 50 years and older, with demonstrated efficacy exceeding 90% against HZO. It is also recommended for immunocompromised adults aged 19 years and older. Shingrix is far superior to the older Zostavax (live attenuated vaccine), which has been discontinued in many countries.

Neurotrophic Keratopathy (Both HSV and HZV)

Both HSV and VZV can damage the sensory nerves of the cornea, producing corneal anesthesia and neurotrophic keratopathy. The Mackie classification stages the disease by severity: Stage 1 presents with punctate epitheliopathy and decreased tear breakup time; Stage 2 involves a persistent epithelial defect with characteristic smooth, rolled edges; and Stage 3 progresses to corneal ulceration with stromal thinning and risk of perforation. Treatment follows an escalating ladder from preservative-free artificial tears and autologous serum drops, through bandage contact lenses and tarsorrhaphy, to amniotic membrane transplantation. Cenegermin, a recombinant nerve growth factor preparation at 0.002% concentration, is FDA-approved specifically for neurotrophic keratitis and works by promoting corneal nerve regeneration and epithelial healing.

<image>Side-by-side slit lamp illustration comparing HSV dendritic ulcer and HZV pseudodendrite. Left panel: HSV dendrite showing a branching linear ulcer with terminal bulbs at the ends of the branches, staining brightly with fluorescein at the ulcer base (cobalt blue illumination). Right panel: HZV pseudodendrite showing a broader, elevated mucous plaque without terminal bulbs, staining poorly with fluorescein but positively with rose bengal at the margins. Label the terminal bulbs, ulcer base, mucous plaque, and staining characteristics.</image>

<image>Clinical progression diagram of HSV keratitis forms. Five sequential panels showing the spectrum of disease: (1) Epithelial dendrite on the corneal surface, (2) Geographic ulcer (enlarged dendritic pattern), (3) Immune stromal keratitis with disc-shaped stromal haze and intact epithelium, (4) Necrotizing stromal keratitis with dense white infiltrate and epithelial breakdown, (5) Endotheliitis with disc-shaped edema and keratic precipitates on the endothelium. Below each panel, indicate the primary pathology (viral replication vs. immune-mediated) and the treatment approach.</image>

<image>Anatomical illustration of herpes zoster ophthalmicus showing the V1 dermatome distribution. Include the trigeminal ganglion with VZV latency, the ophthalmic division branches (frontal, lacrimal, nasociliary), and the dermatomal rash distribution on the forehead and upper eyelid respecting the midline. Highlight the nasociliary nerve branch going to the tip of the nose (Hutchinson sign). An inset shows the ocular structures affected: cornea (pseudodendrite, stromal keratitis), anterior chamber (uveitis), and iris.</image>

Key Clinical Pearls

Topical corticosteroids must never be used for HSV epithelial keratitis -- doing so will convert a dendrite into a geographic ulcer. Whenever topical steroids are prescribed for HSV stromal or endothelial disease, concurrent antiviral cover is mandatory. The HEDS trials proved that oral acyclovir prophylaxis at 400 mg twice daily reduces HSV recurrence by approximately 50%. The distinction between HSV dendrites (with terminal bulbs) and HZV pseudodendrites (without terminal bulbs) is one of the most critical differential diagnoses in corneal disease. The Hutchinson sign in HZO strongly predicts ocular involvement, though its absence does not exclude it. Neurotrophic keratopathy requires treatment directed at promoting healing and nerve regeneration, not antivirals. Corneal sensation should be tested with a Cochet-Bonnet esthesiometer or a simple cotton wisp in all patients with herpetic keratitis. The Shingrix vaccine should be recommended proactively for all patients aged 50 years and older to prevent herpes zoster ophthalmicus.

References

• Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. NEJM. 1998;339(5):300-306.
• Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst Rev. 2015.
• Liesegang TJ. Herpes zoster ophthalmicus: natural history, risk factors, clinical presentation, and morbidity. Ophthalmology. 2008;115(2 Suppl):S3-S12.
• Bonini S, et al. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology. 2018;125(9):1332-1343.
• AAO BCSC Section 8: External Disease and Cornea. 2023-2024.

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