HSV/HZV Keratitis

HSV Latency & Reactivation

Herpes simplex virus establishes lifelong latency in the trigeminal (Gasserian) ganglion after primary ocular or perioral infection. The virus travels retrograde along sensory nerve fibers to reach the ganglion, where it persists in a non-replicating state indefinitely. From there it can reactivate at any point, traveling back down the same nerve to cause a fresh episode of keratitis. This is why herpetic keratitis behaves so differently from the other infectious keratitides on this site: it is not a one-time infection to be cured, but a chronic disease punctuated by recurrences, held in check by the immune system but never cleared by it.

A bedside finding that follows directly from this nerve-based biology is reduced corneal sensation, seen in both HSV and HZV keratitis. Because the virus travels along, and damages, the same trigeminal sensory fibers that supply the cornea, decreased sensation on simple bedside testing points toward a herpetic cause in a patient with recurrent or atypical keratitis. Sensation is typically preserved in bacterial or fungal keratitis, which makes this a useful discriminator at the slit lamp.

HSV Epithelial (Dendritic) Keratitis

Epithelial dendritic keratitis results from active viral replication within corneal epithelial cells. Infected cells lyse along the branching path the virus takes as it spreads cell to cell, producing the classic dendritic ulcer: a branching epithelial defect with swollen, club-shaped terminal bulbs at the tips of each branch, staining brightly with fluorescein.

Because this is a disease of active replication rather than immune-mediated damage, first-line treatment is a topical antiviral. Trifluridine 1% ophthalmic solution is the agent most commonly used in the United States, dosed frequently until the epithelium heals. Topical corticosteroids are contraindicated as monotherapy in active epithelial disease: suppressing local immune defenses removes a check on viral replication and tends to worsen the ulceration rather than help it. That is the reverse of how steroids are used in stromal disease below, and the distinction is the single most board-relevant fact about herpetic keratitis management.

HSV Stromal Keratitis

Stromal keratitis is mechanistically distinct from epithelial disease. Rather than active viral cytolysis, it is driven by a host CD4+ T-cell-mediated delayed-type hypersensitivity response (a Type IV hypersensitivity reaction) against residual viral antigens left in the stroma, producing chronic inflammation and scarring even in the absence of actively replicating virus. This is exactly why the treatment approach flips relative to epithelial disease: judicious topical corticosteroids have a real therapeutic role here, controlling the immune-mediated inflammation that is actually driving the tissue damage and scarring.

Steroids in stromal disease are never used alone. Latent virus in the trigeminal ganglion can reactivate at any time, so corticosteroids must be given together with concurrent antiviral coverage, either oral acyclovir or a topical antiviral, to prevent steroid-induced flares of epithelial disease while the stromal inflammation is being treated.

A related pattern worth distinguishing is disciform keratitis, also known as HSV endotheliitis. Here the inflammation centers on the corneal endothelium rather than the stroma: a central, disc-shaped zone of corneal edema develops, accompanied by keratic precipitates scattered across the posterior cornea and a mild anterior chamber reaction. The epithelium stays intact, and there is no significant stromal infiltrate or ulceration to find on exam. Because this, too, is driven by an immune response to viral antigens rather than active replication, management follows the same combined approach as stromal disease: topical corticosteroids to control the endothelial inflammation, given together with antiviral coverage to guard against reactivation.

Diagnosis

In atypical or recurrent presentations where the classic dendrite is not obvious, PCR detection of HSV DNA from a corneal swab or tear film is highly sensitive and specific, and is especially useful when viral culture would be falsely negative. Reduced corneal sensation on exam, described above, is often the clinical trigger that prompts sending PCR testing in the first place. Persistent epithelial defects with reduced sensation that do not fit a simple infectious pattern should also raise consideration of neurotrophic keratitis, a separate downstream consequence of trigeminal nerve damage from HSV or HZV in which impaired corneal sensation and loss of trophic neuropeptide support, not ongoing infection, are what impair epithelial healing.

The HEDS Trial & Prophylaxis

The Herpetic Eye Disease Study (HEDS) established that long-term low-dose oral acyclovir prophylaxis significantly reduces the rate of recurrent HSV keratitis, both epithelial and stromal, with the largest benefit seen in patients with a prior history of stromal disease. Patients with recurrent herpetic keratitis are therefore often maintained on chronic suppressive oral acyclovir rather than treated only episode by episode. Each recurrence of stromal disease carries its own risk of cumulative scarring, so preventing recurrences outright has real long-term visual benefit.

Herpes Zoster Ophthalmicus

Herpes zoster ophthalmicus (HZO) results from reactivation of latent varicella-zoster virus in the trigeminal ganglion. It is the same ganglion HSV uses, but the virus is VZV rather than HSV, and the primary infection was varicella (chickenpox) rather than a prior ocular HSV episode. Reactivation in the ophthalmic (V1) division of the trigeminal nerve produces the dermatomal vesicular rash of zoster, along with the potential for ocular involvement.

Hutchinson's sign, vesicular skin lesions on the tip, side, or root of the nose, is the single most important clinical predictor in HZO. It marks involvement of the nasociliary branch of the trigeminal nerve, which also innervates the globe itself, so its presence correlates with a substantially higher likelihood of clinically significant ocular involvement (keratitis, uveitis, scleritis) than HZO without it.

Oral antiviral therapy (valacyclovir or famciclovir) most effectively reduces the severity and duration of HZO and its ocular complications when started within 72 hours of rash onset, limiting further viral replication in the trigeminal ganglion and periocular tissues before it can progress. VZV, like HSV, can also cause stromal keratitis, following the same immunopathogenesis as HSV stromal disease: a delayed-type hypersensitivity reaction to residual viral antigens rather than active replication, again treated with an immune-mediated approach rather than antivirals alone.

High-Yield Pearls

• HSV latency lives in the trigeminal ganglion; reactivation travels back down the same nerve, which is why herpetic keratitis recurs rather than resolving permanently.
• Epithelial (dendritic) disease = active replication → antiviral, no steroid monotherapy. Stromal disease = immune-mediated → steroid + antiviral cover together.
• Reduced corneal sensation is a classic clue for any herpetic keratitis, distinguishing it from bacterial/fungal causes.
• HEDS trial: long-term low-dose oral acyclovir reduces recurrence of both epithelial and stromal HSV keratitis.
• Hutchinson's sign (nasociliary nerve) predicts higher risk of ocular involvement in HZO; start oral antivirals within 72 hours of rash onset.

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