Varicella-zoster virus (VZV) causes chickenpox upon primary infection and then establishes latency in sensory ganglia, including the trigeminal ganglion. Reactivation of latent VZV in the first division (ophthalmic branch) of the trigeminal nerve leads to herpes zoster ophthalmicus (HZO). Corneal complications of HZO include stromal keratitis (VZV-SK) and endotheliitis (VZV-E).
In the United States, 95–99% of adults are seropositive for VZV. The incidence of herpes zoster is 1.2–3.4 per 1,000 person-years in younger individuals, increasing to 10–14 in those aged 65 and older. One in three people will develop herpes zoster in their lifetime.
10–20% of herpes zoster cases involve the V1 branch of the trigeminal nerve and are classified as HZO. Among HZO patients with ocular involvement, VZV-SK is seen in 6–16% and VZV-E in 1–7%.
Rash on the side and tip of the nose is called Hutchinson sign. It indicates involvement of the nasociliary nerve and is associated with a significantly higher frequency of ocular complications including keratitis. However, ocular complications can occur even in the absence of Hutchinson sign.
QWhat is the difference between VZV-SK and VZV-E?
A
VZV stromal keratitis (VZV-SK) primarily involves inflammation of the corneal stroma, leading to nummular infiltrates, corneal opacification, neovascularization, and scarring. In contrast, VZV endothelitis (VZV-E) is inflammation targeting the corneal endothelium, characterized by keratic precipitates (KP) and overlying corneal edema. VZV-E can cause a marked decrease in corneal endothelial cells and may lead to irreversible corneal endothelial failure. Clinically, the two conditions may coexist, making clear distinction difficult at times. VZV-SK is more common (6–16% of HZO), while VZV-E is relatively rare (1–7%).
VZV-SK and VZV-E often appear within one month after the onset of dermatitis. Usually, punctate epithelial keratopathy or pseudodendritic lesions precede within 10 days1).
VZV stromal keratitis (VZV-SK)
Anterior stromal keratitis: Often first observed during the second week of the disease. Coin-shaped infiltrates are seen in the stroma just beneath the epithelium. They are smaller and more numerous than those caused by HSV, and larger and fewer than those caused by adenovirus.
Deep stromal keratitis: Rare, but may appear after several months.
Chronicity: If appropriate treatment is not given, neovascularization, corneal scarring, lipid deposition, and immune rings may appear1).
VZV Endotheliitis (VZV-E)
Keratatic precipitates (KP): May precede corneal edema.
Corneal edema: Observed directly over the KP.
Anterior chamber inflammation: Accompanied by mild anterior chamber inflammation, often complicated by uveitis.
Decrease in corneal endothelial cells: May lead to significant reduction and irreversible endothelial failure.
VZV keratitis can be accompanied by various ocular complications. These include follicular conjunctivitis, iritis (granulomatous with mutton-fat KP), iris atrophy, scleritis, oculomotor nerve palsy, retino-uveitis, optic neuritis, and secondary glaucoma. In particular, iris atrophy is quite characteristic of herpes zoster keratitis.
Pseudodendritic keratitis associated with herpes zoster must be differentiated from dendritic keratitis caused by HSV 1). VZV pseudodendritic lesions are small and thin, often taking a shape like the head of Medusa (caput Medusae) with extensions radiating from a central point. The terminal bulbs characteristic of HSV dendritic lesions are absent, and fluorescein staining is weak.
QWhat are the differentiating points between pseudodendritic lesions of HSV keratitis and VZV keratitis?
A
HSV dendritic lesions have terminal bulbs (bulbous ends) and stain strongly with fluorescein. In contrast, VZV pseudodendritic lesions lack terminal bulbs and show a thin, small, stellate morphology. Additionally, VZV pseudodendritic lesions are elevated lesions on the corneal surface and lack a central groove-like depression, which differs from HSV 1). VZV pseudodendritic lesions usually resolve within 4–6 days, but may progress to stromal keratitis afterward. When clinical differentiation is difficult, detection of viral DNA by PCR is useful 1).
Primary VZV infection occurs as chickenpox. After infecting the upper respiratory tract, VZV causes viremia and forms vesicles throughout the body. After resolution, latent infection is established in various ganglia, similar to HSV. Unlike HSV, VZV is thought to latently infect satellite cells of the ganglia. Therefore, upon reactivation, infection spreads to other neurons, resulting in a wider area of involvement compared to HSV.
Hutchinson’s sign: Indicates involvement of the nasociliary nerve and significantly increases the risk of ocular complications.
Severity of rash: There is not necessarily a correlation between rash severity and risk of ocular complications. Ocular complications can occur even in zoster sine herpete (without rash).
The characteristic clinical picture of HZO—unilateral painful vesicular rash along the V1 distribution of the trigeminal nerve (forehead, eyelid, nose)—is usually sufficient for diagnosis. Prodromal symptoms may include unilateral pain or hyperesthesia in the eye, forehead, or scalp on the affected side.
PCR: Detects VZV-DNA in aqueous humor or tears. Unlike HSV, VZV is thought not to undergo spontaneous shedding, so detection of DNA is highly suggestive of etiology 1). However, VZV-DNA may be detected in tears for several months after ophthalmic shingles.
Serum antibody titer: A CF antibody titer of ≥32 suggests recent infection. Unlike HSV, serum antibody titers for VZV rise with shingles, making this test useful for diagnosis.
Tzanck test: Multinucleated giant cells can be identified in corneal scrapings, but this test cannot distinguish between HSV and VZV.
Immunofluorescence assay: Can be used to detect VZV-specific IgM.
Herpesviruses including VZV can cause immune-mediated corneal infiltration, presenting findings similar to bacterial, fungal, and Acanthamoeba keratitis2).
QHow is zoster sine herpete (shingles without rash) diagnosed?
A
Zoster sine herpete (ZSH) is a subtype of shingles that presents with neuralgia or ocular symptoms without a rash. Diagnosis is difficult due to the absence of rash. The presence of unilateral neuralgia is an important clue. Definitive diagnosis requires detection of VZV-DNA by PCR of aqueous humor1). Differentiation from zosteriform simplex (herpes simplex in a zosteriform pattern) caused by HSV is also necessary; however, zosteriform simplex does not involve neuralgia and the rash heals without scarring 1).
Stromal keratitis: Use steroid eye drops according to severity 1). Compared to HSV stromal keratitis, higher concentrations of steroid eye drops are often required 1).
Endotheliitis: Treat similarly to stromal keratitis 1).
Importance of tapering: Abrupt discontinuation can lead to recurrence. Gradually reduce the dose over months, and low-dose steroids may be needed semi-permanently.
Concomitant Antiviral Use
Acyclovir ophthalmic ointment: Apply five times daily. Always use together with steroid eye drops 1).
Valacyclovir oral: Used in combination to prevent viral reactivation.
ZEDS study: Suppressive low-dose valacyclovir for 12 months did not delay new onset of keratitis, but at 18 months, treatment superiority was shown.
For corneal scars that do not improve with medical therapy, consider corneal transplantation. Deep anterior lamellar keratoplasty (DALK) or penetrating keratoplasty (PKP) are options. A longer quiescent period (mean 85–112 months) is associated with graft success and clarity. In cases with severe dry eye or neurotrophic keratopathy, consider concomitant lateral tarsorrhaphy.
QWhy can steroid eye drops be used aggressively for herpes zoster keratitis?
A
Herpes zoster keratitis is primarily driven by immune response rather than viral proliferation. Additionally, unlike HSV keratitis, recurrence of VZV keratitis is rare. Therefore, steroid eye drops can be used more aggressively than in HSV keratitis. However, herpes zoster keratitis often persists or relapses, and discontinuing steroids too quickly can cause recurrence. They need to be tapered and used for a relatively long period. Acyclovir ophthalmic ointment can be used less frequently but must always be combined 1). Even in the presence of pseudodendritic keratitis, if it is due to VZV, the use of steroid eye drops is not problematic.
It has long been thought that corneal stromal damage in VZV-SK is due to immune-mediated inflammatory reactions rather than direct viral cytolytic activity. The nummular infiltrates seen in anterior stromal keratitis are considered immune-mediated reactions to viral antigens.
Recent studies suggest the possibility of direct VZV infection in the cornea. The presence of VZV-DNA in the corneal stroma and viral capsids within keratocytes has been demonstrated. Reports have detected VZV-DNA in the corneal stroma up to 10 years after the onset of HZO, suggesting that the cornea may serve as a long-term reservoir for the virus.
Studies have demonstrated that VZV infection of human corneal keratocytes causes extensive cell death and downregulation of inflammatory pathways.
Evidence for direct viral entry into endothelial cells in VZV-E is limited. One case report found viral capsids within endothelial cells, and VZV-DNA was detected in the perivascular area nearby up to 10 years after infection. In some cases, endothelial damage appeared to occur before anterior chamber flare or KP formation, suggesting the possibility of direct viral entry into the endothelium.
Differences in Latent Infection between VZV and HSV
HSV establishes latency within neurons themselves, and reactivation is often limited to cranial ganglia and sacral ganglia. In contrast, VZV establishes latency in the satellite cells of ganglia and can establish latency along the entire nerve axon. VZV is inactivated quickly once it leaves the cell, so the rash upon recurrence reaches the nerve endings directly, with little spread on the skin surface.
Recombinant zoster vaccine (Shingrix) is recommended as a two-dose series for immunocompetent adults aged 50 years and older. Observational studies of the live vaccine in individuals aged 60 years and older showed a nearly two-thirds reduction in the risk of ocular involvement.
However, enhancement of cell-mediated immunity may trigger recurrence of stromal keratitis in response to persistent viral antigens in the cornea. In patients with a history of VZV keratitis, it is recommended to have a quiescent period of at least one year before vaccination.
The Zoster Eye Disease Study (ZEDS) evaluated the efficacy of low-dose valacyclovir in preventing keratitis and iritis after HZO. Although a delay in new or worsening keratitis was not demonstrated during the 12-month treatment period, superiority of treatment was shown at 18 months, with a reduction in multiple episodes of keratitis and iritis.
VZV-DNA has been detected in the corneal stroma up to 10 years after the onset of HZO, suggesting that the cornea may serve as a reservoir for future recurrences. Whether the virus reactivates from the cornea or from a site near the sensory ganglion in recurrent keratitis remains a topic for future research.
American Academy of Ophthalmology Cornea/External Disease PPP Panel. Bacterial Keratitis Preferred Practice Pattern. Ophthalmology. 2024;131(1):P1-P47.
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