Herpes simplex virus (HSV) infections are quite prevalent: in 2020, an estimated 64% of people under 50 had HSV-1 globally, and 13% of those aged 15 to 49 had HSV-2.1 Epithelial herpetic keratitis remains a leading infectious cause of corneal blindness in developed countries and the scarring that can result from this condition is a major global driver of vision loss.2
Timely recognition and appropriate treatment can substantially influence disease trajectory and visual outcomes; in particular, antiviral prophylaxis can reduce symptomatic episodes by nearly half in patients with recurrent disease.3
Brief overview of HSV-1
HSV‑1 typically establishes latency in the trigeminal ganglion after a primary exposure, with reactivation to the cornea triggered by stress, fever, UV exposure, ocular surface compromise, or immunosuppression.4
The emergence of epithelial disease reflects active viral replication and cytopathic injury confined to the corneal surface; by contrast, stromal disease is an immune‑mediated inflammatory process that must be managed with both appropriate antiviral coverage and immunomodulatory therapy (e.g., topical corticosteroids) once the epithelium is intact.5
Clinical diagnosis: Confirming the dendrite
HSV keratitis is primarily a clinical diagnosis. At the slit lamp, we look for the pathognomonic branching dendrites with terminal bulbs, but presentations can vary and sometimes be difficult to distinguish. Because of this, I learned in fellowship to suspect herpes when faced with a puzzling corneal presentation.
Staining with fluorescein and rose bengal helps outline the lesion and document its size and depth. Polymerase chain reaction testing can be used to confirm the diagnosis—but is not commonly done. In any event, do not delay initiation of empiric antiviral therapy once herpes is suspected.
In patients with suspected herpetic keratitis or a history of recurrence, I always check corneal sensitivity, as reduced sensation indicates a neurotrophic component. In this scenario, I would lower my threshold to protect the surface with preservative-free tears and gel, avoid epitheliotoxic drops, and consider early placement of cryopreserved amniotic membrane (CAM).
My index of concern increases if I see stromal haze or edema, keratouveitis, thinning, or a dendrite that is breaking into a geographic ulcer. While topical corticosteroids should be avoided in the presence of an active epithelial infection, they can help manage stromal disease once the epithelium is intact and adequate antiviral coverage has been established.6
Staging treatment for epithelial herpetic keratitis
For uncomplicated epithelial disease, systemic therapy is the backbone. I use acyclovir 400mg five times daily or valacyclovir 500mg three times daily; my choice typically comes down to access, cost, and likelihood of patient adherence.
These medications have good bioavailability and are generally well tolerated, though dosage may need to be adjusted in patients with preexisting kidney disease. In immunocompetent patients, true antiviral resistance is uncommon, and I only consider this possibility if there is no improvement despite good adherence.7
In my practice, topical antivirals are add‑ons in selected cases. Ganciclovir 0.15% gel five times daily is my go‑to; it performs at least as well as topical trifluridine and is kinder to the ocular surface. Trifluridine 1% (up to nine times daily) still has a role, but I keep courses short due to the potential for epithelial toxicity; the US formulation also contains thimerosal as a preservative, which may be irritating to some patients.8,9
Treating patients with persistent HSV keratitis
I escalate if there is no meaningful improvement at 7 to 14 days, if a dendrite converts to a geographic ulcer, if the lesion threatens the visual axis, and/or if the patient has risk factors such as immunocompromise, a neurotrophic surface, or limited vision in the fellow eye.
Escalation can mean adding a topical agent, increasing visit frequency, and increasing ocular surface protection (e.g., bandage contact lens, when safe, and/or CAM). If I truly suspect antiviral resistance, I confirm adherence, consider switching agents, and loop in an infectious disease colleague.
The use of CAM is helpful in these patients as it brings an anti‑inflammatory, anti‑scarring, pro‑regenerative milieu to the ocular surface. In non‑healing epithelial defects, geographic ulcers, or central defects where the visual axis is at risk—or when a neurotrophic component is present—I place CAM early to shorten epithelial downtime and protect against scarring while the antivirals continue to work.10
I typically bring patients back several days following CAM placement and counsel them on foreign‑body sensation, temporary blur, and activity precautions. When epithelial healing lags, the potential for permanent scarring increases; early and aggressive ocular surface protection reduces the likelihood of needing to manage irregular astigmatism and corneal scarring later on.
For patients with frequent recurrences, especially after stromal disease, I discuss prophylaxis: oral acyclovir 400mg twice daily or valacyclovir 500mg twice daily for 12 months, at which point we can reassess the need for continuing prophylaxis.11
HSV keratitis case study
I recently saw an 85-year-old woman with recurrent herpes epithelial keratitis and resultant neurotrophic keratitis (NK), who presented with a peripheral dendrite that widened toward a geographic ulcer despite oral antiviral therapy. While this patient had a history of recurrences that resolved with oral antiviral therapy, in this case, the epithelial defect was not healing, likely due to corneal nerve damage.
We decided to place CAM for 5 days, and thankfully, the epithelium closed, her discomfort resolved, and her visual axis remained clear. She opted to initiate a 12-month oral antiviral prophylaxis and has had no recurrences to date.
Figure 1: Before CAM treatment, there was a persistent epithelial defect despite oral antiviral therapy.
Figure 1: Courtesy of Ashraf F. Ahmad, MD.
Figure 2: Fully healed epithelium after a 5-day treatment with CAM in combination with continued oral antivirals.
Figure 2: Courtesy of Ashraf F. Ahmad, MD.
Short- and long-term monitoring of epithelial herpetic keratitis
After initiating therapy, my first check is typically at 1 to 2 weeks, or sooner if pain or vision worsens. At each visit, I re‑measure and, when possible, photodocument lesion dimensions. I’m looking for steady contraction of the epithelial defect and any signs of stromal transition.
I also re‑check corneal sensitivity, particularly in recurrent disease. I reiterate to my patients to be vigilant and alert to symptoms of recurrence, and they should not hesitate to return if they notice any of the following: new or worsening redness, changes in vision, pain, photophobia, or a familiar prodrome (e.g., periocular tingling/burning). We do our best to offer patients same‑day clinic access when these symptoms show up.
I also counsel patients that most epithelial dendrites improve clinically within 1 to 2 weeks, though some take longer, and that recurrences can be expected. We can lower the odds of recurrence by avoiding triggers where possible (ex., stress, illness, UV light) and by using oral prophylaxis when appropriate.
I also ask patients to tell us if they start or change immunosuppressive medicines and continue to encourage a low threshold for them to call the clinic if recurrence is suspected.
Key takeaways
- Diagnose early; treat empirically when suspicion is high
- Systemic antivirals are the mainstay
- Add topical ganciclovir for non‑response, geographic ulcer, or high‑risk features
- Use CAM earlier for nonhealing, central, or neurotrophic epithelial defects
- Avoid steroids in active epithelial disease; add only for stromal disease with antiviral cover
- Consider 12‑month oral acyclovir prophylaxis in recurrent disease
Conclusion
Outcomes in herpetic keratitis hinge on early recognition, the use of systemic antivirals as the backbone of therapy, and careful follow‑up to prevent stromal escalation.
When healing is slow or the visual axis is at risk, early use of CAM can protect and speed re‑epithelialization while continuing with antiviral therapy.
It is important to always empower your patients with clear return cues and same‑day clinic access so recurrences are treated before their vision is threatened.
Relevant financial disclosures: Dr. Ahmad is a consultant and speaker for BioTissue and a speaker for Dompé.
