Sanjana Ashok

Introduction

Herpes simplex virus (HSV) keratitis is a major cause of corneal morbidity worldwide and has been said to be the most common infectious cause of corneal blindness in high-income countries (1). The disease is caused predominantly by herpes simplex virus type 1 (HSV-1), with HSV-2 accounting for a smaller proportion of ocular infections. Following primary infection, HSV establishes latency within the trigeminal ganglion, allowing for recurrent ocular disease throughout life. HSV keratitis encompasses a spectrum of disease affecting the corneal epithelium, stroma, and endothelium, each with distinct pathogenic mechanisms and therapeutic implications. Prompt recognition and appropriate management are essential to reduce the risk of visual impairment, corneal scarring, and long-term complications.

Epidemiology

Global estimates for HSV1 and HSV2 infection in 2016 were 3.7 billion people and 291.5 million people respectively (2).  Annually, it is estimated that 1.5 million people are diagnosed with HSV keratitis with 40,000 of these having severe cases of visual impairment (3).

The disease follows a relapsing–remitting course, with recurrence rates reported at 10% within one year, 36% at five years, and up to 60–70% at 20 years following an initial episode in a Minnesota study (4). These recurrence patterns highlight the chronic nature of the disease and the importance of long-term follow-up and secondary prevention strategies.

Risk Factors

HSV reactivation is influenced by a complex interplay of host, viral, and environmental factors. Immunosuppression, including HIV infection, systemic corticosteroid use, atopic disease, and chronic systemic illness, is associated with increased risk of both primary disease and recurrence (5). Previous ocular surgery, particularly corneal transplantation and refractive procedures, is a recognised trigger for HSV reactivation and graft failure (5).

Atopic individuals and children are more likely to develop bilateral disease, and paediatric HSV keratitis carries a risk of amblyopia (5). Psychological stress, ultraviolet light exposure, and hormonal influences have been implicated as potential triggers, although the Herpetic Eye Disease Study did not identify consistent associations in clinical populations (6). Reduced corneal sensation following recurrent disease predisposes patients to neurotrophic keratopathy, further complicating healing and increasing the risk of stromal scarring.

Clinical Presentation

The clinical features of HSV keratitis depend on the depth of corneal involvement:

Epithelial HSV keratitis

Epithelial keratitis is caused by active viral replication and typically presents with pain, photophobia, epiphora, and blurred vision. Early disease may manifest as superficial punctate keratitis, progressing to stellate erosions and the classic dendritic ulcer. These lesions characteristically stain with fluorescein centrally and rose bengal or lissamine green at the margins, reflecting virally infected epithelial cells.

Stromal HSV keratitis

Stromal keratitis is predominantly immune mediated and accounts for the majority of vision-threatening disease. Non-necrotising stromal keratitis presents with stromal haze and oedema without an epithelial defect and is often recurrent. Necrotising stromal keratitis is less common but severe, characterised by stromal ulceration, necrosis, anterior uveitis, and a high risk of corneal thinning and perforation.

Endothelial HSV keratitis

Endothelial keratitis, or endotheliitis, is the least common subtype and results from viral antigen-mediated endothelial dysfunction. It presents with disciform or diffuse corneal oedema, Descemet’s folds, keratic precipitates, raised intraocular pressure due to trabeculitis, and mild to moderate anterior uveitis. Visual acuity may be significantly reduced despite minimal pain.

Investigations

Although HSV keratitis is primarily a clinical diagnosis, investigations are useful in atypical presentations, severe disease, or cases unresponsive to standard therapy. Polymerase chain reaction (PCR) testing of corneal swabs allows rapid detection of HSV DNA and is considered best practice in new cases, endothelial keratitis, or keratouveitis.

In vivo confocal microscopy offers immediate, non-invasive imaging and may demonstrate inflammatory changes such as pseudo-guttata, although findings are non-specific and must be interpreted in clinical context. Additional investigations, including anterior segment optical coherence tomography and corneal scraping, may be required to exclude alternative diagnoses such as acanthamoeba keratitis, particularly in contact lens wearers or treatment-resistant disease.

Management

Management of HSV keratitis is determined by the anatomical subtype and severity of disease. Epithelial keratitis is treated with topical antiviral therapy eg. ganciclovir gel. Adjunctive topical antibiotics are frequently prescribed to prevent secondary bacterial infection. Mechanical debridement may accelerate epithelial healing in selected cases. Topical corticosteroids are contraindicated in active epithelial disease due to the risk of enhanced viral replication and if there is a chance of alternative diagnosis like acanthamoeba keratitis.

Stromal and endothelial keratitis require a combination of antiviral therapy and topical corticosteroids to suppress immune-mediated inflammation. The Herpetic Eye Disease Study demonstrated that topical corticosteroids significantly reduce stromal inflammation and disease duration when used with appropriate antiviral cover (6). Systemic antiviral therapy is used frequently to treat necrotising stromal keratitis and endothelial disease, but has needs a bigger study population than was used in the Herpetic Eyes Disease study to fully prove statistical benefit, although trends did favour this.

Long-term antiviral prophylaxis has been shown to reduce recurrence rates by approximately 45% and should be considered in patients with frequent recurrences, stromal disease, or following corneal transplantation. Slow tapering of topical corticosteroids over several weeks to months is essential to prevent rebound inflammation. Poor response to treatment should prompt reassessment of compliance, diagnostic accuracy, antiviral resistance, and underlying immunosuppression.

References

1. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. 2001;20(1):1–13. doi:10.1097/00003226-200101000-00001
2. James C, Harfouche M, Welton NJ, et al. Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull World Health Organ. 2020;98(5):315-329. doi:10.2471/BLT.19.237149
3. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012;57(5):448–462.
4. Young RC, Hodge DO, Liesegang TJ. Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976–2007. Arch Ophthalmol. 2010;128(9):1178–1183.
5. Arshad S, Petsoglou C, Lee T, Al-Tamimi A, Carnt NA. Twenty years since the Herpetic Eye Disease Study: lessons, developments and applications to clinical practice. Clin Exp Optom. 2021;104(3):396–405.
6. Wilhelmus KR, Gee L, Hauck WW, et al. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994;101(12):1883–1896.
7. Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study: a controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology. 1994;101(12):1871–1882.
8. Wilhelmus KR, Dawson CR, Barron BA, et al. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med. 1998;339(5):300–306.