Ophthalmology – Herpes Simplex Keratitis

Basics

Description

Herpes simplex keratitis (HSK) is a corneal infection caused most commonly by herpes simplex virus type 1 (HSV-1). Primary HSV infection usually occurs in childhood and may be mild or even clinically inapparent. After the initial infection, the virus becomes latent within sensory ganglia, particularly the trigeminal ganglion, where it can remain dormant for years before reactivation.

Reactivation can produce several forms of ocular disease. Superficial epithelial infection may begin with conjunctival inflammation, punctate epithelial keratitis, or small corneal vesicles that evolve into the classic dendritic epithelial ulcer. A dendritic lesion can enlarge and become a broader geographic ulcer.

Deeper forms of HSV keratitis involve the corneal stroma or endothelium. Stromal disease may be immune-mediated, necrotizing, or associated with anterior uveitis. Disciform keratitis, now generally considered a form of HSV endotheliitis, produces localized stromal edema because of inflammation involving the corneal endothelium.

Repeated episodes can lead to corneal scarring, thinning, irregular astigmatism, reduced corneal sensation, and permanent visual loss. Rarely, severe stromal disease can result in perforation.

Epidemiology

HSV is one of the most important infectious causes of corneal blindness worldwide.

Primary systemic HSV-1 infection is very common, but only a minority of infected individuals develop ocular disease.

Herpetic keratitis may occur as an initial episode or as recurrent disease. Recurrences are particularly important because repeated stromal inflammation is a major cause of permanent corneal scarring and visual impairment.

Risk Factors

Reactivation has historically been associated with events such as febrile illness, upper respiratory infection, ocular trauma, psychological stress, menstruation, and contact lens wear, although not all proposed triggers have been consistently proven.

Prior episodes of ocular HSV are the strongest clinical predictor of future recurrence.

Genetics

Genetic susceptibility probably contributes to the likelihood and severity of HSV ocular disease, but no single genetic pattern explains most cases.

General Prevention

Long-term oral antiviral prophylaxis can reduce recurrent ocular HSV in selected patients, particularly those with previous recurrent stromal keratitis or multiple clinically significant episodes.

Pathophysiology

After primary infection, HSV travels along sensory nerves and establishes latency within the trigeminal ganglion.

During reactivation, infectious virus can travel back down sensory axons toward the eye and produce epithelial disease.

Epithelial keratitis is caused primarily by active viral replication within corneal epithelial cells.

Stromal and endothelial disease have a more complicated pathogenesis. They may involve a combination of viral antigen, persistent or recurrent viral activity, and a host immune response that damages corneal tissue.

Repeated inflammation can cause progressive stromal scarring and loss of corneal transparency.

Commonly Associated Conditions

Patients with ocular HSV may have a history of herpes labialis or vesicular lesions around the mouth, nose, eyelids, or periocular skin.

However, the absence of a history of cold sores does not exclude ocular HSV.

Diagnosis

History

Patients may report ocular irritation, foreign-body sensation, pain, redness, photophobia, tearing, or blurred vision.

Blurred vision is more likely when the lesion involves the visual axis or when stromal edema is present.

A previous episode of unilateral red eye, dendritic keratitis, unexplained corneal scarring, or recurrent herpetic disease can be diagnostically helpful.

Physical Examination

A careful slit-lamp examination is essential.

Vital dyes such as fluorescein and, when appropriate, rose bengal or lissamine green can help delineate epithelial lesions.

Corneal sensation should also be assessed because reduced corneal sensitivity is common after recurrent HSV disease.

Epithelial Herpes Simplex Keratitis

The classic lesion is a dendritic ulcer.

It consists of a branching epithelial defect with terminal bulbs.

The central ulcerated portion stains with fluorescein, while the swollen epithelial borders may stain with rose bengal or lissamine green.

Dendrites can enlarge and merge into a broader irregular geographic epithelial ulcer, particularly in patients who have received inappropriate topical corticosteroids.

Stromal Herpes Simplex Keratitis

Stromal disease may be non-necrotizing immune stromal keratitis or necrotizing stromal keratitis.

Immune stromal disease causes stromal haze, edema, and sometimes vascularization without a major epithelial defect.

Necrotizing stromal keratitis is more severe and may involve active viral infection, stromal ulceration, marked inflammation, thinning, and risk of perforation.

HSV Endotheliitis / Disciform Keratitis

HSV can produce endothelial inflammation resulting in disc-shaped stromal edema, keratic precipitates, and sometimes anterior chamber inflammation.

This has historically been termed disciform keratitis.

The corneal epithelium may initially remain intact.

HSV Anterior Uveitis

HSV can also cause anterior uveitis.

Possible findings include keratic precipitates, anterior chamber cells and flare, iris atrophy, and elevated intraocular pressure.

The combination of unilateral anterior uveitis, increased IOP, and sectoral iris atrophy should raise suspicion for herpetic disease.

Diagnostic Tests and Interpretation

Laboratory Testing

Typical dendritic epithelial keratitis is usually diagnosed clinically and generally does not require laboratory confirmation.

When the presentation is atypical, recurrent, severe, or involves deeper structures, laboratory testing can be useful.

PCR of corneal, aqueous, or other ocular samples may detect HSV DNA and can help distinguish HSV from VZV, CMV, and other causes.

Viral culture is less commonly required.

Imaging

Routine imaging is not generally necessary for uncomplicated HSV keratitis.

Anterior-segment photography or OCT may occasionally be useful for documenting severe or chronic corneal disease.

Pathological Findings

Corneal biopsy is rarely necessary.

When tissue is examined, findings vary depending on whether disease involves the epithelium, stroma, or endothelium and may include epithelial necrosis, inflammatory infiltration, stromal scarring, and viral cytopathic changes.

Differential Diagnosis

Important differential diagnoses include herpes zoster keratitis, Acanthamoeba keratitis, fungal keratitis, bacterial keratitis, Epstein-Barr-associated disease, neurotrophic epithelial defects, and other causes of persistent or atypical corneal ulceration.

HSV dendrites should also be distinguished from pseudodendrites, particularly those caused by herpes zoster.

Treatment

Treatment depends on which corneal layer is involved.

Epithelial Keratitis

Active epithelial HSV disease is treated with antiviral therapy.

Topical options include ganciclovir gel or, in some settings, trifluridine.

Oral antivirals such as acyclovir or valacyclovir are also effective and are often used because they are convenient and avoid topical epithelial toxicity.

Topical corticosteroids should not be used for active epithelial dendritic or geographic keratitis unless there is a specific specialist-directed indication with adequate antiviral coverage.

Stromal Keratitis

Immune-mediated stromal keratitis is treated with topical corticosteroids combined with antiviral coverage.

Steroids are tapered slowly according to clinical response because rapid withdrawal can precipitate recurrence.

Oral antiviral therapy is often used during steroid treatment.

Necrotizing Stromal Keratitis

Necrotizing disease requires aggressive antiviral therapy and specialist management.

Topical corticosteroids may be used cautiously when indicated, but only with adequate antiviral coverage because active viral replication may be present.

Endotheliitis and Uveitis

HSV endotheliitis and anterior uveitis are commonly treated with topical corticosteroids plus systemic or topical antiviral therapy.

Elevated intraocular pressure should be treated appropriately.

Because prolonged steroid therapy may be necessary in some cases, careful monitoring for glaucoma and cataract is required.

Long-Term Antiviral Prophylaxis

Suppressive oral antiviral therapy can be considered in patients with recurrent disease, especially those with recurrent stromal keratitis, previous corneal transplantation for HSV, or frequent vision-threatening recurrences.

Long-term prophylaxis reduces the risk of recurrent ocular HSV while therapy is continued.

Surgery

Severe corneal scarring, irregularity, thinning, or perforation may eventually require surgical treatment.

Penetrating keratoplasty or selected lamellar corneal transplantation procedures may be used for visually significant scarring or structural compromise.

Active inflammation should ideally be controlled before elective corneal transplantation because recurrent HSV can affect the graft.

Antiviral prophylaxis is commonly used around and after keratoplasty in patients with prior HSV disease.

Follow-Up

Patients with active dendritic keratitis require serial slit-lamp examinations until the epithelial defect has healed.

Stromal keratitis, endotheliitis, and uveitis usually require longer and closer follow-up, particularly during corticosteroid tapering.

Patients with recurrent disease may require lifelong intermittent ophthalmic monitoring.

Patient Monitoring

Monitoring should include visual acuity, corneal epithelial integrity, stromal inflammation, corneal thickness, corneal sensation, intraocular pressure, and anterior chamber inflammation.

Patients receiving topical corticosteroids should be monitored for steroid-related ocular hypertension and cataract.

Patient Education

Patients should understand that HSV remains latent in the nervous system and may recur even years later.

They should be instructed not to self-treat recurrent red eye with leftover steroid drops because steroids can worsen active epithelial HSV dramatically.

Any recurrence of unilateral redness, pain, photophobia, or decreased vision should prompt an early ophthalmic examination.

Pediatric Considerations

Infants and children can develop ocular HSV after maternal antibodies decline.

Because herpetic epithelial disease may worsen rapidly with corticosteroids, topical steroids should not be used empirically for an unexplained red eye in a child without appropriate ophthalmic examination.

Children also require careful monitoring for amblyopia if corneal scarring or irregular astigmatism develops.

Prognosis

The prognosis is generally good for an initial episode of epithelial dendritic keratitis when promptly treated with antiviral therapy.

The prognosis becomes more guarded with recurrent stromal keratitis, endotheliitis, corneal neovascularization, thinning, or scarring.

Repeated stromal episodes are the major cause of permanent visual morbidity.

Complications

Complications include recurrent epithelial keratitis, neurotrophic keratopathy, stromal scarring, corneal neovascularization, irregular astigmatism, corneal thinning, secondary glaucoma, cataract, and rarely corneal perforation.

The greatest risk of substantial long-term vision loss comes from recurrent stromal HSV disease rather than from a single uncomplicated dendritic epithelial episode.