AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Herpes simplex virus (HSV), a large complex DNA virus, commonly infects the skin and the mucous membranes in the regions of the mouth, genitalia, and eye. Two antigenically related strains of HSV can be distinguished, type 1 and type 2. Type 1 most commonly is associated with infections of the orofacial area and the ocular surface, while type 2 causes genital disease.

Pathophysiology

Infection is spread by direct contact of skin or mucous membranes to infected secretions. The initial attack generally is self-limited and often is subclinical. However, herpetic disease is recurrent, and a wide range of clinical manifestations can result from an infection with this agent. The most common site of primary infection in humans is the skin and the mucous membrane innervated by the trigeminal nerve. The virus is transported via the nerve axon to its cell body in the sensory ganglion where it persists in a latent state until reactivation. Some indication exists that the human cornea also may harbor latent virus. Recurrent disease is the result of reactivation of this latent virus.

Frequency

United States

Of adults in the US, 50-90% have antibodies to HSV type 1, indicating previous exposure to the virus. Incidence of ocular HSV infection is approximately 0.15%.

Mortality/Morbidity

HSV keratitis is the most frequent cause of corneal blindness in the US, with reports of any visual disability as high as 40%.

Sex

This condition has a slightly higher male predominance.

Age

The mean age of presentation is in the late fifth to early sixth decade of life.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

• Patients may present with the following:
• • Red eye
  • Pain
  • Photophobia
  • Tearing
  • Decreased vision
  • Skin (eg, eyelid) rash
• History of previous episodes
• History of corneal abrasion; contact lens wear; or previous nasal, oral, or genital sores

Physical

Primary herpes infection of the eye typically is a unilateral blepharoconjunctivitis, characterized by vesicles on the skin of the lids, follicular conjunctivitis, preauricular adenopathy, and, sometimes, punctate keratitis. After primary infection, recurrent disease may involve any or all layers of the cornea. Since both infectious and immune responses are responsible for ocular disease, it is better to classify the keratitis based upon both the anatomical location (ie, epithelial, stromal, endothelial) and on the pathophysiology (ie, infectious, immune, neurotrophic). Based on this mechanism of classification, 4 major categories of herpes simplex keratitis exist.

• Infectious epithelial keratitis
• • Corneal vesicles: These are minute, raised, clear vesicles in the corneal epithelium that correspond to the vesicles on the skin surface. Within a few hours, these vesicles coalesce and erupt to form a dendritic or geographic ulcer. In immunocompromised individuals, they may coalesce without eruption, forming a raised dendrite without ulceration that shows reverse staining with fluorescein.
  • Dendritic ulcer: This is the most common presentation. The lesion reveals a linear branching pattern with terminal bulbs and heaped borders that contain live virus.
  • Geographic ulcer: As the dendritic ulcer widens, it looses its linear pattern and assumes a geographic form, with scalloped edges and heaped borders. This tends to occur in patients immunocompromised by the use of topical steroids or diseases (eg, HIV).
  • Marginal ulcer: When a dendrite develops close to the limbus its anterior stroma gets infiltrated by leukocytes from the limbal blood vessels, resulting in a dendritic lesion overlying an anterior stromal infiltrate. This often can be mistaken for a marginal staphylococcal ulcer.
• Neurotrophic keratopathy: This is neither infectious nor immune in nature, but the result of abnormal corneal innervation and poor tear production. A nonhealing, oval epithelial defect develops. This defect has smooth borders in contrast to geographic ulcers, which have scalloped borders. Over time, stromal ulceration and opacification develop under the epithelial defect. Corneal perforation can occur.
• Stromal keratitis develops in 25% of patients with epithelial disease.
• • Necrotizing stromal keratitis presents as necrosis and dense infiltration of the stroma, with an overlying epithelial defect. This is a result of direct stromal invasion by the virus. This entity may resemble bacterial or fungal keratitis. The use of topical corticosteroids without antiviral coverage is a risk factor in developing necrotizing keratitis.
  • Nonnecrotizing stromal keratitis also is called immune stromal keratitis and interstitial keratitis. An antigen antibody inflammatory response is believed to be triggered by retained viral antigens in the corneal stroma. Stromal infiltration with or without neovascularization occurs. The overlying epithelium is intact, unless a concomitant infectious or neurotrophic keratitis is present.
• Endotheliitis is an immune reaction at the level of the endothelium that may occur months to years after an episode of infectious keratitis. Characteristic findings include keratic precipitates (KP), overlying stromal and possibly epithelial edema, and iritis. Unlike stromal edema from primary stromal keratitis, no stromal infiltrates or neovascularization is present. Patients present with pain, photophobia, and injection. Based on the distribution of the KP, 3 recognized forms of endotheliitis can be identified.
• • Disciform endotheliitis presents as a round area of central or paracentral stromal edema overlying an area of KP.
  • Diffuse endotheliitis presents with scattered KP and diffuse edema.
  • Linear endotheliitis: Keratic precipitates develop in the peripheral cornea and proceed centrally. Associated corneal edema is isolated to the peripheral corneal stroma and epithelium.

Causes

Primary herpes keratitis is a ubiquitous disease with no apparent risk factors. Recurrent infection due to reactivation, and occasionally reinfection, can be triggered by many events, including the following:

• Stress
• Sunlight
• Fever
• Menstruation
• Trauma including surgical trauma (eg, lamellar keratoplasty, peripheral iridectomy)
• Antiglaucoma medication latanoprost, a prostaglandin analogue because of its ability to induce release of endogenous prostaglandins in the iris and ciliary muscles can induce reactivation of HSV keratitis

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Impetigo
Tyrosinemia
Acanthamoeba keratitis
Staphylococcus marginal ulcer
Cogan syndrome
Measles and mumps
Neurotrophic keratitis

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Diagnosis usually is clinical, based on the presence of lid lesions or a characteristic dendrite. If the diagnosis is in doubt, laboratory diagnosis can be made using the following:
• • Giemsa stain
  • Papanicolaou stain
  • Viral culture
  • Immunohistochemistry looking for viral antigens
  • Polymerase chain reaction (PCR)

Histologic Findings

Giemsa stain of scrapings of the corneal or skin lesions shows multinucleated giant cells. Papanicolaou stain will show intranuclear eosinophilic inclusion bodies.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

• Primary ocular herpes infection with lid vesicles and acute follicular conjunctivitis is a self-limited disease, but treatment is recommended to limit corneal involvement. Treatment options include the following:
• • Trifluridine 1% drops, 9 times a day
  • Vidarabine 3% ointment, 5 times a day
  • Oral acyclovir 400 mg, 5 times a day for 10 days (Oral acyclovir is the preferred treatment in patients unable to tolerate topical medications and with good renal function.)
  • A cycloplegic agent may be added to any of the above regimens for comfort from ciliary spasm.
• Dendritic, geographic, and marginal corneal ulcers are treated with the following:
• • Debridement of the infected epithelium. Debridement is performed after instillation of topical anesthetic (4% cocaine or 0.5% proparacaine) into the conjunctival sac. The loose epithelium at the edge of the dendritic figure is wiped away with a sterile cotton-tipped applicator or with the edge of a knife blade or platinum spatula.
  • Trifluridine 1% drops, 9 times a day; or vidarabine 3% ointment, 5 times a day; or 2 g of oral acyclovir once per day
  • Two new antiviral agents, 0.2% cidofovir eye drops and 3% penciclovir ointment have been effective in the rabbit model in treating herpetic epithelial keratitis and may have a role in humans in the future.
  • Cycloplegic agent
  • Topical steroids may be required after several days of antiviral treatment in patients with marginal ulcers or associated stromal disease to quell the immune response.
  • The attempt to augment or modify the host's immunologic milieu has led some investigators to study the role of cimetidine as an adjunct to standard antiviral therapy. The efficacy of this modality has not been fully established. In vitro studies using both fusion proteins (that block the interaction of T cells with antigen-presenting cells) and basic fibroblastic growth factors have shown a beneficial effect of these as adjunctive treatments in decreasing the incidence of stromal keratitis and iridocyclitis.
• Stromal keratitis - Prior to treatment of stromal disease, the status of the epithelium needs to be evaluated. If stromal disease is accompanied with a concomitant epithelial defect, it is treated similar to epithelial keratitis with a topical antiviral and a cycloplegic agent until the epithelium has healed. Both necrotizing and nonnecrotizing stromal disease without associated epithelial disease or after resolution of the epithelial defect are treated with the following:
• • Topical corticosteroids - The strategy for topical corticosteroid therapy is frequent initial administration (q1-4h) followed by slowly tapering the dose to the lowest effective amount.
  • Topical or oral antivirals are recommended to prevent or limit epithelial disease during the course of treatment with corticosteroids. Many recommendations are available on the frequency of administration of antivirals for prophylaxis. A most commonly used regimen includes administering the drops as often as the recommended therapeutic dose needed to treat epithelial disease. Another regimen includes initiating and tapering the antiviral in the same dosage as the corticosteroid until corticosteroid therapy tapers down to once a day, at which time the topical antiviral is discontinued. The Herpetic Eye Disease Study group recommended using trifluridine, 4 times a day for 3 weeks and 2 times a day thereafter.
  • Associated elevated intraocular pressure should be treated with timolol and systemic acetazolamide, as necessary.
  • Topical cyclosporin A 2% drops in an uncontrolled study showed efficacy in the treatment of stromal disease without the use of corticosteroids. A role may exist for this medication in those patients unable to use corticosteroids.
  • Indolent stromal ulceration is managed with antiviral and corticosteroid therapy along with a soft contact lens to prevent corneal drying. When melting of the cornea occurs, care must be taken not to stop corticosteroid therapy abruptly, as doing so may lead to rebound inflammation and increase the melting process, thereby resulting in perforation. The anticollagenolytic activity of tetracycline may help retard corneal melting when applied as a topical ointment. Consider the possibility of medication-induced toxicity or an anesthetic cornea when faced with chronic, nonhealing, epithelial defects associated with stromal inflammation. Occasionally, a lateral tarsorrhaphy may be required to treat a nonhealing epithelial defect.

Surgical Care

• Keratoplasty should be considered for the following:
• • Corneal scarring and opacity that significantly reduces vision
  • Descemetocele formation and imminent perforation from stromal loss
  • Persistent inflammation not responsive to treatment
• Keratoplasty for corneal scarring secondary to stromal HSV should be performed with caution. The most important factors in determining graft survival are preoperative corneal vascularity and inflammation. Most corneal transplant surgeons wish to have the patient remain without recurrent disease for 6-12 months before considering the procedure. Topical steroids are recommended as an adjunct to keratoplasty preoperatively to help control both inflammation and vascularity, and postoperatively to prevent rejection and graft failure. Most surgeons use a systemic antiviral agent (eg, acyclovir 400 mg bid) for at least 6-12 months after penetrating keratoplasty.
• If the cornea perforates, the best management depends on the size and location of the perforation. Small peripheral perforations may be well treated by cyanoacrylate tissue adhesive. Large or central perforations are best treated with a penetrating keratoplasty. Sealing of a perforated descemetocele with a tissue adhesive and fitting with a soft contact lens often result in reformation of the anterior chamber in preparation for definitive corneal transplantation. Interestingly, because recurrent HSV disease is the result of reactivation of latent virus in the nerve ganglion, the rate of recurrence is not altered after penetrating keratoplasty.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The goal of pharmacotherapy is to reduce morbidity and to prevent complications.

Drug Category: Antivirals

Therapy of viral infections begins with mechanical debridement of the involved rim along with a rim of normal epithelium. This is followed by the topical instillation of antiviral medications (eg, vidarabine, trifluridine).

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Outpatient Care

• The major difficulties in treating herpetic keratitis are related to the tendency for recurrences and the management of stromal disease. In its latent form, HSV can be present in the cells of the cornea and in the central connections of the trigeminal nerve, particularly in the trigeminal ganglion. Disturbance of the nerve results in reactivation of the virus and its subsequent passage centrifugally along the nerve, with shedding from the nerve endings. Lesions tend to occur when the balance between latency and host defenses is disturbed, such as during febrile illnesses, during menses, or on exposure to sunlight. Once trigger factors are identified they need to be avoided. Using 400 mg of acyclovir once or twice a day as prophylaxis can reduce the incidence of recurrence. This is recommended for patients with recurrent stromal disease or more than 2 episodes of epithelial disease per year.

In/Out Patient Meds

• Acyclovir 400 mg bid as prophylaxis to prevent reoccurrence

Deterrence/Prevention

• Acyclovir 400 mg qd or bid as prophylaxis to prevent reoccurrence

Complications

• Even with proper treatment corneal scarring can occur, and, if it is central, visual acuity can be lost.

Prognosis

• Prognosis is generally favorable with aggressive treatment.

Patient Education

• Early recognition of symptoms is important for treatment of reoccurrences.
• For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center and Teeth and Mouth Center. Also, see eMedicine's patient education articles Genital Herpes and Oral Herpes.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Early diagnosis and treatment can help to shorten the visual therapy.

Special Concerns

• The major problem related to therapy is the difficulty in achieving a precise debridement that does not damage the Bowman layer. Some forms of debridement are particularly injurious. The use of sharp instruments, cryotherapy, or strong chemicals (eg, phenol, iodine) should be avoided because they can cause unnecessary damage. Adequate debridement usually can be achieved by brushing the epithelial lesions with a cotton-tipped applicator, a technique that is not only convenient but effective in that epithelial healing is rapid (usually within 24 h) with resultant early disappearance of pain and discomfort. Any tendency for recurrent lesions to form in the early period after healing can be overcome by using a topical antiviral for 7-10 days after debridement.
• Topical corticosteroids are effective in suppressing the inflammatory response of herpetic keratitis. However, their inappropriate use may result in severe epithelial disease or stromal necrosis, corneal perforation, increased tendency toward recurrence, secondary microbial infections, elevation of the intraocular pressure, and lenticular changes. Patients requiring topical corticosteroids for suppression of the inflammatory response usually require the drug for a period of months, and withdrawal often is complicated by recurrence of inflammation. The immunosuppressive complications of steroid administration (eg, recurrent epithelial disease) largely can be avoided by the concurrent administration of antiviral therapy. Patient cooperation is a prerequisite for the safe administration of corticosteroids in herpetic keratitis. An extremely slow corticosteroid taper typically is required.
• All topical antiviral medications currently available for clinical use in the US are toxic, with signs of toxicity being similar for all such drugs. Punctate epithelial keratopathy, limbal follicles, a follicular conjunctival response, ptosis, punctal stenosis, and contact dermatitis can occur at any time after 10-14 days of therapy. In mild cases of antiviral toxicity, epithelial changes may be the only manifestation. The toxic potential of antiviral agents always should be considered in patients who heal poorly, because these agents are inhibitors of cell division.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Anisha Judge, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Jun 18, 2006