Recurrent infections may occur at any age. 20-25 percent of patients with primary infection will have a recurrence. Half of patients with recurrent infection will have another attack in 2 years.

Symptoms

• May be asymptomatic
• Redness
• Itching
• Irritation
• Blurred vision
• Tearing
• Photophobia
• Foreign body sensation
• Rarely pain

Signs

• Corneal lesions more common than the lid and conjunctival lesions

  Types of corneal lesions:

  • Epithelial keratitis (dendritic or amoeboid)
  • Stromal keratitis (disciform and necrotizing)

• Rarely lid margin ulcerations
• Rarely follicular conjunctivitis; mild conjunctival hyperemia or ciliary injection (eye often not very red)

Epithelial lesions: active viral replication

• Coarse punctate epithelial keratitis
• Stellate or microdendrites coalescing in a few days into dendritic ulcers--linear, fine, lacy, branching lesion with terminal end bulbs
• Geographic/amoebic ulcers (progressive enlargement of ulcer); often topical steroid-induced
• Single or multiple
• Swollen epithelial cells at the edges stain with rose bengal/lissamine green, and necrotic cells in base/center stain with NaFl
• Central or limbal lesions (more resistant to treatment; may resemble marginal keratitis)
• Sterile trophic or metaherpetic
• Decreased corneal sensitivity; cotton wisp test, initially localized; with more recurrences, more generalized anesthesia
• Occasionally associated with mild subepithelial infiltrates and mild stromal edema appearing under the ulcer; often resolves once epithelium heals
• Following healing, the epithelium may manifest "pseudodendrites"--don't mistake for active infection
• Mild corneal scarring; nebular/ghost scars--especially after attacks
• Patients with AIDS are more likely to have marginal dendrite, longer to heal

Laboratory evaluations rarely performed

• Enzyme-linked immunosorbent assay (ELISA) is simple, rapid, and reliable diagnostic test even if treatment has been started. SureCellª (Kodak) and MicroTrak¨ (Syva).
• Viral cultures

• Herpes zoster ophthalmicus (HZO) keratitis
• Healing corneal abrasion
• Contact lens wear
• Acanthamoeba keratitis
• Toxic keratitis

Treatment of HSK is primarily based on whether the corneal condition is caused solely by active virus, as in dendritic keratitis, or has an immune response component, as in disciform keratitis.

Management of Dendritic Keratitis

Goals

• Preserving vision
• Preventing recurrent attacks
• Aggressive and early treatment to reduce the possibility of stromal disease and scarring

Treatment

• Decide whether active virus is present with rose bengal or lissamine green dye; if uncertain, re-evaluate in 24 hours
• Self-limited (if untreated) in 50% in 1 to 2 weeks
• Initial treatment with topical antivirals; rarely mechanical debridement

  Topical Antiviral Solutions Viroptic 1% ophthalmic solution q2h x 2 days 9 times daily, then q3-4h until the lesion resolves completely, then have patient continue the medication qid/tid for another week to ensure suppression of the virus. (Others say full dose by 14-21 days, continue therapy after healing, may taper for 2-3 weeks.) 97% of cases resolve within 2 weeks. Viroptic Solution (1%Trifluridine) Monarch Pharmaceuticals Preservative: Thimerosal 7.5 ml retail cost approximately $100 (2005) Stored under refrigeration Generic available; still expensive Approved for use in patients 6 yrs & older Interfers with DNA synthesis Also effective is Acyclovir 3% ointment 5 times per day as well as new ganciclovir 0.15% gel--although neither are yet available in the United States. Possible adverse reactions from topical antivirals Hypersensitivity reactions--contact dermatitis Punctate epithelial keratopathy--filamentary keratitis Follicular conjunctivitis Punctal stenosis Avoid use in treating pregnant and nursing women unless benefits outweigh the potential risks Trifluridine is the drug of choice in US, but use an alternative antiviral drug if adverse reactions occur. The normal response to treatment is dramatic with breaking up of an ulcer into smaller islands ("Morse Code" healing). If no response in 7 days--then consider compliance, resistance, proper diagnosis, and different antiviral. The routine use of topical antibiotics is not necessary; they may enhance corneal toxicity. May need to prescribe 5% homatropine bid.

• Debridement

  While debridement was the choice of treatment in the past, most recent studies show that debridement may not be as effective as antiviral therapy. It may, however, be used in conjunction with antivirals. Use a cotton swab or spatula with topical anesthetic (caution if lesion central; more scarring?); return in 24 hours.

Herpes Simplex Blepharoconjuntivitis

• Lid lesions without corneal involvement
• Viroptic drops qid until lid lesion resolves
• Oral acyclovir 400 mg 5x/day x 7 days?

Neurotrophic Keratitis/Indolent Ulcers

Result of . . .

• Basement membrane damaged from previous keratitis
• Anesthetic cornea
• Abnormal tear film

No active viral replication; sterile erosion of the epithelium.

Appearance: round, oval epithelial defect with rolled edges, mild uveitis. May lead to stromal thinning and perforation.

Trophic/neurotrophic ulcer is difficult to treat. Discontinue antivirals and treat with:

• Instill antibiotic ointment (e.g., Polysporin/Erythromycin 2-4 times daily plus cycloplegic agent bid)
• May try pressure patching or bandage lens
• Mild topical steroids?
• Tarsorrhapaphy
• Monitor closely for secondary infection (may need cultures) and progression to perforation
• Refer to corneal subspecialist if not healing

Topical steroids are contraindicated in epithelial active virus disease. Enhanced viral replication and prolongation of disease may result in deeper lesions, and disciform keratitis is more likely. Secondary bacterial and fungal infections may occur. Increased IOP and formation of cataracts are possible.

Disciform Keratitis

• Antigen/antibody response, delayed cell mediated hypersensitivity
• 10-20 percent of those with epithelial dendrites will have concurrent or delayed stromal disciform keratitis.
• 5-10 days after dendrite or several months or years later, even with no history of infection
• Photophobia, pain, red eye, and reduced VA
• Appearance of stromal edema in a disc-shaped area, cell infiltrate, folds in Descemet's, epithelium intact, microcystic edema, KPs, pseudoguttata, AC reaction, elevated IOPs (trabeculitis), often results in stromal scarring

Treatment of disciform keratitis includes a cycloplegic, topical steroids, B-blockers for elevated IOP, and antiviral coverage. If very mild and off the visual axis, use cycloplegics (e.g., 5% homatropine 3 times daily and lubricating drops for comfort) to control uveitis. If affecting the vision because of its severity or location, then use topical steroids (1% Prednisolone acetate [Pred Forte] or Lotemax qid), trying to use the lowest dose possible--refer to HEDS (Herpetic Eye Disease Study). Topical antivirals (1% Viroptic solution) should be administered concurrently any time steroids are used. Usually 4 times daily is adequate prophylaxis.

Tapering of Medications: Disciform keratitis usually responds quickly to steroids, but the patient's Pred Forte must be tapered very slowly. Continue taper with Pred Mild or Alrex. Patient may be on these drops for several months or years. Once the steroid is only once daily, you can discontinue the antiviral agents.

Disciform keratitis may leave a scar. If scarring is visually significant, may need PKP (penetrating keratoplasty). Recurrences in graft are common.

Necrotizing Stromal Keratitis

• Live virus in stroma
• Appearance of stromal abscess with necrotizing, cheesy, white infiltrate in all layers of the cornea, stromal edema, vascularization , WessleyÕs immune rings, uveitis, hypopyon, iris rubeosis
• Can lead to scarring, thinning, perforation

Treatment of necrotising stromal keratitis is similar to treatment of disciform keratitis (includes a cycloplegic, antivirals, topical steroids); however, a poorer response is typical. Rule out other infections (culture?). Refer to corneal subspecialist.

Herpetic Eye Disease Study The Herpetic Eye Disease Study (HEDS) was originally undertaken to evaluate the usefulness of oral acyclovir in stromal HSV disease. It became much more as it progressed from September 1992 to December 1996. Over 700 patients with various manifestations of ocular HSV infection were examined. Many subgroups were studied. HEDS Findings Stromal disease can occur in the absence of previous epithelial lesions. 400mg of oral acyclovir (Famvir not studied) twice per day for one year resulted in a 45% decrease in the rate of recurrence for all forms of ocular complications. Over the six months after discontinuation, there was no rebound increase but no continued benefit. Interestingly, the benefit mostly applied to those with previous stromal disease, not previous dendrites alone!. Oral acyclovir did not improve outcomes in cases of stromal keratitis, with the possible exception of necrotizing disease (small sample). Steroids are very effective in managing stromal infections and do not increase the rate of recurrence. Oral acyclovir may benefit HSV iridocyclitis (small sample size). Treatment of patients with epithelial dendrites with oral acyclovir does not reduce the rate of stromal disease or iritis. Prophylactic Systemic Therapy Oral acyclovir 400mg bid for 1 year or longer reduces the rate of recurrent epithelial and stromal keratitis by about 45%. Effect disappears when drug is stopped. Consider if 2 or more attacks of dendritic within a year or recurrent disciform keratitis. NEI--HERPETIC EYE DISEASE STUDY Group Acyclovir for the prevention of recurrent herpes simplex virus eye disease N Engl J Med 1998 Jul 30;339(5): 300-6. Herpetic Eye Disease Study--Acyclovir Prevention Trial Recurrence rate of any form of ocular herpes was significantly lower in the acyclovir group (19%) than placebo group (32%). Represents a reduction by 41%. Rate of recurrence of stromal keratitis from 28% to 14% (50% reduction) Oral acyclovir 400mg bid x 1 year? Oral Anti-Virals Acyclovir (Zovirax) HZ: 800mg 5x/day x 7 days HS: 400mg 5x/day x 7 days Valacyclovir (Valtrex) HZ: two 500mg tabs tid x 7 days HS: 500mg tabs tid x 7 days Famciclovir (Famvir) HZ: 500mg tid x 7 days HS: 500mg bid x 7 days Examples of When to Use Oral Antivirals Patients with an allergy to topical Viroptic Patients with primary HSV blepharodermatitis with/ without concurrent HSV keratitis Patient with stromal keratitis when topical steroids are needed & patient had toxic reaction to Viroptic