Herpes Simplex Keratitis Treatment & Management
- Author: Jim C Wang (王崇安), MD; Chief Editor: Hampton Roy, Sr, MD more...
Since most cases of herpes simplex virus (HSV) epithelial keratitis resolve spontaneously within 3 weeks, the rationale for treatment is to minimize stromal damage and scarring. Gentle epithelial debridement may be performed to remove infectious virus and viral antigens that may induce stromal keratitis. Antiviral therapy, topical or oral, is an effective treatment for epithelial herpes infection.
Treatment options for primary ocular herpes infection include the following:
Ganciclovir ophthalmic gel 0.15% - 5 times daily
Trifluridine 1% drops - 9 times daily
Vidarabine 3% ointment - 5 times daily
Oral acyclovir 400 mg - 5 times daily 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.
Topical ganciclovir ophthalmic gel, approved by the US Food and Drug Administration (FDA) in 2009, has the advantages of low corneal toxicity, less frequent applications, and gel formulation. Trifluridine solution and vidarabine ointment are also effective in treating HSV keratitis. However, epithelial toxicity is a frequent adverse effect, especially with prolonged use.
Response to topical therapy usually occurs in 2-5 days, with complete resolution in 2 weeks. Topical therapy should be tapered rapidly after initial response and discontinued after complete healing, generally within 10-14 days. Failure of epithelial healing after 2-3 weeks of antiviral therapy suggests epithelial toxicity, neurotrophic keratopathy, or, rarely, drug-resistant strains of HSV. Vidarabine is often effective against HSV strains that are resistant to trifluridine and acyclovir.
Oral acyclovir has been reported to be as effective as topical antivirals for infectious epithelial keratitis with the added advantage of no ocular toxicity. The use of systemic acyclovir is increasingly preferred over topical agents in the treatment of HSV keratitis, particularly for patients with preexisting ocular surface disease who are at high risk for toxicity from topical medications, for patients who are immunocompromised, and for pediatric patients. Some physicians prescribe both oral and topical antiviral agents in conjunction when treating infectious HSV keratitis.
Newer oral antiviral drugs, such as valacyclovir and famciclovir, further simplify the dosing regimens; however, the optimal dose for ocular disease has not been determined.
Patients with frequent recurrences of ocular HSV may be placed on a long-term regimen of oral antiviral medication at the prophylactic maintenance dose. Valacyclovir has been shown to be as effective as acyclovir in reducing the recurrence of ocular HSV disease.
A 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 harmful. The use of sharp instruments, cryotherapy, or strong chemicals (eg, phenol, iodine) should be avoided because they can cause unnecessary damage.
Adequate debridement can usually be achieved by brushing the epithelial lesions with a cotton-tipped applicator. This technique is both convenient and effective; epithelial healing is rapid (usually within 48 hours) 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.
Cases refractory to standard management or in which multiple recurrences develop may be referred to a corneal specialist.
Infectious Epithelial Keratitis
Dendritic, geographic, and marginal corneal ulcers can be treated as follows:
Débridement of the infected epithelium - 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 a platinum spatula
Ganciclovir 0.15% gel, 5 times daily; trifluridine 1% drops, 9 times daily; vidarabine 3% ointment, 5 times daily; or 2 g of oral acyclovir, once daily
Topical steroids - May be used 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.[21, 22] In vitro studies using fusion proteins (which 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.
Prior to the 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 similarly to epithelial keratitis, with a topical antiviral agent and a cycloplegic agent administered until the epithelium has healed. Immune stromal keratitis without associated epithelial disease or necrotizing stromal keratitis after resolution of the epithelial defect are treated with the following:
Topical or oral antivirals
The strategy for topical corticosteroid therapy is frequent initial administration (q1-4h) followed by slow tapering of 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 daily for 3 weeks and 2 times daily thereafter.
Associated elevated intraocular pressure can 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.
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.
Anti-VEGF agents (bevacizumab, ranibizumab), fine-needle diathermy, and photodynamic therapy have all been reported as successful in treating stable persistent corneal neovascularization due to HSV keratitis.
Endotheliitis and Neurotrophic Keratopathy
Endotheliitis is treated with combined corticosteroid and antiviral therapy. Frequent topical steroid therapy is initially prescribed. The dose is subsequently titrated, based on clinical response, to the lowest dosage necessary to control inflammation.
Neurotrophic keratopathy is managed with nonpreserved lubricants, eyelid patching, bandage contact lenses, and autologous serum. Potentially epithelial-toxic medications should be discontinued. Ulcers that fail to respond to the above measures may heal with tarsorrhaphy. Stromal thinning and perforation may necessitate surgical intervention.
Patients with HSV keratitis need to be monitored closely in an outpatient clinic until the disease is inactive. Any suspicious corneal infiltrate in the presence of HSV epithelial keratitis should be cultured for possible secondary microbial infection and then managed with topical antibacterial or antifungal agents. Persistence of an epithelial defect despite antiviral treatment should raise the suspicion of topical corneal toxicity and neurotrophic disease. Discontinuation of topical antivirals or even tarsorrhaphy may be required.
Contact lens wear, although not contraindicated in patients with previous HSV keratitis, should be used with caution. Patients should understand that contact lens wear may increase the risk of secondary infection with HSV epithelial keratitis. They should be instructed to discontinue contact lens wear at the earliest symptoms of HSV keratitis recurrence.
Irregular astigmatism resulting from chronic stromal keratitis may be correctable with rigid, gas-permeable contact lenses. Patients with visually significant corneal opacities or corneal perforations may require keratoplasty for visual rehabilitation.
Although an uncommon occurrence, progressive necrotizing stromal keratitis and impending corneal perforation may be better managed with tissue glue and bandage contact lens before considering keratoplasty.
If possible, a small descemetocele or perforation in an inflamed eye may initially be managed with tissue adhesive, a bandage contact lens, and/or amniotic membrane transplantation. Corneal transplantation should ideally be deferred until the eye is less inflamed.
The prognosis for a successful graft approaches 80% in eyes without inflammation prior to surgery. Prophylactic oral antiviral therapy following penetrating keratoplasty reduces recurrent ocular HSV disease and graft rejection episodes and improves graft survival. Most surgeons use a systemic antiviral agent (eg, acyclovir 400 mg bid) for at least 6-12 months after penetrating keratoplasty.[29, 30, 31] Interestingly, because recurrent HSV disease is the result of reactivation of latent virus in the nerve ganglion, the rate of disease recurrence is not altered after penetrating keratoplasty. Anterior lamellar keratoplasty may be considered in lieu of penetrating keratoplasty in patients with healthy corneal endothelium.
Deterrence and Prevention
The major difficulties in treating herpetic keratitis relate to the tendency for recurrences and to 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 host defense results in reactivation of the virus, its subsequent passage centrifugally along the nerve, and resultant shedding from the nerve endings. Corneal lesions occur when the balance between latency and reactivation 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 daily as prophylaxis can reduce the incidence of recurrence.[32, 33] This is recommended for patients with recurrent stromal disease or more than 2 episodes of epithelial disease per year.[34, 35]
Active HSV keratitis is an absolute contraindication to laser corneal refractive surgery (ie, LASIK, PRK) or other corneal procedures (collagen cross-linking). Inactive keratitis or a history of previous HSV disease is also considered a relative contraindication. Recurrence of HSV keratitis after refractive surgery is a well-known complication. However, case reports have documented good refractive surgery outcomes in selected patients whose keratitis has been inactive for at least 1 year and in whom perioperative systemic antiviral prophylaxis is used.[36, 37, 38]
Ongoing research into HSV vaccination is being conducted. While nearly all developmental vaccines are targeting HSV-2 and genital herpes, evidence suggests that these vaccines may offer cross-protection in preventing ocular HSV-1 infections. However, concerns remain that a boost in immune response to HSV after vaccination may exacerbate herpetic stromal keratitis.
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