Herpes simplex virus (HSV) keratitis is the most frequent cause of blindness due to corneal disease in the United States and the most common source of infectious blindness in the Western world. The prognosis in HSV keratitis, however, is generally favorable with aggressive treatment.
Signs and symptoms
Patients with HSV keratitis may complain of the following:
Pain
Photophobia
Blurred vision
Tearing
Redness
The earliest sign of active viral replication in the corneal epithelium is the development of small, raised, clear vesicles.
Dendritic ulcers are the most common presentation of HSV keratitis. Prominent features of a dendritic ulcer include a linear branching pattern with terminal bulbs at the ends of the branches, swollen epithelial borders of the branches, and central ulceration through the basement membrane.
The earliest signs of neurotrophic keratopathy include an irregular corneal surface and punctate epithelial erosions. These erosions may progress to a persistent epithelial defect and eventual stromal ulceration.
Necrotizing stromal keratitis is characterized by dense stromal infiltrate, ulceration, and necrosis. Immune stromal keratitis (ISK) may present clinically with focal, multifocal, or diffuse cellular infiltrates; immune rings; neovascularization; or ghost vessels at any level of the cornea.
Clinical signs of endotheliitis include keratic precipitates (KP), overlying stromal and epithelial edema, and absence of stromal infiltrate or neovascularization. A mild to moderate iritis is frequently seen. Patients present with pain, photophobia, and injection.
See Clinical Presentation for more detail.
Diagnosis
HSV keratitis remains primarily a clinical diagnosis based on characteristic features of the corneal lesion.[1] If the diagnosis is in doubt, however, laboratory diagnosis can be made using the following[2] :
Giemsa stain - Scrapings of the corneal or skin lesions show multinucleated giant cells
Papanicolaou stain - This shows intranuclear eosinophilic inclusion bodies
Viral culture
Immunohistochemistry looking for herpes simplex viral antigens
Polymerase chain reaction (PCR) assay[3]
See Workup for more detail.
Management
Since most cases of HSV epithelial keratitis resolve spontaneously within 3 weeks, the rationale for treatment is to minimize stromal damage and scarring. Gentle epithelial débridement 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.[4]
HSV is a DNA virus that commonly affects humans. Infection occurs by direct contact of skin or mucous membrane with virus-laden lesions or secretions. HSV type 1 (HSV-1) is primarily responsible for orofacial and ocular infections, whereas HSV type 2 (HSV-2) generally is transmitted sexually and causes genital disease. HSV-2 may rarely infect the eye by means of orofacial contact with genital lesions and occasionally is transmitted to neonates as they pass through the birth canal of a mother with genital HSV-2 infection.
Primary HSV-1 infection occurs most commonly in the mucocutaneous distribution of the trigeminal nerve. It is often asymptomatic but may manifest as a nonspecific upper respiratory tract infection. After the primary infection, the virus spreads from the infected epithelial cells to nearby sensory nerve endings and is transported along the nerve axon to the cell body located in the trigeminal ganglion. There, the virus genome enters the nucleus of a neuron, where it persists indefinitely in a latent state.
Primary infection of any of the 3 (ie, ophthalmic, maxillary, mandibular) branches of cranial nerve V can lead to latent infection of nerve cells in the trigeminal ganglion. Interneuronal spread of HSV within the ganglion allows patients to develop subsequent ocular disease without ever having had primary ocular HSV infection.[5]
Recurrence
Recurrent ocular HSV infection has traditionally been thought of as reactivation of the virus in the trigeminal ganglion, which migrates down the nerve axon to produce a lytic infection in ocular tissue. Evidence suggests that the virus may also subsist latently within corneal tissue, serving as another potential source of recurrent disease and causing donor-derived HSV disease in transplanted corneas. However, corneal HSV latency as a cause of recurrent disease remains controversial.
A prospective, multicenter trial failed to find an association between anecdotal environment triggers (eg, stress, systemic infections, sunlight exposure, menstruation, contact lens wear, eye injury) and ocular HSV recurrence.[6, 7, 8]
HSV reactivation with the use of latanoprost has been reported in patients with glaucoma. HSV reactivation has also been associated with the use of systemic, local, and topical steroid medications, including intravitreal triamcinolone injection.[9]
Causes of the various manifestations of HSV keratitis include the following:
Infectious epithelial keratitis - Results from active viral replication within the corneal epithelium
Neurotrophic keratopathy - A poorly understood disease; the cause is thought to be multifactorial
Necrotizing stromal keratitis - Arises from direct infection of the corneal stroma and the resultant severe host inflammatory response ; the use of topical corticosteroids without antiviral coverage may be a possible risk factor for its development
Immune stromal keratitis - An antibody-complement cascade triggered by retained viral antigen or altered host antigen within the stroma
Endotheliitis - Believed to be primarily an immunologic reaction to an antigen in endothelial cells; however, the role of live virus has been speculated
Neurotrophic keratopathy develops in patients with previous HSV epithelial disease. Traditionally thought of as neither infectious nor immunologic in origin, neurotrophic keratopathy arises from impaired corneal innervation and decreased tear formation (as a result of prior HSV infection of the sensory nerves), exacerbated by long-term use of topical medications, especially antiviral agents. However, evidence suggests that HSV replication may occur in persistent epithelial defects.
Herpes simplex virus (HSV) keratitis encompasses a variety of disease processes that HSV can cause in the human cornea. A variety of clinical manifestations of infectious and immunologic etiologies, such as infectious epithelial keratitis, neurotrophic keratopathy, necrotizing stromal keratitis, immune stromal keratitis (ISK), and endotheliitis, can affect all levels of the cornea. (See Pathophysiology, Etiology, and Presentation.)
Although more common as a manifestation of recurrent HSV infection, HSV keratitis may also be seen during a primary HSV infection. (See Workup.)
Patient education
For patient education information, see the Eye and Vision Center, as well as Corneal Ulcer.
Of adults in the United States, 50-90% have antibodies to HSV-1, indicating previous exposure to the virus. Incidence of ocular HSV infection is about 0.15%.[10]
Approximately 20,000 new cases (as well as more than 28,000 reactivations) of ocular HSV occur annually in the United States. Ocular HSV is one of the most frequent causes of blindness in the United States, with 500,000 people experiencing HSV-related ocular disease.
International occurrence
HSV infection is ubiquitous, with an estimated one third of the population worldwide suffering from recurrent infections.[11] Most of these individuals develop recurrent mucocutaneous lesions such as oral cold sores.
Sex- and age-related demographics
Herpes simplex has a slightly higher male predominance. Most HSV eye disease occurs in adults, developing many years after the primary infection (mean age of presentation, late fifth to early sixth decade of life). Herpetic keratitis in children commonly involves the corneal epithelium and stroma and is marked by a disproportionate risk of bilateral disease, high recurrence rate, and amblyopia.[12, 13]
HSV keratitis is the most frequent cause of corneal blindness in the United States and is a leading indication for corneal transplantation. It is also the most common cause of infectious blindness in the Western world.
The prognosis in HSV keratitis is generally favorable with aggressive treatment. Even with proper therapy, however, corneal scarring can occur. If the scarring develops centrally, visual acuity can be lost.
Stromal keratitis
Significant anterior chamber inflammation may accompany stromal keratitis. Permanent stromal scarring may lead to profound visual loss. In addition, all stromal keratitis types may develop uveitis, trabeculitis, and secondary glaucoma.
Patients with herpes simplex virus (HSV) keratitis may report the following:
Pain
Photophobia
Blurred vision
Tearing
Redness
A history of prior episodes in patients with recurrent disease may exist. Patients with ocular HSV who have previous stromal involvement have a significantly higher risk of subsequent stromal keratitis; in contrast, patients with epithelial keratitis alone have no increased rate of recurrent HSV disease.
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.[14, 15] After primary infection, recurrent disease may involve any or all layers of the cornea.
Since infectious responses and immune responses are responsible for ocular disease, it is better to classify the keratitis based on the anatomic location (ie, epithelial, stromal, endothelial) and the pathophysiology (ie, infectious, immune, neurotrophic). As a result, the following 4 major categories of HSV keratitis exist[16] :
Infectious epithelial keratitis
Neurotrophic keratopathy
Stromal keratitis
Endotheliitis
Infectious epithelial keratitis
Infectious epithelial keratitis is characterized by the following lesions:
Corneal vesicles
Dendritic ulcers
Geographic ulcers
Marginal ulcers
Corneal vesicles
The earliest sign of active viral replication in the corneal epithelium is the development of small, raised, clear vesicles that are analogous to the vesicular eruptions seen in mucocutaneous herpes infection elsewhere in the body. These infectious epithelial vesicles are rarely seen or recognized during a patient's first presentation. However, in patients with a known history of HSV keratitis, infectious epithelial vesicles may be observed even in the absence of any clinical symptoms.
Within several hours, the corneal vesicles coalesce into a dendritic pattern. In some patients, particularly patients who are immunocompromised, the recurring infection may be arrested at the vesicle stage. As the disease progresses, a central epithelial defect develops. The resultant dendritic ulcer is the most common presentation of HSV keratitis.
Dendritic ulcers
This is the most common presentation of HSV keratitis. Prominent features of a dendritic ulcer include a linear branching pattern within the corneal epithelium with terminal bulbs, swollen epithelial borders that contain live viruses, and central ulceration through the basement membrane. (See the images below.)
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Herpes simplex virus dendritic ulcer.
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Herpes simplex virus dendritic ulcer stained with fluorescein.
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Large paracentral herpes simplex virus dendritic corneal ulcer.
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Recurrent herpes simplex virus dendritic ulcer stained with rose bengal, with an adjacent stromal scar.
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Healing herpes simplex virus dendritic ulcer stained with fluorescein.
Geographic ulcers
If the infectious ulcer enlarges, its shape is no longer linear. It is then referred to as a geographic ulcer. The swollen epithelial cells and the scalloped or geographic borders differentiate this infectious lesion from the smooth borders of a neurotrophic ulcer. (See the image below.)
View Image
Herpes simplex virus geographic ulcer stained with fluorescein and rose bengal.
Marginal ulcers
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
The earliest signs of neurotrophic keratopathy include an irregular corneal surface and punctate epithelial erosions. These erosions may progress to a persistent epithelial defect and eventual stromal ulceration.
In contrast to the irregular shape and scalloped borders of an infectious geographic ulcer, a neurotrophic ulcer is typically oval with smooth borders and often lies within the interpalpebral fissures, located in the central or inferior paracentral area of the cornea. Decreased corneal sensitivity helps confirm the diagnosis.
Complications of neurotrophic keratopathy include stromal scarring, neovascularization, necrosis, and perforation. (See the images below.)
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Neurotrophic keratopathy with epithelial defect stained with rose bengal.
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Large neurotrophic ulcer stained with rose bengal.
Stromal keratitis
Corneal stromal inflammation may be the primary manifestation of HSV keratitis, or it may be seen secondary to infectious epithelial keratitis, neurotrophic keratopathy, or endotheliitis.[17] Stromal keratitis develops in 25% of patients with epithelial disease.[18]
The 2 forms of primary stromal involvement are necrotizing stromal keratitis and immune stromal keratitis (ISK).
Necrotizing stromal keratitis
Necrotizing stromal keratitis, characterized by dense stromal infiltrate, ulceration, and necrosis, is believed to result from viral replication in stromal keratocytes and severe host inflammatory response. This destructive intrastromal inflammation may lead to thinning and perforation within a short period of time.
Immune stromal keratitis
ISK, also known as nonnecrotizing stromal keratitis and interstitial keratitis, is a common manifestation of chronic, recurrent ocular HSV disease; ISK may present clinically with focal, multifocal, or diffuse cellular infiltrates; immune rings; neovascularization of the corneal stroma; or ghost vessels at any level of the cornea. (See the images below.)
View Image
Active immune stromal keratitis.
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Inactive immune stromal keratitis.
Endotheliitis
The inflammation directed at the endothelium may cause endothelial decompensation and overlying stromal and epithelial edema.
Clinical signs of endotheliitis include keratic precipitates (KP), overlying stromal and epithelial edema, and absence of stromal infiltrate or neovascularization. A mild to moderate iritis is frequently seen. Patients present with pain, photophobia, and injection.
HSV endotheliitis can be classified as follows:
Disciform endotheliitis - Presents with a round area of corneal edema in a central or paracentral region with a clear demarcation between involved and uninvolved cornea (see the image below)
Diffuse endotheliitis - Shows scattered KP and may stem from a previous disciform area of involvement
Linear endotheliitis - Appears as a line of KP progressing centrally from the limbus, with peripheral corneal edema trailing the migrating line of KP; the line of KP can be sectoral or circumferential and may take on either a straight or serpiginous pattern
View Image
Disciform endotheliitis with secondary stromal corneal ulceration.
Herpes simplex virus (HSV) keratitis remains primarily a clinical diagnosis based on characteristic features of the corneal lesion.[1] Laboratory studies may help to confirm the clinical suspicion in cases lacking typical findings, but they are not readily available in most clinical settings.
If the diagnosis is in doubt, however, laboratory diagnosis can be made using the following[2] :
Giemsa stain - Scrapings of the corneal or skin lesions show multinucleated giant cells
Papanicolaou stain - This shows intranuclear eosinophilic inclusion bodies
Epithelial scrapings with Giemsa stain may show multinucleated giant cells, resulting from coalescence of infected corneal epithelial cells and intranuclear viral inclusions. However, negative cytology results do not exclude HSV infection.
Viral cultures obtained within several days of onset of disease and prior to antiviral therapy have a sensitivity of up to 70% and also allow for identification of the HSV subtypes. Various techniques (eg, conventional tube culture, shell vial assay, suspension infection method) are available.
HSV-antigen detection tests, such as the enzyme-linked virus-inducible system (ELVIS), are very specific for detecting herpes infection, but they are limited by their lower sensitivity. Cell culture for confirmation of HSV is recommended when the ELVIS test result is negative.
PCR assay using tear samples, corneal epithelium, anterior chamber tap, or corneal buttons may detect viral DNA in cases of herpetic keratitis or keratouveitis. However, it does not distinguish between latent or active HSV infections.
A study by Inoue et al indicated that an immunochromatographic assay (ICGA) kit developed for the identification of HSV is clinically useful in the diagnosis of HSV epithelial keratitis. The investigators found that the ICGA had moderate sensitivity and high specificity, showing positive results for 35 out of 75 patients (46.7%) diagnosed with epithelial keratitis and negative results for 39 out of 39 patients (100%) who did not have the disease.[19]
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.[4]
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[20] ; 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 therapy
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 therapy
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.
Recurrence
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.[20]
Debridement
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 after applying a topical anesthetic drop. 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.
Consultations
Cases refractory to standard management or in which multiple recurrences develop may be referred to a corneal specialist.
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
Cycloplegic agent
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 and reduce long-term scarring
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.[23] Immune stromal keratitis without associated epithelial disease or necrotizing stromal keratitis after resolution of the epithelial defect are treated with the following:
Topical corticosteroids
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.[24]
Topical or oral antivirals are recommended to prevent or limit epithelial disease during treatment with corticosteroids.[25] 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.[26]
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 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
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.[27]
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.[28] 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.
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]
Vaccines
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.[39] However, concerns remain that a boost in immune response to HSV after vaccination may exacerbate herpetic stromal keratitis.[22]
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 a 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.
Antiviral agents, topical or oral, are prescribed to inhibit viral replication in infected cells. All topical antiviral medications available for clinical use in the United States 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.[40]
Clinical Context:
A structural analogue of thymidine, this agent inhibits viral DNA polymerase. Viroptic has better penetration through the cornea and greater efficacy (95% heal rate) than other topical agents. If no response occurs in 7-14 days, consider other treatments.
Clinical Context:
Valacyclovir is a prodrug that is rapidly converted to the active drug acyclovir. It produces a greater serum concentration of acyclovir with smaller oral dosing. Valacyclovir is more expensive than acyclovir but can be as effective with a more convenient dosing regimen.[19] The optimal dose for ocular disease has not been determined.
Clinical Context:
This agent is a prodrug that, when biotransformed into its active metabolite, penciclovir, may inhibit viral DNA synthesis/replication. It has been used successfully in the suppression of genital herpes. Its efficacy in HSV keratitis currently is under study.
Clinical Context:
Acyclovir is a synthetic guanosine analogue that requires activation by viral thymidine kinase. The activated acyclovir triphosphate, concentrated 50-100 times in HSV-infected cells, suppresses viral replication by preferentially inhibiting viral DNA polymerase, serving as a DNA chain terminator and inducing irreversible binding between polymerase enzyme and the interrupted DNA chain.
Acyclovir is a potent inhibitor of viral growth with minimal toxicity to uninfected epithelial cells. Oral acyclovir at a dose of 2 g/day for 10 days has been reported to be as effective as topical agents for epithelial keratitis, with the advantage of no ocular toxicity.
Clinical Context:
This agent is an acyclic nucleoside analogue of 2'deoxyguanasine. It phosphorylates first to monophosphate form by a viral-encoded protein kinase homologue, and then to diphosphate and triphosphate forms by cellular kinases. This allows for greater concentration of ganciclovir in virus-infected cells, possibly because of preferential phosphorylation of this agent in infected cells.
Ganciclovir is thought to inhibit HSV replication by competitive inhibition of viral DNA polymerases and by incorporating itself into viral DNA, causing termination of viral DNA elongation. Like acyclovir, ganciclovir is virostatic and exerts its effect only on replicating virus.
These agents inhibit herpes simplex virus (HSV) replication. Treatment 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, trifluridine, ganciclovir).[41]
What is herpes simplex virus (HSV) keratitis?What are the signs and symptoms of herpes simplex virus (HSV) keratitis?What is the role of lab testing in the diagnosis of herpes simplex virus (HSV) keratitis?What is included in the treatment of herpes simplex virus (HSV) keratitis?What is the pathophysiology of herpes simplex virus (HSV) keratitis?What is the pathophysiology of recurrent herpes simplex virus (HSV) keratitis?What causes herpes simplex virus (HSV) keratitis?What is herpes simplex virus (HSV) keratitis?Where can patient education resources for herpes simplex virus (HSV) keratitis be found?What is the incidence of herpes simplex virus (HSV) keratitis in the US?What is the prevalence of herpes simplex virus (HSV) infection?Which patient groups have the highest prevalence of herpes simplex virus (HSV) keratitis?What is the prognosis of herpes simplex virus (HSV) keratitis?What are the signs and symptoms of herpes simplex virus (HSV) keratitis?How is infectious epithelial keratitis characterized?What are physical findings characteristic of herpes simplex virus (HSV) keratitis?How is herpes simplex virus (HSV) keratitis categorized?How are the corneal vesicles of infectious epithelial keratitis characterized?How are the dendritic ulcers of infectious epithelial keratitis characterized?How are the geographic ulcers of infectious epithelial keratitis characterized?How are the marginal ulcers of infectious epithelial keratitis characterized?What is the characteristic presentation of neurotrophic keratopathy?What is stromal keratitis?How is necrotizing stromal keratitis characterized?How is immune stromal keratitis (ASK) characterized?How is herpes simplex virus (HSV) endotheliitis characterized?How is herpes simplex virus (HSV) endotheliitis classified?Which conditions should be included in the differential diagnoses of herpes simplex virus (HSV) keratitis?What are the differential diagnoses for Herpes Simplex Virus (HSV) Keratitis?How is herpes simplex virus (HSV) keratitis diagnosed?What is the role of lab studies in the diagnosis of herpes simplex virus (HSV) keratitis?Which lab studies are performed in the workup of herpes simplex virus (HSV) keratitis?What is the role of slit-lamp photography in the workup of herpes simplex virus (HSV) keratitis?What is the focus of treatment for herpes simplex virus (HSV) keratitis?What are treatment options for primary ocular herpes infection in patients with herpes simplex virus (HSV) keratitis?What is the role of topical therapy for the management of herpes simplex virus (HSV) keratitis?What is the role of antiviral therapy for the management of herpes simplex virus (HSV) keratitis?What is the role of debridement in the management of herpes simplex virus (HSV) keratitis?Which specialists should be consulted in the treatment of herpes simplex virus (HSV) keratitis?What are the treatment options for dendritic, geographic, and marginal corneal ulcers in herpes simplex virus (HSV) keratitis?What is included in the treatment of stromal keratitis?How is herpes simplex virus (HSV) endotheliitis treated?How is neurotrophic keratopathy treated in patients with herpes simplex virus (HSV) keratitis?What is included in the long-term monitoring of patients with herpes simplex virus (HSV) keratitis?What is the role of keratoplasty in the treatment of herpes simplex virus (HSV) keratitis?How is recurrent herpes simplex virus (HSV) keratitis prevented?What is the role of vaccines in the prevention of herpes simplex virus (HSV) keratitis?What is the role of medications in the treatment of herpes simplex virus (HSV) keratitis?Which medications in the drug class Antiviral agents are used in the treatment of Herpes Simplex Virus (HSV) Keratitis?
Jim C Wang (王崇安), MD, Vitreo-Retinal and Cornea/Anterior Segment Subspecialist, Department of Ophthalmology, Kaiser Permanente Fontana Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
David C Ritterband, MD, FACS, Assistant Director of Cornea Service, New York Eye and Ear Infirmary; Clinical Professor of Ophthalmology, Icahn School of Medicine at Mount Sinai
Disclosure: Nothing to disclose.
Chief Editor
Andrew A Dahl, MD, FACS, Assistant Professor of Surgery (Ophthalmology), New York College of Medicine (NYCOM); Director of Residency Ophthalmology Training, The Institute for Family Health and Mid-Hudson Family Practice Residency Program; Staff Ophthalmologist, Telluride Medical Center
Disclosure: Nothing to disclose.
Acknowledgements
Kerry Assil, MD Medical Director and CEO, The Sinskey Eye Institute
Kerry Assil, MD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, Association for Research in Vision and Ophthalmology, and Contact Lens Association of Ophthalmologists
Disclosure: Nothing to disclose.
Kilbourn Gordon III, MD, FACEP Urgent Care Physician
Kilbourn Gordon III, MD, FACEP is a member of the following medical societies: American Academy of Ophthalmology and Wilderness Medical Society
Disclosure: Nothing to disclose.
Robert H Graham, MD Consultant, Department of Ophthalmology, Mayo Clinic, Scottsdale, Arizona
Robert H Graham, MD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, and Arizona Ophthalmological Society
Disclosure: Medscape/WebMD Salary Employment
Anisha Judge, MD Consulting Staff, Department of Ophthalmology, Kaiser Permanente at West Los Angeles Medical Center
Disclosure: Nothing to disclose.
Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine
Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.
Christopher J Rapuano, MD Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Institute
Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, and International Society of Refractive Surgery
Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; RPS Ownership interest Other; Bausch & Lomb Honoraria Speaking and teaching; Merck Consulting fee Consulting; Bausch & Lomb Consulting; Merck Honoraria Speaking and teaching
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Jack L Wilson, PhD Distinguished Professor, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center College of Medicine
Jack L Wilson, PhD is a member of the following medical societies: American Association of Anatomists, American Association of Clinical Anatomists, and American Heart Association
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