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Keratitis, Herpes Simplex
Article Last Updated: Dec 19, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Jim C Wang, MD, Retina/Vitreous Fellow, Department of Ophthalmology, West Virginia University; Cornea/Anterior Segment Subspecialist, Department of Ophthalmology, Kaiser Permanente Fontana Medical Center
Jim C Wang is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, and American Society of Retina Specialists
Coauthor(s):
David C Ritterband, MD, Assistant Director of Cornea & External Disease, Clinical Assistant Professor, Department of Ophthalmology, New York Eye and Ear Infirmary, New York Medical College
Editors: Jack L Wilson, PhD, Distinguished Professor, Department of Anatomy and Neurobiology, University of Tennessee at Memphis; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Jefferson Medical College; Co-Chairman of the Cornea Service, Co-Chairman of Refractive Surgery Department, Wills Eye Hospital; Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri; Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Author and Editor Disclosure
Synonyms and related keywords:
herpes simplex keratitis, herpetic keratitis, herpes simplex virus keratitis, HSV keratitis, neurotrophic keratopathy, neurotrophic ulcer, metaherpetic ulcer, trophic ulcer, interstitial keratitis, stromal keratitis, disciform keratitis, keratouveitis, herpetic endotheliitis
Background
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. Although more common as a manifestation of recurrent HSV infection, HSV keratitis may also be seen during a primary infection.
Pathophysiology
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. 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.
Frequency
United States
Approximately 20,000 new cases of ocular HSV occur in the United States annually, and more than 28,000 reactivations occur in the United States annually. It is one of the most frequent causes of blindness in the United States with 500,000 people experiencing HSV-related ocular disease.
International
HSV infection is ubiquitous, with an estimated one third of the population worldwide suffering from recurrent infections.
Mortality/Morbidity
HSV keratitis is the most frequent cause of corneal blindness in the United States and is a leading indication for corneal transplantation. HSV keratitis is also the most common cause of infectious blindness in the Western world.
Age
Most HSV eye disease occurs in adults, and it occurs many years after the primary infection. However, herpetic keratitis in children almost always involves the corneal epithelium and is marked by a disproportionate risk of binocular disease, a high recurrence rate, and amblyopia.
History
- Patients with HSV keratitis may complain of the following:
- Pain
- Photophobia
- Blurred vision
- Tearing
- Redness
- A history of prior episodes in patients with recurrent disease may exist. Among patients with ocular HSV, those with previous stromal involvement have a significantly higher risk of subsequent stromal keratitis; in contrast, patients with epithelial keratitis have no increased rate of recurrent HSV disease.
Physical
HSV keratitis may be divided into 4 categories: infectious epithelial keratitis, neurotrophic keratopathy, stromal keratitis, and endotheliitis. - Infectious epithelial keratitis is characterized by corneal vesicles, dendritic ulcers, and geographic ulcers.
- The earliest sign of active viral replication in the corneal epithelium is 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, these 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.
- Prominent features of a HSV dendritic ulcer include branching terminal bulbs, swollen epithelial borders that contain live viruses, and central ulceration through the basement membrane.
- 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.
- 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, exacerbated by long-term use of topical medications, especially antiviral agents. However, evidence suggests that HSV replication may occur in persistent epithelial defects.
- 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.
- Corneal stromal inflammation may be the primary manifestation of HSV keratitis or may be seen secondary to infectious epithelial keratitis, neurotrophic keratopathy, or endotheliitis. The 2 forms of primary stromal involvement are necrotizing stromal keratitis and ISK.
- 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. The use of topical corticosteroids without antiviral coverage may be a possible risk factor for its development.
- ISK is a common manifestation of chronic recurrent ocular HSV disease. An antibody-complement cascade to retained viral antigen within the stroma is believed to be the underlying mechanism. ISK may present clinically with focal, multifocal, or diffuse cellular infiltrates; immune rings; neovascularization; or ghost vessels at any level of the cornea.
- 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.
- Endotheliitis
- Clinical signs of endotheliitis include keratic precipitates (KP), overlying stromal and epithelial edema, and absence of stroma infiltrate or neovascularization. A mild-to-moderate iritis is frequently seen.
- Immunologic reaction to viral antigens within corneal endothelial cells has been proposed as the underlying pathogenesis; however, active viral replication may also play a role. The inflammation directed at the endothelium may cause endothelial decompensation and overlying stromal and epithelial edema.
- HSV endotheliitis can be classified as disciform, diffuse, or linear. 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. 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; it may take on either a straight pattern or a more serpiginous pattern.
Causes
- Infectious epithelial keratitis results from active viral replication within the corneal epithelium.
- Neurotrophic keratopathy is poorly understood. The cause is thought to be multifactorial and includes decreased corneal innervation and tear secretion (as a result of prior HSV infection of the sensory nerves), toxicity from topical agents, and underlying stromal inflammation. Evidence suggests that active HSV reproduction may also play a role.
- Necrotizing stromal keratitis arises from direct infection of the corneal stroma and the resultant severe host inflammatory response.
- ISK is an antibody-complement cascade triggered by a retained viral antigen within the stroma.
- Endotheliitis is believed to be primarily an immunologic reaction to an antigen in endothelial cells; however, the role of live virus has been speculated.
Corneal Abrasion
Corneal Erosion, Recurrent
Herpes Zoster
Keratitis, Bacterial
Keratitis, Fungal
Keratitis, Interstitial
Keratoconjunctivitis, Sicca
Ulcer, Corneal
Other Problems to be Considered
Acanthamoeba keratitis
Lab Studies
- HSV keratitis remains primarily a clinical diagnosis based on characteristic features of the corneal lesion. Laboratory studies may help confirm the clinical suspicion in cases lacking typical findings, but they are not readily available in most clinical settings.
- 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.
- Polymerase chain reaction 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.
Imaging Studies
- High-resolution optical coherence tomography (OCT) may have future application in HSV keratitis.
Medical Care
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 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 of epithelial herpes infection. Either topical trifluridine 1% solution 8 times daily or vidarabine 3% ointment 5 times daily has equal efficacy in treating a dendritic ulcer; however, trifluridine is more effective than vidarabine for treatment of a geographic ulcer. Response to topical therapy usually occurs in 2-5 days, with complete resolution in 2 weeks. Corneal toxicity is a frequent adverse effect of topical antiviral agents. Therefore, 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 (2 g/d) 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. 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. Stromal keratitis and endotheliitis are 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. Concurrent antiviral medication is used to prevent or limit lytic epithelial keratitis. The optimal dose and the route of administration have not been determined. One common recommendation is to use a topical antiviral agent and a corticosteroid with equal frequency until the steroid dosage can be reduced to a once-daily or less regimen. Alternatively, oral acyclovir in moderate doses (1-2 g/d) achieves therapeutic concentrations in the aqueous humor and may be more effective than topical agents in treating HSV keratouveitis. In necrotizing stromal keratitis, systemic antiviral is also preferred because of corneal toxicity concerns. 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 frequent recurrences of ocular HSV may be placed on a long-term regimen of oral antiviral medication at the prophylactic maintenance dose.
Surgical Care
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 penetrating keratoplasty for visual rehabilitation. If possible, a small descemetocele or perforation in an inflamed eye initially may be managed with tissue adhesive and bandage contact lens. Corneal transplant should be deferred until the eye is less inflamed.
The prognosis for a successful graft approaches 80% in eyes without inflammation prior to surgery. Prophylactic antiviral therapy following penetrating keratoplasty decreases the rate of recurrent HSV dendritic keratitis and possibly improves graft survival. Oral antiviral therapy for 12 months has been shown to reduce the rate of recurrent ocular HSV disease.
Consultations
Cases refractory to standard management or multiple recurrences after corneal transplant may be referred to a corneal specialist.
Antiviral agents, topical or oral, are prescribed to inhibit viral replication in infected cells. Topical steroids are used to suppress the destructive inflammatory reaction to HSV antigen by the host. Prophylactic antibiotic eye drops are sometimes used concurrently to prevent a secondary bacterial infection while on steroid therapy.
Drug Category: Antiviral medications
Inhibit HSV replication. In addition to the antiviral medications listed below, cidofovir (Vistide) is a nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viruses. Has shown success in suppressing HSV only in rabbit models. No commercially available topical formulations yet.
| Drug Name | Trifluridine (Viroptic) |
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| Description | A structural analog of thymidine; inhibits viral DNA polymerase. Viroptic has better penetration through the cornea and greater efficacy (95% heal rate) than other topical agents. If no response in 7-14 d, consider other treatments. |
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| Adult Dose | 1% ophthalmic solution: 1 gtt into affected eye(s) q2h, not to exceed 8 gtt/d for up to 10 d; followed by 1 gtt q4h for another 7 d, not to exceed 21 d |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity |
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| Interactions | None reported |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
|
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| Precautions | Significant corneal epithelial toxicity complicates prolonged use; may cause mild, local irritation of conjunctiva and cornea upon instillation; cross-resistance does not seem to occur with vidarabine |
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| Drug Name | Acyclovir (Zovirax) |
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| Description | A synthetic guanosine analog 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. Potent inhibition of viral growth with minimal toxicity to uninfected epithelial cells. Oral acyclovir at a dose of 2 g/d for 10 d has been reported to be as effective as topical agents for epithelial keratitis with the advantage of no ocular toxicity. Topical acyclovir formulation (3% ointment), which is equal in efficacy to trifluridine but less toxic, is not commercially available in the United States. |
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| Adult Dose | Acute disease: 400 mg PO 5 times/d
Prophylactic maintenance: 400-mg tab PO bid
|
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity of acyclovir |
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| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
|
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| Precautions | Excreted by the kidney via glomerular filtration as well as tubular secretion; may interfere with renally excreted drugs; caution in renal failure or when using nephrotoxic drugs |
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| Drug Name | Valacyclovir (Valtrex) |
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| Description | Prodrug rapidly converted to the active drug acyclovir. Produces greater serum concentration of acyclovir with smaller oral dosing. More expensive but has a more convenient dosing regimen than acyclovir. Optimal dose for ocular disease has not been determined. |
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| Adult Dose | Acute disease: 1000 mg PO bid for 10 d
Prophylactic maintenance: 500 mg or 1000 mg PO qd
|
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Probenecid, zidovudine, or cimetidine coadministration prolongs half-life and increases CNS toxicity of valacyclovir |
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| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
|
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| Precautions | Can cause thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome in severely immunocompromised patients; caution in renal failure and coadministration of nephrotoxic drugs |
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| Drug Name | Famciclovir (Famvir) |
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| Description | Prodrug that when biotransformed into active metabolite, penciclovir, may inhibit viral DNA synthesis/replication. Has been used successfully in the suppression of genital herpes. Its efficacy in HSV keratitis currently is under study. |
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| Adult Dose | Acute disease: 250 mg PO tid for 10 d
Prophylactic maintenance: 250 mg PO bid |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Coadministration of probenecid or cimetidine may increase toxicity; coadministration increases bioavailability of digoxin |
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| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
|
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| Precautions | Caution in renal failure or coadministration of nephrotoxic drugs |
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| Drug Name | Vidarabine (Vira-A) |
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| Description | An adenine analog that interferes with early steps of viral DNA synthesis. Vira-A is less effective than trifluridine in treating geographic ulcers, but it is often effective against HSV strains resistant to trifluridine and acyclovir. If no signs of improvement after 7 d or incomplete reepithelialization in 21 d, consider alternative therapy. Severe cases may require longer treatment. After reepithelialization occurs, treat bid for another 7 d to prevent recurrence. |
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| Adult Dose | 3% ophthalmic ointment: Apply 0.5-inch ribbon into lower conjunctival sac(s) 5 times/d for 10 d |
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| Pediatric Dose | Apply as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | None reported |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Topical corneal toxicity; viral resistance to vidarabine is possible but none reported |
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Further Outpatient Care
- 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. Although an uncommon occurrence, progressive necrotizing stromal keratitis and impending corneal perforation might be better managed in an inpatient setting. Tissue glue with bandage contact lens should be attempted prior to keratoplasty.
In/Out Patient Meds
Deterrence/Prevention
- Ongoing research for HSV vaccination is being conducted. Therapeutic vaccination for ocular HSV is conceptually hazardous because of its possible role of HSV-specific immunity in mediating ocular damage.
Prognosis
- Visual prognosis depends on the extent of the corneal scarring.
Patient Education
Medical/Legal Pitfalls
- Active HSV keratitis is an absolute contraindication to having incisional or laser corneal refractive surgery. Inactive keratitis or a history of previous HSV disease is also considered a strong relative contraindication. Recurrence of HSV keratitis after refractive surgery is a well-known complication. However, case reports have documented good refractive surgery outcomes with the use of perioperative antiviral medications.
- 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.
Special Concerns
- HSV reactivation with use of latanoprost has been reported in patients with glaucoma.
| Media file 1:
Herpes simplex virus dendritic ulcer stained with rose bengal. |
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| Media file 2:
Herpes simplex virus dendritic ulcer stained with fluorescein. |
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| Media file 3:
Large paracentral herpes simplex virus dendritic ulcer. |
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| Media file 4:
Recurrent herpes simplex virus dendritic ulcer with an adjacent stromal scar. |
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| Media file 11:
Disciform endotheliitis with secondary stromal ulceration. |
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Keratitis, Herpes Simplex excerpt Article Last Updated: Dec 19, 2007
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