The herpesviruses are major contributors to infectious disease in humans, and include such threats to personal and public health as cytomegalovirus and Epstein-Barr virus. But perhaps the most recognizable members of this family are human herpesviruses 1, 2 and 3. They are also known, respectively, as herpes simplex type 1, simplex type 2 and varicella-zoster virus.
The varicella-zoster virus, which is the herpesvirus famous for causing childhood chickenpox, can be reactivated in adult years as herpes zoster, commonly known as shingles. Herpes zoster accounts for 1 percent of all visits to dermatologists. “As we have become an older population, the incidence of herpes zoster has increased,” said Vincent P. de Luise, MD, assistant clinical professor at Yale University.
Diagnosis. There are one million new cases of zoster each year in the United States, and between 25 percent and 40 percent of all cases have ophthalmic complications, according to Dr. de Luise. In most cases, herpes zoster ophthalmicus is mild, and usually results in short-term inflammation, such as a temporary keratitis, which usually resolves without topical antiviral treatment.
However, a minority of patients can go on to develop recurrent iritis, and are at risk for secondary glaucoma, cataracts, corneal scarring or retinitis that can be sight-threatening. People who are immunocompromised, such as those with HIV or those undergoing treatment with chemotherapy, are especially at risk for serious complications of zoster ophthalmicus, according to Dr. de Luise.
Zoster can affect the eye when the trigeminal nerve is involved in the infection. Typically, the virus manifests in an initial painful eruption of vesicles on the forehead, the side of the nose, upper eyelid and eye.
The most problematic aspect of zoster is the development of chronic and persistent pain, called postherpetic neuralgia (PHN). In zoster ophthalmicus, PHN usually affects the forehead as well as the eye. The pain of PHN can be severe and disabling, and can so affect patients’ quality of life that they can develop secondary depression and even, rarely, become suicidal. “When PHN develops from the trigeminal nerve, it can be very severe around the eye, and the pain can be incapacitating,” Dr. de Luise said. “It can be devastating.”
Treatment. The treatment of herpes zoster includes oral antivirals, administered ideally within the first 72 hours of onset. These medications decrease pain, shorten the duration of viral shedding, and decrease the incidence of keratitis or iritis. Unfortunately, they do not affect the incidence or severity of PHN.
There are several antivirals available for herpes zoster infection, including acyclovir (Zovirax), famciclovir (Famvir) and valacyclovir (Valtrex). Dr. de Luise usually uses valacyclovir, since it has the best bioavailability. Artificial tears can also decrease discomfort from the virus. If inflammatory keratitis is problematic, corticosteroid drops and cycloplegics are an option. And if PHN develops, the ophthalmologist should refer the patient to a pain specialist, since the management of this condition is complex.
Prevention. With the May 2006 approval of a new vaccine for herpes zoster, Zostavax, the future picture of this condition has become brighter. Results of a clinical trial showed that the new vaccine decreased the incidence of herpes zoster by more than 50 percent and the incidence of PHN by over 65 percent in the age 60-and-older population, the population most at risk for herpes zoster.1
The CDC Advisory Committee on Immunization Practice recently recommended that adults 60 years of age and older be vaccinated with Zostavax.
Herpes Simplex 1 and 2
There are two strains of HSV that are clinically important. Historically, most oral and ocular herpes simplex infections have been caused by HSV-1, while most genital herpes infections have been caused by HSV-2. But increasing numbers of ocular infection with HSV-2 are being reported.
Diagnosis. Most frequently, initial HSV infection is asymptomatic, with the virus taking up silent residence in the trigeminal ganglion. More than 90 percent of adults demonstrate antibodies to HSV-1, though most cannot recall a symptomatic herpes simplex infection. Most cases of symptomatic herpes are reactivations of the virus.
According to David B. Glasser, MD, assistant professor of ophthalmology at Johns Hopkins University, ocular involvement typically includes a follicular conjunctivitis with a tender preauricular node or blepharoconjunctivitis, with vesicular skin lesions. Systemic symptoms and a low-grade fever may be present. Lid margin ulcers and dendritic conjunctival or corneal lesions may also be seen. Most cases are unilateral, Dr. Glasser said.
Birth canal exposure can lead to primary HSV infection in newborns. Serious sequelae in infants can include disseminated skin lesions, encephalitis and even death. Survivors may present later with retinal necrosis.
According to a 2006 study, one in four people over age 30 is infected with HSV-2.2 “The recent epidemic of genital herpes simplex type 2 infection is likely to result in an increase in neonatal ocular herpes and in delayed cases of acute retinal necrosis syndrome,” the authors of the paper write.
Treatment. Treatment calls for topical trifluridine, 1 percent, every two hours until significant epithelial healing has occurred, and then every four hours for approximately one week. Epithelial toxicity due to topical antivirals is inevitable after 10 to 14 days of continuous use. Topical cycloplegics and lubricants may be useful adjuncts. Debridement of the dendritic lesion in addition to use of antivirals may be useful as well, and theoretically reduces viral antigen load presented to the stroma.
Dr. Glasser noted that systemic antivirals enter the tear film in sufficient concentrations to treat ocular disease, and can be an effective alternative to topical therapy. “They avoid the epithelial toxicity associated with topical drops, and can be particularly useful in children, where tearing dilutes the topically applied medications,” he said.
Systemic antivirals include acyclovir, 400 mg, five times per day, valacyclovir, 1 gm, two times daily, or famciclovir, 250 mg, three times a day. Because of the convenience of less frequent dosing, most patients and clinicians prefer valacyclovir.
Dr. Glasser described some complications of ocular herpes and its treatment. “Trophic epithelial ulceration may follow the occurrence of a dendritic lesion. It is important to differentiate trophic ulceration and antiviral toxicity from ongoing epithelial infectious disease. Trophic ulcers are due to abnormal epithelial healing, with no replicating virus. They often demonstrate a raised, rolled edge with pooling of fluorescein or rose bengal in the base, but no epithelial staining as would be seen in a dendritic lesion. Trophic ulcers are treated with aggressive preservative-free lubricants and cessation of topical antivirals. Recalcitrant cases may respond to autologous serum drops or amniotic membrane transplantation.
“These patients need to be monitored carefully for development of stromal thinning or superinfection,” he said. “Stromal disease is seen in about 20 percent of those with recurrent ocular HSV, with rates as high as 60 percent in children. Stromal involvement, resulting in scarring and irregular astigmatism, accounts for most visual loss due to HSV. Nonnecrotizing stromal disease is primarily an immune phenomenon, and may encompass interstitial keratitis with unifocal or multifocal patchy interstitial opacities or disciform edema, with a round or oval area of epithelial and stromal edema. Necrotizing stromal keratitis is less common.”
Dr. Glasser described the mainstay of therapy for stromal HSV disease as topical corticosteroids, such as prednisolone, with an antiviral cover to prevent recurrence of active infectious keratitis. “The antiviral cover should be continued until the topical steroid has been reduced to the equivalent of one drop of 1 percent prednisolone per day. Topical trifluridine is effective, but prolonged use can lead to epithelial toxicity. Twice a day dosing with oral acyclovir, 400 mg, or valacyclovir, 500 mg, is also effective, penetrating better than topical drops for treatment of deep stromal disease, and avoiding the risk of epithelial toxicity. Topical lubricants and cycloplegics, and systemic matrix metalloproteinase inhibitors such as tetracyclines are useful adjuncts.”
Prevention. Dr. Glasser added that the control of herpes recurrences is paramount in reducing the risk of visual loss due to stromal disease. Oral acyclovir, 400 mg, twice a day, has been shown to reduce the risk of both epithelial and stromal recurrences by about half.3 Many clinicians now use valacyclovir, 500 to1000 mg once daily for prophylaxis.
1 Oxman, M. et al. N Engl J Med 2005;352:2271–2284.
2 Pepose, J. S. et al. Am J Ophthalmol 2006;141:547–557.
3 Rezende, R. A. et al. Am J Ophthalmol 2006;141:1120–1125.