Other Viral Diseases

Pathogenesis

It is difficult to know how much of the ocular inflammation is caused by direct viral infection, an immune response against the virus, or induced autoimmunity as a result of molecular mimicry. Each may play a role and vary among patients. A similar disease to herpes stromal keratitis can be induced in experimental animals by infecting them with HSV type 1 (HSV-1). ^, A herpes protein, UL6, has been identified as a viral protein resembling corneal protein. Interestingly, both tolerance and autoimmunity can be induced in the same model, depending on host susceptibility to keratitis ( Fig. 14.1 ).

Diagnosis

The diagnosis of HSV keratouveitis is most easily made in patients with a known history of HSV keratitis confirmed by typical dendritic epithelial defects ( Fig. 14.2 ) or stromal disease confirmed on the basis of culture results (see Case 14-1). The disease should also be suspected in patients with significant corneal opacity that is accompanied by synechiae and anterior chamber cells. Keratic precipitates (KPs) in the area of corneal disease, hypopyon, and hyphema may be seen in some patients. In some patients, the corneal disease may make it difficult to examine the anterior chamber. Bacterial keratitis and possible secondary bacterial infection must be ruled out. The use of polymerase chain reaction (PCR) is starting to aid in the identification of HSV as the causative agent in patients with uveitis of unknown etiology.

It remains unclear whether the uveitis associated with HSV keratitis is a secondary inflammatory response to the corneal disease or whether it is induced by invasion of a virus into the anterior uvea. Nevertheless, HSV has been isolated from the aqueous humor in some patients with the disorder. In experimentally induced HSV uveitis, the combination of sensitized T lymphocytes, herpes-specific antibody, and HSV antigen is required for the production of inflammation. In addition, topical cyclosporin A was shown to effectively reduce stromal haze and inflammation in experimental HSV keratitis. If this situation applies to human disease, therapy that inhibits the cellular arm of the immune system could control inflammation but enhance viral replication.

Experts differ on whether environmental factors could precipitate disease. Psychological stress has been cited as a potential trigger for recurrences of HSV-related ocular disease. However, with control of recall bias, a study failed to find an association between psychological stress and disease recurrence.

Treatment

Findings from numerous randomized controlled trials (RCTs) have helped guide clinicians on how to best care for patients with herpetic eye disease. HSV keratitis is treated with topical antiviral therapy, such as with trifluridine solution (Viroptic) every 2 hours or vidarabine ointment (Vira A) every 3 hours. Cycloplegic agents are also employed to reduce pain and prevent synechiae. In addition, topical corticosteroids should be used in patients with associated uveitis, but their use is sometimes delayed until the corneal epithelial disease resolves. In a controlled trial of topical corticosteroids for HSV stromal keratitis, Wilhelmus et al. showed that prednisolone phosphate was significantly better than placebo in reducing persistence or progression of stromal keratitis and in reducing the time to resolution of uveitis. In this study, both groups received topical trifluridine. Although some episodes may resolve without therapy, inflammation may lead to severe ocular damage.

Oral acyclovir does not appear to be beneficial for patients with HSV epithelial keratitis treated with topical antiviral agents. In an initial study, Barron et al., for the Herpetic Eye Disease Study Group, reported no statistically or clinically significant beneficial effect of oral acyclovir in treating the stromal keratitis caused by HSV in patients receiving concomitant topical corticosteroids and trifluridine. The Herpetic Eye Disease Study Group also conducted a well-controlled RCT of oral acyclovir for the prevention of stromal keratitis or iritis in patients with HSV epithelial keratitis. Patients with HSV epithelial keratitis of 1 week or less duration were treated with topical trifluridine and then randomly assigned to receive a 3-week course of oral acyclovir 400 mg five times a day or placebo. The study showed that stromal keratitis or iritis developed in 17 (11%) of the 153 patients treated with acyclovir and in 14 (10%) of the 134 patients treated with placebo. In a second clinical trial, the effect of oral acyclovir therapy for recurrences of HSV eye disease was investigated in 703 immunocompetent patients. In this study, the cumulative probability of a recurrence of any type of ocular HSV disease was 19% in patients receiving acyclovir and 32% in patients receiving placebo. A benefit was seen for prevention of both epithelial and stromal keratitis. There were only three patients with iritis; therefore the effect of treatment on uveitis could not be determined in this study. However, in another trial, the Herpetic Eye Disease Study Group assessed the benefit of adding oral acyclovir to a regimen of a topical corticosteroid and trifluridine for the treatment of HSV-associated iridocyclitis. Patients with HSV iridocyclitis were randomly assigned to receive a 10-week course of either oral acyclovir 400 mg five times daily or placebo in conjunction with topical trifluridine and a topical corticosteroid. The trial was stopped early because of slow recruitment after only 50 of the planned 104 patients were enrolled. Treatment failure, defined as persistence or worsening of ocular inflammation, withdrawal of medication because of toxicity, or withdrawal for any reason occurred in 11 (50%) of 22 patients receiving acyclovir and in 19 (68%) of the 28 patients receiving placebo. Although the difference in failure rates was not statistically significant between the two groups, there was a trend toward a better outcome in the patients receiving oral acyclovir. Finally, oral acyclovir effectively prevents herpes-related recurrences after penetrating keratoplasty in herpetic eye disease, supporting the use of the drug.

Valacyclovir and famciclovir are dosed less frequently than oral acyclovir and may be a useful alternative. In a small, prospective RCT of 52 immunocompetent patients, oral valacyclovir (500 mg daily) was as effective and well tolerated as acyclovir (400 mg twice daily) in reducing the rate of recurrent ocular HSV disease. In another small RCT, oral valacyclovir had efficacy similar to that of topical acyclovir ointment in patients with HSV keratitis. Wilhelmus compared the effects of various therapeutic interventions for dendritic or geographic HSV epithelial keratitis by searching the Cochrane Central Register of Controlled Trials. The conclusion of the review was that the commercially available antiviral agents are effective and nearly equivalent. The author also noted that the combination of a nucleoside antiviral with either debridement or interferon (IFN) seemed to speed healing.

Work to develop a vaccine for HSV infection is ongoing. In a small RCT, the use of a vaccine with heat shock–inactivated HSV-1 seemed to reduce the number and duration of relapses in HSV-1–related keratitis or keratouveitis.

Secondary glaucoma is associated with herpetic keratouveitis and may be difficult to control, especially in patients with rubeosis. Glaucoma in these patients often requires surgical treatment with a drainage device. Nevertheless, vision loss related to glaucoma is common in these patients.

HSV retinitis is clearly caused by direct infection of the retina by the virus. As already stated, some cases of acute retinal necrosis may be caused by HSV infection (see Chapter 13 ). In addition, HSV retinitis can occur in congenital HSV infection associated with herpes encephalitis. This infection is usually caused by herpes simplex virus type 2 (HSV-2) and may be acquired in utero rather than during birth. Many patients with congenital HSV retinitis also have corneal and anterior chamber involvement, which obscures a clear view of the retina. When retinal lesions are seen clinically or pathologically, they appear as large, white retinal infiltrates associated with vitritis and retinal vascular sheathing. After the lesions heal, there are large areas of atrophic and scarred retina. The systemic infection by HSV is often overwhelming and fatal.

HSV retinitis has also been reported in patients who have undergone chemotherapeutic immunosuppression, and again, viral encephalitis often accompanies this ocular condition. Large areas of white retinitis with retinal necrosis result from the viral infection. The disorder may also occur in patients without immunosuppression, and in some patients, diagnosis has been made after chorioretinal biopsy. In some patients, the disorder appears to respond to treatment with intravenous acyclovir.

Ophthalmic Manifestations

Ocular involvement is noted in two-thirds of patients with HZV ophthalmicus. Involvement of the tip of the nose with skin lesions (Hutchinson sign) has been associated with a greater risk for ocular disease. A list of the ophthalmic manifestations of HZV ophthalmicus are listed in Box 14.1 . Anterior uveitis can accompany herpes zoster ophthalmicus and may result from vascular occlusion and secondary ischemia or an immune response against virus in the eye. Intraocular inflammation occurs in one-third to one-half of patients. ^, Severe glaucoma often arises in patients with severe inflammatory disease, and corneal disease manifested by dendritic keratitis, stromal keratitis, or exposure keratitis is a common finding. Large KPs and posterior synechiae accompany anterior uveitis. Although anterior uveitis may appear with the initial cutaneous lesions, it often develops 1 to 2 weeks after the onset of dermatologic disease. In a small number of patients, scleritis may be seen. The iris should be closely examined because it may be the key to correct diagnosis. Sector and patchy iris atrophy consistent with ischemic damage is characteristic of the disorder. Hyphema may occur, and some eyes develop phthisis because of severe ischemic destruction of the iris and the ciliary body. Histologic study in severe disease reveals vascular inflammation and a granulomatous cellular infiltrate in the uvea. Occasionally, retinal vascular occlusive disease or severe choroiditis with associated vitreal inflammation may be seen.

Treatment

Treatment with oral acyclovir early in the course of HZV infection, when the cutaneous lesions are still active, appears to reduce viral proliferation and the complications of the infection, including anterior uveitis. In immunocompetent patients, the usual dose of acyclovir is 800 mg five times daily for 7 to 10 days. Famciclovir at a dose of 500 mg three times daily had efficacy similar to that of acyclovir for treating patients with ophthalmic zoster, and valacyclovir, usually dosed 1 g three times daily for 7 days, has also been used effectively to treat the severity and duration of HZV infection. In contrast, acyclovir appears to have little effect on the development of postherpetic neuralgia. A Cochrane review was unable to discern the relative benefits and harms of valacyclovir versus acyclovir in the treatment of HZV ophthalmicus in immunocompetent patients, and the authors suggested that additional well-controlled RCTs are needed. Another review of 1515 articles and abstracts concluded that oral famciclovir and valacyclovir are reasonable alternatives to oral acyclovir in the treatment of active HZV ophthalmicus in immunocompetent individuals.

The value of antiviral therapy for uveitis later in the course of the disease is unclear. It appears that weeks into the course of the disease, anterior uveitis may not be caused by active viral replication but by ischemia. Therefore antiviral therapy appears to be no longer useful. Anterior uveitis and glaucoma may persist for weeks to months and must be treated with topical corticosteroids, cycloplegics, and appropriate glaucoma therapy. It is not clear whether the prolonged inflammatory course is solely caused by residual ischemia or whether an immunologic response against retained viral antigen in the ocular tissue also promotes persistent inflammation.

Although oral corticosteroids are sometimes necessary to treat postherpetic neuralgia, they should be used cautiously in the acute phase of ophthalmic zoster infection because of reports of associated ipsilateral cerebrovascular occlusion with contralateral hemiparesis. Systemic corticosteroids should also be used cautiously in patients with HZV infection associated with acquired immunodeficiency syndrome (AIDS) because these agents may cause increased immunosuppression. Local corticosteroid therapy should be used with caution in these patients, especially early in the course of disease if no antiviral therapy has been started. Local corticosteroids, including intravitreous corticosteroids, have been reported to decrease inflammation and improve vision without reactivation of infectious ocular disease. Topical therapy for skin lesions, including treatment for postherpetic neuralgia, should also be considered.

Therapy requires a commitment to long-term management because even after the acute inflammation resolves, residual damage that limits acuity may be surgically repaired. Many patients are left with severe visual loss. A combination of dry eye, corneal disease, cataract, and posterior synechiae contributes to visual loss and often precludes a thorough evaluation of the posterior segment of the eye. Because the optic nerve and the retina may also be involved in the disease process, it is often difficult to determine the exact cause of visual loss in any given patient. Nevertheless, it is important to try to ensure that the retina and optic nerve are not severely damaged before surgery for cataract, corneal disease, or glaucoma is performed.

In 2006, the U.S. Food and Drug Administration (FDA) approved a live attenuated vaccine for the prevention of herpes zoster and its sequelae. In a large, placebo-controlled clinical trial, the zoster vaccine reduced the overall incidence of zoster by 51.3%. The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of persons 60 years of age and older. The labeled indication was expanded to patients age 50 years and older. In 2017, a recombinant zoster vaccine was approved for adults 50 years of age and older. This vaccination requires a two-dose series of injections. Zoster vaccine should not be administered to persons with primary or acquired immunodeficiency.

In 2018, the American Academy of Ophthalmology (AAO) published a policy statement with recommendations for a herpes zoster vaccine for patients age 50 years and older. It is noted that people with a history of herpes zoster ophthalmicus may be at risk for recurrent eye disease after vaccination with either of the approved vaccines. ^, The CDC recommends the recombinant zoster vaccine based on efficacy, but the live vaccine is an option where compliance with two doses is an issue, especially in immunocompetent adults 50 to 59 years of age, in whom efficacy was good and fewer systemic reactions were noted. The AAO Policy Statement states, “Ophthalmologists should recommend strongly that patients 50 years of age and older without contraindications obtain vaccination with the recombinant zoster vaccine and should work with primary care physicians, internists, dermatologists, other medical doctors, and health care professionals to recommend vaccination strongly against herpes zoster starting at 50 years of age.”