- •
Herpes simplex virus (HSV) is a common cause of inflammatory eye disease.
- •
Keratitis and anterior uveitis are frequent manifestations of HSV disease; secondary glaucoma is an important cause of vision loss.
- •
A number of randomized controlled trials help guide therapy for HSV ocular disease. Topical antiviral therapy is indicated for HSV keratitis. Although oral aciclovir did not improve outcome in patients with active epithelial keratitis receiving topical antiviral therapy, it did reduce recurrence and progression of HSV disease and appears to be beneficial for patients with HSV-associated uveitis.
- •
Varicella causes two distinct forms of disease: primary infection with varicella (chickenpox) and herpes zoster disease. Uveitis most commonly occurs with herpes zoster infection.
- •
Treatment with oral antiviral therapy appears to improve outcome in patients with herpes zoster infection.
- •
Viral infections associated with a transient mild uveitis during the acute stages of infection include measles (rubeola), mumps, influenza, dengue fever, Epstein–Barr virus (EBV), and human T-lymphotropic virus type I (HTLV-1).
Viruses are important causes of human disease and play a pathogenic role in a number of inflammatory eye diseases. Viruses were first identified in the late 1800s. The specific viral etiology of diseases such as foot-and-mouth disease and yellow fever soon followed. Viruses were first classified as a distinct group based on their small size. We now know that viral genomes are composed of either RNA or DNA, and can encode several to hundreds of proteins based on their size. By learning more about how viruses attach, infect, and replicate in cells has allowed new therapeutic approaches to fighting viral infection. Importantly, better detection of viruses has allowed us to determine a viral etiology for diseases previously thought to be idiopathic. For example, high-throughput sequencing of RNA obtained from the livers and kidneys of a cluster of patients with fatal transplant-associated diseases allowed the identification of a new arenavirus as the cause of the outbreak.
Herpes simplex virus kerititis and keratouveitis
Although many viruses can induce intraocular inflammation, herpes simplex keratitis is probably the most common ocular disease associated with uveitis. Patients with stromal keratitis often have a concurrent anterior uveitis. Although in some patients this uveitis develops during the initial onset of epithelial disease, most patients have uveitis with stromal involvement. Recurrent episodes are common and can severely damage the eye. Anterior uveitis may also occur in patients with a history of previous epithelial herpetic infection without currently active corneal disease. Herpetic keratouveitis manifests as a red, photophobic, and often very painful eye with decreased vision. Secondary glaucoma frequently accompanies severe inflammatory episodes and can lead to vision loss.
Pathogenesis
It is difficult to know how much of the ocular inflammation is due to 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 between patients. A similar disease to herpes stromal keratitis can be induced in experimental animals by infecting them with HSV type 1. , A herpes protein, UL6, has been identified as a viral protein resembling corneal progein. Interestingly, both tolerance and autoimmunity can be induced in the same model, depending on host susceptibility to keratitis ( Fig. 13-1 ).
Diagnosis
The diagnosis of herpes simplex keratouveitis is most easily made in patients with a known history of herpes simplex keratitis confirmed by typical dendritic epithelial defects ( Fig. 13-2 ) or stromal disease confirmed by culture data. The disease should also be suspected in patients with a significant corneal opacity accompanied by synechiae and anterior chamber cells. Keratic precipitates in the area of corneal disease, hypopyon, and hyphema may be seen in some patients. In some patients the corneal disease may obscure the examination of the anterior chamber. Bacterial keratitis must be ruled out, as well as the possibility of secondary bacterial infection. The use of PCR is starting to help in identifying HSV as the causative agent in patients with uveitis of unknown etiology.
It remains unclear whether the uveitis associated with herpes simplex keratitis is a secondary inflammatory response to the corneal disease or whether it is induced by invasion of virus into the anterior uvea. Nevertheless, herpes simplex virus (HSV) has been isolated from the aqueous humor in some patients with the disorder. In experimentally induced herpes simplex uveitis the combination of sensitized T lymphocytes, herpes-specific antibody, and herpes simplex antigen is required to produce inflammation. In addition, topical ciclosporin A was shown to effectively reduce stromal haze and inflammation in experimental herpes simplex keratitis. If this situation applies to human disease, therapy that inhibits the cellular arm of the immune system could control the inflammation but enhance viral replication.
Experts differ on whether environmental factors can precipitate disease. Psychological stress has been cited as a potential trigger for recurrences of HSV ocular disease. However, when recall bias is controlled, a recent study failed to find an association between psychological stress and disease recurrence.
Treatment
Herpetic eye disease is a disorder where numerous randomized clinical trials help guide clinicians on how to best care for patients. Herpes simplex keratitis is treated with topical antiviral therapy such as 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 recent controlled trial of topical corticosteroids for herpes simplex stromal keratitis, Wilhelmus and colleagues showed that prednisolone phosphate was significantly better than placebo in reducing persistence or progression of stromal keratitis, as well as 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 aciclovir does not appear to be beneficial for patients with HSV epithelial keratitis treated with topical antiviral agents. In an initial study, Barron and colleagues for the Herpetic Eye Disease Study Group reported no statistically or clinically significant beneficial effect of oral aciclovir 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, randomized clinical trial of oral aciclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex virus 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 aciclovir 400 mg five times a day or placebo. The study showed that stromal keratitis or iritis developed in 17 of the 153 patients (11%) treated with aciclovir and in 14 of the 134 patients (10%) treated with placebo. In a second clinical trial the effect of oral aciclovir 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 the patients receiving aciclovir 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 aciclovir 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 aciclovir 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 of 22 patients (50%) receiving aciclovir and in 19 of the 28 patients (68%) 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 aciclovir. Finally, oral aciclovir effectively prevents herpes-related recurrences after penetrating keratoplasty in herpetic eye disease, supporting the use of the drug.
Valaciclovir and famciclovir are dosed less frequently than oral aciclovir and may be a useful alternative. In a small, prospective, randomized clincal trial of 52 immunocompetent patients oral valaciclovir (500 mg daily was as effective and well tolerated as aciclovir (400 mg twice daily) in reducing the rate of recurrent ocular herpes simplex virus disease. In another small randomized clinical trial, oral valaciclovir had similar efficacy to topical aciclovir ointment in patients with herpes simplex 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 currently available antiviral agents are effective and nearly equivalent. The author also noted that the combination of a nucleoside antiviral with either debridement or with interferon seemed to speed healing.
Work to develop a vaccine for HSV infection is ongoing. In a small randomized clinical trial, the use of a vaccination with heat shock-inactivated herpes simplex virus type 1 (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.
Herpes simplex 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 12 ). In addition, herpes simplex retinitis can occur in congenital HSV infection associated with herpes encephalitis. This infection is usually caused by herpes simplex type 2 (HSV-2) and may be acquired in utero rather than during birth. Many patients with congenital herpes simplex retinitis have corneal and anterior chamber involvement as well, obscuring 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 with herpes simplex is often overwhelming and fatal.
Herpes simplex retinitis has also been reported in patients who have undergone chemotherapeutic immunosuppression, and again a 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 diagnosis in some patients has been made after chorioretinal biopsy. In some patients the disorder appears to respond to treatment with intravenous aciclovir.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
