Long-term oral acyclovir therapy. Effect on recurrent infectious herpes simplex keratitis in patients with and without grafts.

PURPOSE: To evaluate the efficacy of long-term oral acyclovir therapy in reducing recurrences of dendritic or geographic herpes simplex keratitis (HSK). METHODS: Thirteen patients with a history of frequently recurring HSK were followed before (mean, 27 months) and during long-term systemic acyclovir, and eight were followed after the acyclovir was discontinued. RESULTS: Treatment ranged from 8.5 to 62 months (mean, 34 months). During treatment, the number of recurrences per month decreased from 0.15 to 0.03, and the average duration of relapses decreased from 12.6 to 7.8 days. Recurrences correlated with daily doses of oral acyclovir of 800 mg or less, intraocular surgery within 6 weeks of initiating treatment, and discontinuation of therapy against medical advice. CONCLUSION: The results of this small study appear to demonstrate the efficacy of long-term oral acyclovir in prophylaxis of recurrent epithelial herpes simplex infection: therapeutic doses of oral acyclovir reduce both the rate and duration of recurrences of infectious herpetic keratitis. A multicenter, double-masked, placebo-controlled study is indicated.

Detecting herpesvirus DNA in uveitis using the polymerase chain reaction.

BACKGROUND: Herpesviruses are involved in the pathogenesis of many ocular diseases including keratitis, iridocyclitis, and acute retinal necrosis syndrome. The rapid and accurate diagnosis of herpetic infections has become increasingly important with the rising incidence of immunosuppressive diseases. The purpose of this study was to evaluate the use of the polymerase chain reaction (PCR) to detect herpesvirus DNA in uveitis patients. METHODS: Aqueous samples were aspirated from 11 patients with active uveitis of suspected viral origin. Using PCR, masked samples were assayed for herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV) to assist in supporting the clinical diagnosis of viral aetiology. Masked controls included 10 aqueous humour specimens from normal patients undergoing cataract surgery and specimens from seven patients diagnosed with active non-viral uveitis--Behçet's disease, sarcoidosis, Fuchs' heterochromic iridocyclitis, or Harada's disease. RESULTS: Ten of 11 cases clinically diagnosed as being of possible viral aetiology yielded aqueous PCR positive for a herpesvirus. Eight patients were PCR positive for amplified HSV DNA, of whom two had acute retinal necrosis, one had corneal endotheliitis, and five had recurrent iridocyclitis. VZV DNA was detected in one case of iridocyclitis, and CMV DNA in one case of chorioretinitis. Successful therapy was based on the PCR results. Ten normal aqueous specimens and the seven uveitis samples from cases not suspected of a viral aetiology were PCR negative for HSV, VZV, and CMV. CONCLUSION: These results demonstrate that detecting herpesvirus DNA in the aqueous humour is useful to support a clinical diagnosis of viral uveitis.

Possible role of herpes simplex virus in the origin of Posner-Schlossman syndrome.

PURPOSE/METHODS: We conducted this study to determine if the herpesviruses are possible etiologic agents in Posner-Schlossman syndrome. We aspirated aqueous humor samples from patients during acute attacks of the syndrome. Ten normal aqueous humor specimens from patients undergoing cataract surgery were used as controls. DNA was extracted and subjected to polymerase chain reaction amplification and Southern blot hybridization. RESULTS/CONCLUSION: All three specimens were positive for amplified genomic fragments of herpes simplex virus and negative for varicella-zoster virus and cytomegalovirus. Ten normal aqueous specimens were negative for all three. Herpes simplex virus may play a role in the origin of Posner-Schlossman syndrome.

Herpetic keratitis: persistence of viral particles despite topical and systemic antiviral therapy. Report of two cases and review of the literature.

OBJECTIVE: First, to characterize the histologic features of corneal buttons taken from two patients with chronic active herpetic stromal keratitis. Both eyes had suffered frequent and prolonged viral epithelial recurrences despite topical and systemic antiviral therapy and developed uniquely rapid deposition of chalklike stromal deposits. Second, to determine the clinical outcome of surgical intervention in eyes with such a pattern of herpetic disease. DESIGN: Patients received topical antiviral medication and 200 to 400 mg of acyclovir five times daily for 2 or 5 months until penetrating keratoplasty. They received tapered doses of acyclovir after surgery. Corneal buttons were evaluated with light microscopy and electron microscopy. RESULTS: Light microscopy of the specimens revealed calcium in the area of the chalklike deposits and a few cocci in the deep stroma. Electron microscopy showed numerous herpetic viral particles at various stages of maturity, including completely enveloped organisms, in the basal cells and keratocytes, and a few cocci in basal cells. Apart from one minor recurrence of a dendritic ulcer, both patients were free of herpetic disease at 13 and 22 months, required little to no medication, and had clear grafts. CONCLUSIONS: Rapid calcium deposition in herpetic corneas may indicate disease of sufficient severity to warrant surgical intervention for removal of a stromal viral reservoir. Such intervention can stop further recurrences of keratitis that is poorly controlled by antiviral therapy. Such chronically diseased eyes may also harbor unsuspected bacterial infection.

Trimethoprim-sulfamethoxazole for scleritis associated with limited Wegener's granulomatosis: use of histopathology and anti-neutrophil cytoplasmic antibody (ANCA) test.

Ophthalmic involvement may be noted in < or = 58% of Wegener's granulomatosis cases, scleritis being one of the most frequent and potentially devastating manifestations. Cytotoxic immunosuppressive drug therapy is effective treatment for this disorder but potentially highly toxic. Recent uncontrolled and anecdotal reports have suggested a possible therapeutic role for a much less toxic agent, trimethoprim/sulfamethoxazole, in limited Wegener's granulomatosis. We report a patient who had a conjunctival nodule and scleritis. Biopsy of the nodule suggested Wegener's granulomatosis, confirmed serologically with serum anti-neutrophil cytoplasmic antibody (ANCA) testing. Treatment with oral trimethoprim/sulfamethoxazole was successful. Clinical response was paralleled by normalization of serial anti-neutrophil cytoplasmic antibody titers. This case is the first well-documented ophthalmologic report of limited Wegener's granulomatosis responding to trimethoprim/sulfamethoxazole and adds to the body of literature suggesting a potential role for this drug in selected cases of limited Wegener's granulomatosis.

Rapid detection of herpes simplex virus (HSV) antigen in human ocular infections.

The new HERPCHEK (Dupont, No. Billerica, MA) enzyme immunosorbent assay (EIA) was used in a double-blind clinical study for rapid and specific detection of ocular herpes simplex virus (HSV) infection. This 4-hour assay can be used to demonstrate conclusively the presence of HSV antigen without culture and thereby rapidly differentiate between HSV and other clinically similar ocular infectious diseases. Ocular samples were collected from 180 individuals including 30 patients with acute HSV, 90 with latent HSV (ie, currently asymptomatic but with a positive history), 11 with acute or latent varicella zoster virus, 30 with nonherpetic infections (due to adenovirus, Acanthamoeba or bacteria), and 19 normal controls. A clinical diagnosis was made by one of us (DPL) and duplicate tear-film samples obtained by swabbing the conjunctival cul-de-sac and cornea. Coded samples were tested by routine viral culture on Vero cell monolayers and also were run independently in the HERPCHEK test. During active HSV infection, the HERPCHEK correlated 100% with clinical diagnosis, and virus culture correlated 90% with clinical diagnosis. In all latent HSV ocular infections, other nonherpetic ocular infections and normal samples, both the HERPCHEK and culture assays were negative.

In vitro effect of (E)-5-(2-bromovinyl)-2'-deoxyuridine, 5'-amino-5-iodo-2',5'-dideoxyuridine and 2-deoxy-D-glucose on latent ganglionic herpes simplex virus infection.

(E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVDU) and 5'-amino-5-iodo-2',5'-dideoxy-uridine AIdUrd, blocked the reactivation of latent ganglionic herpes simplex virus in vitro. Furthermore, BVDU, but not AIdUrd, blocked the multiplication of reactivated latent virus and transiently suppressed emergence of reactivated virus from the sensory ganglia after removal of drug from the medium. 2-Deoxy-D-glucose (2-DG) neither prevented the in vitro reactivation of latent virus nor blocked the further multiplication of reactivated latent virus.

Ocular viral infections.

The most important viral organisms involving the eye are the DNA viruses herpes simplex, varicella-zoster, cytomegalovirus, adenovirus, and vaccinia virus. All of these agents except CMV may cause acute epithelial infection, sterile trophic ulceration due to basement membrane damage, deep corneal stromal immune reaction, and iritis. Although there are three excellent antiviral drugs commercially available, only HSV and vaccinia virus are highly sensitive to therapy with these antimetabolites; varicella-zoster virus and CMV are equivocally responsive and adenovirus has not been shown to be susceptible to these agents. In selected situations, topical or systemic corticosteroids are useful for managing any associated immune reactions in the eyes, but patients on these drugs should be monitored carefully both for superinfections and for interference with tissue healing that might ultimately threaten the integrity of the globe.

Development of oral HSV-1 infection model in mice. Evaluation of efficacy of 5'-amino-5-iodo-2',5'-dideoxyuridine.

We developed a new model of oral HSV-1 infection in mice. After oral inoculation, 100 percent of mice developed the clinical lesions at the inoculated area and latent HVS infection in their trigeminal ganglia without mortality. The antiherpetic efficacy of AIdUrd, an agent specifically activated by herpesvirus-encoded enzyme, has been evaluated in this animal model. Early topical or systemic treatment of AIdUrd notably reduced the development of clinical lesions and the virus content in the inoculated lips. However, the establishment of latent HSV infection in the sensory ganglia was not influenced by AIdUrd treatment.

Topical therapeutic efficacy of 9-(2-hydroxyethoxymethyl)guanine and 5-iodo-5'-amino-2',5'-dideoxyuridine on oral infection with herpes simplex virus in mice.

The therapeutic efficacy of two new antiviral agents, 5-iodo-5'-amino-2', 5'-dideoxyuridine (AIdUrd) and 9-(2-hydroxyethoxymethyl)guanine (ACV), in the model of mouse lip inoculated with herpes simplex virus type 2 is reported. The effects on development of clinical lesions, viral replication in the inoculated lips, and establishment of latent viral infection in the trigeminal ganglia were observed. The earlier the treatment with AIdUrd and ACV was initiated after inoculation, the better was the chemotherapeutic effect. AIdUrd and ACV treatment, when initiated 48 and 72 hr after inoculation, respectively, showed no chemotherapeutic efficacy. Establishment of viral latent infection in sensory ganglia was significantly prevented only when ACV treatment was initiated very early (1 or 3 hr) after inoculation. The results indicate that both drugs have significant antiviral activity, in part dependent on the time of initiation of therapy, and that ACV is superior to AIdUrd as a topical agent for therapy of herpes simplex virus type 2 infections.

Ocular surface manifestations of the major viruses.

The ocular surface is often the first site of involvement by viral infections. Background information, clinical presentations, and current treatment of three major viruses--herpes simplex, varicella-zoster, and adenovirus, have been presented in detail in this chapter. The effects of adenoviruses are usually transient and may be regarded as a nuisance. Infection with herpes simplex or varicella-zoster may lead to prolonged activity of the disease and life-long treatment with occasional loss of useful vision. It is apparent that our understanding of the clinical behavior of the major viruses has increased in recent years. Therapeutic criteria and modalities have also improved for some of the complications of the viruses. Much work needs to be done for some of the other manifestations, i.e., failure of reepithelialization, stromal melting, scarring, vascularization, and inflammation.

Corneal wound healing and antiviral medication.

Masked, controlled rabbit studies were done to determine the toxic effects on corneal wound healing of 0.1 percent idoxuridine drops, 3 percent adenine arabinoside monophosphate drops, and 1 percent trifluorothymidine drops, the clinically used concentrations. Neither idoxuridine nor trifluorothymidine significantly retarded closure of epithelial wounds. All three drugs caused toxic changes in the regenerating epithelium clinically and by histopathologic examination. Treatment with arabinoside monophosphate, the monophosphate ester of vidarabine, significantly retarded closure of epithelial wounds and caused impressive toxic changes in the regenerating epithelium. Vascularization of the corneal stroma was present in all eyes treated with this drug. The trifluorothymidine and idoxuridine had much milder toxic effects on regenerating epithelium and appeared equal in regard to production of such effects. The strength of stromal wounds was somewhat reduced by idoxuridine and trifluorothymidine and significantly increased by arabinoside monophosphate when compared to controls, These findings were confirmed by hydroxyproline assay of the stromal scars.

Ara AMP- a highly soluble new antiviral drug.

While vidarabine (Ara A) is in several ways superior to idoxuridine (IDU) it still has the disadvantages of rapid inactivation and poor solubility. The monophosphate ester or vidarabine, Ara AMP, however, is metabolized very slowly in humans and is extremely soluble with good tissue penetrance. The present study indicates that Ara AMP drops are equipotent or superior to vidarabine ointment in treatment of type 1 and type 2 herpes simplex keratitis. While iritis was significantly less in all treated groups, a suspicion of chemical side effect was raised but could not be proven in subsequent toxicity tests.

Recent advances in antiviral therapy.

It has been demonstrated in clinical trials that (1) the antimetabolites Ara A and F3T are both significantly better than IDU in the treatment of many forms of ocular herpes, and (2) they are not significantly different from each other. In preclinical trials, the IDU ocular insert also has shown itself to be significantly better than IDU drop-ointment therapy, while exposing the eye to 40 percent less drug and adding tremendous convenience and ease of compliance by patients to an otherwise difficult medication schedule. Both photodynamic inactivation and cryotherapy have been shown in clinical trials to have notable therapeutic efficacy against herpes, but undesirable and occasionally severe side-effects have slowed down and possibly stopped the further development of these techniques.