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.

Delayed herpes zoster pseudodendrites. Polymerase chain reaction detection of viral DNA and a role for antiviral therapy.

BACKGROUND: The late-onset pseudodendrites, delayed corneal mucous plaques, of herpes zoster ophthalmicus are reported to be of mechanical or immune origin and to be worsened by antiviral therapy. OBJECTIVE: To study pseudodendrites to ascertain a viral presence in the lesions and their response to antiviral therapy. DESIGN: Prospective clinical study. SETTING: Outpatient and inpatient hospital-based corneal specialty referral practice; molecular virology laboratory. PATIENTS: Six patients, aged 33 to 89 years, four with delayed herpes zoster ophthalmicus pseudodendrites and two with herpes zoster ophthalmicus neurotrophic ulceration. One patient was immunosuppressed. MAIN OUTCOME MEASURES: Findings from clinical evaluation; polymerase chain reaction assays of lesions and tear film of six patients; polymerase chain reaction and light and electron microscopy of the corneal button from one patient; and the clinical response of four patients to various antiviral drugs. RESULTS: In contrast to reports in the current literature, delayed pseudodendrites may also be infectious, as they are positive for zoster DNA by polymerase chain reaction and appear responsive to certain antiviral therapy. The corneal button from an immunosuppressed patient had mature and immature viral particles in the basal cells within 2 weeks of transplantation. CONCLUSIONS: To our knowledge, this is the first report of viral DNA in delayed zoster pseudodendrites. Recurrent viral infection may play a role in this form of zoster keratopathy and warrant antiviral therapy.

Acanthamoeba keratitis. Contact lens and noncontact lens characteristics.

PURPOSE: To identify potential differences in time to diagnosis and final visual outcome between contact lens and noncontact lens users with Acanthamoeba keratitis. BACKGROUND: Prior studies have shown early diagnosis and therapy to be related to outcome but have not analyzed differences among patients with and without contact lenses. METHODS: A retrospective analysis of 11 consecutive cases (involving 13 eyes) of Acanthamoeba keratitis diagnosed at one institution over a 3-year period. RESULTS: Mean time to diagnosis was significantly longer in noncontact lens users versus those who wore contact lenses (mean, 5.8 versus 3.3 weeks). Fifty percent of patients who did not wear contact lenses had a poor outcome (visual acuity worse than 20/40 or penetrating keratoplasty) versus 14% of patients who wore contact lenses. CONCLUSION: Diagnoses were made later in patients without contact lenses, and these patients had a worse visual outcome than those with Acanthamoeba keratitis who wore contact lenses. All patients with unresponsive microbial keratitis, even those without contact lens use, should be evaluated for Acanthamoeba.

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.

A rabbit model for human cytomegalovirus-induced chorioretinal disease.

AD169, a well-characterized laboratory strain of human cytomegalovirus (HCMV), was used to establish an animal model of progressive HCMV chorioretinal disease by injection of 10(5) pfu into the rabbit vitreous. Chorioretinal, vitreous, and pulmonary disease were monitored by HCMV recovery, clinical observation, antigen localization, and histopathology. Vitritis and focal areas of immune cellular infiltrates were seen in inner retinal layers on days 2-4 after inoculation. Disease progressed with more severe vitritis and to involve the outer retinal layers in areas of mixed monocytic cellular infiltrates, retinal destruction, choroidal edema, and congestion. HCMV was recovered from chorioretinal cell sonicate cultures in titers ranging from 10(4) to 10(5) pfu during peak disease, and HCMV antigens were detected focally by immunofluorescence in retinal layers on days 2 and 4 after inoculation. A rabbit model of HCMV chorioretinitis similar to human CMV disease allows investigation of HCMV pathogenesis and new antiviral therapies and evaluation of immune system modulation of the HCMV ocular infection.

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.

Delayed onset of varicella keratitis.

Although varicella is one of the most common infectious diseases in the United States, systemic and ocular complications are rare. We report a patient who developed disciform edema followed by microdendritic keratitis 1 and 2 months, respectively, after resolution of the acute phase of varicella. Cultures were negative, but serologic analysis found positive antibodies against varicella zoster virus and negative antibodies against herpes simplex virus. Based on this case and on a review of the literature, we believe that this delayed onset of keratitis represents a distinct category of varicella corneal complications.

HSV-1-inducible proteins bind to NF-kappa B-like sites in the HSV-1 genome.

Several putative NF-kappa B-binding sites in the ICP0 and Vmw65 herpes simplex virus type-1 (HSV-1) genes have been identified. Oligonucleotides encoding some of these sites bind specifically to purified NF-kappa B protein and an NF-kappa B-like protein in nuclear extracts of phorbol ester- or cycloheximide-induced human embryonic lung (HEL) cells. HSV-1 infection of HEL cells induced a nuclear factor that binds specifically to kappa B sites in the ICP0 and Vmw65 gene regions and comigrates with complexes formed by purified NF-kappa B. The HSV-1-inducible nuclear factor bound to the authentic immunoglobulin (Ig) kappa B site. Transient expression of chloramphenicol acetyltransferase (CAT) plasmids containing two copies of the Ig kappa B site upstream of the c-fos promoter (kappa B2-CAT) showed activity in HEL cells. HSV-1 infection of kappa B2-CAT-transfected HEL cells, however, induced a dramatic increase in CAT activity; mutation in the NF-kappa B-binding site of kappa B2-CAT abolished the inducibility of CAT gene expression. Our results demonstrate that the HSV-1 ICP0 and Vmw65 gene regions contain binding sites for NF-kappa B, and that HSV-1-inducible proteins bind to NF-kappa B-like sites in the HSV-1 genome.

Detection of herpes simplex virus thymidine kinase and latency-associated transcript gene sequences in human herpetic corneas by polymerase chain reaction amplification.

Herpes simplex virus (HSV) latency in sensory ganglion neurons is well documented, but the existence of extraneuronal corneal latency is less well defined. To investigate the possibility of extraneuronal latency during ocular HSV infection, corneal specimens from 18 patients with quiescent herpes simplex keratitis (HSK) were obtained at the time of keratoplasty. Polymerase chain reaction (PCR) amplification followed by southern blot hybridization with a radiolabeled oligonucleotide probe was done to detect the presence of HSV-1 genome in these human corneal samples. Two pairs of oligonucleotides from the region of the HSV thymidine kinase (TK) gene and the latency-associated transcript (LAT) gene were used as primers in the PCR amplification. The DNA sequences from either the TK or the LAT gene were identified in 15 of 18 HSK corneas (83%). These results demonstrate that the HSV genome was retained, at least in part, in human corneas during quiescent HSV infection, giving further support to the concept of corneal extraneuronal latency.

Multicenter clinical evaluation of the Du Pont Herpchek HSV ELISA, a new rapid diagnostic test for the direct detection of herpes simplex virus.

A new 4h rapid enzyme-immunoassay for direct detection of herpes simplex virus (HSV) antigen (Du Pont Herpchek) was evaluated with 743 clinical samples collected at obstetrics and gynecology (OB/GYN), sexually transmitted diseases (STD), and ophthalmology clinics. The sensitivity and specificity of Herpchek was 98.0% and 98.4% respectively compared to virus isolation in cell culture. Confirmatory blocking ELISA tests, clinical history and follow up indicate that the true specificity of the test is 100%.