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Purpose: To analyze the clinical presentation, characteristics, treatment, recurrences, and final outcomes and complications of herpes simplex virus (HSV) disease of the anterior segment in patients aged 17 years or younger., Methods: This is an observational and retrospective study with review of the medical records of all the children diagnosed with herpes simplex infection of the anterior segment at an ophthalmologic referral center, from 2002 to 2012. The diagnosis was made on the basis of the history and examination of patients and in specific cases by viral culture and the polymerase chain reaction. Main outcome measurements included final visual acuity, bilateral disease, and recurrence. Recurrent disease was analyzed with Kaplan-Meier curves., Results: A total of 103 patients were included with a median age at presentation of 9 years. Of them, 6 had bilateral and simultaneous disease. The median follow-up time was 18 months (range, 18 days-12 years). The most common clinical manifestations were epithelial dendritic keratitis in 42 eyes (38.5%) and interstitial keratitis in 39 eyes (35.7%), with 15 patients presenting multiple forms of HSV disease. The median final visual acuity in the group of patients was 20/40. Recurrent disease was evident in 42 (38.5%) of the eyes, with a median recurrence time of 15 months (95% confidence interval, 8.1-26.2 months)., Conclusions: In this study, epithelial dendritic and interstitial keratitis were the most frequent forms of disease in the pediatric population with HSV of the anterior segment. A high rate of recurrent disease was present.

Purpose: To determine the prevalence of herpes simplex virus type 1 (HSV-1) DNA in failed Descemet membrane stripping automated endothelial keratoplasty (DSAEK) grafts., Methods: A retrospective interventional case series of patients with DSAEK graft failure treated at the New York Eye and Ear Infirmary between January 2009 and July 2012 was performed. Repeat DSAEK, penetrating keratoplasty, or keratoprosthesis procedure was subsequently performed on eyes with failed grafts. All failed grafts were examined immunohistochemically and with qualitative real-time polymerase chain reaction for HSV-1 DNA. In HSV-1-positive cases, corneoscleral donor rims from the original DSAEK procedures were also examined immunohistochemically and with polymerase chain reaction., Results: Fifty-one failed DSAEK grafts from 50 eyes of 49 patients were identified. Indications for DSAEK were pseudophakic bullous keratopathy (28/51, 55%), Fuchs corneal endothelial dystrophy (12/51, 23%), failed penetrating keratoplasty (7/51, 14%), corneal decompensation from glaucoma (2/51, 4%), herpetic endotheliitis (1/51, 2%), and failed DSAEK (1/51, 2%). Forty-three grafts (83%) were primary DSAEK graft failure. HSV-1 DNA was isolated from 2 of 51 failed DSAEK grafts (4.0%). The corresponding corneoscleral donor rims did not demonstrate the presence of HSV-1., Conclusions: Based on our results, HSV-1 infection plays a minor role in DSAEK graft failure. The data suggest that recipient reactivation, rather than donor transmission, plays a role in HSV infection.

Herpes simplex virus type 1 (HSV-1) establishes a latent infection in sensory neurons that can sometimes be reactivated. HSV-1 keratitis often recurs and can be vision threatening. Reactivation of the latent virus can be stimulated by stress, immunosuppression, trauma, adrenergic iontophoresis, and UV radiation. Healthy and asymptomatic individuals are known to shed HSV-1, and this is a major factor in the spread of the virus. We investigated the frequency of shedding of HSV-1 DNA in tears of dry eye patients and individuals with conjunctivitis. Subjects were divided into 3 groups: normal (12 eyes), dry eye (11 eyes), and conjunctivitis (15 eyes). Quantitative real-time polymerase chain reaction was used for HSV DNA detection. The incidences of HSV positivity in the normal, dry eye, and conjunctivitis groups were 1 of 12 (8.3%), 3 of 11 (27.3%), and 4 of 15 (26.7%), respectively. We have previously shown that bromfenac sodium eye drops, intramuscular adenosine monophosphate, and geldanamycin effectively lower HSV-1 recurrence rates in a mouse model. Recently, we also found that nuclear factor κ-B, an IκB kinase-β inhibitor, could be a candidate for reducing HSV-1 reactivation. We sampled recipients' corneal buttons during keratoplasty and performed polymerase chain reaction. Cytomegalovirus (CMV) DNA was detected in corneas obtained from some patients, and the copy number of the detected CMV DNA was quantified. CMV DNA-positive samples were taken from 2 of the 3 patients with ocular pemphigoid; thus, in future work, the relationship between CMV in the cornea and the incidence/onset of ocular diseases of the anterior segment needs to be evaluated.

Purpose: : The purpose of this study was to determine the association of human herpes virus 6 (HHV-6) and/or other human herpesviruses in corneal inflammation using polymerase chain reaction (PCR)., Methods: : We collected tear films, conjunctival smears, and a corneal button of inflamed cornea, and the presence of HHV-6 and other herpesviruses in these samples were assessed by a nested PCR., Results: : In tear films collected from 3 of 9 patients with dendritic keratitis, HHV-6 DNA was positive twice, together with herpes simplex virus (HSV) or varicella zoster virus DNA most often, during the acute phase of the disease. Two other patients in this group were either positive for HSV-1 and varicella zoster virus or for HSV-1 and Epstein-Barr virus DNA but negative for HHV-6. When another 12 patients' smear samples from corneal ulcer or keratouveitis were examined, 9 were positive for HHV-6 DNA. Of these, 4 were positive for HSV-1 simultaneously, whereas the remaining 5 patients were negative for HSV-1. One patient's smear was positive for HSV-1 but not for HHV-6. In the corneal button, both HSV and HHV-6 DNAs were positive by nested PCR. HHV-6 was also positive by nested PCR in the conjunctival swab obtained from the contralateral inflamed eye of the patient., Conclusions: : In 22 patients with corneal inflammation, HHV-6 was positive in 14 of 22 patients and HSV-1 was found in 9 of those patients. These data indicated that the association of HHV-6 with disease was more frequent than with other herpesviruses and that HHV-6 may be another sole causative agent for corneal inflammation.

Purpose: We detected herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), varicella zoster virus (VZV), and cytomegalovirus (CMV) DNAs in recipient corneal buttons taken at the time of penetrating keratoplasty., Methods: Twenty-seven corneal buttons were obtained from 27 patients (10 men and 17 women), 7 of whom had a history of HSV keratitis. Excised corneal buttons were immediately frozen in liquid nitrogen in the operating theater and then stored at -80°C until DNA extraction. The detection of HSV-1, HSV-2, VZV, and CMV DNAs was carried out by a nested polymerase chain reaction (PCR) method. The genome copy numbers for the nested PCR-positive samples were subsequently quantified by real-time PCR., Results: HSV-1, HSV-2, VZV, and CMV DNAs were detected in 10, 1, 9, and 2 of the 27 recipient corneal buttons, respectively. HSV-1 or HSV-2 DNAs were also detected in 5 of 7 patients with a history of HSV keratitis. Both CMV-positive patients (patients 2 and 3) had ocular pemphigoid. Among the nested PCR-positive samples, 2 HSV-1, 1 HSV-2, 1 VZV, and 1 CMV sample could be quantified by real-time PCR. Copy numbers ranged from 19 to 928 copies., Conclusions: All 4 herpesviruses, including CMV, were detected in the corneal buttons. The relationship between CMV in the cornea and ocular diseases of the anterior segment should be further evaluated.

Purpose: To characterize confocal scan features of keratic precipitates (KPs) in Fuchs heterochromic iridocyclitis., Methods: Confocal scans of KPs in patients with Fuchs uveitis were performed. Polymerase chain reaction technique of aqueous for herpes simplex, herpes zoster, Toxoplasma, cytomegalovirus, and rubella was performed for 4 patients., Results: Confocal scan was performed in 40 eyes of 34 patients [18 males and 16 females, mean age 30.7 +/- 10.5 years (range 18-57 years)]. Fuchs heterochromic iridocyclitis was bilateral in 6 and unilateral in 28 patients. All eyes had KPs: globular KPs were found in 34 eyes, infiltrating and dendritiform in 31 eyes, stippled in 27 eyes, and cruciform in 19 eyes. Polymerase chain reaction of aqueous specimens for the above-mentioned infectious agents was negative in 4 eyes of 4 individuals who had infiltrating and dendritiform KPs on confocal scan, with no other concurrent disorder., Conclusions: Confocal features of KPs in Fuchs uveitis are diverse. The presence of dendritiform and infiltrating KPs on confocal scan may not be suggestive of an infectious etiology.

Purpose: To report a case of herpetic epithelial keratitis that developed after intravitreal bevacizumab (Avastin) injection., Methods: A 63-year-old man with diabetes with proliferative diabetic retinopathy and macular edema received intravitreal injection of bevacizumab (Avastin) in his right eye., Results: Three days after the injection, the patient presented with foreign body sensation, redness, tearing, photophobia, and decreased visual acuity in the right eye. The cornea showed an arborizing dendritic epithelial lesion with terminal bulb typical of herpes simplex virus (HSV) epithelial keratitis. HSV-DNA was detected in corneal scrapings using polymerase chain reaction. A diagnosis for herpes simplex epithelial keratitis was made. Topical acyclovir ointment therapy was initiated with good resolution of HSV signs and symptoms., Conclusions: Herpes simplex epithelial keratitis can be a possible complication of intravitreal bevacizumab (Avastin) injection. To our knowledge, this case is the first report of herpetic epithelial keratitis after intravitreal bevacizumab (Avastin) injection.

Purpose: To report the clinical characteristics and visual outcomes of pediatric herpes simplex virus (HSV) keratitis., Methods: The medical records of 29 patients younger than 16 years with HSV keratitis who were diagnosed and treated at Chang Gung Memorial Hospital, Taoyuan, Taiwan, between 1996 and 2004 were retrospectively reviewed. The diagnosis of HSV keratitis was proven by a positive viral culture and/or real-time quantitative polymerase chain reaction or by a clear history of dendritic keratitis or herpetic kerato-uveitis. Type of HSV keratitis, recurrence rate, and visual outcome were analyzed., Results: The average age at the entry into the study was 5.7 years (range: 7 months to 15 years). Mean follow-up time was 35.3 months (range: 2-69 months). Epithelial keratitis including dendritic and geographic ulcers was noted in 14 eyes, stromal keratitis in 2 eyes, stromal keratitis concurrent with epithelial keratitis in 8 eyes, and endotheliitis in 6 eyes. One patient had sequential involvement of both eyes. Thirteen patients (45%) developed recurrent HSV keratitis after the first documented episode. Female gender (but not age or the type of keratitis) was significantly associated with recurrences. Five patients who were maintained on oral valacyclovir prophylaxis up to 1 year had no recurrence during the period. Fifteen of 21 patients younger than 8 years of age had best-corrected visual acuity available at last follow-up, and 10 patients developed amblyopia., Conclusions: Children with HSV keratitis are at risk for recurrent keratitis and amblyopia. Prolonged systemic antiviral prophylaxis may help to prevent such consequences.

Purpose: To evaluate the presence of herpes simplex virus (HSV) in pterygia to study the possible association between HSV and pterygia in Taiwan, a tropical country with a high prevalence of pterygium., Methods: Sixty-five pterygia, 10 normal conjunctiva, 8 conjunctival nevi, and 2 malignant conjunctival melanomas were obtained. Clinical histories were recorded for each patient. HSV detection was accomplished by polymerase chain reaction amplification of viral sequences. HSV-positive specimens underwent subsequent DNA in situ hybridization. Results were statistically analyzed., Results: By using polymerase chain reaction, HSV was detected in 3 (5%) pterygia, and no conjunctival control displayed HSV. All 3 HSV-positive pterygia studies were DNA in situ hybridization negative. There was no statistically significant correlation between pterygium and the presence of HSV., Conclusions: HSV is not associated with pterygium formation in Taiwan; the pathogenesis of pterygia is still incompletely understood.

Purpose: To detect herpes simplex virus (HSV) genome in the cornea, we sampled the limbal corneas and scleras of the imported eye bank eyes and recipient's corneal buttons and quantitated HSV genome in them by real-time polymerase chain reaction (PCR)., Methods: Forty-four recipient corneas including 7 corneas with and 37 corneas without a history of herpetic keratitis, 70 eye bank donor limbal corneas, and 35 eye bank donor scleras were obtained. Primers for real-time PCR were synthesized using the HSV-1 and -2 common regions of the viral DNA polymerase. Primers for conventional PCR were designed to detect HSV-1 and -2 and varicella zoster virus (VZV)., Results: Significantly higher copy number of HSV DNA was detected in corneas with a history of herpetic keratitis 85.7% (6/7), with an average of 1.6 x 10(4) copies/mg tissue weight than in corneas without a history of herpetic keratitis 10.8% (4/37), with an average of 8.7 copies/mg tissue weight (P < 0.05, Mann-Whitney U test). HSV DNA was detected in 5.7% (4/70) of the eye bank donor corneas, with an average of 4.9 x 10(2) copies/mg tissue weight, and in 8.6% (3/35) of the donor scleras, with an average of 10.6 copies/mg tissue weight. HSV-2 and VZV-DNA were not detected in these samples., Conclusions: Real-time PCR quantitated HSV genome in the cornea even at a quiescent phase of infection. HSV genome was detected in the corneas and scleras without a past history of herpetic keratitis by this method.

Purpose: To introduce into the clinical nomenclature a sign frequently observed in our patients with persistent corneal inflammation associated with herpetic stromal keratitis., Methods: Case reports and review of the literature., Results: Four representative patients with herpesvirus stromal keratitis are presented. Herpes simplex virus-1 (HSV-1) was confirmed by culture in 1 case and by polymerase chain reaction in a second case. In the remaining 2 cases, the diagnosis was made based on characteristic clinical findings for herpes simplex virus and varicella zoster virus (VZV). On clinical examination, all 4 representative cases of stromal keratitis revealed a well-defined, localized region of intertwined, metallic-like, polychromatic material in the corneal stroma, a sign we have termed steel wool keratopathy. We have only rarely observed this finding in patients with stromal keratitis not caused by a herpesvirus., Conclusion: Steel wool keratopathy seems to represent a focal region of stromal degeneration or deposition associated with chronic inflammation. Although we most often observe this finding in patients with stromal keratitis secondary to HSV or VZV, we cannot exclude the possibility that this sign represents the sequelae of chronic/recurrent inflammation rather than a specific pathologic response to herpetic antigens.

Objective: To report recurrent herpetic keratouveitis following YAG laser peripheral iridotomy., Methods: Case report., Results: A 64-year-old woman with a history of dendritic keratitis underwent Nd:YAG laser peripheral iridotomy and developed geographic epithelial keratitis with stromal keratouveitis. Culture of a corneal swab grew herpes simplex virus type I. Keratouveitis subsided with acyclovir and corticosteroid therapy., Conclusions: Recurrent herpetic keratouveitis may be induced by YAG laser iridotomy.

Objective: To report three cases of herpetic infection in recipients of organ-cultured donor corneas among 586 consecutive corneal transplantation procedures., Methods: Three patients with no history of symptomatic herpes infection underwent corneal transplantation for keratoconus (2 patients) and Fuchs dystrophy (1 patient). Two patients developed keratouveitis and primary graft failure. The third patient developed dendritic keratitis in the graft. Culture of corneal scrapings and the patient's bandage contact lens were positive for herpes simplex virus type 1 (HSV-1). Donor and recipient sera were tested for HSV serology by EIA. Recipient corneal buttons were studied by means of transmission electron microscopy and immunohistochemistry. The three HSV-1 strains were genotyped by sequencing part of a variable antigenic domain of glycoprotein B (gB)., Results: None of the donor corneas showed endothelial cell necrosis after organ culture. All keratoplasties performed with the three mate donor corneas had an uncomplicated course. All three donor sera were positive for HSV. Preoperative recipient sera were positive for HSV. Analysis of the recipient corneal buttons showed no evidence of herpetic infection. Sequence analysis revealed three different gB genotypes., Conclusion: Ascertaining that a postoperative herpetic infection in a corneal transplant originates from the donor tissue is still difficult. Although some features of the reported cases suggest donor-to-host transmission of herpes simplex virus, the recipients could have been the source of the virus.

Purpose: To present a cluster of four patients with primary graft failure (PGF) who consecutively underwent a penetrating keratoplasty (PKP) during a period of 17 days in one institution. PKP was performed for reasons unrelated to herpes simplex infection. Herpes simplex virus type 1 (HSV-1) is presented as the possible cause of these PGFs., Methods: Viral culture of conjunctival swabs and of a bandage contact lens was performed on VERO, MRC-5, and Hep-2 cells. The four patients underwent subsequent regrafting. Polymerase chain reaction (PCR) for HSV-1 was carried out on aqueous humor and on a sample of iris and cornea with primers. Aqueous humor specimens were pretreated by boiling, and a qiagen extraction was performed according to the instructions of the manufacturer on biopsies of iris and cornea. Immunohistopathology was performed with polyclonal antibodies directed against HSV-1 and -2., Results: Culture of a conjunctival swab in three patients and culture of a bandage contact lens in the fourth patient were positive for HSV-1. In three of the four patients, PCR was positive for HSV-1 on aqueous humor and corneal graft tissue. PCR on iris tissue was positive in all patients. In three patients, culture for HSV-1 of aqueous humor and of iris tissue could not be carried out because of insufficient sample. Viral culture of the iris tissue in one patient and of the corneal graft in the four patients were negative. Immunohistopathologic examination was positive for HSV-1 in three cases., Conclusion: These case reports strongly support the hypothesis that HSV-1 can be the cause of PGF.

Purpose: Determinants of the natural history of recurrent herpes simplex virus (HSV) keratitis have not been consistently established. We assessed how previous HSV eye disease affects the risk of recurrent HSV keratitis and evaluated whether demographic and other variables play any predictive role., Methods: Three hundred forty-six patients in the placebo group of the Herpetic Eye Disease Study's Acyclovir Prevention Trial who had experienced an episode of HSV eye disease in the previous year were followed up for 18 months. Recurrences were categorized according to the type of involvement. Relative rates of recurrence were compared for categories of demographic variables, types and number of previous ocular HSV episodes, previous nonocular HSV infection, and month of the year., Results: Fifty-eight (18%) of the 346 patients developed epithelial keratitis and 59 (18%) developed stromal keratitis during the 18 months of follow-up. Previous epithelial keratitis did not significantly affect the risk of epithelial keratitis (p = 0.84). In contrast, previous stromal keratitis increased the risk of stromal keratitis 10-fold (p < 0.001), and the risk was strongly related to the number of previous episodes (p < 0.001). Age, gender, ethnicity, and nonocular herpes were not significantly associated with recurrences, and no seasonal effects were observed., Conclusion: Among patients who experienced active ocular HSV disease in the previous year, a history of epithelial keratitis was not a risk factor for recurrent epithelial keratitis. In contrast, previous, especially multiple, episodes of stromal keratitis markedly increased the probability of subsequent stromal keratitis.

Purpose: To evaluate the presence of herpes simplex virus (HSV) and human papilloma virus (HPV) in pterygia and phenotypically normal conjunctiva and the possible relation between viral presence and clinical information., Methods: Fifty pterygia and respective conjunctival specimens were obtained. A personal and family history was recorded for each patient. HSV and HPV detection and typing were accomplished by polymerase chain reaction amplification of viral sequences. Results were statistically analyzed., Results: HSV (type 1) was detected in 11 (22%), HPV (type 18) in 12 (24%), and both HSV-1 and HPV-18 in 3 (6%) of pterygia. No conjunctival specimen displayed HSV, whereas HPV was detected in four (8%). Postoperative recurrence and history of conjunctivitis were significantly more common in patients with simultaneous detection of HSV and HPV., Conclusion: The fact that HSV was not detected in conjunctival specimens implies a more specific correlation with pterygium, as compared with HPV. The detection of potentially oncogenic viruses, such as HSV and HPV, supports the concept that pterygium can be considered a neoplastic condition. The correlation of postoperative recurrence and a history of conjunctivitis with the simultaneous detection of HPV and HSV, implies a possible viral cooperation affecting the clinical profile of pterygium.

Purpose: To demonstrate the presence of an active herpetic dendrite in an eye-bank cornea., Case Report: One eye-bank cornea was studied. Viral cultures and polymerase chain reaction (PCR) testing were performed 4 days after tissue preservation. The presence or absence of herpes simplex virus (HSV) type 1 was investigated., Results: The presence of an active HSV dendrite in an eye-bank cornea was verified. HSV type 1 was confirmed using PCR amplification and restriction endonuclease DNA fragment analysis., Conclusion: This case suggests that HSV may remain viable in stored corneal tissue at 4 degrees C.

Purpose: A new class of antiviral agent, cobalt chelates (the CTC series), was evaluated for treating epithelial herpetic keratitis, consequent stromal disease being the major infectious cause of blindness in industrial nations., Methods: Effects of CTC complexes were monitored in cell cultures and in a rabbit eye model, either infected with herpes simplex virus type 1 (HSV-1) or uninfected. Several antiviral concentrations of CTC complexes nontoxic to Vero cells were administered to rabbit eyes with HSV-1-induced keratitis. Corneal surface virus titers were measured, and corneal lesions of epithelial keratitis were monitored by slit-lamp microscopy and scored. Recovery rates and incidence were compared in eyes treated with CTC complexes, placebo, or clinically formulated trifluorothymidine (Viroptic), using nonparametric statistics., Results: All CTC complexes inhibited HSV-1 replication in vitro, CTC-96 being best. CTC-96, CTC-23, and CTC-67 eliminated (<1 plaque-forming unit[pfu]) corneal surface HSV-1 (otherwise >10(5) pfu) in order of descending potency, but CTC-82 was ineffective. CTC-96 (either 5 microg/ml six times daily or 10 microg/ml five times daily) accelerated herpetic dendritic keratitis recovery better than or the same as trifluorothymidine (10 mg/ml nine times daily). CTC complexes were nontoxic to Vero cells continuously exposed to < or =25 microg/ml; 50 microg/ml of CTC 96 nine times daily did not irritate uninfected rabbit eyes., Conclusion: Topical CTC-96 applications were at least as effective as Viroptic in diminishing disease signs and corneal surface virus at concentrations less than one-thousandth that of Viroptic.

The purpose of our study was to develop a method for detecting herpes simplex virus (HSV) DNA that combined the high sensitivity of the polymerase chain reaction (PCR) with the precise anatomical localization provided by in situ hybridization (ISH). We used in situ PCR (ISPCR), ISH, and standard PCR methods to determine the proportion of Vero cells carrying HSV-1-specific DNA before and after 1, 2, and 4 h of infection with HSV-1 or with HSV-2. Uninfected Vero cells and Vero cells infected with HSV-2 were never found to be positive for HSV-1 DNA by either ISPCR, ISH, or PCR. In contrast, using ISPCR, HSV-1 infected Vero cells showed an increase in the percentage of cells containing HSV-1 DNA from 20% at 1 h to 76% at 4 h after infection. Comparing the ISPCR results with ISH and standard PCR demonstrated that ISPCR was markedly more sensitive than ISH; in fact, the sensitivity of in situ PCR was similar to that seen with standard PCR. These results demonstrate that ISPCR is a highly sensitive method for amplifying genomic DNA sequences within intact single cells. This technique combines the exquisite sensitivity of conventional PCR technology with the precise cellular localization afforded by ISH. In addition, it allows for an accurate quantitative determination of the number of virally infected cells.

Three corneoscleral discs (from two donors) underwent subtotal endothelial loss during routine "long-term" organ culture storage. Laboratory studies of these corneas revealed evidence of herpes simplex virus (HSV) infection. The fellow cornea from one of the donors had been issued for transplant to a patient with keratoconus. Deterioration of the graft was noted 5 days after surgery; the disc was removed at 2 months and was shown to be infected with HSV. In an experiment designed to simulate initial "cleansing" of donor globes, 0.1% polyvinylpyrolidone-iodine protected cells from infection with HSV. It was concluded that the detection of HSV in these corneas could not be explained by external contamination of the ocular surface. Furthermore, culture of conjunctival and pharangeal swabs taken from 47 consecutive donors confirmed that HSV is rarely isolated at or around the time of death. Five pairs of donor corneas destined for use in transplantation were selected at random and investigated for the presence of HSV. HSV DNA was detected by polymerase chain reaction (PCR) in tissue from two of the corneal donors. Sequential stepwise sectioning suggested that HSV DNA when present was distributed in discrete foci within the cornea. These observations suggest that HSV infection may be a cause of severe endothelial loss during corneal organ culture and possibly provide an explanation for some "failures" of corneal grafting.