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PURPOSE To report the clinical outcome and postoperative course of Descemet membrane endothelial keratoplasty (DMEK) in irreversible corneal edema due to herpes simplex virus (HSV) endotheliitis. METHODS This is a retrospective, noncomparative, interventional case series. Nineteen eyes of 19 patients underwent standard DMEK combined with cataract surgery (triple DMEK) between May 2016 and April 2018. All patients received perioperative oral acyclovir (ACV) and prednisolone. Patients were followed up on day 1, on day 7, at 1 month, and then at 3 monthly intervals. Preoperative and postoperative best spectacle-corrected visual acuity (BSCVA), graft clarity, pachymetry, and endothelial cell loss after 1 year were recorded. Postoperative complications and HSV recurrence were noted until the last follow-up visit. RESULTS All eyes were phakic with variable grades of cataract with a preoperative BSCVA of 1.0 logarithm of the minimum angle of resolution or worse. The mean follow-up period was 19.3 ± 5.4 months. After 1 year, 14 (73.7%) eyes achieved a BSCVA of 0.3 or better. Seventeen (89.5%) patients had a clear graft at the last visit without any rejection episode. One graft failed after 16 months. After 3 months, the mean pachymetry reduced from 667.1 ± 62.1 to 512.8 ± 27.1 μm (P < 0.001). The mean endothelial cell loss after 1 year was 36.7 ± 13.4%. Three (15.8%) eyes had recurrence: one with recurrent endotheliitis and 2 with dendritic keratitis despite oral ACV, which responded to oral valacyclovir and ACV eye ointment. One patient had re-recurrence of endotheliitis after 20 months. CONCLUSIONS DMEK in persistent corneal edema after HSV endotheliitis remains challenging but has encouraging outcomes. The postoperative course may be complicated by HSV recurrence. Prophylactic oral antivirals for 1 year or more and topical antivirals are useful for the prevention of recurrence.

PURPOSE To report an atypical presentation of herpes simplex virus (HSV) keratitis followed up using expression levels of HSV DNA in tears. METHODS A 22-year-old Japanese woman with hyperemia and foreign body sensation in her left eye was diagnosed with atypical dendritic keratitis. A slit-lamp examination at presentation indicated the presence of a rush of dendritic lesions with a sparse branching pattern and poor development of terminal bulbs; follicular conjunctivitis was also observed. Positivity for house-dust-mite- and cedar pollen-specific IgE antibodies in her serum indicated atopic diathesis. The HSV DNA levels in her tears were measured by a real-time polymerase chain reaction. RESULTS At the initial visit, the HSV DNA levels in tears were 6.4 × 10 copies/sample in the right eye and 1.6 × 10 copies/sample in the left eye. The keratitis improved after treatment with topical acyclovir ointment, 5 times a day for 7 days, and systemic valacyclovir 1000 mg/d for 5 days. Multiple punctate subepithelial opacities developed in her left eye on day 7, with undetectable HSV DNA in tears, bilaterally. CONCLUSIONS We have successfully monitored the HSV DNA levels in tears using quantitative real-time polymerase chain reaction in HSV keratitis where the corneal findings progressed from atypical dendritic keratitis to multiple punctate corneal subepithelial opacities during the treatment period.

Herpes simplex virus (HSV) can present as a variety of ocular diseases. Keratitis, including epithelial and stromal, is a leading cause of infectious corneal blindness, particularly in developed countries. Most humans are infected with HSV-1 in early childhood and maintain latent infection throughout their lifetime. While majority remain asymptomatic, some can reactivate and also experience recurrences. Recent epidemiological studies show that the incidence and prevalence of ocular HSV are on the rise. This chapter reviews the clinical disease, traditional and evolving medical and surgical therapeutic options, and future directions in prevention strategies, including development of vaccination.

Purpose: To report the outcome of self-retained amniotic membrane after debridement in recurrent dendritic keratitis. Observations: A 70-year-old female with a recurrent dendritic corneal ulcer received debridement followed by placement of self-retained amniotic membrane. Five days after treatment, the patient experienced a complete resolution of symptoms, marked reduction of inflammation, complete re-epithelialization of the cornea and improvement of visual acuity. The corneal surface remained stable for 18 months despite noncompliance in using antiviral therapy. Conclusions and importance: Self-retained amniotic membrane after debridement appears effective in treating dendritic keratitis. While early debridement is crucial to remove the infected corneal epithelium, amniotic membrane was shown to enhance the healing without scarring or recurrence. Besides the known anti-inflammatory and anti-scarring effects of the amniotic membrane, it may have a potential topical antiviral effect that warrants further investigation.

Objective: Bacterial keratitis occurs worldwide, and despite recent developments, it remains a potentially blinding condition. This study assesses the presence of herpes simplex virus (HSV-1 and -2) and varicella zoster virus (VZV) by quantitative real-time polymerase chain reaction (qPCR) in corneal scrapings from patients with bacterial keratitis. Methods: A total of 65 patients with clinical diagnoses of infectious corneal ulcers prospectively underwent clinical eye examinations. Corneal scrapings were investigated by Gram staining, Giemsa staining, culture, and qPCR (the study group). Risk factors and epidemiological data were recorded. The control group comprising 25 eyes with typical herpes dendritic keratitis was also analyzed by qPCR. Results: From the study group (n=65), nine patients (13.8%) had negative smears, cultures, and qPCR findings. Fifty-six (86.2%) patients had positive cultures: 51 for bacteria, 4 for fungi, and 1 for amoebae. Of the patients who had positive bacterial cultures, qPCR identified 10 patients who were also positive for virus: one for VZV and nine for HSV-1. Of the 25 patients in the control group, 21 tested positive for HSV-1 by qPCR analysis. Conclusions: Herpes may be present in patients with bacterial corneal ulcers, and qPCR may be useful in its detection. RESUMO Objetivo: Ceratites bacterianas ocorrem mundialmente e apesar dos novos desenvolvimentos permanece como uma condição que pode levar à cegueira. Avaliar a presença de herpes simples (-1 e -2) e vírus varicella zoster (VZV) por reação em cadeia quantitativa de polimerase em tempo real (qPCR) em raspados corneanos de pacientes com ceratite bacteriana. Métodos: Sessenta e cinco pacientes com ceratite infecciosa foram submetidos a raspados corneanos estudados para gram, Giemsa, cultura e qPCR (grupo de estudo). Foram avaliados fatores de risco e epidemiológicos. O grupo controle foi composto por 25 casos de úlcera dendrítica típica por herpes analisados por qPCR. Resultados: Do grupo de estudo (n=65), nove pacientes (13,8%) apresentaram cultura, qPCR e raspado negativos. Cinquenta e seis (86,2%) pacientes apresentaram cultura positiva, 51 para bacteria, 4 para fungo e 1 para ameba. A qPCR identificou 10 pacientes do grupo de cultura positiva para bactéria que também foram positivos para vírus, um VZV e 9 para HSV-1. Dos 25 pacientes que compunham o grupo controle, 21 apresentaram qPCR positivo para HSV-1. Conclusão: Herpes pode estar presente em pacientes com úlceras de córnea bacterianas e a qPCR pode ser útil na sua detecção.

Purpose: Herpes simplex is a common cause of visual disability, and there are published evidence-based guidelines for therapy. This survey aims to determine the preferred practice patterns of ophthalmologists in Gulf Coast Countries regarding herpetic eye disease, as well as identify areas of controversy or barriers to acceptance of evidence-based protocols. Methods: Anonymous web-based survey of ophthalmologists in Saudi Arabia, Bahrain, the United Arab Emirates, and Oman. Results: There were 48 responses to the survey. For a first episode of epithelial dendritic keratitis, 28.2% reported “observation” rather than specific therapy. The majority of respondents utilize oral or topical antiviral for epithelial keratitis, with oral antiviral being the most popular (43.6%). The majority also included a corticosteroid with antiviral for stromal keratitis (83.9%) or iritis (70.3%). Over 90% prescribe a prophylactic antiviral after keratoplasty for herpetic eye disease, although the length of therapy ranged widely from

Fourty-three eyes with active dendritic keratitis, nearly one third of which had failed to respond to other antiviral agents, were treated with acyclovir with or without preceding debridement. The patients were randomly selected. No statistical difference could be demonstrated between the 2 groups in terms of rate of healing or in efficacy of cure. Acyclovir also seemed to be effective in stromal corneal lesions. There were only minor side effects.

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.

Immunology and Microbiology A Herpes Simplex Virus Type 1 Human Asymptomatic CD8 þ T-Cell Epitopes-Based Vaccine Protects Against Ocular Herpes in a ‘‘Humanized’’ HLA Transgenic Rabbit Model Ruchi Srivastava, 1 Arif A. Khan, 1 Jiawei Huang, 1 Anthony B. Nesburn, 1 Steven L. Wechsler, 1–3 and Lbachir BenMohamed 1,4,5 1 Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, California, United States Department of Microbiology and Molecular Genetics, University of California Irvine, School of Medicine, Irvine, California, United States 3 Center for Virus Research, University of California Irvine, Irvine, California, United States Department of Molecular Biology & Biochemistry Institute for Immunology, University of California Irvine, School of Medicine, Irvine, California, United States Correspondence: Lbachir BenMo- hamed, Laboratory of Cellular and Molecular Immunology, Gavin Her- bert Eye Institute; Ophthalmology Research Laboratories, Hewitt Hall, Room 2032, 843 Health Sciences Road, Irvine, CA 92697-4390, USA; Lbenmoha@uci.edu. RS and AAK contributed equally to the work presented here and should therefore be regarded as equivalent authors. Submitted: April 10, 2015 Accepted: May 23, 2015 Citation: Srivastava R, Khan AA, Huang J, Nesburn AB, Wechsler SL, BenMohamed L. A herpes simplex virus type 1 human asymptomatic CD8 þ T-cell epitopes-based vaccine protects against ocular herpes in a ‘‘humanized’’ HLA transgenic rabbit model. Invest Ophthalmol Vis Sci. 2015;56:4013–4028. DOI:10.1167/ iovs.15-17074 P URPOSE . A clinical vaccine that protects from ocular herpes simplex virus type 1 (HSV-1) infection and disease still is lacking. In the present study, preclinical vaccine trials of nine asymptomatic (ASYMP) peptides, selected from HSV-1 glycoproteins B (gB), and tegument proteins VP11/12 and VP13/14, were performed in the ‘‘humanized’’ HLA–transgenic rabbit (HLA-Tg rabbit) model of ocular herpes. We recently reported that these peptides are highly recognized by CD8 þ T cells from ‘‘naturally’’ protected HSV-1–seropositive healthy ASYMP individuals (who have never had clinical herpes disease). M ETHODS . Mixtures of three ASYMP CD8 þ T-cell peptides derived from either HSV-1 gB, VP11/ 12, or VP13/14 were delivered subcutaneously to different groups of HLA-Tg rabbits (n ¼ 10) in incomplete Freund’s adjuvant, twice at 15-day intervals. The frequency and function of HSV-1 epitope-specific CD8 þ T cells induced by these peptides and their protective efficacy, in terms of survival, virus replication in the eye, and ocular herpetic disease were assessed after an ocular challenge with HSV-1 (strain McKrae). R ESULTS . All mixtures elicited strong and polyfunctional IFN-c– and TNF-a–producing CD107 þ CD8 þ cytotoxic T cells, associated with a significant reduction in death, ocular herpes infection, and disease (P < 0.015). C ONCLUSIONS . The results of this preclinical trial support the screening strategy used to select the HSV-1 ASYMP CD8 þ T-cell epitopes, emphasize their valuable immunogenic and protective efficacy against ocular herpes, and provide a prototype vaccine formulation that may be highly efficacious for preventing ocular herpes in humans. Keywords: HSV-1, HLA transgenic rabbit, animal model, T cell, glycoprotein B, VP11/12, VP13/14, vaccine, ocular ith a staggering one billion individuals worldwide currently carrying herpes simplex virus type 1 (HSV-1), herpes remains one of the most prevalent viral infections of the eye. 1–7 Ocular herpes infection causes a spectrum of clinical manifestations ranging from blepharitis, conjunctivitis, and dendritic keratitis to disciform stromal edema and blinding stromal keratitis (HSK). 8,9 In the United States alone, over 450,000 people have a history of recurrent ocular HSV requiring doctor visits, antiviral drug treatments, and, in severe cases, corneal transplants. 10–12 Despite the availability of many intervention strategies, the global picture for ocular herpes continues to deteriorate. 13 Current antiviral drug therapies (e.g., acyclovir and derivatives) do not eliminate the virus and reduce recurrent herpetic disease by only approximately 45%. 14 The development of an effective vaccine would present an unparalleled alternative to antiviral drugs, as it would be a powerful and cost-effective means to reduce HSV-1 ocular infection and lessen associated blinding ocular herpetic disease (reviewed previously 1 ). Our long-term goal is to develop a vaccine to prevent HSV-1 infection and protect against ocular herpes disease. The most recent vaccine clinical trials that used recombinant HSV proteins failed to protect despite inducing strong HSV-specific neutralizing antibodies. These failures emphasize three major gaps in knowledge: the need to induce strong T-cell responses (in addition to humoral responses) for protection against ocular herpes, 15 the need to identify protective human herpes T-cell epitopes from HSV antigens (Ags) to be incorporated in the next generation HSV vaccines, 15 and the preclinical evaluation of protective efficacy of human herpes T-cell epitopes in a reliable animal model of ocular herpes infection and disease. One ‘‘common denominator’’ among previously failed vaccine clinical trials is that they either used the whole virus or whole HSV proteins (e.g., HSV glycoprotein B and/or D [gB Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc. iovs.arvojournals.org j ISSN: 1552-5783 W

Background This objective of the review and analysis is to demonstrate that acyclovir (ACV) 3% ophthalmic ointment is superior to idoxuridine (IDU) in treating herpetic keratitis (HK) presenting as dendritic and geographic ulcer sub-types. Methods Data sources: Publications in human subjects were identified by searching the Ovid MEDLINE database through April 2011, combining medical subject headings (MESH) “Keratitis, Herpetic/” AND “Acyclovir/” limiting by the key words “topical” OR “ointment” and also restricted to MESH “Administration, Topical/” OR “Ointments/”. The results were cross checked with the references used in the Cochrane Database Syst Rev. 1:1–134, 2009 and GlaxoSmithKline clinical documents related to acyclovir. Study selection: Randomized, double-masked studies in subjects diagnosed with HK with head to head comparator arms of ACV ophthalmic ointment and topical IDU that had actual or calculable healing rates at Day seven. Data extraction: Data independently extracted from identified articles by two authors of this manuscript. Data synthesis: Data from seven randomized, controlled trials (RCT) evaluating 432 subjects that met inclusion criteria (214 were treated with ACV and 218 were treated with IDU) and had Day seven healing rates calculable. All sub-classified lesions were identified as either dendritic ulcers (n = 185) or geographic ulcers (n = 35). The Cochran-Mantel-Haenszel (CMH) method in Biometrics 10:417-51, 1954 and JNCI 22:719-48, 1959, controlling for study, was performed as the primary analysis using SAS v9. Homogeneity was assessed using Breslow-Day-Tarone (BDT) test in IARC 1:1-32, 1980 and Biometrika 72:91-5, 1985. The analysis was performed with outliers removed to assess their impact. Results ACV showed statistically significant greater odds of healing HK at Day seven in all subjects (Odds Ratio 3.95, 95% CI2.60, 6.00, p

Die in Europa haufige Keratitis herpetischer Genese wird meist durch das Herpes-simplex-Virus Typ I (HSV) verursacht und ist in seiner Auspragung ein Chamaleon. Sie kann i. d. R. erfolgreich behandelt werden, wenn man die verschiedenen, typischerweise einseitigen Auspragungsformen dieser Krankheit kennt: 1. epitheliale Keratitis (dendritica/geographica), 2. stromale Keratitis (nekrotisierend vs. nicht nekrotisierend = „interstitiell“), 3. Endotheliitis (= „disziforme Keratitis“), 4. sog. „metaherpetische Keratitis“ (= neurotrophe Keratopathie), 5. (vaskularisierte) Hornhautnarben. Das Therapieschema wird bewusst auf die Auspragungsform abstimmt. Eine begleitende okulare Hypertension sollte im Akutstadium vornehmlich medikamentos behandelt werden (auf Prostaglandinanaloga verzichten!). Nach Keratoplastik und bei haufigen schweren Keratitisschuben ist die systemische Aciclovir-Applikation (2 × 400 mg/Tag) fur mindestens 1 Jahr aktueller Standard!

A 69-year-old man presented to his general ophthalmologist for cataract surgery, reporting blurry vision in the left eye that had been present for approximately 2 years.Hewas found tohavean irregular corneal surface in the left eye.His ocular history includesa corneal abrasion 5 months before presentation, although he stated that his vision was bothersome before the abrasion. His medical history includes gastrointestinal reflux disease, hearing loss, and seasonal allergies but is otherwise negative. He has no known drug allergies. Medications included acetylsalicylic acid 81 mg each day. His family ocular history is negative, and he does not take ocular medications. He drinks alcohol on occasion and denied tobacco and recreational drug use. On initial presentation, the patient’s uncorrected distance visual acuity (UDVA) was 20/40 in the right eye and 20/150 in the left eye. The UDVA in the left eye improved to 20/100 with manifest refraction. On examination, mild blepharitis was noted in both eyes and the left cornea had pinpoints of epithelial infiltrates and a large dendritic pattern of irregular epithelium extending 6.0 mm from the superior cornea inferiorly that stained with fluorescein.Noscarsor evidenceof a corneal abrasion were seen, and mild anterior subcapsular cataract was seen in both eyes. The patient was treated for chronic herpes dendritic keratitis with valacyclovir (Valtrex)2 timesaday for 1week,ganciclovir ophthalmicgel (Zirgan) 5 times a day for 1 week and then 3 times a day for 1moreweek, and preservative-free artificial tears as needed until the next assigned appointment. One week later, the patient’s UDVA in the left eye had improved to 20/100 and examination of the cornea showed the same dendritic pattern, which was slightly fainter than at the previous examination. The patient was started on prednisolone acetate (Omnipred) 4 times a day and advised to continue the ganciclovir 3 times a day for 1 more week, preservative-free artificial tears 6 to 7 times a day, and valacyclovir once every day until told otherwise. The patient returned 2 weeks later reporting continued blurry vision in the left eye and a constant foreign-body sensation. The UDVA in the left eye had improved to 20/60, the cornea showed superficial epithelial infiltrates and superficial punctate keratopathy with the same staining pattern as before, and the superior limbus showed confluent superficial punctate keratopathy. A lid examination with the lid everted showed papillae. The patient was advised to continue taking prednisolone acetate 1.0% and valacyclovir.

Objective: To describe a case of keratomycosis caused by Arthrographis kalrae, mimicking Acanthamoeba keratitis. Methods: Case report. Results: A 23-year-old female contact lens wearer developed dendritic keratitis in heramblyopic eye (OD). Baseline vision was 20/50. Treatment with trifluridine 1% resulted in resolution of the dendrite, but an area of stromal haze developed, spreading to a discontinuous ring shape, and the vision dropped to 20/200. Photophobia was intense, and pain was out of proportion to the examination. Cultures were sent, and empiric treatment of Acanthamoeba was begun, without subsequent improvement. After 4 weeks, cultures were positive for a fungal species. Amphotericin 0.5% drops were begun, with moderately rapid resolution of the active keratitis. At last follow-up, best-corrected vision was 20/100. Review of the culture showed the organism to be Arthrographis kalrae. Conclusion: Arthrographis kalrae has been reported only once before as an ocular pathogen. As in the previously reported case of Arthrographis, our patient's presentation was strongly suggestive of Acanthamoeba keratitis.

Herpetic keratitis is manifested in various corneal disorders, for example, dendritic keratitis, persistent epithelial defect, disciform keratitis, and endotheliitis. In this paper, we report on the quantity of herpes simplex virus (HSV) genome in tears from patients with various types of herpetic keratitis in an attempt to understand the role of HSV in these conditions.We collected tear samples from both eyes of 56 consecutive patients with herpetic keratitis who visited Kinki University Hospital between June 2000 and May 2002. All patients had unilateral herpetic keratitis: epithelial keratitis in 27 eyes; persistent epithelial defect in 6; active disciform stromal keratitis in 14; silent stromal keratitis in 6; and endotheliitis in 3. We measured levels of HSV genome in these tear samples using a real-time polymerase chain reaction (PCR) method.In epithelial keratitis, HSV DNA was detected in all 27 samples from affected eyes (6.4 +/- 4.4 x 10(5) copies/sample). In persistent epithelial defect, HSV DNA was detected in all 6 samples from affected eyes (8.5 +/- 3.3 x 10(4) copies/sample). In active disciform stromal keratitis, HSV DNA was detected in 8 of the 14 affected eyes (1.4 +/- 1.1 x 10(5) copies/sample including zero values in negative samples). HSV DNA was not detected in samples from unaffected eyes or eyes affected by silent stromal keratitis or endotheliitis.Real-time PCR is a useful method for quantifying HSV DNA in tear samples from patients with herpetic keratitis. Using this method, we demonstrate that HSV reproduction occurs in persistent epithelial defect and disciform stromal keratitis.

Background Viral infections of Herpes origin are the most commonly encountered ones in man. The most important member of this family is the Herpes simplex virus (HSV), two varieties of which are known to exist: HSV-1 affects predominantly the upper half of the body, whereas HSV-2 is associated mainly with diseases of the urogenital tract. In the immunocompetent host, viral replication is usually confined to cutaneous and mucocutaneous sites, invasion of subcutaneous tissues being impeded by an early onset of non-specific defence mechanisms. These are rapidly complemented by the specific, mainly cellular, immune response. Patients Epithelial dendritic keratitis is the first symptomatic clinical finding, and after several recurrences, the corneal stroma may become involved. This condition of herpetic stromal keratitis (HSK), which, in contrast to the epithelial one, is believed to be directed by a predominantly immunopathological process, is one of the leading causes of infectious blindness in developed countries. Results The mechanisms underlying HSK, and the establishment of viral latency and reactivation are poorly understood. But on the basis of studies with mice as well as clinical immunohistological observations, evidence is now accumulating in support of a cell-mediated mechanism being responsible for corneal destruction. Conclusion Our present knowledge of the pathogenesis of herpetic keratitis is incomplete. The different pathophysiological aspects reflecting our current understanding, such as that of a virally induced autoimmune disease, form the basis of accepted clinical treatment concepts.

Human herpesviruses can infect the eye and be excreted subsequently in tears. The aim of the present study was to use a multiplex PCR to detect herpesviruses (HSV-1, -2, VZV, CMV, EBV, HHV-6) in tears from normal subjects and from patients with pathological conditions (acute herpes, zoster, papillary conjunctivitis, and dry eye). Schirmer test strips were used to collect tear fluid from 93 patients, sampling both eyes. DNA was then extracted from the 186 samples by chromatography, and viral DNA amplified using a commercialised multiplex “stair primer” method. Thirty-four samples (18.3%) contained Taq inhibitors. The multiplex test gave positive results for HSV and VZV in tear fluid from patients with acute dendritic keratitis (3 patients) and acute ocular zoster (4 patients) and was, therefore, considered effective in testing samples from patients with acute lesions. HSV-1 and HSV-2 were found in two samples from patients with metaherpetic corneal scarring. Among 28 cases of dry eye, two were positive for HHV-6, the latter being associated with EBV in one patient. HHV-6 was also found in 4 out of 54 cases of papillary conjunctivitis. This raised occurrence of HHV-6 in dry eye or papillary conjunctivitis, suggests new clinical patterns for HHV-6 latency or reactivation. Detection of EBV in 1 out of 80 healthy eyes confirms previous evidence that lacrimal glands constitute potentially a site for latent-phase EBV. J. Med. Virol. 66:506–511, 2002. © 2002 Wiley-Liss, Inc.

Twenty patients with dendritic keratitis were treated in a double-blind analysis study with either phosphonoformate 3% or trifluorthymidine 1% drops. Nineteen cases were virologically confirmed. Follow-up was performed until closure of the corneal lesion was registered and a pair comparison between both substances was made. Healing time was longer for phosphonoformate (7.16 days) than for trifluorthymidine (5.83 days). There was no significant difference between phosphonoformate and trifluorthymidine. One drug failure was registered in each series. No side effects were observed.

To investigate the role of cytokines in the pathogenesis of acute herpetic keratitis (HK), we examined the kinetics of cytokine expression in the corneas and the trigeminal ganglia (TG) of C57BL/6Cr (B6) mice after herpes simplex virus type 1 (HSV-1) infection and observed the influence of the targeted disruption of interferon-gamma (IFN-gamma) gene on the clinical course of HK and/or viral clearance. Following corneal infection with HSV-1 Amakata strain, all corneas developed a typical dendritic keratitis. Quantitative analysis using enzyme-linked immunosorbent assay (ELISA) revealed that the expression of interleukin-1alpha (IL-1alpha), IL-5, IL-6, and IFN-gamma in corneas and TGs significantly elevated immediately after infection, peaked between days 2 and 7 postinfection (p.i.), and then diminished. One exception was IFN-gamma, whose expression significantly persisted in the TGs until day 30 p.i. An additional experiment using IFN-gamma-/- (gko) mice revealed that there was no significant difference in the peak level of viral replication in corneas and TGs between gko and B6 mice, although gko mice showed a significant delay of virus clearance in both corneas and TGs (p < 0.005) and higher mortality rate than B6 mice after HSV-1 infection (p < 0.01). These data suggest that the production of proinflammatory cytokines closely correlates with the pathogenesis of HK, and that IFN-gamma plays an important role in enhancing viral clearance from the cornea and TG.

Purpose To investigate the role of excimer laser keratectomy as a trigger for the reactivation of latent HSV type 1 (HSV-1) in the New Zealand rabbit ocular model. There are conflicting reports in the current literature about reactivation of HSV-1 after excimer laser photoablation. Methods New Zealand rabbits were inoculated topically with HSV-1 McKrae or W strain in each eye, and culture-positive dendritic keratitis was documented on day 7. After the establishment of latency (21+ days), animals were divided into three groups: group I animals underwent excimer laser photoablation in each eye; group II animals received intrastromal injections of sterile water to act as positive controls (a standard method); and group III animals received no treatment and represented spontaneous shedders. All eyes were swabbed daily from days 1 through 10 and plated on A549 cells. Recovery of HSV-1 on days 1 through 10 postinduction was analyzed to compare the efficiency of the different methods of viral reactivation. Results Reactivation of latent HSV-1 after excimer treatment was observed in nine (45%) of 20 eyes and was equivalent to the rate of reactivation seen in the positive control animals (eight [44.4%] of 18 eyes) (P =.99). Both of these rates were significantly greater than those of the untreated animals (one [5.6%] of 18 eyes) (P =.018). Conclusion Excimer laser keratectomy appears to be an efficient trigger for the reactivation of latent HSV-1 in the New Zealand rabbit ocular model.

Reverse transcription polymerase chain reaction (RT-PCR) was applied in the detection of herpes simplex virus-1 (HSV-1) mRNA from tear film and corneal epithelium in a murine herpetic keratitis model. The diagnostic value of this new technique for acute herpetic keratitis was evaluated in comparison with direct PCR for genomic DNA and viral culture. On day 2 postinfection (PI) of HSV, all mice showed dendritic keratitis, and PCR, RT-PCR, and viral culture were positive in all samples. On day 8 PI, no dendritic keratitis was observed in any mouse, PCR was positive in all samples, while RT-PCR was positive in only 5 of 12 samples and viral culture in only 2 of 12. The sensitivity of RT-PCR was lower than that of PCR, and approximately the same as viral culture; however, the findings of RT-PCR more closely concurred with clinical observations than the findings of PCR. These results show the potential of RT-PCR for rapid, specific diagnosis of acute herpetic keratitis.

To determine the efficacy of a new helicase-primase inhibitor, ASP2151, for treating herpetic keratitis.Murine corneas were infected with herpes simplex virus type 1 (HSV-1). ASP2151 was administered orally or topically, and the severity of epithelial dendritic keratitis was determined. The effectiveness of ASP2151 was compared with that of acyclovir and valacyclovir. The reduction of the amount of HSV in tears, enucleated eyes and trigeminal ganglia was determined by real-time PCR or plaque assay.Orally administered ASP2151 reduced the epithelial keratitis score significantly more than that of the vehicle-treated group (p0.01). It also lowered the HSV-DNA levels in the tears significantly more than that by valacyclovir (p0.01). ASP2151 ointment resulted in the same reduction of the keratitis score as acyclovir ointment, and lowered the HSV DNA in tears more than acyclovir ointment. Topical instillation of ASP2151 improved the herpetic dendritic keratitis score significantly and reduced the titre of HSV DNA in the tears in a dose-responsive way.ASP2151 had significantly better anti-HSV activity against herpes simplex keratitis than valacyclovir and acyclovir after systemic or topical use. These findings indicate that ASP2151 should be considered as an alternative treatment for herpes simplex keratitis.

9-(4-Hydroxybutyl)- N 2 -phenylguanine (HBPG) is a new viral thymidine kinase inhibitor that we tested for the ability to prevent recurrences of herpetic keratitis. Eighteen squirrel monkeys ( Saimiri scuireus ) were infected in both corneas with the Rodanus strain of herpes simplex virus type 1 (HSV-1). All corneas showed typical dendritic keratitis 3 days after infection, followed by spontaneous healing. On day 21, the monkeys were randomized into two coded groups and ocular examinations were begun. One group received intraperitoneal (i.p.) injections of HBPG, 150 mg/kg, in a corn oil suspension every 8 h, and the other group received i.p. injections of the corn oil vehicle only. On day 22, recurrences were induced by reducing the temperature of the room in the late afternoon so that a low of 18°C was achieved during the night. After the morning treatment, room temperature was raised to the normal ambient temperature (24–27°C), and treatment was discontinued. Treatment was reinstituted on day 27, the room temperature was lowered again on day 28, and treatment was again discontinued as before. Third and fourth cycles of treatment and cold stress were begun on days 34 and 69. Ocular examinations were continued until day 73, at which point the code was broken. We found that the HBPG treatment significantly reduced the number of corneas with recurrences during the treatment periods, compared with recurrences in untreated, cold-stressed animals ( P =0.01).

Caso clínico: Varón de 62 años de edad con trasplante renal y tratamiento inmunosupresor que acude por disminución de la visión (20/100) en ojo izquierdo, edema corneal y presión intraocular de 46mmHg. Un mes después aparece queratitis dendrítica marginal inferior. El raspado corneal y la proteína C reactiva demuestran la presencia de un virus del herpes simple (HVS). Discusión: La epiteliopatía corneal autoinmunitaria o endotelitis idiopática corneal se caracteriza por edema corneal y precipitados queráticos. Se cree que el HVS podría ser secretado desde el trabeculum, inervado por el nervio trigémino, apoyado clínicamente por la progresión del edema estromal desde la periferia. Case report: A 62-year-old man with previous renal transplant and immunosuppressive treatment presented with decreased visual acuity (20/100) in his left eye, corneal oedema and intraocular pressure of 46mmHg. One month later an inferior marginal dendritic keratitis appeared. Corneal scraping and real-time polymerase chain reaction showed herpes simplex virus (HSV). Discussion: The autoimmune corneal endotheliopathy or acute idiopathic corneal endotheliitis is characterised by corneal stromal oedema and keratic precipitates. HSV might be secreted from the trabeculum, innervated by the trigeminal nerve. This hypothesis is supported by the clinical observation that the corneal stromal oedema usually starts from the periphery.