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Background: Herpes simplex virus (HSV) keratitis remains a leading infectious cause of blindness worldwide. Although all forms of HSV keratitis are commonly recurrent, the risk is greatest in stromal keratitis, which is the most likely to result in corneal scarring, thinning, and neovascularization. Recent studies showed the ability of Optical Coherence Tomography Angiography (OCTA) to detect and study vascular abnormalities in the anterior segment, including abnormal corneal vessels. This study intends to investigate the potential of OCTA device to image and describe quantitatively the vascularization in eyes diagnosed with herpetic leucoma and to discuss and review the usefulness of this technique in this pathology., Methods: A Cross-sectional study was made, including 17 eyes of 15 patients with leucoma secondary to herpetic keratitis. All eyes underwent anterior segment Slit-Lamp photography (SLP), and OCTA with en-face, b-scans and c-scans imaging. The vessel density (VD) was analyzed in the inferior, nasal and temporal corneal margin in all patients, and in the central area, in eyes with central corneal neovascularization (CoNV). The measurements were calculated after binarization with ImageJ software, using OCTA scans with 6 × 6 mm in a depth of 800 μm., Results: Patients included had a mean age 53.267 ± 21.542 (years ± SD). The mean total vessel area was 50.907% ± 3.435%. VD was higher in the nasal quadrant (51.156% ± 4.276%) but there were no significant differences between the three analyzed areas (p = 0.940). OCTA was able to identify abnormal vessels when SLP apparently showed no abnormal vessels; OCTA was able to distinguish between larger and smaller vessels even in central cornea; OCTA scans allowed the investigation of several corneal planes and the relation of them with clinical findings., Conclusions: OCTA can be useful in both qualitative and quantitative follow-up of patients and may become a non-invasive alternative to objectively monitor treatment response in eyes with corneal vascularization due to herpetic infection., (© 2022. The Author(s).)

Background/objectives: To describe the predisposing factors, pathogens and outcomes in patients with clinical presumed concomitant microbial and herpes simplex keratitis (HSK) at Sydney Eye Hospital, Australia over a 5-year period., Subjects/methods: A retrospective case review was conducted. Patients with clinical presumed concomitant microbial and HSK from 2012 to 2016 were identified from pathology and hospital coding databases. Data were extracted from the medical records. VA was converted to the logarithm of the minimum angle of resolution (logMAR). 'Poor' outcome was defined as final VA worse than 6/60, or decrease in VA during treatment, or presence of complication, or needed surgical intervention., Results: 126 episodes in 121 patients were included; median age 70 years (range 18-96); 56% male. Predisposing factors included blepharitis 20/126 (16%) cases, and corneal transplantation 19 (15%). Forty-six (37%) cases had prior HSK. Coagulase-negative staphylococci 51/116 (44%), Staphylococcus aureus 11 (9%), and Pseudomonas aeruginosa 11 (9%) were the most common isolates. The median VA at initial visit was 1.7 logMAR (range 0.04-2.7) and at final visit, 0.98 logMAR (range 0-2.7) (P < 0.05). Complications occurred in 70 episodes: persistent epithelial defect in 38 (30%); intraocular pressure elevation in 15 (12%), and corneal perforation in 12 (10%). 'Poor' outcome was recorded in 46/75 (61%) episodes., Conclusions: Patients with clinical presumed concomitant microbial and HSK face significant ocular morbidity and poor visual outcome. In our setting, previous HSK, corneal and ocular surface disease, were common predisposing factors and Gram-positive bacteria were the most commonly associated organisms., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

To investigate the acute clinical, immunological, and corneal nerve changes following corneal HSV-1 KOS-63 strain inoculation. Corneas of C57BL/6 mice were inoculated with either low dose (Ld) or high dose (Hd) HSV-1 KOS-63 or culture medium. Clinical evaluation was conducted up to 7 days post inoculation (dpi). Viral titers were assessed by standard plaque assay. Excised corneas were stained for CD45 and beta-III tubulin. Corneal flow cytometry was performed to assess changes in leukocyte subpopulations. Corneal sensation was measured using a Cochet-Bonnet esthesiometer. Naïve, sham-infected (post scarification), and McKrae-infected C57BL/6 corneas served as two negative and positive controls, respectively. Compared to Ld infected mice, Hd HSV-1 KOS-63 demonstrated higher incidence of corneal opacity (1.5 ×) and neovascularization (2.6 × ; p < 0.05). At 7 dpi Hd infected mice showed more severe corneal opacity (2.23 vs. 0.87; p = 0.0003), neovascularization (6.00 vs. 0.75; p < 0.0001), and blepharitis (3.11 vs. 2.06; p = 0.001) compared to the Ld group. At 3 dpi epitheliopathy was significantly larger in the Hd group (23.59% vs. 3.44%; p = 0.001). Similarly, corneal opacity was significantly higher in Hd McKrae-infected corneas as compared with Ld McKrae-infected corneas at 3 and 5 dpi. No significant corneal opacity, neovascularization, blepharitis, and epitheliopathy were observed in naïve or sham-infected mice. Higher viral titers were detected in corneas (1 and 3 dpi) and trigeminal ganglia (TG) (3 and 5 dpi) in Hd versus Ld KOS-63 groups (p < 0.05). Leukocyte density showed a gradual increase over time from 1 to 7 dpi in both KOS-63 and McKrae-infected corneas. Corneal flow cytometric analysis (3 dpi) demonstrated a higher percentage of Gr-1 + (71.6 vs. 26.3) and CD11b + (90.6 vs. 41.1) cells in Hd versus Ld KOS-63 groups. Corneal nerve density significantly decreased in both Hd KOS-63 and Hd McKrae infected corneas in comparison with naïve and sham-infected corneas. At 3 dpi corneal nerve density was lower in the Hd versus Ld KOS-63 groups (16.79 vs. 57.41 mm/mm2; p = 0.004). Corneal sensation decreased accordingly at 5 and 7 dpi in both Ld and Hd KOS-63-infected mice. Corneal inoculation with HSV-1 KOS-63 strain shows acute keratitis and nerve degeneration in a dose-dependent fashion, demonstrating virulence of this strain.

Purpose: The purpose of this study is to examine the expression of tenascin-C and matrilin-2 in three different disorders, which frequently require corneal transplantation. These pathological conditions include bullous keratopathy (BK), Fuchs' endothelial corneal dystrophy (FECD), and corneal scarring in herpetic keratitis., Methods: Histological sections of corneal buttons removed during keratoplasty were analyzed in BK (n = 20), FECD (n = 9), herpetic keratitis (n = 12), and cadaveric control (n = 10) groups with light microscopy following chromogenic immunohistochemistry. The sections were evaluated by three investigators, and semiquantitative scoring (0 to 3+) was applied according to standardized methods at 400X magnification. Each layer of the cornea was investigated; moreover, the stroma was subdivided into subepithelial, middle, and pre-Descemet's membrane areas for more detailed analysis., Results: Excessive epithelial and stromal expression of tenascin-C was identified in all investigated conditions; the results were most pronounced in the pre-Descemet's membrane. Regarding matrilin-2, when examined in BK, there was increased labeling intensity in the epithelium (p<0.001) and stromal layers (p<0.05), and a decrease in the endothelium (p<0.001). In the other investigated conditions, only a low degree of stromal localization (p<0.05) of matrilin-2 was detected., Conclusions: The expression of tenascin-C and matrilin-2 differs when examined in various corneal pathologies resulting in opacification. Both molecules seem to be involved in regeneration and wound healing of the corneal matrix in these diseases., (Copyright © 2021 Molecular Vision.)

Background/objectives: The aim of this study was to identify risk factors, prognosis, and management in patients with concomitant herpetic keratitis and acute retinal necrosis (ARN)., Subjects/methods: In this retrospective observational series, ARN patients in the Greater Vancouver area from 2004 to 2018 were identified through key words, billing codes, and dispensing data from medical records of affiliate researchers and the pharmacy at Vancouver General Hospital., Results: Twenty-eight patients were diagnosed with ARN during this period. Five of those were also diagnosed with herpetic keratitis. Thus, the incidence of combined keratitis and ARN was 18% of patients with ARN. The two diseases occurred concomitantly in four out of five patients. Mean age at diagnosis was 55 ± 17 years. Of the five patients with both corneal and retinal involvement, three patients were immunocompromised and three had a history of herpetic diseases. Three developed disciform keratitis and two developed stromal immune keratitis. Clinical management and outcomes of these patients did not differ from patients with ARN alone, except for a lower rate of retinal detachment (p = 0.006) and a higher proportion with visual acuity ≥ 20/200 (p = 0.01)., Conclusions: Keratitis may complicate the clinical picture of one out of five to six patients with ARN. Comprehensive ophthalmic examination, including careful anterior segment exams in patients with ARN and sequential dilated fundus exams in patients with herpetic keratitis, should always be conducted to identify cases of concomitant disease.

Purpose: Corneal opacity and neovascularization (NV) are often described as outcomes of severe herpes simplex virus type 1 (HSV-1) infection. The current study investigated the role of colony-stimulating factor 1 receptor (CSF1R)+ cells and soluble factors in the progression of HSV-1-induced corneal NV and opacity., Methods: MaFIA mice were infected with 500 plaque-forming units of HSV-1 in the cornea following scarification. From day 10 to day 13 post-infection (pi), mice were treated with 40 µg/day of AP20187 (macrophage ablation) or vehicle intraperitoneally. For osteopontin (OPN) neutralization experiments, C57BL/6 mice were infected as above and treated with 2 µg of goat anti-mouse OPN or isotypic control IgG subconjunctivally every 2 days from day 4 to day 12 pi. Mice were euthanized on day 14 pi, and tissue was processed for immunohistochemistry to quantify NV and opacity by confocal microscopy and absorbance or detection of pro- and anti-angiogenic and inflammatory factors and cells by suspension array analysis and flow cytometry, respectively., Results: In the absence of CSF1R+ cells, HSV-1-induced blood and lymphatic vessel growth was muted. These results correlated with a loss in fibroblast growth factor type 2 (FGF-2) and an increase in OPN expression in the infected cornea. However, a reduction in OPN expression in mice did not alter corneal NV but significantly reduced opacity., Conclusions: Our data suggest that CSF1R+ cell depletion results in a significant reduction in HSV-1-induced corneal NV that correlates with the loss of FGF-2 expression. A reduction in OPN expression was aligned with a significant drop in opacity associated with reduced corneal collagen disruption.

Whether complement dysregulation directly contributes to the pathogenesis of peripheral nervous system diseases, including sensory neuropathies, is unclear. We addressed this important question in a mouse model of ocular HSV-1 infection, where sensory nerve damage is a common clinical problem. Through genetic and pharmacologic targeting, we uncovered a central role for C3 in sensory nerve damage at the morphological and functional levels. Interestingly, CD4 T cells were central in facilitating this complement-mediated damage. This same C3/CD4 T cell axis triggered corneal sensory nerve damage in a mouse model of ocular graft-versus-host disease (GVHD). However, this was not the case in a T-dependent allergic eye disease (AED) model, suggesting that this inflammatory neuroimmune pathology is specific to certain disease etiologies. Collectively, these findings uncover a central role for complement in CD4 T cell-dependent corneal nerve damage in multiple disease settings and indicate the possibility for complement-targeted therapeutics to mitigate sensory neuropathies., Competing Interests: DR, JE, LL, GG, RM, DS, VP, DC No competing interests declared, (© 2019, Royer et al.)

Background and objectives: The purpose of this study was to describe corneal sensitivity and the morphological changes of sub-basal corneal nerves using in vivo laser scanning confocal microscopy (LSCM) in herpes simplex virus (HSV) keratitis-affected eyes, and to compare with both contralateral eyes and with the eyes of patients with a previous history of herpes labialis but no history of herpetic eye disease, and with healthy patients with no history of any HSV diseases, during the acute phase of the disease and after six months. Materials and Methods: A prospective clinical study included 269 patients. All of them underwent a complete ophthalmological examination, Cochet-Bonnet aesthesiometry and LSCM within the central 5 mm of the cornea. After six months, all the patients with herpetic eye disease underwent the same examination. Serology tests of the serum to detect HSV 1/2 IgG and IgM were performed. Results: HSV-affected eyes compared with contralateral eyes, herpes labialis and healthy control group eyes demonstrated a significant decrease in corneal sensitivity, corneal nerve fibre density, corneal nerve branch density, corneal nerve fibre length and corneal nerve total branch density ( p < 0.05). During follow up after six months, corneal sensitivity and sub-basal nerve parameters had increased but did not reach the parameters of contralateral eyes ( p < 0.05). Previous herpes labialis did not influence corneal sensitivity and was not a risk factor for herpetic eye disease. Conclusions: Corneal sensitivity and sub-basal nerve changes in HSV-affected eyes revealed a significant decrease compared with contralateral eyes, and with the eyes of patients with a previous history of herpes labialis, and of healthy controls. Following six months, corneal sensitivity and sub-basal nerve parameters increased; however, they did not reach the parameters of contralateral eyes and the eyes of healthy controls. The best recovery of corneal sensitivity was seen in patients with epithelial keratitis. Herpes labialis was not a risk factor for herpetic eye disease., Competing Interests: The authors declare that they have no competing interests.

Rationale: To report a case of herpes simplex virus (HSV) linear endotheliitis in a 57-year-old male who had underwent keratoplasty 10 years ago. The characteristic linear keratic precipitates (KPs) resembled the Khodadoust line in graft rejection. The differential diagnosis is essential, because the treatment regimen is different between HSV linear endotheliitis and graft rejection., Patient Concerns: The patient developed a sudden onset of ocular pain and a decrease in visual acuity in his right eye. The patient had received penetrating keratoplasty in the eye 10 years ago., Diagnoses: The ocular disease was evaluated using several ocular examinations, including best-corrected visual acuity (BCVA), intraocular pressure, slit lamp examination, fundus examination, and aqueous humor tap. Characteristic linear endothelial KPs were found both in the host cornea and graft cornea. Stromal edema was evident in both the donor and recipient corneas. The aqueous humor was sampled for viral polymerase chain reaction (PCR) analysis. The sample was investigated for the possible presence of HSV I, HSV II, cytomegalovirus, and varicella zoster virus. The PCR was positive for HSV I and negative for HSV II, cytomegalovirus, and varicella zoster virus., Interventions: The patient was treated with both antiviral and steroid treatments for 1 month. Thereafter, prophylactic antiviral treatment was continued., Outcomes: The subjective symptoms had improved and the cornea edema and the linear endothelial KPs had disappeared. The BCVA improved from 20/200 to 20/80., Lessons: HSV linear endotheliitis is the most severe form of HSV endotheliitis. This case showed characteristic endothelial KPs, which were different from the Khodadoust line of graft rejection.

Background: Herpes uveitis has been previously reported to present with hyphema, but hemorrhagic hypopyon is rarely reported as a herpetic uveitis manifestation. We report a case of herpes simplex virus (HSV) presenting with hemorrhagic hypopyon, and speculate on the underlying pathophysiology with relation to an intravascular lymphoma which was subsequently diagnosed as a result., Case Presentation: We present a case wherein a 62-year-old Japanese rheumatoid arthritis woman, with HSV uveitis, presented with hemorrhagic hypopyon in the anterior chamber and a fever with photophobia. Patient was treated with antiviral drugs which improved the hyphema and corneal lesions, but lesions recurred 3 months later. This rare presentation of HSV induced uveitis, and its subsequent recurrence, aroused suspicion of an additional hypopyon-inducing pathology. On account of previous history of lung opacities and elevated LDH, intravascular lymphoma was eventually diagnosed via lung biopsy. She was treated for the lymphoma which also completely resolved all ocular symptoms without any recurrence as of 1.5 years later., Conclusion: The exceedingly rare presentation of hemorrhagic hypopyon may have been enabled by an interaction of the HSV with the intravascular lymphoma. HSV involvement was indicated by the dendritic lesions, IgG assay, and response to anti-viral drugs. The ocular involvement of the intravascular lymphoma seems to be indicated by virtue of the anti-tumor drugs completely resolving all ocular symptoms.

Background: Microsporidial stromal keratitis poses several diagnostic challenges. Patients may present with corneal ulceration, marked stromal thinning, or even as a quite corneal scar. The presentation of microsporidial stromal keratitis commonly mimics viral keratitis. Microbiology scrapings are usually helpful; however, scraping and culture-negative cases pose a significant diagnostic dilemma. Histopathological examination is diagnostic but shows varying degree of inflammation, predominantly composed of polymorphonuclear leukocytes. Granulomatous inflammation, in microsporidial stromal keratitis, is never well described, and the authors in this article aim to describe the presence of granulomatous inflammation in microsporidial stromal keratitis, in patients with associated herpes simplex virus (HSV) keratitis., Methods: This was a retrospective and observational study conducted at a tertiary eye care center., Results: Of 263 patients who underwent therapeutic penetrating keratoplasty for infectious keratitis, during 2011-2013, seven patients were diagnosed as microsporidial stromal keratitis. Microsporidial spores could be demonstrated on microbiological scrapings in 5/7 (71%) of cases, but identified on histopathological examination and also confirmed on polymerase chain reaction (PCR) for microsporidium in 100% of cases. There was evidence of diffuse stromal necrosis with markedly severe degree of polymorphonuclear leukocytic infiltrates, with granulomatous inflammation in 42% of cases. Interestingly, these were positive for HSV-1 DNA on PCR. Review of medical records revealed much severe clinical presentations in patients with granulomatous inflammation, in comparison to cases without granulomatous inflammation., Conclusions: The authors hereby recommend that severe clinical presentation in patients with microsporidial stromal keratitis, markedly dense polymorphonuclear leukocytic infiltrates or the presence of granulomatous inflammation on the histopathological examination, should be investigated further for the presence of HSV-1 DNA for better patient management and good visual outcome.

Purpose: Most of the inflammation in murine herpes simplex virus type 1 (HSV-1)-induced stromal keratitis (HSK) is due to exposure stress resulting from loss of corneal nerves and blink reflex. Corneal grafts often fail when placed on corneal beds with a history of HSK. We asked if corneal exposure contributes to the severe pathology of corneal grafts on HSV-1-infected corneal beds., Methods: Herpes simplex virus type 1-infected corneas were tested for blink reflex. Opacity and vascularization were monitored in allogeneic and syngeneic corneal grafts that were transplanted to corneal beds with no blink reflex or to those that retained blink reflex in at least one quadrant following infection., Results: Retention of any level of blink reflex significantly reduced inflammation in HSV-1-infected corneas. Corneal allografts placed on HSV-1-infected beds lacking corneal blink reflex developed opacity faster and more frequently than those placed on infected beds that partially or completely retained blink reflex. Corneal grafts placed on infected corneal beds with no blink reflex rapidly became opaque to a level that would be considered rejection. However, protecting these grafts from exposure by tarsorrhaphy prevented or reversed the opacity in both syngeneic and allogenic grafts., Conclusions: Exposure due to HSV-1-engendered hypoesthesia causes rapid, severe, persistent, but reversible opacification of both allogeneic and syngeneic corneal grafts. This opacity should not be interpreted as immunologic rejection. Exposure stress may contribute to the high rate of corneal graft pathology in patients with recurrent HSK.

Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis characterized by decreased corneal sensation because of damage to the corneal sensory fibers. We and others have reported regression of corneal nerves during acute HSV-1 infection. To determine whether denervation is caused directly by the virus or indirectly by the elicited immune response, mice were infected with HSV-1 and topically treated with dexamethasone (DEX) or control eye drops. Corneal sensitivity was measured using a Cochet-Bonnet esthesiometer and nerve network structure via immunohistochemistry. Corneas were assessed for viral content by plaque assay, leukocyte influx by flow cytometry, and content of chemokines and inflammatory cytokines by suspension array. DEX significantly preserved corneal nerve structure and sensitivity on infection. DEX reduced myeloid and T-cell populations in the cornea and did not affect viral contents at 4 and 8 days post infection. The elevated protein contents of chemokines and inflammatory cytokines on infection were greatly suppressed by DEX. Subconjunctival delivery of neutralizing antibody against IL-6 to infected mice resulted in partial preservation of corneal nerve structure and sensitivity. Our study supports a role for the immune response, but not local virus replication in the development of HSV-1-induced neurotrophic keratitis. IL-6 is one of the factors produced by the elicited inflammatory response to HSV-1 infection contributing to nerve regression., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Ocular Baylisascaris procyonis infection results from ingestion of infective eggs of B. procyonis, the raccoon ascarid. Herpes simplex virus type 2 (HSV-2) infection of the retina is the result of either primary infection or reactivated disease. Herein, we report a case of a 12-year-old female resident of the Bronx in New York City, who presented with pan-uveitis and vision loss. Initial evaluation for etiologic causes was nondiagnostic. Serology for anti-Baylisascaris procyonis antibodies in serum and vitreous fluid were both positive. Polymerase chain reaction (PCR) of vitreous fluid was positive for HSV-2. Treatment with vitrectomy, albendazole, and acyclovir resulted in mild improvement of visual acuity. The atypical presentation of B. procyonis in this case, as ocular larva migrans with a peripheral granuloma and retinal detachment, underscores the importance of maintaining a high degree of suspicion for this pathogen even in non-diffuse unilateral subacute neuroretinitis (DUSN) patients in urban areas. This case further illustrates that it is possible to have coexisting infections in cases of posterior uveitis., (© The American Society of Tropical Medicine and Hygiene.)

Unlabelled: Acquired immune deficiency syndrome (AIDS) is associated with a wide spectrum of systemic and ocular infectious diseases. Little information is known about Herpes Simplex Virus type 1 (HSV-1) keratoconjunctivitis in association with AIDS. Because HSV-1 is becoming, day by day, a common eye disease (nearly 100% patients of over 60 years old harbor HSV in their trigeminal ganglia at autopsy), this article discussing a worldwide public health problem., Aim: The purpose of this paper is to compare the incidence and clinical aspects of HSV-1 Keratitis in HIV/ AIDS patients compared with the general population who develops HSV- 1 Keratitis., Method: The study is retrospective and comparative. Each patient was examined thoroughly at the biomicroscope ocular slit after corneal staining with fluorescein or rose bengal. Visual acuity, intraocular pressure and corneal sensitivity were also examined., Results: From 170 patients with HIV and ocular anterior segment disorders, 47 patients had viral etiology. 58 patients had keratitis; 14 of them were HSV-1 keratitis., Conclusion: Doctors should be aware of the existence of the ocular damage in HIV/ AIDS and emphasize the importance of regular ophthalmologic examination of patients with HIV/ AIDS as HSV infection is common nowadays among the general population.

A 20-year-old man presented with a recurrent episode of herpetic keratouveitis in his right eye. The patient was treated with oral acyclovir and topical steroids. One week later the patient reported a sudden diminution of vision. Slitlamp biomicroscopy revealed the presence of a central anterior capsular defect and anterior subcapsular cataract. Dosage of steroids was temporarily increased and progression of cataract monitored. Subsequently, the anterior chamber reaction decreased and steroids were tapered., (2014 BMJ Publishing Group Ltd.)

We present the case of a 42-year-old man with AIDS who had lost complete vision of his left eye for the past 15 days. MRI and brightness scan ultrasonography were performed on his eyes that suggested of endophthalmitis with dendritic involvement in the left eye. Viral DNA PCR was performed in aqueous humour sample that confirmed the presence of herpes simplex virus and showed a negative result for cytomegalovirus. The patient was treated with a high dose of oral acyclovir for 10 days and long-term topical acyclovir. Neodymium-doped yttrium aluminum garnet procedure was performed to clear up the cornea, and intraocular pressure was controlled with brimonidine and timolol maleate. The patient was diagnosed to have disseminated tuberculosis (tuberculoma of the brain) and was started with antituberculosis therapy. His condition improved significantly after the treatment, and keratitis in cornea started to clean up.

Objective: To explore the clinical safety and efficacy of deep lamellar keratoplasty for corneal macula after viral keratitis., Methods: A total of 16 patients (16 eyes) of corneal macula after viral keratitis at our center from January 2009 to June 2011 received anti-virus eye-drops and then underwent deep lamellar keratoplasty when inflammation were dissolved or quiescent. And the corneal graft diaphaneity and corneal graft rejection reactions were observed., Results: All 16 patients were recovered with a success rate of 100%. After a follow-up of 18-24 months, all corneal grafts were transparent and best-corrected visual acuity was 0.2-0.6. There was no reoccurrence during the follow-up period. After a follow-up of several months, 2 of them had rejection reaction and were controlled after treatment. No rejection reaction occurred during the long-term follow-up., Conclusion: As a safe and efficacious procedure, deep lamellar keratoplasty can significantly raise vision acuity with few complications.

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MicroRNAs (miRNAs) are small regulatory molecules that control diverse biological processes that include angiogenesis. Herpes simplex virus (HSV) causes a chronic immuno-inflammatory response in the eye that may result in corneal neovascularization during blinding immunopathological lesion stromal keratitis (SK). miR-132 is a highly conserved miRNA that is induced in endothelial cells in response to growth factors, such as vascular endothelial growth factor (VEGF). In this study, we show that miR-132 expression was up-regulated (10- to 20-fold) after ocular infection with HSV, an event that involved the production of both VEGF-A and IL-17. Consequently, blockade of VEGF-A activity using soluble VEGF receptor 1 resulted in significantly lower levels of corneal miR-132 after HSV infection. In addition, low levels of corneal miR-132 were detected in IL-17 receptor knockout mice after HSV infection. In vivo silencing of miR-132 by the provision of anti-miR-132 (antagomir-132) nanoparticles to HSV-infected mice led to reduced corneal neovascularization and diminished SK lesions. The anti-angiogenic effect of antagomir-132 was reflected by a reduction in angiogenic Ras activity in corneal CD31-enriched cells (presumably blood vessel endothelial cells) during SK. To our knowledge, this is one of the first reports of miRNA involvement in an infectious ocular disease. Manipulating miRNA expression holds promise as a therapeutic approach to control an ocular lesion that is an important cause of human blindness., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

When the cornea of the eye dissolves, most commonly secondary to infection or trauma, the ventral wall of the anterior chamber of the eye is no longer supported and thus bulges forward, enlarging the anterior chamber volume. This is referred to as a corneal melt, and it has a unique CT appearance that has not been previously described.

Innate immune deficiencies result in a spectrum of severe clinical outcomes following infection. In particular, there is a strong association between loss of the signal transducer and activator of transcription (Stat) pathway, breach of the blood-brain barrier (BBB), and virus-induced neuropathology. The gene signatures that characterize resistance, disease, and mortality in the virus-infected nervous system have not been defined. Herpes simplex virus type 1 (HSV-1) is commonly associated with encephalitis in humans, and humans and mice lacking Stat1 display increased susceptibility to HSV central nervous system (CNS) infections. In this study, two HSV-1 strains were used, KOS (wild type [WT]), and Δvhs, an avirulent recombinant lacking the virion host shutoff (vhs) function. In addition, two mouse strains were used: strain 129 (control) and a Stat1-deficient (Stat1(-/-)) strain. Using combinations of these virus and mouse strains, we established a model of infection resulting in three different outcomes: viral clearance without neurological disease (Δvhs infection of control mice), neurological disease followed by viral clearance (Δvhs infection of Stat1(-/-) mice and WT infection of control mice), or neurological disease followed by death (WT infection of Stat1(-/-) mice). Through the use of functional genomics on the infected brain stems, we determined gene signatures that were representative of the three infection outcomes. We demonstrated a pathological signature in the brain stem of Stat1-deficient mice characterized by upregulation of transcripts encoding chemokine receptors, inflammatory markers, neutrophil chemoattractants, leukocyte adhesion proteins, and matrix metalloproteases. Additionally, there was a greater than 100-fold increase in the inflammatory markers interleukin 1β (IL-1β) and IL-6. Consistent with this gene signature, we demonstrated profound CNS inflammation with a concomitant lethal breach of the BBB. Taken together, our results indicated an essential role for normal Stat1-dependent signaling in mediating a nonpathological immune response to viral CNS infection.

Purpose: To assess the relative impact of elevated T-helper 2 (T(H)2)- and reduced T-Helper 1 (T(H)1)-dependent immune responses on ocular herpes simplex virus type 1 (HSV-1) infection., Methods: Signal transducer and activator of transcription protein 4 knockout mice (BALB/c-STAT4(-/-)) and wild-type BALB/c control mice were immunized with avirulent HSV-1 strain KOS or were mock-immunized. Three weeks after the third immunization, neutralizing antibody titers were determined by plaque reduction assays. Following ocular infection with virulent HSV-1 strain McKrae, viral replication in the eye, blepharitis, corneal scarring (CS), survival, and immunoglobulin (Ig) isotypes in sera were determined., Results: Vaccinated STAT4(-/-) and BALB/c mice contained significant and similar neutralizing antibody titers and were completely protected against HSV-1-induced death and CS. In contrast to vaccinated STAT4(-/-) mice, mock-vaccinated STAT4(-/-) mice had higher ocular HSV-1 titers than mock-vaccinated BALB/c mice on days 2-3 post-ocular infection. There were also significant differences in the levels of IgG2a, IgG2b, and IgG3 in the sera of STAT4(-/-) mice when compared to the control BALB/c mice., Conclusions: These results suggest that the absence of T(H)1 cytokine responses did alter protection against viral replication and IgG isotypes but not eye disease or survival.

Complications in urinary tract nervous routes due to herpes viruses as VZV and HSV-2 are well known. Acute urinary retention and chronic neuropathic pain are not rare when sacral dermatomes are involved by these viruses. However, an analogous condition has not yet been clearly ascribed to HSV-1 infection. We present a 32-year-old immunocompetent patient with fever, lumbar pain and acute urinary retention who had never had herpetic clinical manifestations. Urodynamic studies diagnosed a neurologic bladder with an absent filling sensation. Cystoscopic assessment revealed the presence of reddened and isolated small mucosal areas in the bladder walls. The search for herpes viruses in plasma and CSF by PCR assay were positive for HSV-1. After treatment with antiviral therapy the disease resolved. Intermittent catheterization was necessary and voiding dysfunction resolved after three weeks by its appearance. Neurological damage to the central nervous system (CNS) and/or PNS due to HSV-1 seems to be the most likely reason. The course of disease was benign and self-remitting.

Aim: To determine the incidence, methods of diagnosis, treatment strategies and outcomes for acute retinal necrosis (ARN) in the UK., Methods: A 12-month active case ascertainment study was carried out between March 2001 and March 2002 to record cases of ARN presenting to ophthalmologists via the British Ophthalmological Surveillance Unit (BOSU) reporting system. Questionnaires were sent to the reporting consultants, requesting data on patient characteristics, presentation, clinical findings, investigations and treatment. Diagnosis was made using the American Uveitis Society diagnostic criteria. Further questionnaires were sent at 2 weeks and 6 months to assess outcome and therapies., Results: 74 cases of ARN were reported by 58 consultants between March 2001 and March 2002. Questionnaires were returned for 49 cases (66.2%), of which 18 (36.7%) were excluded. Of the 31 cases included, 22 (71.0%) were male and 9 (29.0%) were female. The age range was 13 to 85 years (mean 54.3 years). 28 cases (90.3%) were unilateral, with 3 patients (9.7%) presenting with bilateral ARN. An aqueous or vitreous biopsy was performed in only 18 patients, with one patient having both. Herpes viral DNA analysis was performed on all 19 biopsies, with identification of the viral DNA in 16; results from 3 biopsies were not documented. Varicella zoster virus (VZV) was the commonest cause identified in 10 patients (56%). Of the 31 subjects, 27 (87.1%) were treated for ARN with systemic antiviral treatment: with intravenous antiviral in 23 cases (85.2%) and oral antiviral in 4 cases (14.8%). 21 of these patients went on to receive oral antiviral maintenance therapy. In addition to antiviral treatment, systemic steroids were given to 16 subjects (51.6%). Surgical intervention for retinal detachment was performed on 5 patients., Conclusions: During the 12-month study period, 31 cases of ARN met the diagnostic criteria set by the American Uveitis Society. The incidence in the UK based on this study is approximately 1 case per 1.6 to 2.0 million population per year. We have ascertained that the management of ARN throughout the UK is variable, suggesting that national guidelines would be of benefit.

A 76-year-old man presented with features of bilateral herpes simplex virus (HSV) keratitis. It was found to be recurrence of bilateral HSV keratitis following the use of Bimatoprost eye drops for uncontrolled intraocular pressure in a case of bilateral primary open-angle glaucoma.

Purpose: To record the natural history of herpes simplex keratitis and estimate visual impairment in eyes of patients diagnosed with herpes simplex keratitis., Materials: This was a retrospective, descriptive case study for five years of the eyes of patients with clinically diagnosed herpes simplex keratitis. These patients had presented to the cornea services and a cornea specialist carried out the ocular examination under slit-lamp magnification. The medical records were reviewed by the authors. Visual acuity at presentation and clinical details on examination were recorded and, diagnosis of the stage of disease given in the case record was noted. Statistical analysis was done using chi-square-test and Fisher exact test., Results: Of a total of 212 patients (220 eyes), there were 144 males and 68 females; 118 eyes presented with stromal lesions, 44 eyes with epithelial lesions, 39 eyes with epithelial and stromal lesions and 19 eyes with endothelitis. The improvement in visual acuity to more than 20/40 in the four clinical groups was 23 out of 44 eyes with epithelial lesion (52.27%), 83 out of the 118 eyes with stromal lesions (70.33%), 23 out of 39 eyes with epithelial and stromal lesions (58.97%) and 8 out of the 19 eyes with endothelitis (42.10%). The mean improvement in visual acuity was 3.44 lines (SD +/- 4.06)., Conclusion: Most patients had mild disease. The majority of the patients attained the final visual acuity of 6/12 or better in the affected eye. Thus, there was only a temporary visual morbidity with fairly good functional visual outcome in majority of the patients.

The last decade has seen herpes simplex virus (HSV)-induced stromal keratitis (SK) research shift from being a topic only of interest to vision researchers to one that fascinates the general field of inflammatory disease. Studies on experimental mouse lesions have uncovered several fundamental processes that explain lesion development. In this model, the chronic immuno-inflammatory lesions are mainly orchestrated by CD4+ T cells, but multiple early events occur that set the stage for the subsequent pathology. These include virus replication, the production of key cytokines and chemokines, neovascularization of the avascular cornea and the influx of certain inflammatory cell types. Many of these early events are subject to modulation, providing an approach to controlling this important cause of human blindness. We also comment on events ongoing during chronic SK, debating whether or not these represent virus-induced or autoimmune lesions.

Ocular neovascularization often results in vision impairment. Frequently vascular endothelial cell growth factors (VEGFs) are mainly responsible for the pathological neovascularization as in the case in neovascularization induced by CpG oligodeoxynucleotides and herpes simplex virus infection in this report. siRNAs targeting either VEGFA, VEGFR1, VEGFR2, or a mix of the three were shown to significantly inhibit neovascularization induced by CpG when given locally or systemically. The efficacy of systemic administration was facilitated by the use of a polymer delivery vehicle. Additional experiments showed a significant inhibitory effect of the siRNAs mix when given either locally or systemically in vehicle against herpes simplex virus-induced angiogenesis as well as against lesions of stromal keratitis. These results indicate that the use of VEGF pathway-specific siRNAs represents a useful therapy against neovascularization-related eye diseases.

We have studied the susceptibility to Herpes Simplex Virus Type 1 (HSV-1) infection in malnourished rats. Groups of 10 rats were undernourished during suckling by offspring duplication. The animals were put on commercial diet and at 1, 2, 3, 5 and 8 weeks after weaning, infected in the eye by scarification with HSV-1, strain F. Significant differences in morbidity and mortality were observed between malnourished and control groups infected three weeks after weaning. Viral titres were higher in ocular washings and brains obtained from the malnourished group. This group showed a diminution in antigen dependent lymphocyte proliferation compared to control, and significantly lower delayed type hypersensitivity reaction against inactivated virus (malnourished = 0.16 +/- 0.02 mm, control = 0.26 +/- 0.03 mm, p < 0.05). Neutralizing antibodies in serum were lower in the malnourished group and lower levels of interferon were obtained in the malnourished group 24 h post-infection. We conclude that malnutrition during suckling induces a delay in the capability to overcome HSV infection.

This report analyzes the role of vascular endothelial growth factor (VEGF)-induced angiogenesis in the immunoinflammatory lesion stromal keratitis induced by ocular infection with herpes simplex virus (HSV). Our results show that infection with replication-competent, but not mutant, viruses results in the expression of VEGF mRNA and protein in the cornea. This a rapid event, with VEGF mRNA detectable by 12 h postinfection (p.i.) and proteins detectable by 24 h p.i. VEGF production occurred both in the virus-infected corneal epithelium and in the underlying stroma, in which viral antigens were undetectable. In the stroma, VEGF was produced by inflammatory cells; these initially were predominantly polymorphonuclear leukocytes (PMN), but at later time points both PMN and macrophage-like cells were VEGF producers. In the epithelium, the major site of VEGF-expressing cells in early infection, the infected cells themselves were usually negative for VEGF. Similarly, in vitro infection studies indicated that the cells which produced VEGF were not those which expressed virus. Attesting to the possible role of VEGF-induced angiogenesis in the pathogenesis of herpetic stromal keratitis were experiments showing that VEGF inhibition with mFlt(1-3)-immunoglobulin G diminished angiogenesis and the severity of lesions after HSV infection. These observations are the first to evaluate VEGF-induced angiogenesis in the pathogenesis of stromal keratitis. Our results indicate that the control of angiogenesis represents a useful adjunct to therapy of herpetic ocular disease, an important cause of human blindness.

Fungi belonging to the genus Acremonium Link ex Fries 1821 are ubiquitous environmental contaminants and soil saprophytes, but are infrequent pathogens in humans. These filamentous fungi (previously known as Cephalosporium) are an uncommon cause of mycotic keratitis. As in the case of other filamentous fungi, corneal trauma with contaminated matter is the most frequent risk factor for the infection. We report in this paper a case of keratomycosis caused by Acremoniumpotronii, in a patient with a history of herpetic keratitis. Medical treatment with amphotericin B was unsuccessful and the infection eventually resolved with penetrating keratoplasty.

Chronic infection of the cornea by Herpes simplex virus (HSV) continues to be an important cause of unilateral blindness. Despite considerable progress in the understanding of the virus at cellular and molecular levels, the prospect of prevention still appears to be long way off. The development of non-toxic topical antiviral agents has been an important step forward in management. However, correct diagnosis and treatment, in particular, the avoidance of inappropriate use of topical steroid remains as important as ever. This article reviews the virological and clinical aspects of HSV keratitis including the current concepts of pathogenesis and management.

Background: Acyclovir (ACV) ophthalmic ointment is effective in the treatment of herpetic keratitis. However, when applied, the ointment has an unpleasant feeling and some cases are resistant to ACV. A new antiviral compound, carbocyclic oxetanocin G (C.OXT-G) has potent anti-herpes simplex virus activity and high water solubility, so the clinical effect of C.OXT-G eyedrops on ulcerative herpetic keratitis was evaluated., Methods: Studies were conducted on the corneal ulcers in 37 eyes of 27 patients. Patients with typical dendritic or geographic corneal ulcers were treated with 0.1% C.OXT-G eyedrops, applied five times a day, together with eyedrops of an antibiotic applied four times a day. The eyes were examined at least twice a week until the ulcers healed, and thereafter at intervals for up to 3 months., Results: All of the ulcers healed, their average healing time being 4.9 (SD 2.2) (range 2 to 9) days. The ulcers in 20 of the 37 eyes were induced by the use of corticosteroid or immunosuppressive drugs, and their average healing time was 4.8 (2.3) days. No adverse drug reactions were seen during the observation period in this trial., Conclusion: Eyedrops containing 0.1% C.OXT-G are excellent and safe for treatment of herpes simplex corneal ulcers in humans.

Ophthalmic findings are reported in 31 eyes of 28 children with herpes simplex keratitis. Twenty two had dendritic ulcers, and nine had geographic ulcers or disciform stromal keratitis. After resolution of keratitis, 80% (19/22) of children with dendritic ulcers achieved corrected visual acuity of 6/9 or better, 50% (11/22) had induced astigmatism, 45% (9/22) had one to five recurrences. In the group with geographic or disciform lesions, 89% (8/9) had reduced corrected vision, 78% (7/9) had induced astigmatism which was predominantly against the rule, and 87% (7/9) had one to six recurrences.

Corneal neovascularization, which is associated with complications in corneal diseases, can cause lipid deposit, decreasing vision, and graft rejection after penetrating keratoplasty (PKP). Corneal laser photocoagulation using an argon laser or yellow dye laser for ablation of corneal neovascularization has been described. We performed corneal argon laser photocoagulation (CALP) in two male patients with corneal neovascularization after herpetic keratitis. One PKP was performed after CALP and restored good vision with no rejection of the graft during an 8 month follow-up period. In the other case we observed visual improvement and no recurrence of corneal neovascularization after CALP.

Of 103 patients who presented to a rural clinic in Africa with corneal ulceration, 62 (60.2%) had corneal ulcers which on clinical diagnosis were attributable to herpes simplex virus. There was a strong association between herpetic ulceration and a history of recent malaria; 37 of 62 (59.7%) herpetic ulcers occurred in the 3 month period from April to June which corresponds to the end of the peak season for malaria compared with 14 of 41 (34%) of the non-herpetic ulcers. Fifty per cent of herpetic ulcers had a geographic morphology, 27.4% were dendritic, and 22.6% presumed herpetic ulcers were stromal: 38.7% of herpetic ulcers occurred in children under 5 years of age. Bilateral herpetic ulcers occurred in 16.1% of patients but were more common in children under 2 years of age. Geographic and stromal ulcers tended to heal more slowly than dendritic ulcers (mean time to healing 12.6, 12.2, and 6.6 days respectively), and were more likely to result in severe corneal scarring (45%, 29%, and 0% respectively). Herpes simplex keratitis is a major cause of corneal scarring in Africa. It is often seen in children, may be bilateral, commonly is geographic in morphology, and has a strong association with malaria infection. Because it is not easily preventable, more effort must be made to ensure early diagnosis and prompt, effective treatment in order to prevent severe scarring and visual loss.