Herpetic Eye Disease Study: A Controlled Trial of Topical Corticosteroids for Herpes Simplex Stromal Keratitis.

PURPOSE: To evaluate the efficacy of topical corticosteroids in treating herpes simplex stromal keratitis. METHODS: The authors performed a randomized, double-masked, placebo-con- trolled, multicenter clinical trial of 106 patients with active herpes simplex stromal keratitis who had not received any corticosteroids for at least 10 days before study enrollment. Patients were assigned to the placebo group (n = 49) or the steroid group (topical prednisolone phosphate; n = 57); both regimens were tapered over 10 weeks. Both groups received topical trifluridine. Visual acuity assessment and slit-lamp biomicroscopy were performed weekly for 10 weeks, every other week for an additional 6 weeks or until removal from the trial, and at 6 months after randomization. RESULTS: The time to treatment failure (defined by specific criteria as persistent or progressive stromal keratouveitis or an adverse event) was significantly longer in the steroid group compared with the placebo group. Compared with placebo, corticosteroid therapy reduced the risk of persistent or progressive stromal keratouveitis by 68%. The time from randomization to resolution of stromal keratitis and uveitis was significantly shorter in the steroid group compared with the placebo group even though both groups included patients who were removed from the study and treated with topical corticosteroids according to best medical judgment. Nineteen (33%) of the steroid-treated patients and 11 (22%) of the placebo-treated patients completed the 10 weeks of protocol therapy and had stable, noninflamed corneas after 16 weeks. At 6 months after randomization, no clinically or statistically significant differences in visual outcome or recurrent herpetic eye disease were identified between the steroid and placebo groups. CONCLUSIONS: The topical corticosteroid regimen used in this study was significantly better than placebo in reducing persistence or progression of stromal inflammation and in shortening the duration of herpes simplex stromal keratitis. Postponing steroids during careful observation for a few weeks delayed resolution of stromal keratitis but had no detrimental effect as assessed by visual outcome at 6 months.

Trends in fungal keratitis in the United States, 2001 to 2007.

OBJECTIVE: Fungal keratitis is a serious ocular infection that is considered to be rare among contact lens wearers. The recent Fusarium keratitis outbreak raised questions regarding the background rate of Fusarium-related keratitis and other fungal keratitis in this population. DESIGN: Retrospective, multicenter case series. PARTICIPANTS: Six hundred ninety-five cases of fungal keratitis cases who presented to 1 of 10 tertiary medical centers from 2001 to 2007. METHODS: Ten tertiary care centers in the United States performed a retrospective review of culture-positive fungal keratitis cases at their centers between January 2001 and December 2007. Cases were identified using microbiology, pathology, and/or confocal microscopy records. Information was collected on contact lens status, method of diagnosis, and organism(s) identified. The quarterly number of cases by contact lens status was calculated and Poisson regression was used to evaluate presence of trends. The Johns Hopkins Medicine Institutional Review Board (IRB) and the IRBs at each participating center approved the research. MAIN OUTCOME MEASURES: Quarterly number of fungal keratitis cases and fungal species. RESULTS: We identified 695 fungal keratitis cases; 283 involved the use of contact lenses. The quarterly number of Fusarium cases increased among contact lens wearers (CLWs) during the period that ReNu with MoistureLoc (Bausch & Lomb, Rochester, NY) was on the market, but returned to prior levels after withdrawal of the product from the market. The quarterly frequency of other filamentous fungi cases showed a statistically significant increase among CLWs comparing October 2004 through June 2006 with July 2006 through December 2007 with January 2001 through September 2004 (P < 0.0001). CONCLUSIONS: The quarterly number of Fusarium fungal keratitis cases among CLWs returned to pre-Renu with Moistureloc levels after removal of the product from the market. However, the number of other filamentous fungal keratitis cases, although small, seems to have increased among refractive CLWs. Reasons for these apparent increases are unclear.

National outbreak of Acanthamoeba keratitis associated with use of a contact lens solution, United States.

An outbreak of Acanthamoeba keratitis, a rare, potentially blinding, corneal infection, was detected in the United States in 2007; cases had been increasing since 2004. A case-control study was conducted to investigate the outbreak. We interviewed 105 case-patients from 30 states and 184 controls matched geographically and by contact lens use. Available contact lenses, cases, solutions, and corneal specimens from case-patients were cultured and tested by molecular methods. In multivariate analyses, case-patients had significantly greater odds of having used Advanced Medical Optics Complete Moisture Plus (AMOCMP) solution (odds ratio 16.9, 95% confidence interval 4.8-59.5). AMOCMP manufacturing lot information was available for 22 case-patients, but none of the lots were identical. Three unopened bottles of AMOCMP tested negative for Acanthamoeba spp. Our findings suggest that the solution was not intrinsically contaminated and that its anti-Acanthamoeba efficacy was likely insufficient. Premarket standardized testing of contact lens solutions for activity against Acanthamoeba spp. is warranted.

Glial cell-derived neurotrophic factor gene delivery enhances survival of human corneal epithelium in culture and the overexpression of GDNF in bioengineered constructs.

This paper evaluates the effects of adenoviral vector-mediated glial cell-derived neurotrophic factor (GDNF) gene delivery on survival of primary human corneal epithelial cells (PHCEC) established from limbal explants in vitro and the overexpression of GDNF gene in bioengineered human corneal constructs on substrate of corneal stromal discs followed by autograft ex vivo. In vitro, the overexpression of GDNF in the supernatant of PHCEC peaked at day 4, but lasted for at least 4 weeks after the transduction mediated by adenoviral vector. At day 10, the cell viability was 2-fold greater (P < 0.001), the number of terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL)-positive cells was more than 50% lower (P < 0.01) in the GDNF transduction group than the non-transduction group. 5 weeks after the transduction, the living cell population was greater in the GDNF transduction group than the non-transduction group (P < 0.01). In the ex vivo autograft of the bioengineered human corneal constructs, outgrowth of enhanced green fluorescent protein (eGFP) positive cells on the recipient corneoscleral tissue was observed. Overexpression of GDNF in the supernatant peaked at day 2, but was observed for at least 4 weeks after transplantation. At day 5, immunofluorescent staining showed expression of GDNF by all layers of epithelial cells on the graft. Our findings revealed that GDNF is a survival growth factor for cultured human corneal epithelium. The use of bioengineered human corneal constructs containing GDNF-transduced epithelial cells represents a novel method for delivering of this gene to promote survival of transplanted corneal epithelium to treat various corneal surface diseases.

Bilateral acanthamoeba keratitis.

PURPOSE: To determine the prevalence and characteristics of binocular involvement among patients with Acanthamoeba keratitis. DESIGN: Retrospective case series. METHODS: Risk factors and outcomes of bilateral infection were explored among consecutive cases of Acanthamoeba keratitis diagnosed at a single institution from 1997 through mid 2007. RESULTS: Fifty eyes were confirmed to have Acanthamoeba keratitis by microbiologic or histopathologic testing; two-thirds occurred during a regional outbreak beginning in 2004. Five (11%) of 45 patients had infection of both eyes, including three with concurrent involvement and two with successive disease of the contralateral cornea. Three binocularly infected patients used soft contact lenses, and two wore rigid gas-permeable lenses. Nine of 10 eyes achieved visual acuity of 20/30 or better after antiamebic therapy. CONCLUSIONS: Bilateral Acanthamoeba keratitis is an infectious complication of contact lens wear. With laboratory confirmation, vision often can be restored with medical therapy.

Patterned expression of neurotrophic factors and receptors in human limbal and corneal regions.

PURPOSE: To evaluate the expression patterns of neurotrophic factors (NTFs) and their receptors in the human cornea with the intention of exploring the role of NTFs in maintaining corneal epithelial stem cells in the limbus. METHODS: Fresh human corneoscleral tissues were prepared for frozen sections. Immunofluorescent staining was performed with primary antibodies against six members of three NTF families and their six receptors. To confirm the specificity of NTF primary antibodies, neutralization experiments with their corresponding peptides and western blot analysis were performed. RESULTS: Based on spatial and differential immuno-localization, three patterns of NTF expression were potentially involved in epithelial-mesenchymal interaction on the ocular surface: (1) the epithelial type: nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF); (2) the paracrine type: neurotrophin (NT)-3 and NT-4/5; and (3) the reciprocal type: brain-derived neurotrophic factor (BDNF). The stem cell-enriched basal cells of the limbal epithelium expressed three unique staining patterns for NTFs: (1) exclusively positive for NGF, GDNF, and their corresponding receptors, TrkA and GDNF family receptor alpha (GFRalpha)-1; (2) relatively high levels of BDNF; and (3) negative for NT-3 and NT-4. Additionally, the neurotrophin common low-affinity receptor, p75NTR, was mainly expressed by the basal layer of the entire corneal and limbal epithelia, and TrkB and TrkC were evenly expressed by the entire corneal and limbal epithelia. BDNF, p75NTR, TrkB, and TrkC are also abundantly expressed by limbal stroma cells. No specific immunoreactivity to ciliary neurotrophic factor (CNTF) and its receptor, CNTFRalpha, was detected in cornea tissue in situ. CONCLUSIONS: Our findings revealed patterned expression of NTFs and their receptors in the human ocular surface, suggesting that they may play a vital role in maintaining corneal epithelial stem cells in the limbus. NGF, GDNF, GFRalpha-1, TrkA, and BDNF may serve as new limbal basal cell markers defining the corneal epithelial stem cell phenotype.

Clinical characteristics and outcome of Candida keratitis.

PURPOSE: To characterize the clinical features and therapeutic outcome of Candida keratitis. DESIGN: Retrospective, observational case series. METHODS: We reviewed 26 patients treated for Candida keratitis, including two with recurrent keratitis and one with bilateral infection. RESULTS: Of 29 keratitis episodes resulting from Candida albicans (n = 20) or Candida parapsilosis (n = 9), 16 (55%) complicated chronic ocular surface disease, and nine (31%) followed previous keratoplasty. Only two were clinically suspected to have keratomycosis at initial presentation, and 21 (72%) used antibacterial therapy before corneal scrapings. Reconstructive keratoplasty occurred more often in previously grafted eyes (P = .03). Visual outcome was 20/60 or better in six (100%) medically treated eyes with good presenting visual acuity but in only five eyes (24%) with worse initial vision (P = .002). CONCLUSIONS: Candida keratitis is an opportunistic infection of a compromised cornea that often is misdiagnosed initially and, despite antifungal therapy, occasionally requires corneal grafting.

Adult-onset syphilitic stromal keratitis.

PURPOSE: To characterize the clinical features and therapeutic outcome of stromal keratitis associated with syphilis in adults. DESIGN: Observational case series. METHODS: We examined the clinical and laboratory records at a single center of individuals with active stromal keratitis who had serological evidence of syphilis by a treponemal specific test. RESULTS: Five patients, 36 to 81 years of age, developed stromal keratitis during late syphilis. One patient with developmental signs of congenital syphilis had bilateral stromal keratitis. The others were otherwise healthy when they presented with unilateral, nonulcerative, infiltrative keratitis with stromal edema of the peripheral or paracentral cornea and mild to moderate corneal vascularization. All had an appropriate response to topical corticosteroid therapy, and two recovered good vision. Stromal keratitis recurred in two patients months to years later. CONCLUSIONS: Nonulcerative stromal keratitis presents in adults with syphilis as marginal, central, or multifocal stromal inflammation with neovascularization that responds to corticosteroid therapy but occasionally recurs.

Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution.

CONTEXT: Fusarium keratitis is a serious corneal infection, most commonly associated with corneal injury. Beginning in March 2006, the Centers for Disease Control and Prevention received multiple reports of Fusarium keratitis among contact lens wearers. OBJECTIVE: To define the specific activities, contact lens hygiene practices, or products associated with this outbreak. DESIGN, SETTING, AND PARTICIPANTS: Epidemiological investigation of Fusarium keratitis occurring in the United States. A confirmed case was defined as keratitis with illness onset after June 1, 2005, with no history of recent ocular trauma and a corneal culture growing Fusarium species. Data were obtained by patient and ophthalmologist interviews for case patients and neighborhood-matched controls by trained personnel. Available Fusarium isolates from patients' clinical and environmental specimens were genotyped by multilocus sequence typing. Environmental sampling for Fusarium was conducted at a contact lens solution manufacturing plant. MAIN OUTCOME MEASURES: Keratitis infection with Fusarium species. RESULTS: As of June 30, 2006, we identified 164 confirmed case patients in 33 states and 1 US territory. Median age was 41 years (range, 12-83 years). Corneal transplantation was required or planned in 55 (34%). One hundred fifty-four (94%) of the confirmed case patients wore soft contact lenses. Forty-five case patients and 78 controls were included in the case-control study. Case patients were significantly more likely than controls to report using a specific contact lens solution, ReNu with MoistureLoc (69% vs 15%; odds ratio, 13.3; 95% confidence interval, 3.1-119.5). The prevalence of reported use of ReNu MultiPlus solution was similar between case patients and controls (18% vs 20%; odds ratio, 0.7; 95% confidence interval, 0.2-2.8). Fusarium was not recovered from the factory, warehouse, solution filtrate, or unopened solution bottles; production of implicated lots was not clustered in time. Among 39 isolates tested, at least 10 different Fusarium species were identified, comprising 19 unique multilocus genotypes. CONCLUSIONS: The findings from this investigation indicate that this outbreak of Fusarium keratitis was associated with use of ReNu with MoistureLoc contact lens solution. Contact lens users should not use ReNu with MoistureLoc.

Sex, Race, and the Quality of Life Factors Most Important to Patients' Well-Being Among Those Seeking Bariatric Surgery.

BACKGROUND: Evidence suggests obesity-related social stigma and impairment in work function may be the two most detrimental quality of life (QOL) factors to overall well-being among patients seeking weight loss surgery (WLS); whether the relative importance of QOL factors varies across patient sex and race/ethnicity is unclear. METHODS: We interviewed 574 patients seeking WLS at two centers. We measured patient's health utility (preference-based well-being measure) as determined via standard gamble scenarios assessing patients' willingness to risk death to achieve weight loss or perfect health. Multivariable models assessed associations between patients' utility and five weight-related QOL domains stratified by gender and race: social stigma, self-esteem, physical function, public distress (weight stigma), and work life. RESULTS: Depending on patients' sex and race/ethnicity, mean utilities ranged from 0.85 to 0.91, reflecting an average willingness to assume a 9-15 % risk of death to achieve their most desired health/weight state. After adjustment, African Americans (AAs) reported higher utility than Caucasians (+0.054, p = 0.03), but utilities did not vary significantly by sex. Among Caucasian and AA men, impairment in physical functioning was the most important factor associated with diminished utility; social stigma was also a leading factor for Caucasian men. Among Caucasian women, self-esteem and work function appeared equally important. Social stigma was the leading contributor to utility among AA women; QOL factors did not appear as important among Hispanic patients. CONCLUSION: AAs reported higher utilities than Caucasian patients. Individual QOL domains that drive diminished well-being varied across race/ethnicity and sex.

Altered Mucosal Microbiome Diversity and Disease Severity in Sjögren Syndrome.

There is mounting evidence that the microbiome has potent immunoregulatory functions. We assessed the effects of intestinal dysbiosis in a model of Sjögren syndrome (SS) by subjecting mice to desiccating stress (DS) and antibiotics (ABX). We characterized the conjunctival, tongue and fecal microbiome profiles of patients with SS. Severity of ocular surface and systemic disease was graded. 16S ribosomal RNA gene sequencing characterized the microbiota. ABX + DS mice had a significantly worse dry eye phenotype compared to controls, a decrease in Clostridium and an increase in Enterobacter, Escherichia/Shigella, and Pseudomonas in stool after ABX + DS for 10 days. Goblet cell density was significantly lower in ABX treated groups compared to controls. Stool from SS subjects had greater relative abundances of Pseudobutyrivibrio, Escherichia/Shigella, Blautia, and Streptococcus, while relative abundance of Bacteroides, Parabacteroides, Faecalibacterium, and Prevotella was reduced compared to controls. The severity of SS ocular and systemic disease was inversely correlated with microbial diversity. These findings suggest that SS is marked by a dysbiotic intestinal microbiome driven by low relative abundance of commensal bacteria and high relative abundance of potentially pathogenic genera that is associated with worse ocular mucosal disease in a mouse model of SS and in SS patients.

Pathways of corneal and ocular surface inflammation: a perspective from the cullen symposium.

The goal of this symposium was to coalesce information presented by 22 investigators in the field of corneal and ocular surface inflammation into common pathways of inflammation. The perspective elucidated in this article defines the components of the normal ocular surface immune architecture and describes the consensus reached on the mechanisms/pathways involved in 1) acute inflammation; 2) late-stage (chronic) response; and 3) allergic disease. Seven diagrams didactically illustrate mechanisms. This paper is the introductory article in a supplement containing 18 articles by the symposium participants.

Herpes simplex virus keratitis in children.

PURPOSE: To describe the spectrum and recurrence of herpes simplex virus (HSV) keratitis in children and adolescents. DESIGN: Retrospective cohort study. METHODS: Twenty-three patients younger than age 16 years were diagnosed with HSV keratitis at one institution. RESULTS: All children presented with dendritic or punctate epithelial keratitis, and stromal keratitis occurred concurrently with epithelial keratitis in 14 patients (61%). Six patients (26%) had bilateral HSV keratitis. Eleven patients (48%) developed recurrent HSV keratitis at a median of 15 months after the first documented episode. Amblyopia occurred in three children. CONCLUSION: Children with herpetic keratitis may have bilateral ocular involvement and are at risk for recurrent keratitis and amblyopia.

Activity of voriconazole against corneal isolates of Scedosporium apiospermum.

PURPOSE: To determine the in vitro antifungal activity of voriconazole, a new triazole, compared with other polyene and imidazole antifungal agents against corneal isolates of Scedosporium apiospermum. METHODS: Macro-broth dilution susceptibility testing was performed on five isolates of S. apiospermum obtained from patients with keratomycosis to determine the minimal inhibitory concentrations (MICs) for amphotericin B, natamycin, ketoconazole, itraconazole, and voriconazole. The use of oral voriconazole in the management of a patient with posttraumatic S. apiospermum keratitis is described. RESULTS: S. apiospermum is generally resistant to commonly used topical ophthalmic antifungal agents. The MIC of voriconazole was 0.5 microg/mL, a concentration lower than that of other imidazoles. CONCLUSION: Voriconazole has promising activity against and may prove useful in the management of fungal keratitis.

Acanthamoeba keratitis: the persistence of cases following a multistate outbreak.

PURPOSE: To describe the trend of Acanthamoeba keratitis case reports following an outbreak and the recall of a multipurpose contact lens disinfection solution. Acanthamoeba keratitis is a serious eye infection caused by the free-living amoeba Acanthamoeba that primarily affects contact lens users. METHODS: A convenience sample of 13 ophthalmology centers and laboratories in the USA, provided annual numbers of Acanthamoeba keratitis cases diagnosed between 1999-2009 and monthly numbers of cases diagnosed between 2007-2009. Data on ophthalmic preparations of anti-Acanthamoeba therapies were collected from a national compounding pharmacy. RESULTS: Data from sentinel site ophthalmology centers and laboratories revealed that the yearly number of cases gradually increased from 22 in 1999 to 43 in 2003, with a marked increase beginning in 2004 (93 cases) that continued through 2007 (170 cases; p < 0.0001). The outbreak identified from these sentinel sites resulted in the recall of a contact lens disinfecting solution. There was a statistically significant (p ≤ 0.0001) decrease in monthly cases reported from 28 cases in June 2007 (following the recall) to seven cases in June 2008, followed by an increase (p = 0.0004) in reported cases thereafter; cases have remained higher than pre-outbreak levels. A similar trend was seen in prescriptions for Acanthamoeba keratitis chemotherapy. Cases were significantly more likely to be reported during summer than during other seasons. CONCLUSION: The persistently elevated number of reported cases supports the need to understand the risk factors and environmental exposures associated with Acanthamoeba keratitis. Further prevention efforts are needed to reduce the number of cases occurring among contact lens wearers.

Management and outcome of microbial anterior scleritis.

PURPOSE: To evaluate the prevalence, predisposing factors, and outcomes of bacterial and fungal scleritis. METHODS: We reviewed the clinical findings, therapeutic interventions, and visual outcomes of patients with suppurative scleral inflammation without preceding microbial keratitis who had microorganisms isolated from scleral scrapings. DESIGN: Retrospective interventional case series. RESULTS: Of 349 patients with scleritis diagnosed from 1999 to 2009, 6 adults (1.7%) presented with suppurative inflammation of the anterior sclera due to Pseudomonas aeruginosa (2), Streptococcus pneumoniae (2), Staphylococcus aureus (1), and Scedosporium apiospermum/Pseudallescheria boydii (1). Each had ocular surgery of the affected eye before presentation. Intraocular extension occurred in 2 eyes. After local and systemic antimicrobial therapy, all improved without evisceration or enucleation, and 4 attained vision of 20/60 or better. CONCLUSIONS: Bacterial or fungal scleritis is an uncommon ocular infection that can belatedly follow anterior segment procedures. Antimicrobial therapy and surgical intervention can successfully control progressive suppuration and reduce vision-limiting complications.

Atypical corneal immunoglobulin deposition in a patient with dysproteinemia.

PURPOSE: The purpose of this study was to report an unusual pattern of immunoglobulin deposition in the corneas of a patient with dysproteinemia. METHODS: Clinical examination, slit lamp examination, a deep lamellar corneal biopsy, and serum and aqueous protein electrophoresis were obtained. RESULTS: Slit lamp evaluation revealed amorphous, cloud-like opacities in the midperiphery at the level of deep stroma and Descemet's membrane. Electron microscopy demonstrated deep lamellar extracellular deposits consistent with immunoglobin. The serum protein electrophoresis revealed a monoclonal IgG kappa band, but the aqueous electrophoresis showed no bands in the gamma region. CONCLUSION: This case documents a rare pattern of immunoglobulin deposition in the corneas in a patient with gammopathy. Despite its deep corneal distribution, the analysis of the aqueous specimen suggests that the source of the immunoglobulin is through a route other than from the aqueous.

Slitlamp biomicroscopy and photographic image analysis of herpes simplex virus stromal keratitis.

OBJECTIVE: To validate photographic bioimaging for evaluating the severity of herpes simplex virus keratitis. METHODS: Stromal keratitis of patients in the Herpetic Eye Disease Study was clinically measured with a slitbeam micrometer and then photographed at trial entry. Calibrated images of 169 eyes were analyzed for the size, location, and density of stromal keratitis and endotheliitis, with shape factor as a function of area and perimeter. Validity was assessed by comparing clinical and computerized measurements and by correlating the keratitis area with visual acuity. Logistic regression explored characteristics associated with larger or denser corneal inflammation. RESULTS: Stromal keratitis had a median area of 22.4 mm(2) (interquartile range, 12.8-31.6 mm(2)) with a median shape factor of 0.69 (interquartile range, 0.56-0.79); 126 eyes (75%) had their midpoint within 2 mm of the cornea's geometric center. Photoanalytical area estimates of herpetic stromal keratitis correlated closely with clinical measurements (correlation coefficient, 0.83). Eyes with larger stromal keratitis had worse vision (correlation coefficient, 0.32) and were more likely to have iritis (P = .01). Necrotizing stromal keratitis was significantly whiter (P = .02). CONCLUSIONS: Image analysis validly assesses the disciform geometry of herpetic stromal keratitis and confirms that increased severity is associated with uveitis and reduced vision.