Cornea

Cornea Publications

Craig JP, Nelson DJ, Azar DT, Belmonte C, Bron AJ, Chauhan SK, de Paiva CS, Gomes JAP, Hammitt KM, Jones L, Nichols JJ, Nichols KK, Novack GD, Stapleton FJ, Willcox MDP, Wolffsohn JS, Sullivan DA. The TFOS Dry Eye Workshop II: Executive Summary. Ocul Surf 2017;Abstract
This article presents an Executive Summary of the conclusions and recommendations of the 10-chapter TFOS DEWS II report. The entire TFOS DEWS II report was published in the July 2017 issue of The Ocular Surface. A downloadable version of the document and additional material, including videos of diagnostic and management techniques, are available on the TFOS website: www.TearFilm.org.
Sullivan DA, Rocha EM, Aragona P, Clayton JA, Ding J, Golebiowski B, Hampel U, McDermott AM, Schaumberg DA, Srinivasan S, Versura P, Willcox MDP. TFOS DEWS II Sex, Gender, and Hormones Report. Ocul Surf 2017;15(3):284-333.Abstract
One of the most compelling features of dry eye disease (DED) is that it occurs more frequently in women than men. In fact, the female sex is a significant risk factor for the development of DED. This sex-related difference in DED prevalence is attributed in large part to the effects of sex steroids (e.g. androgens, estrogens), hypothalamic-pituitary hormones, glucocorticoids, insulin, insulin-like growth factor 1 and thyroid hormones, as well as to the sex chromosome complement, sex-specific autosomal factors and epigenetics (e.g. microRNAs). In addition to sex, gender also appears to be a risk factor for DED. "Gender" and "sex" are words that are often used interchangeably, but they have distinct meanings. "Gender" refers to a person's self-representation as a man or woman, whereas "sex" distinguishes males and females based on their biological characteristics. Both gender and sex affect DED risk, presentation of the disease, immune responses, pain, care-seeking behaviors, service utilization, and myriad other facets of eye health. Overall, sex, gender and hormones play a major role in the regulation of ocular surface and adnexal tissues, and in the difference in DED prevalence between women and men. The purpose of this Subcommittee report is to review and critique the nature of this role, as well as to recommend areas for future research to advance our understanding of the interrelationships between sex, gender, hormones and DED.
Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, Na K-S, Schaumberg D, Uchino M, Vehof J, Viso E, Vitale S, Jones L. TFOS DEWS II Epidemiology Report. Ocul Surf 2017;15(3):334-365.Abstract
The subcommittee reviewed the prevalence, incidence, risk factors, natural history, morbidity and questionnaires reported in epidemiological studies of dry eye disease (DED). A meta-analysis of published prevalence data estimated the impact of age and sex. Global mapping of prevalence was undertaken. The prevalence of DED ranged from 5 to 50%. The prevalence of signs was higher and more variable than symptoms. There were limited prevalence studies in youth and in populations south of the equator. The meta-analysis confirmed that prevalence increases with age, however signs showed a greater increase per decade than symptoms. Women have a higher prevalence of DED than men, although differences become significant only with age. Risk factors were categorized as modifiable/non-modifiable, and as consistent, probable or inconclusive. Asian ethnicity was a mostly consistent risk factor. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable, particularly costs due to reduced work productivity. Questionnaires used to evaluate DED vary in their utility. Future research should establish the prevalence of disease of varying severity, the incidence in different populations and potential risk factors such as youth and digital device usage. Geospatial mapping might elucidate the impact of climate, environment and socioeconomic factors. Given the limited study of the natural history of treated and untreated DED, this remains an important area for future research.
Willcox MDP, Argüeso P, Georgiev GA, Holopainen JM, Laurie GW, Millar TJ, Papas EB, Rolland JP, Schmidt TA, Stahl U, Suarez T, Subbaraman LN, Uçakhan OÖ, Jones L. TFOS DEWS II Tear Film Report. Ocul Surf 2017;15(3):366-403.Abstract
The members of the Tear Film Subcommittee reviewed the role of the tear film in dry eye disease (DED). The Subcommittee reviewed biophysical and biochemical aspects of tears and how these change in DED. Clinically, DED is characterized by loss of tear volume, more rapid breakup of the tear film and increased evaporation of tears from the ocular surface. The tear film is composed of many substances including lipids, proteins, mucins and electrolytes. All of these contribute to the integrity of the tear film but exactly how they interact is still an area of active research. Tear film osmolarity increases in DED. Changes to other components such as proteins and mucins can be used as biomarkers for DED. The Subcommittee recommended areas for future research to advance our understanding of the tear film and how this changes with DED. The final report was written after review by all Subcommittee members and the entire TFOS DEWS II membership.
Novack GD, Asbell P, Barabino S, Bergamini MVW, Ciolino JB, Foulks GN, Goldstein M, Lemp MA, Schrader S, Woods C, Stapleton F. TFOS DEWS II Clinical Trial Design Report. Ocul Surf 2017;15(3):629-649.Abstract
The development of novel therapies for Dry Eye Disease (DED) is formidable, and relatively few treatments evaluated have been approved for marketing. In this report, the Subcommittee reviewed challenges in designing and conducting quality trials, with special reference to issues in trials in patients with DED and present the regulatory perspective on DED therapies. The Subcommittee reviewed the literature and while there are some observations about the possible reasons why so many trials have failed, there is no obvious single reason other than the lack of correlation between signs and symptoms in DED. Therefore the report advocates for conducting good quality studies, as described, going forward. A key recommendation for future studies is conduct consistent with Good Clinical Practice (GCP), including use of Good Manufacturing Practice (GMP) quality clinical trial material. The report also recommends that the design, treatments, and sample size be consistent with the investigational treatment, the objectives of the study, and the phase of development. Other recommendations for pivotal studies are a priori selection of the outcome measure, and an appropriate sample size.
Nelson DJ, Craig JP, Akpek EK, Azar DT, Belmonte C, Bron AJ, Clayton JA, Dogru M, Dua HS, Foulks GN, Gomes JAP, Hammitt KM, Holopainen J, Jones L, Joo C-K, Liu Z, Nichols JJ, Nichols KK, Novack GD, Sangwan V, Stapleton F, Tomlinson A, Tsubota K, Willcox MDP, Wolffsohn JS, Sullivan DA. TFOS DEWS II Introduction. Ocul Surf 2017;15(3):269-275.
Rong SS, Ma STU, Yu XT, Ma L, Chu WK, Chan TCY, Wang YM, Young AL, Pang CP, Jhanji V, Chen LJ. Genetic associations for keratoconus: a systematic review and meta-analysis. Sci Rep 2017;7(1):4620.Abstract
Genetic associations for keratoconus could be useful for understanding disease pathogenesis and discovering biomarkers for early detection of the disease. We conducted a systematic review and meta-analysis to summarize all reported genetic associations for the disease. We searched in the MEDLINE, Embase, Web of Science, and HuGENET databases for genetic studies of keratoconus published from 1950 to June 2016. The summary odds ratio and 95% confidence intervals of all polymorphisms were estimated using the random-effect model. Among 639 reports that were retrieved, 24 fulfilled required criteria as eligible studies for meta-analysis, involving a total of 53 polymorphisms in 28 genes/loci. Results of our meta-analysis lead to the prioritization of 8 single-nucleotide polymorphisms (SNPs) in 6 genes/loci for keratoconus in Whites. Of them 5 genes/loci were originally detected in genome-wide association studies, including FOXO1 (rs2721051, P = 5.6 × 10(-11)), RXRA-COL5A1 (rs1536482, P = 2.5 × 10(-9)), FNDC3B (rs4894535, P = 1.4 × 10(-8)), IMMP2L (rs757219, P = 6.1 × 10(-7); rs214884, P = 2.3 × 10(-5)), and BANP-ZNF469 (rs9938149, P = 1.3 × 10(-5)). The gene COL4A4 (rs2229813, P = 1.3 × 10(-12); rs2228557, P = 4.5 × 10(-7)) was identified in previous candidate gene studies. We also found SNPs in 10 genes/loci that had a summary P value < 0.05. Sensitivity analysis indicated that the results were robust. Replication studies and understanding the roles of these genes in keratoconus are warranted.
Kheirkhah A, Syed ZA, Satitpitakul V, Goyal S, Müller R, Tu EY, Dana R. Sensitivity and Specificity of Laser-Scanning In Vivo Confocal Microscopy for Filamentous Fungal Keratitis: Role of Observer Experience. Am J Ophthalmol 2017;179:81-89.Abstract
PURPOSE: To determine sensitivity and specificity of laser-scanning in vivo confocal microscopy (LS-IVCM) for detection of filamentous fungi in patients with microbial keratitis and to evaluate the effect of observer's imaging experience on these parameters. DESIGN: Retrospective reliability study. METHODS: This study included 21 patients with filamentous fungal keratitis and 24 patients with bacterial keratitis (as controls). The etiology of infection was confirmed based on the response to specific therapy regardless of culture results. All patients had undergone full-thickness corneal imaging by a LS-IVCM (Heidelberg Retina Tomograph 3 with Rostock Cornea Module; Heidelberg Engineering, Heidelberg, Germany). The images were evaluated for the presence of fungal filaments by 2 experienced observers and 2 inexperienced observers. All observers were masked to the clinical and microbiologic data. RESULTS: The mean number of images obtained per eye was 917 ± 353. The average sensitivity of LS-IVCM for detecting fungal filaments was 71.4% ± 0% for the experienced observers and 42.9% ± 6.7% for the inexperienced observers. The average specificity was 89.6% ± 3.0% and 87.5% ± 17.7% for these 2 groups of observers, respectively. Although there was a good agreement between the 2 experienced observers (κ = 0.77), the inexperienced observers showed only a moderate interobserver agreement (κ = 0.51). The LS-IVCM sensitivity was higher in patients with fungal infections who had positive culture or longer duration of the disease. CONCLUSIONS: Although LS-IVCM has a high specificity for diagnosing filamentous fungal keratitis, its sensitivity is moderate and highly dependent on the level of the observer's experience and training with this imaging modality.
Jones L, Downie LE, Korb D, Benitez-Del-Castillo JM, Dana R, Deng SX, Dong PN, Geerling G, Hida RY, Liu Y, Seo KY, Tauber J, Wakamatsu TH, Xu J, Wolffsohn JS, Craig JP. TFOS DEWS II Management and Therapy Report. Ocul Surf 2017;15(3):575-628.Abstract
The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype.
Farrand KF, Fridman M, Stillman IÖ, Schaumberg DA. Prevalence of Diagnosed Dry Eye Disease in the United States Among Adults Aged 18 Years and Older. Am J Ophthalmol 2017;Abstract
PURPOSE: To provide current estimates of the prevalence of diagnosed dry eye disease (DED) and associated demographics among US adults aged ≥18 years. DESIGN: Cross-sectional, population-based survey. METHODS: Data were analyzed from 75,000 participants in the 2013 National Health and Wellness Survey to estimate prevalence/risk of diagnosed DED overall, and by age, sex, insurance, and other demographic factors. We weighted the observed DED prevalence to project estimates to the US adult population and examined associations between demographic factors and DED using multivariable logistic regression. RESULTS: Based on weighted estimates, 6.8% of the US adult population was projected to have diagnosed DED (∼16.4 million people). Prevalence increased with age (18-34 years: 2.7%; ≥75 years: 18.6%) and was higher among women (8.8%; ∼11.1 million) than men (4.5%; ∼5.3 million). After adjustment, there were no substantial differences in prevalence/risk of diagnosed DED by race, education, or US census region. However, there was higher risk of diagnosed DED among those aged 45-54 years (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.74-2.20) and ≥75 years (OR: 4.95; 95% CI: 4.26-5.74), vs those aged 18-34 years. Risk was also higher among women vs men (OR: 2.00; 95% CI: 1.88-2.13) and insured vs uninsured participants (OR: 2.12; 95% CI: 1.85-2.43 for those on government and private insurance vs none). CONCLUSIONS: We estimate that >16 million US adults have diagnosed DED. Prevalence is higher among women than men, increases with age, and is notable among those aged 18-34 years.
Belmonte C, Nichols JJ, Cox SM, Brock JA, Begley CG, Bereiter DA, Dartt DA, Galor A, Hamrah P, Ivanusic JJ, Jacobs DS, McNamara NA, Rosenblatt MI, Stapleton F, Wolffsohn JS. TFOS DEWS II pain and sensation report. Ocul Surf 2017;15(3):404-437.Abstract
Pain associated with mechanical, chemical, and thermal heat stimulation of the ocular surface is mediated by trigeminal ganglion neurons, while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of meibomian gland secretion or mucin release have not been identified. In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy.
Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, Knop E, Markoulli M, Ogawa Y, Perez V, Uchino Y, Yokoi N, Zoukhri D, Sullivan DA. TFOS DEWS II pathophysiology report. Ocul Surf 2017;15(3):438-510.Abstract
The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjögren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.
Amparo F, Yin J, Di Zazzo A, Abud T, Jurkunas UV, Hamrah P, Dana R. Evaluating Changes in Ocular Redness Using a Novel Automated Method. Transl Vis Sci Technol 2017;6(4):13.Abstract
PURPOSE: To evaluate interobserver concordance in measured ocular redness among a group of raters using an objective computer-assisted method (ocular redness index [ORI]) and a group of clinicians using an ordinal comparative scale. METHODS: We conducted a prospective study to evaluate ocular redness in clinical photographs of 12 patients undergoing pterygium surgery. Photographs were acquired preoperatively, and at 1 week and 1 month postoperatively. One group of clinicians graded conjunctival redness in the photographs using an image-based comparative scale. A second group applied the ORI to measure redness in the same photographs. We evaluated redness change between time points, level of agreement among raters, and assessed redness score differences among observers within each group. RESULTS: Interobserver agreement using the image-based redness scale was 0.458 (P < 0.001). Interobserver agreement with the ORI was 0.997 (P < 0.001). We observed statistically significant differences among clinicians' measurements obtained with the image-based redness scale (P < 0.001). There were no significant differences among measurements obtained with the ORI (P = 0.27). We observed a significant change in redness between baseline and follow-up visits with all scoring methods. Detailed analysis of redness change was performed only in the ORI group due to availability of continuous scores. CONCLUSION: Our findings suggest that the ORI scores provide higher consistency among raters than ordinal scales, and can discriminate redness changes that clinical observers often can miss. TRANSLATIONAL RELEVANCE: The ORI may be a reliable alternative to measure ocular redness objectively in the clinic and in clinical trials.
Benischke A-S, Vasanth S, Miyai T, Katikireddy KR, White T, Chen Y, Halilovic A, Price M, Price F, Liton PB, Jurkunas UV. Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy. Sci Rep 2017;7(1):6656.Abstract
Human corneal endothelial cells (HCEnCs) are terminally differentiated cells that have limited regenerative potential. The large numbers of mitochondria in HCEnCs are critical for pump and barrier function required for corneal hydration and transparency. Fuchs Endothelial Corneal Dystrophy (FECD) is a highly prevalent late-onset oxidative stress disorder characterized by progressive loss of HCEnCs. We previously reported increased mitochondrial fragmentation and reduced ATP and mtDNA copy number in FECD. Herein, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitochondrial depolarization decreased mitochondrial mass and Mfn2 levels, which were rescued with mitophagy blocker, bafilomycin, in FECD. Moreover, electron transport chain complex (I, V) decrease in FECD indicated deficient mitochondrial bioenergetics. Transmission electron microscopy of FECD tissues displayed an increased number of autophagic vacuoles containing degenerated and swollen mitochondria with cristolysis. An elevation of LC3-II and LAMP1 and downregulation of Mfn2 in mitochondrial fractions suggested that loss of fusion capacity targets fragmented mitochondria to the pre-autophagic pool and upregulates mitophagy. CCCP-induced mitochondrial fragmentation leads to Mfn2 and LC3 co-localization without activation of proteosome, suggesting a novel Mfn2 degradation pathway via mitophagy. These data indicate constitutive activation of mitophagy results in reduction of mitochondrial mass and abrogates cellular bioenergetics during degeneration of post-mitotic cells of ocular tissue.
Zhang Y, Kam WR, Liu Y, Chen X, Sullivan DA. Influence of Pilocarpine and Timolol on Human Meibomian Gland Epithelial Cells. Cornea 2017;36(6):719-724.Abstract
PURPOSE: Investigators have discovered that topical antiglaucoma drugs may induce meibomian gland dysfunction. This response may contribute to the dry eye disease commonly found in patients with glaucoma taking such medications. We hypothesize that drug action involves a direct effect on human meibomian gland epithelial cells (HMGECs). To test this hypothesis, we examined the influence of the antiglaucoma drugs, pilocarpine and timolol, on the morphology, survival, proliferation, and differentiation of HMGECs. METHODS: Immortalized (I) HMGECs (n = 2-3 wells/treatment/experiment) were cultured with multiple concentrations of pilocarpine or timolol for up to 7 days. Experiments included positive controls for proliferation (epidermal growth factor and bovine pituitary extract) and differentiation (azithromycin). Cells were enumerated using a hemocytometer and evaluated for morphology, neutral lipid staining, and lysosome accumulation. RESULTS: Our results demonstrate that pilocarpine and timolol cause a dose-dependent decrease in the survival of IHMGECs. The clinically used concentrations are toxic and lead to cell atrophy, poor adherence, or death. By contrast, drug levels that are known to accumulate within the conjunctiva, adjacent to the meibomian glands, do not influence IHMGEC survival. These latter concentrations also have no effect on IHMGEC proliferation or differentiation, and they do not interfere with the ability of azithromycin to stimulate cellular neutral lipid and lysosome accumulation. This dose of pilocarpine, though, did suppress the epidermal growth factor+bovine pituitary extract-induced proliferation of IHMGECs. CONCLUSIONS: Our results support our hypothesis and demonstrate that these antiglaucoma drugs, pilocarpine and timolol, have direct effects on HMGECs that may influence their morphology, survival, and proliferative capacity.

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