Corneal Fluorescein Staining in FDA-Reviewed Dry Eye Registrational Clinical Trials: Evidence of Limited Endpoint Responsiveness

Spdef Null Mice Lack Conjunctival Goblet Cells and Provide a Model of Dry Eye

To compare the efficacy of topical cyclosporine 0.05% (tCsA) and combined treatment with 1% methylprednisolone acetate for the treatment of moderate-to-severe chronic dry eye. Forty-four patients with moderate-to-severe dry eye who had not responded to conventional treatment were treated with tCsA for 3 months. Twenty-one subjects (Group 1) were treated with 1% methyl prednisolone acetate and tCsA for the initial 3 weeks, and treated with tCsA only thereafter, and 23 subjects (Group 2) were treated with tCsA only. Symptom scores, tear break-up time (TBUT), Schirmer score, and corneal and conjunctival fluorescein staining were evaluated before and at 1, 2, and 3 months after treatment. Proinflammatory factors, interleukin-6 (IL-6), and interleukin-8 (IL-8) tear concentration were measured before treatment and at 3 months. Symptom scores, Schirmer scores, TBUT score, corneal fluorescein, and conjunctival staining showed significant improvement at 1 month compared to baseline in group 1 (all P < 0.001), and all the same but few exceptions in group 2 (P = 0.002 on Schirmer, P = 0.267 on cornea stating). In symptom scores, Schirmer scores, and corneal staining, greater improvements were observed for group 1 at 1 month compared to group 2 (P < 0.001, P = 0.039, P = 0.01, respectively). However, in TBUT score and conjunctival staining, there were no between-group differences (P = 0.277, P = 0.254, respectively). The time interval from treatment initiation to symptom relief was shorter for group 1 than group 2. Both groups showed decreased tear IL-6 and IL-8 concentrations at 3 months compared to baseline levels (P < 0.05). However, no between-group differences were noted in mean concentrations of IL-6 and IL-8 at baseline and at 3 months. Treatment with tCsA appears to be safe and effective in moderate-to-severe chronic dry eye. Additional short-term use of a topical steroid had the benefit of providing faster symptom relief and improvement of ocular sign without serious complications.

Lacrimal Gland-Associated Immune Deviation in the Rat

Sjögren’s Syndrome-Like Ocular Surface Disease in Thrombospondin-1 Deficient Mice

Effect of hinge position on corneal sensation and dry eye after laser in situ keratomileusis using a femtosecond laser

The effect of time on grading corneal fluorescein and conjunctival lissamine green staining

To determine the effects of povidone iodine 5% (Betadine 5%) applied to the eye on visual function, corneal integrity, and subjective complaints. Ten subjects were chosen to participate in this study (average age 40.6 ± 19.6; age range 22-68). LogMAR acuity, contrast sensitivity, corneal fluorescein staining, and subjective complaints were measured before and after 60 μl of Betadine 5% or saline were applied to one eye (eligibility visit, baseline, 5, 30, and 60 minutes and 4 and 24 hours post-application). Contrast sensitivity at 14 cpd was determined with a spatial two-alternative, forced choice procedure (Beethoven software). The National Eye Institute (NEI) grid pattern was used to grade corneal staining with sodium fluorescein. To avoid the detrimental effects of sodium fluorescein administration on functional vision, the corneal staining baseline was measured at the eligibility visit. Subjective complaints were monitored using the Schein dry eye questionnaire. The data were analyzed with an ANOVA. Saline administration did not alter logMAR acuity, contrast sensitivity, corneal fluorescein staining, or subjective complaints at any visit. Betadine administration significantly reduced the logMAR acuity, compared to baseline and the saline data, at the 30- and 60-minute visits (all P values <.05). The contrast sensitivity was significantly reduced compared to the baseline and the saline results at 5, 30, and 60 minutes after Betadine application (all P values <.05). The Betadine significantly increased the Schein questionnaire score, compared both to baseline and the saline data, at the 1- and 4-hour visits (all P values <.05). Total corneal staining and the maximum NEI sector staining were significantly different from baseline and from the saline results at every visit (all P values <.05). Betadine 5% application significantly decreases epithelial integrity of the cornea, decreases functional vision, and increases subjective complaints.

Understanding the Dual Dilemma of Dry Eye and Glaucoma: An International Review.

Purpose: To evaluate effects of a novel multi-ingredient artificial tear formulation containing carboxymethylcellulose (CMC) and hyaluronic acid (HA) in a murine dry eye model.Methods: Dry eye was induced in mice (C57BL/6) using an intelligently controlled environmental system (ICES). CMC+HA (Optive Fusion™), CMC-only (Refresh Tears®), and HA-only (Hycosan®) artificial tears and control phosphate-buffered saline (PBS) were administered 4 times daily and compared with no treatment (n = 64 eyes per group). During regimen 1 (prevention regimen), mice were administered artificial tears or PBS for 14 days (starting day 0) while they were exposed to ICES, and assessed on days 0 and 14. During regimen 2 (treatment regimen), mice exposed to ICES for 14 days with no intervention were administered artificial tears or PBS for 14 days (starting day 14) while continuing exposure to ICES, and assessed on days 0, 14, and 28. Corneal fluorescein staining and conjunctival goblet cell density were measured.Results: Artificial tear-treated mice had significantly better outcomes than control groups on corneal staining and goblet cell density (P < 0.01). Mice administered CMC+HA also showed significantly lower corneal fluorescein staining and higher goblet cell density, compared with CMC (P < 0.01) and HA (P < 0.05) in both regimens 1 and 2.Conclusions: The artificial tear formulation containing CMC and HA was effective in preventing and treating environmentally induced dry eye. Improvements observed for corneal fluorescein staining and conjunctival goblet cell retention suggest that this combination may be a viable treatment option for dry eye disease.

Sjogren's syndrome in optometric practices in North America.

A clinical evaluation of Systane

PurposeThis paper examines the tear concentration of cystatin S (CST4), calcyclin (S100A6), calgranulin A (S100A8), and matrix metalloproteinase 9 (MMP9), and the correlation between biomarker expression, clinical parameters, and disease severity in patients suffering from dry eye (DE). A comparison of the results is obtained via ELISA tests and customized antibody microarrays for protein quantification.MethodsThis single-center, observational study recruited 59 participants (45 DE and 14 controls). Clinical evaluation included an Ocular Surface Disease Index (OSDI) questionnaire, a tear osmolarity (OSM) test, the Schirmer test (SCH), tear breakup time (TBUT), fluorescein (FLUO) and lissamine green (LG) corneal staining, and meibomian gland evaluation (MGE). Tear concentrations of CST4, S100A6, S100A8, and MMP9 were measured using standard individual ELISA assays. The levels of CST4, S100A6, and MMP9 were also measured using customized multiplexed antibody microarrays. Correlations between variables were evaluated, and a significance level was p value <0.05.ResultsThe quantification of tear protein biomarkers with ELISA showed that the concentration of CST4 was significantly (2.14-fold) reduced in tears of DE patients in comparison with control (CT) subjects (p < 0.001). S100A6 and S100A8 concentrations were significantly higher in the tears of DE patients (1.36- and 2.29-fold; p < 0.001 and 0.025, respectively) in comparison with CT. The MMP9 level was also higher in DE patients (5.83-fold), but not significantly (p = 0.22). The changes in CST4 and S100A6 concentrations were significantly correlated with dry eye disease (DED) severity. Quantification of CST4, S100A6, and MMP9, using antibody microarrays, confirmed the ELISA results. Similar trends were observed: 1.83-fold reduction for CST4 (p value 0.01), 8.63-fold increase for S100A6 (p value <0.001) and 9.67-fold increase for MMP9 (p value 0.94), but with higher sensitivity. The biomarker concentrations were significantly associated with the signs and symptoms related with DED.ConclusionsS100A6, S100A8, and CST4 diagnostic biomarkers strongly correlate with DED clinical parameters. S100A6 and CST4 are also useful for grading DE severity. The multiplexed antibody microarray technique, used here for tear multi-marker quantification, appears more sensitive than standard ELISA tests.

To compare the symptoms and signs of dry eye disease (DED) in children with systemic lupus erythematosus (SLE) with those in healthy children using common diagnostic tools. Prospective, observational, single-center cohort study. Thirty-four subjects with SLE and 15 healthy subjects were recruited from the Hospital for Sick Children in Toronto, Canada. Subjects underwent subjective and objective dry eye assessments using the Canadian Dry Eye Assessment (CDEA) questionnaire, tear film osmolarity, slit lamp examination, tear film break-up time, corneal fluorescein staining, Schirmer test 1, and conjunctival lissamine green staining. No difference in symptoms was found between children with SLE and healthy children (CDEA score 6.4 ± 5.4 vs. 3.8 ± 3.2; P = 0.09). Corneal staining was more prevalent in children with SLE than in healthy children (58.8% vs. 20.0%; P = 0.01), and children with SLE had higher mean corneal fluorescein staining scores (1.7 ± 1.7 vs. 0.2 ± 0.4; P = 0.002). No statistically significant differences in tear osmolarity, inter-eye differences in tear osmolarity, tear film break-up time, Schirmer test 1, or lissamine green staining scores were observed between the 2 groups. In healthy children, CDEA scores weakly correlated with corneal fluorescein staining score (r = 0.53, P = 0.04). In children with SLE, no correlation between CDEA score and any of the diagnostic test outcomes was found. There is discordance between symptoms and signs of DED in children with SLE. Corneal fluorescein staining is essential for the diagnosis of DED in these children.

Purpose: A pilot study was conducted to evaluate human corneal epithelial cell shedding in response to wearing a silicone hydrogel contact lens/solution combination inducing corneal staining. The nature of ex vivo collected cells staining with fluorescein was also examined.Methods: A contralateral eye study was conducted in which up to eight participants were unilaterally exposed to a multipurpose contact lens solution/silicone hydrogel lens combination previously shown to induce corneal staining (renu® fresh™ and balafilcon A; test eye), with the other eye using a combination of balafilcon A soaked in a hydrogen peroxide care system (Clear Care®; control eye). Lenses were worn for 2, 4 or 6 hours. Corneal staining was graded after lens removal. The Ocular Surface Cell Collection Apparatus was used to collect cells from the cornea and the contact lens.Results: In the test eye, maximum solution-induced corneal staining (SICS) was observed after 2 hours of lens wear (reducing significantly by 4 hours; p < 0.001). There were significantly more cells collected from the test eye after 4 hours of lens wear when compared to the control eye and the collection from the test eye after 2 hours (for both; n = 5; p < 0.001). The total cell yield at 4 hours was 813 ± 333 and 455 ± 218 for the test and control eyes, respectively (N = 5, triplicate, p = 0.003). A number of cells were observed to have taken up the fluorescein dye from the initial fluorescein instillation. Confocal microscopy of fluorescein-stained cells revealed that fluorescein was present throughout the cell cytoplasm and was retained in the cells for many hours after recovery from the corneal surface.Conclusion: This pilot study indicates that increased epithelial cell shedding was associated with a lens-solution combination which induces SICS. Our data provides insight into the transient nature of the SICS reaction and the nature of fluorescein staining observed in SICS.

PurposeThe aim of this study was to analyze dry eye disease (DED) in patients with functioning filtering blebs and to explore the relationship between the morphology of filtering blebs and ocular surface instability.MethodsThis was a cross-sectional, case-comparison study. Seventy glaucomatous patients (70 eyes) with functioning blebs who had undergone trabeculectomy more than 6 months prior (study group) and 35 control subjects (35 eyes) (control group) were included. All subjects completed an ocular symptom questionnaire that referred to the Shihpai Eye Study. Evaluation of meibomian gland obstruction, a tear film break-up time test (TFBUT), fluorescein corneal staining and a Schirmer’s tear test were then performed. Filtering bleb morphology was analyzed using Wuerzburg bleb classification scoring criteria in the study group. The presence of DED was defined as the concomitant presence of TFBUT <10 seconds and the presence of superficial punctate keratitis.ResultsThe patients with functioning blebs presented higher corneal staining scores (P = 0.012) and lower TFBUT values (P = 0.043) than the control group. DED was present in 28/70 patients in the study group and 6/35 patients in the control group (P = 0.018). More patients in the study group complained of dryness (P = 0.001), a gritty or sandy sensation (P < 0.001) and redness (P = 0.048). In the study group, the patients with DED were significantly different from the patients without DED in both TFBUT (P < 0.001) and corneal staining (P < 0.001). More patients in the DED group were likely to report dryness (P = 0.013) and watery or teary eyes (P = 0.012). The differences in meibomian gland obstruction scores between the study and the control group, the DED and the non-DED group were not significant (P = 0.105 and P = 0.077, respectively). The values for microcysts and bleb heights were significantly higher in the DED group (P = 0.040 and P = 0.011, respectively). A Spearman’s rank correlation showed that microcysts were positively correlated with corneal staining (r = 0.270, P = 0.024). Bleb height was negatively correlated with TFBUT (r = -0.299, P = 0.012) and positively correlated with corneal staining (r = 0.275, P = 0.021). The relationships between DED and microcysts and between DED and bleb height were significant (r = 0.247, P = 0.039 and r = 0.307, P = 0.010, respectively).ConclusionDED is relatively common in patients with functioning filtering blebs following trabeculectomy. In DED patients, dryness and watery are common symptoms. Microcysts and bleb height are related to ocular surface instability and DED.