Validation of the Modified Schein Dry Eye Symptom Questionnaire and Comparison With the Ocular Surface Disease Index.

PURPOSE: This study evaluated the validity and diagnostic efficacy of a modified Schein dry eye questionnaire and compared it to the Ocular Surface Disease Index (OSDI). METHODS: The original Schein survey was modified to allow numerical scoring on a 0 to 24 scale and evaluated in prospective studies in normal and dry eye subjects. Receiver operating characteristic (ROC) analysis for test efficacy in aqueous deficient dry eye (ADDE) and evaporative dry eye (EDE) related to meibomian gland dysfunction was determined. RESULTS: Dry eye subtype, age and gender were statistically significant in explaining variation in modified Schein scores (n = 377; general linear model; all P values < 0.006) whereas for Ocular Surface Disease Index (OSDI) only age and gender were significant, but not dry eye subtype. The modified Schein ROC curve had an area under the curve (AUC) of 0.693 (95% confidence interval [CI], 0.635-0.753), with cutpoint of 7.5 (sensitivity of 0.75, specificity of 0.55). Similarly, the OSDI had an AUC of 0.685 (95% CI, 0.610-0.760), at a cutpoint of 10.4 (sensitivity of 0.75, specificity of 0.55). Modified Schein and OSDI correlated well (Pearson r = 0.81; P < 0.001). Symptom change for the modified Schein with artificial tear treatment was significant in EDE subjects (Dunnet's tests, P value < 0.001). CONCLUSIONS: The modified Schein questionnaire is rapid to administer and score and compares well with the OSDI for test efficacy. Moreover, it differentiates normals from ADDE and EDE subtypes and is responsive to dry eye treatment. These attributes make the modified Schein survey an attractive dry eye symptom characterization instrument. TRANSLATIONAL RELEVANCE: The modified Schein symptom survey, validated against clinical diagnosis and an existing survey, provides a new, efficacious diagnostic and treatment monitoring instrument in dry eye disease.

Development of a Meibomian Gland Dysfunction-Specific Symptom Questionnaire.

OBJECTIVES: The aim of this study was to develop and evaluate, using psychometric approaches, a meibomian gland dysfunction (MGD)-specific questionnaire in noncontact lens wearers. METHODS: The MGD subjects were recruited and classified as the MGD dry eye subtype based on accepted tests (e.g., Schein symptom survey, tear breakup time, corneal and conjunctival staining, abnormal meibum or meibomian gland atrophy, and a normal Schirmer test). The MGD questionnaire items were drawn from published and anecdotal sources. The preliminary instrument contained 24 items targeting the frequency and intensity of 12 symptoms. Rasch analysis was used for psychometric evaluation of the survey items. RESULTS: Sixty nine MGD subjects completed the survey and clinical testing. Sample severity levels were as follows: none subclinical, 10 minimal, 43 mild, 16 moderate, and none severe. Three iterations of analysis, eliminating INFIT and OUTFIT scores <, and >3.0, and using subject responses reduced the final questionnaire to seven question pairs. Final analysis for the remaining 14 items demonstrated an excellent fit to the Rasch model (e.g., for persons, INFIT MNSQ=0.97; ZSTD=-0.2; OUTFIT MNSQ=0.96; ZSTD=-0.2; item fit statistics were similar). Construct validity also seems good (e.g., correlation to Schein and change with treatment). CONCLUSIONS: The MGD-specific instrument is a valid quantitative measure of the symptoms stemming from MGD sufferers. Further research is necessary to determine whether diagnostic efficacy is sufficient to differentiate the MGD dry eye subtype in an independent sample of normals and both major dry eye subtypes exhibiting a broad severity range.

Biophysical and morphological evaluation of human normal and dry eye meibum using hot stage polarized light microscopy.

PURPOSE: To study melting characteristics and the morphology of human and mouse meibum. METHODS: Hot stage cross-polarized light microscopy (HSPM) and immunohistochemical approaches were used. RESULTS: Isolated human meibum, and meibum of mice (either isolated or within the meibomian ducts of mice), were found to be in liquid-crystal state at physiological temperatures. Melting of both types of meibum started at approximately 10°C and was completed at approximately 40°C. Melting curves of isolated meibum and meibum inside the meibomian ducts were multiphasic with at least two or three clearly defined phase transition temperatures, typically at approximately 12 ± 2°C (minor transition), 21 ± 3°C, and 32 ± 3°C, regardless the source of meibum. Melting was highly cooperative in nature. Samples of abnormal human meibum collected from dry eye patients with meibomian gland dysfunction often showed an increased presence of nonlipid, nonmelting, nonbirefringent, chloroform-insoluble inclusions of a protein nature. The inclusions were positively stained for cytokeratins. The presence of these inclusions was semiquantitatively characterized using a newly proposed 0 to 4 scale. In the presence of large amounts of these inclusions, melting characteristics of meibum and its structural integrity were altered. CONCLUSIONS: HSPM is an effective tool that is suitable for biophysical and morphological evaluation of meibum. Morphological properties and melting characteristics of human meibum were found to be similar to those of mice. Abnormal meibum of many dry eye patients contained large quantities of nonlipid, protein-like inclusions, which were routinely absent in meibum of normal controls.

Lens parameter changes under in vitro and ex vivo conditions and their effect on the conjunctiva.

PURPOSE: To quantify changes in contact lens parameters induced by lens wear and determine whether these changes are associated with contact lens-induced conjunctival staining (CLICS). METHODS: In vitro: Lens diameter, sag, edge shape, base curve of six contact lens brands (balafilcon, comfilcon, etafilcon, lotrafilcon B, omafilcon and senofilcon) measured at 21°C and 35°C (eye temperature). Ex vivo: Diameter of lenses collected from a prospective, randomised, contra-lateral, cross-over clinical trial from 36 subjects wearing all lens types for 1 week daily wear, measured in 35°C PBS after removal. Ocular surface was examined for lens-induced conjunctival staining by masked examiner. RESULTS: In vitro: Changes in diameter and base curve outside ISO tolerance were found with etafilcon A and omafilcon A. Ex vivo: Comfilcon A and etafilcon A had greatest shrinkage in diameter (0.18mm) and base curve (0.11mm steeper) with temperature increase from 21°C to 35°C. Senofilcon A, lotrafilcon B and balafilcon A maintained most stable parameters between 21°C and 35°C. Changes in diameter and base curve from lens wear were not correlated with CLICS (p>0.49). Multivariate analysis showed significantly greater levels of lens induced staining were associated with lens modulus (p<0.001) and knife (p<0.001) and chisel (p<0.001) edge shapes. CONCLUSIONS: Parameter changes induced by lens wear were associated with increasing temperature, but these changes in lens diameter and base curve did not induce CLICS. Modulus and edge shape were associated with increased CLICS. The susceptibility of etafilcon A and omafilcon A lenses to parameter changes might be related to their high water content.

Molecular structure of interfacial human meibum films.

Meibum is the primary component of the tear film lipid layer. Thought to play a role in tear film stabilization, understanding the physical properties of meibum and how they change with disease will be valuable in identifying dry eye treatment targets. Grazing incidence X-ray diffraction and X-ray reflectivity were applied to meibum films at an air-water interface to identify molecular organization. At room temperature, interfacial meibum films formed two coexisting scattering phases with rectangular lattices and next-nearest neighbor tilts, similar to the Ov phase previously identified in fatty acids. The intensity of the diffraction peaks increased with compression, although the lattice spacing and molecular tilt angle remained constant. Reflectivity measurements at surface pressures of 18 mN/m and above revealed multilayers with d-spacings of 50 Å, suggesting that vertical organization rather than lateral was predominantly affected by meibum-film compression.

Dendritic immune cell densities in the central cornea associated with soft contact lens types and lens care solution types: a pilot study.

BACKGROUND: The purpose of this study was to assess whether differences in central corneal dendritic immune cell densities associated with combinations of soft contact lenses and lens care solutions could be detected by in vivo confocal microscopy. METHODS: Participants were adults naïve to contact lens wear (n = 10) or who wore soft contact lenses habitually on a daily-wear schedule (n = 38) or on a study-assigned schedule for 30 days with daily disposable silicone hydrogel lenses (n = 15). Central corneas were scanned using an in vivo confocal microscope. Cell densities were compared among groups by demographic parameters, lens materials, and lens care solutions (polyhexamethylene biguanide [PHMB], polyquaternium-1 and myristamidopropyl dimethylamine [PQ/MAPD], peroxide, or blister pack solution [for daily disposable lenses]). RESULTS: Among lens wearers, no associations were observed between immune cell densities and age, gender, or years of lens-wearing experience. Mean cell density was significantly lower (P < 0.01) in nonwearers (29 ± 23 cells/mm(2), n = 10) than in lens wearers (64 ± 71 cells/mm(2), n = 53). Mean cell density was lower (P = 0.21) with traditional polymer lenses (47 ± 44 cells/mm(2), n = 12) than with silicone hydrogel lenses (69 ± 77 cells/mm(2), n = 41). Lowest to highest mean density of immune cells among lens wearers was as follows: PQ/MAPD solution (49 ± 28 cells/mm(2)), blister pack solution (63 ± 81 cells/mm(2)), PHMB solution (66 ± 44 cells/mm(2)), and peroxide solution (85 ± 112 cells/mm(2)). CONCLUSION: In this pilot study, in vivo confocal microscopy was useful for detecting an elevated immune response associated with soft contact lenses, and for identifying lens-related and solution-related immune responses that merit further research.

Temperature-induced transitions in the structure and interfacial rheology of human meibum.

Meibomian lipids are the primary component of the lipid layer of the tear film. Composed primarily of a mixture of lipids, meibum exhibits a range of melt temperatures. Compositional changes that occur with disease may alter the temperature at which meibum melts. Here we explore how the mechanical properties and structure of meibum from healthy subjects depend on temperature. Interfacial films of meibum were highly viscoelastic at 17°C, but as the films were heated to 30°C the surface moduli decreased by more than two orders of magnitude. Brewster angle microscopy revealed the presence of micron-scale inhomogeneities in meibum films at higher temperatures. Crystalline structure was probed by small angle x-ray scattering of bulk meibum, which showed evidence of a majority crystalline structure in all samples with lamellar spacing of 49 Å that melted at 34°C. A minority structure was observed in some samples with d-spacing at 110 Å that persisted up to 40°C. The melting of crystalline phases accompanied by a reduction in interfacial viscosity and elasticity has implications in meibum behavior in the tear film. If the melt temperature of meibum was altered significantly from disease-induced compositional changes, the resultant change in viscosity could alter secretion of lipids from meibomian glands, or tear-film stabilization properties of the lipid layer.

A preliminary study of silicone hydrogel lens material and care solution bioincompatibilities.

PURPOSE: The study purpose was to evaluate corneal barrier function and staining relative to potential bioincompatibilities. METHODS: This was a randomized double-masked study (n = 25 subjects). Three lens material-care solution combinations were tested: (1) lotrafilcon B/polyhexamethylene biguanide (PHMB)-based multipurpose (MPS) solution (MPS-1); (2) lotrafilcon B/polyquaternium-1 and myristamidopropyl dimethylamine-based solution (MPS-2); and (3) lotrafilcon B and another PHMB-based solution (MPS-3). Saline served as the control. New lenses were soaked in the preserved solutions or saline and then worn for 2 hours before corneal measurements. Barrier function was characterized by the fluorescein penetration rate, corneal amount, both measured with an objective scanning fluorometer. The dye penetration rate ratio, test to control; amount ratio, test to control, and corneal staining were evaluated. RESULTS: The mean rate ratios (± SD) for the combinations were 2.98 (± 3.04), 1.23 (± 1.01), and 1.83 (± 1.77) for MPS-1, MPS-2, and MPS-3 solutions, respectively. Significant ratio differences were found across regimens (P = 0.007); for MPS-1 compared with baseline (P = 0.031) and for MPS-1 compared with MPS-2 (P = 0.007). The statistical results for staining were similar. CONCLUSIONS: Use of an objective quantitative physiological method suggests that significant differences in lens solution bioincompatibilities occur that mirror corneal staining data relative to corneal compromise.

Charge regulation enables anionic hydroxypropyl guar-borate adsorption onto anionic and cationic polystyrene latex.

Reported are adsorption isotherms for guar and hydroxypropyl guar (HPG), with and without the presence of borate ions, onto surfactant free anionic polystyrene latex. Guar and HPG formed adsorbed monolayers on the hydrophobic latex. The presence of borate ions converted the nonionic guar and HPG into an anionic polyelectrolyte. However, there was no measurable influence of bound borate ions on the adsorption of guar or HPG onto anionic, hydrophobic latex. To underscore the unusual behavior of HPG-borate, a sample of HPG was oxidized to introduce carboxyl groups, and the adsorption of the carboxylated HPG onto anionic polystyrene was measured. Unlike HPG-borate, oxidized HPG did not adsorb onto negative polystyrene latex at neutral pH because of electrostatic repulsion. To explain the adsorption of negative HPG-borate onto negative latex, we proposed that as HPG-borate segments approach the latex surface, the negative electrostatic potential near the latex surface induces the detachment of the labile borate groups from HPG.

Not all anionic polyelectrolytes complex with DTAB.

The influence of hydroxypropyl guar (HPG), with and without boric acid, on dodecyltrimethyl ammonium bromide (DTAB) micellization was characterized by surface tension measurements, isothermal titration calorimetry, and small-angle neutron scattering. Although HPG is a nonionic water-soluble polymer, borate ions form weak bonds with HPG, transforming it into an anionic polyelectrolyte, HPG-borate. Surprisingly, the three independent measurements showed that HPG-borate does not promote DTAB micellization or phase separation normally seen when mixing oppositely charged polyelectrolytes and surfactants. However, the neutron scattering results suggested that HPG-borate binds to and flocculates existing DTAB micelles. The unusual behavior of HPG-borate with DTAB was underscored by showing that carboxymethyl guar (CMG) formed precipitates with DTAB.

Reversible flocculation with hydroxypropyl guar-borate, a labile anionic polyelectrolyte.

Cationic polystyrene latex was flocculated with mixtures of hydroxypropyl guar (HPG) and boric acid, which form an anionic polyelectrolyte HPG-borate. Flocculation could be reversed by either lowering pH or by adding fructoseboth procedures remove labile borate ions weakly bound to the HPG chains. Mixtures of phenyl boronic acid (PBA) and HPG also flocculate latex although the range of HPG-PBA concentrations, giving flocculation was much narrower than HPG-borate. The differences were explained by the tendency of borate ion to cross-link HPG chains, whereas PBA is monofunctional and cannot cross-link HPG.

Precorneal residence time of artificial tears measured in dry eye subjects.

PURPOSE: The purpose of this investigation was to measure the precorneal residence time of saline and five marketed artificial tears in dry eye subjects using fluorometry. METHODS: FITC-dextran, 70 kDa molecular weight, was admixed under sterile conditions (0.1% wt/vol) into buffered saline and the marketed artificial tear formulations of varying viscosity. Precorneal residence time (RT) was measured directly in 16 mild to moderate dry eye subjects, classified by sub-type, in a six-way cross-over, masked and randomized study. FITC-dextran tracer decay with a scanning fluorometer was used to estimate the gross RT (i.e., the time in minutes for the signal to return to baseline). RESULTS: All subjects were classified as having non-inflammatory meibomian gland dysfunction except one, who had a mixture of aqueous deficiency and meibomian gland dysfunction. In two separate determinations, the saline RTs were 19.1 +/- 7.4 and 17.6 +/- 8.2 min. The RTs for the formulations varied to some degree by viscosity, with two higher viscosity formulations demonstrating the longest RTs of 36 to 41 min, approximately twice that of saline (p < 0.001 for both 0.4% polyethylene glycol/0.3% propylene glycol, and 1.0% carboxymethylcellulose). An oil emulsion, low viscosity carboxymethylcellulose and moderate viscosity hydroxypropylmethylcellulose-containing formulation were not statistically different from saline (RTs of 18, 22 and 24 min, p values = 0.983, 0.818 and 0.099, respectively). CONCLUSIONS: More than two-fold RT differences were found for the higher viscosity, more muco-adhesive formulations compared to saline. However, other formulations provided RTs close to saline, suggesting that RT is influenced by factors other than simple viscosity. Future studies should examine the interplay of spreading characteristics, pseudoplasticity and muco-adhesion relative to RT to determine the individual and cumulative effects on formulation retention.

Biocide uptake in contact lenses and loss of fungicidal activity during storage of contact lenses.

PURPOSE: With recent outbreaks of Fusarium keratitis related to contact lens wear, studies were conducted to determine the biocide uptake during lens storage, and the resulting effect on antifungal activity of related products. METHODS: ACUVUE 2 (etafilcon A) soft, hydrophilic contact lenses (group IV) were soaked from 1 hour to 7 days in OPTI-FREE Express and OPTI-FREE RepleniSH multipurpose disinfecting solutions with POLYQUAD (polyquaternium-1) and ALDOX (myristamidopropyl dimethylamine) biocides and multipurpose solutions, Bausch & Lomb ReNu with MoistureLoc (Alexidine), ReNu MultiPlus (polyhexamethylene biguanide [PHMB]), and AMO Complete MoisturePLUS (PHMB). Storage solutions were tested to evaluate the effect of preservative uptake on the residual biocide activity against Fusarium solani. RESULTS: Approximately 30% to 60% of the PHMB and Alexidine were depleted by 6 hours, with comparable loss of antimicrobial activity. Decreasing activity was noted with corresponding decreases in active concentration throughout the course of the evaluation. The POLYQUAD systems retained nearly 100% of the biocide and fungicidal activity and maintained their concentration in the solution. CONCLUSIONS: OPTI-FREE Express and OPTI-FREE RepleniSH multipurpose disinfecting solutions maintained fungicidal efficacy after storage of lenses. The Alexidine- and PHMB-based multipurpose solutions tested showed significant uptake of preservative into group IV lenses, resulting in a decrease in the residual activity of the storage solution. The POLYQUAD systems showed a low uptake of biocide and maintained fungicidal efficacy against F. solani.

Hydroxypropyl guar-borate interactions with tear film mucin and lysozyme.

The interactions of hydroxypropyl guar (HPG) with boric acid, lysozyme, and mucin were characterized by rheology, light scattering, electrophoresis, and isothermal titration calorimetry to help understand how HPG interacts with tear film components. Borate binds to guar under pH, temperature, and ionic strength conditions representative of those found in the eye. The HPG-borate complexes behave as anionic polyelectrolytes and thus interact with cationic lysozyme, a major tear film protein, whereas HPG-borate does not appear to bind to mucin, an anionic glycoprotein. The interactions of HPG, borate, lysozyme, and mucin can be explained by two physical interactions: (1) pH-dependent binding of borate to carbohydrates and (2) the electrostatic attraction of oppositely charged macromolecules.

Dynamic wettability properties of a soft contact lens hydrogel.

The wettability of poly[2-hydroxyethyl methacrylate-co-methacrylic acid] (pHEMA-MAA) soft contact lenses was investigated in the absence and presence of block copolymer surfactants and lysozyme using the sessile drop method. The advancing dynamic contact angles (Thetaw/a) values are reported for water as a function of sequential wetting and drying cycles. The Thetaw/a values for the pHEMA-MAA in the absence of surfactant and lysozyme increased from approximately 20 degrees to 100 degrees as the number of cycles increased from two to ten, and they were independent of the pHEMA-MAA bulk water content. The change from the highly hydrophilic to hydrophobic pHEMA-MAA surface could not be reversed using the sequential wetting and drying cycles even under repeated exposures to saline solution. The effect of block copolymer surfactants with different molecular weights (MW) and hydrophilic-lipophilic balance (HLB) values on the pHEMA-MAA wettability were also studied. Low Theta(w/a) values were observed for pHEMA-MAA hydrogels that were treated with T1304 (MW 10500, HLB 14) and T904 (MW 6700, HLB 15). The surface tension data indicated that these surfactants were incompletely desorbed from the pHEMA-MAA and that the rate of desorption was slow in the timescale of the cycling experiments. Comparatively, poor wettability was observed for pHEMA-MAA surfaces presoaked in T304 (MW 1650, HLB 16) and T1107 (MW 15000, HLB 24) as Thetaw/a values greater than 90 degrees were measured for these surfactants. The surface tension data indicated that the rate of desorption of T304 and T1107 from the pHEMA-MAA was rapid and that they had a low affinity to the pHEMA-MAA. High contact angles were observed for the pHEMA-MAA hydrogels treated with lysozyme and also for the T1107 presoaked pHEMA-MAA that was also treated with lysozyme. Zero wetting angles throughout the sequential cycling were observed for the T1304 pre-treated pHEMA-MAA that had been treated with lysozyme. These results suggested that the adsorbed lysozyme on the pHEMA-MAA hydrogel had no significant influence on its wetting properties when the hydrogel was pre-treated with T1304.

Pre-clinical investigation of the efficacy of an artificial tear solution containing hydroxypropyl-guar as a gelling agent.

PURPOSE: Pre-clinical studies of a new artificial tear product (Systane Lubricating Eye Drops Alcon Laboratories, Inc., Fort Worth, TX) containing the novel gelling agent hydroxypropyl-guar (HP-guar) and two demulcents, polyethylene glycol 400 (PEG) and propylene glycol (PG) were conducted to determine the ability of the product to protect ocular surface epithelial cells from desiccation in vivo and in vitro, and to promote recovery of the damaged corneal epithelial barrier in vivo. Other leading artificial tear products were also evaluated as comparators to determine the relative effectiveness of different polymer systems. METHODS: Damage due to desiccation was assessed by measuring corneal uptake of methylene blue compared to untreated corneas. Corneas of anesthetized rabbits were treated with the new artificial tear product and subjected to desiccation by holding the eyelids open for 2 hours with a speculum. Control eyes were subjected to desiccation without application of a tear formulation. To measure recovery of the corneal epithelium from damage, corneas of anethesthetized rabbits were exposed to 0.01% benzalkonium chloride (BAC) for 5 minutes to increase epithelial permeability. The corneas were exposed to the new artificial tear for 1.5 hours followed by measurement of uptake of 5,6 carboxyfluorescein (CF). In the desiccation and CF uptake experiments, the new tear product was also compared to a tear product formulation without HP-guar and to a commercially available artificial tear containing carboxymethyl cellulose (CMC) and Purite. In a third set of experiments, immortalized human corneal epithelial cells and Chang conjunctival cells in culture were exposed to the PEG/PG/HP-guar tear product, the control formulation without HP-guar, a tear formulation preserved with BAC, or the artificial tear containing CMC/Purite for 15min. The tear formulation was removed and the cells were exposed to desiccating conditions in a laboratory safety hood for 10 or 30min. Cell viability was determined using the MTT assay. RESULTS: The in vivo desiccation model, showed that the new tear product, Systane, offered complete protection of the cornea from desiccation (methylene blue uptake not different than naïve control). Following exposure to 0.01% BAC, the new artificial tear product also provided an environment in which the corneal epithelium recovered completely from damage (CF uptake not different than normal, untreated cornea). This level of protection was not observed when corneas were treated with other formulations. Results from the in vitro desiccation procedure indicated that viability of corneal epithelial and Chang cells treated with the PEG/PG/HP-guar product was significantly greater than viability of cells treated with the tear product without HP-guar or the tear products containing BAC or CMC/Purite. CONCLUSIONS: The tear product containing HP-guar, PEG 400 and propylene glycol satisfies several pre-clinical criteria for an appropriate artificial tear formulation. It gives long-term desiccation protection of the intact cornea and also epithelial cells in culture and has no apparent deleterious affects on cells. It also provides conditions in which a damaged corneal epithelium can recover normal barrier function. The combination of ingredients in the formulation appears to provide an effective mucomimetic artificial tear product. These pre-clinical data suggest that the product will be effective in providing superior relief for the dry eye sufferer.

Clinical evaluation of an HP-guar gellable lubricant eye drop for the relief of dryness of the eye.

PURPOSE: To evaluate the efficacy of a new lubricant eye drop containing polyethylene glycol 400 and propylene glycol demulcents with hydroxypropyl-guar as a gelling agent (Test Product) to a system with carboxymethylcellulose (Control Product) for reducing dry eye signs and symptoms. METHODS: Eighty-seven dry eye volunteers were enrolled at seven sites for this six-week, concurrently controlled, double-masked clinical study. RESULTS: The Test Product significantly reduced conjunctival staining (p = 0.025) and temporal corneal staining (p = 0.024) compared to the Control. The Test Product also significantly reduced symptoms of dryness in the morning and evening, compared to the Control (p = 0.015 and p = 0.023, respectively). Subjects in the Test treatment group reported lower frequencies of foreign body sensation and felt their eyes were "refreshed longer" compared to those in the Control group (p = 0.033 and p = 0.037, respectively). CONCLUSIONS: The Test Product was more effective at reducing both the signs and symptoms of dry eye compared to the carboxymethylcellulose containing Control.