Investigation of extended blinks and interblink intervals in subjects with and without dry eye

Background: The purpose of this study was to investigate the occurrence and duration of extended blinks ≥ 70 msec and their associated interblink intervals in normal subjects and in subjects with mild to moderate dry eye. Methods: This single-center, prospective, double-blind study included 11 subjects with dry eye and eight subjects with normal eyes. Extended blinks were defined as lid closure in at least two successive video frames (≥70 msec). Digital video imaging of each subject’s eyes was recorded while the subject viewed a 10-minute documentary. The subjects did not know that blink was the outcome being measured. Following capture, the videos were manually analyzed in a masked fashion for the occurrence of extended blinks. The length of the interblink interval (ie, time between blinks) before and after these extended blinks (the interblink interval ratio) was calculated, as well as differences in lid contact times. Results: The dry eye group had a median extended blink duration which was 2.53 times longer than that of the normal group. For subjects with dry eye, interblink intervals post-extended blink were significantly longer than interblink intervals pre-extended blink (P < 0.001). Interblink intervals did not lengthen significantly in normal subjects. In both groups, the duration of the extended blink was significantly (P = 0.001) and positively correlated with interblink interval ratio (post-extended to pre-extended blink interblink interval), such that for each doubling of extended blink duration, the interblink interval ratio increased by 10%. Blinks longer than one second in duration occurred almost exclusively in subjects with dry eye. Conclusion: This study reports three central findings: blink duration tended to be longer in subjects with dry eye; a lengthening of the interblink interval after an extended blink occurred in subjects with dry eye but not in those without dry eye; and a longer blink duration was associated with a significantly increased interblink interval ratio in all subjects

Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial

Michael A Patane&amp;sup1;, Amy Cohen&amp;sup1;, Stephen From&amp;sup1;, Gail Torkildsen&amp;sup2;, Donna Welch&amp;sup3;, George W Ousler III&amp;sup3;&amp;sup1;Eyegate Pharmaceuticals, Inc, Waltham, MA, USA; &amp;sup2;Andover Eye Associates, Andover, MA, USA; &amp;sup3;Ora, Inc, Andover, MA, USAPurpose: To assess safety and efficacy of EGP-437 (dexamethasone phosphate 40 mg/mL [DP]) in dry eye patients.Methods: The study employed a prospective, single-center, double-masked design utilizing a Controlled Adverse Environment (CAE). Patients (n = 103) with confirmed signs and symptoms of dry eye syndrome were randomized into 1 of 3 iontophoresis treatment groups: 7.5 mA-min at 2.5 mA (DP 7.5, n = 41); 10.5 mA-min at 3.5 mA (DP 10.5, n = 37); or 10.5 mA-min at 3.5 mA (placebo, n = 25). Three CAE visits and 4 follow-up visits occurred over 3 weeks. Patients meeting enrollment criteria received iontophoresis in both eyes after the second CAE exposure (visit 3) and before the third CAE exposure (visit 5). Primary efficacy endpoints were corneal staining and ocular discomfort. Secondary endpoints included tear film break-up time, ocular protection index (OPI), and symptomatology.Results: The DP 7.5 and DP 10.5 treatment groups showed statistically significant improvements in signs and symptoms of dry eye at various time points; however, the primary endpoints were not achieved. The DP 7.5 treatment group exhibited statistically significant improvements in corneal staining (when comparing the differences between study entry and exit, 3 weeks, P = 0.039), OPI (immediately following the second treatment, P = 0.048) and ocular discomfort at follow-up visits (a week after the first treatment, P = 0.032; 24 hours after the second treatment, P = 0.0032). Treatment-emergent adverse events (AEs) were experienced by 87% of patients and were consistent across all treatment groups. Most AEs were mild and no severe AEs were observed.Conclusion: Ocular iontophoresis of EGP-437 demonstrated statistically and clinically significant improvements in signs and symptoms of dry eye syndrome within a CAE model.Keywords: iontophoresis, dry eye, Controlled Adverse Environment (CAE), ocular protection index (OPI

Automated grading system for evaluation of ocular redness associated with dry eye

Background: We have observed that dry eye redness is characterized by a prominence of fine horizontal conjunctival vessels in the exposed ocular surface of the interpalpebral fissure, and have incorporated this feature into the grading of redness in clinical studies of dry eye. Aim To develop an automated method of grading dry eye-associated ocular redness in order to expand on the clinical grading system currently used. Methods: Ninety nine images from 26 dry eye subjects were evaluated by five graders using a 0–4 (in 0.5 increments) dry eye redness (Ora Calibra™ Dry Eye Redness Scale [OCDER]) scale. For the automated method, the Opencv computer vision library was used to develop software for calculating redness and horizontal conjunctival vessels (noted as “horizontality”). From original photograph, the region of interest (ROI) was selected manually using the open source ImageJ software. Total average redness intensity (Com-Red) was calculated as a single channel 8-bit image as R – 0.83G – 0.17B, where R, G and B were the respective intensities of the red, green and blue channels. The location of vessels was detected by normalizing the blue channel and selecting pixels with an intensity of less than 97% of the mean. The horizontal component (Com-Hor) was calculated by the first order Sobel derivative in the vertical direction and the score was calculated as the average blue channel image intensity of this vertical derivative. Pearson correlation coefficients, accuracy and concordance correlation coefficients (CCC) were calculated after regression and standardized regression of the dataset. Results: The agreement (both Pearson’s and CCC) among investigators using the OCDER scale was 0.67, while the agreement of investigator to computer was 0.76. A multiple regression using both redness and horizontality improved the agreement CCC from 0.66 and 0.69 to 0.76, demonstrating the contribution of vessel geometry to the overall grade. Computer analysis of a given image has 100% repeatability and zero variability from session to session. Conclusion: This objective means of grading ocular redness in a unified fashion has potential significance as a new clinical endpoint. In comparisons between computer and investigator, computer grading proved to be more reliable than another investigator using the OCDER scale. The best fitting model based on the present sample, and usable for future studies, was C4=−12.24+2.12C2HOR+0.88C2RED:C4 is the predicted investigator grade, and C2HOR and C2RED are logarithmic transformations of the computer calculated parameters COM-Hor and COM-Red. Considering the superior repeatability, computer automated grading might be preferable to investigator grading in multicentered dry eye studies in which the subtle differences in redness incurred by treatment have been historically difficult to define

Exacerbation of signs and symptoms of allergic conjunctivitis by a controlled adverse environment challenge in subjects with a history of dry eye and ocular allergy

Background: The goal of this study was to assess the effect of a controlled adverse environment (CAE) challenge on subjects with both allergic conjunctivitis and dry eye. Methods: Thirty-three subjects were screened and 17 completed this institutional review board-approved study. Subjects underwent baseline ocular assessments and conjunctival allergen challenge (CAC) on days 0 and 3. Those who met the ocular redness and itching criteria were randomized to receive either the controlled adverse environment (CAE) challenge (group A, n = 9) or no challenge (group B, n = 8) at day 6. Thirty minutes after CAE/no-CAE, subjects were challenged with allergen and their signs and symptoms graded. Exploratory confocal microscopy was carried out in a subset of subjects at hourly intervals for 5 hours post-CAC on days 3 and 6. Results: Seven minutes post-CAC, subjects exposed to the CAE had significantly greater itching (difference between groups, 0.55 ± 0.25, P = 0.028), conjunctival redness (0.59 ± 0.19, P = 0.002), episcleral redness (0.56 ± 0.19, P = 0.003) and mean overall redness (mean of conjunctival, episcleral, and ciliary redness, 0.59 ± 0.14, P < 0.001). The mean score at 7, 15, and 20 minutes post-CAC for conjunctival redness (0.43 ± 0.17, P = 0.012), episcleral redness (0.49 ± 0.15, P = 0.001), mean overall redness in all regions (0.43 ± 0.15, P = 0.005), and mean chemosis (0.20 ± 0.08, P = 0.017) were also all significantly greater in CAE-treated subjects. Confocal microscopic images of conjunctival vessels after CAC showed more inflammation in CAE-treated subjects. Conclusion: In subjects with both dry eye and allergic conjunctivitis, exposure to adverse environmental conditions causes an ocular surface perturbation that can intensify allergic reactions

Blink patterns and lid-contact times in dry-eye and normal subjects

Purpose To classify blinks in dry eye and normal subjects into six subtypes, and to define the blink rate and duration within each type of blink, as well as the total lid-contact time/minute. Materials and methods This was a single-centered, prospective, double-blind study of eleven dry-eye and ten normal subjects. Predefined subjects watched a video while blinks were recorded for 10 minutes. Partial blinks were classified by percentage closure of maximal palpebral fissure opening: 25%, 50%, 75%. Complete blinks were characterized as full (>0 seconds), extended (>0.1 seconds), or superextended (>0.5 seconds). The mean duration of each type of blink was determined and standardized per minute as total lid-contact time. Results: Total blinks observed were 4,990 (1,414 normal, 3,756 dry eye): 1,809 (50.59%) partial and 1,767 (49.41%) complete blinks among dry-eye subjects versus 741 (52.90%) partial and 673 (47.60%) complete blinks among normal subjects. Only superextended blinks of ≥0.5-second duration were significantly more frequent in dry-eye subjects than normals (2.3% versus 0.2%, respectively; P=0.023). Total contact time was seven times higher in dry-eye subjects than normals (0.565 versus 0.080 seconds, respectively; P0.1 second), the average contact time (seconds) was four times longer in dry-eye versus normal subjects (2.459 in dry eye, 0.575 in normals; P=0.003). Isolating only superextended blinks (>0.5 seconds), average contact time was also significantly different (7.134 in dry eye, 1.589 in normals; P<0.001). The contact rate for all full closures was 6.4 times longer in dry-eye (0.045 versus 0.007, P<0.001) than normal subjects. Conclusion: Dry-eye subjects spent 4.5% of a minute with their eyes closed, while normal subjects spent 0.7% of a minute with their eyes closed. Contact time might play a role in the visual function decay associated with increased blink rates

Blink patterns and lid-contact times in dry-eye and normal subjects

Purpose To classify blinks in dry eye and normal subjects into six subtypes, and to define the blink rate and duration within each type of blink, as well as the total lid-contact time/minute. Materials and methods This was a single-centered, prospective, double-blind study of eleven dry-eye and ten normal subjects. Predefined subjects watched a video while blinks were recorded for 10 minutes. Partial blinks were classified by percentage closure of maximal palpebral fissure opening: 25%, 50%, 75%. Complete blinks were characterized as full (>0 seconds), extended (>0.1 seconds), or superextended (>0.5 seconds). The mean duration of each type of blink was determined and standardized per minute as total lid-contact time. Results: Total blinks observed were 4,990 (1,414 normal, 3,756 dry eye): 1,809 (50.59%) partial and 1,767 (49.41%) complete blinks among dry-eye subjects versus 741 (52.90%) partial and 673 (47.60%) complete blinks among normal subjects. Only superextended blinks of ≥0.5-second duration were significantly more frequent in dry-eye subjects than normals (2.3% versus 0.2%, respectively; P=0.023). Total contact time was seven times higher in dry-eye subjects than normals (0.565 versus 0.080 seconds, respectively; P0.1 second), the average contact time (seconds) was four times longer in dry-eye versus normal subjects (2.459 in dry eye, 0.575 in normals; P=0.003). Isolating only superextended blinks (>0.5 seconds), average contact time was also significantly different (7.134 in dry eye, 1.589 in normals; P<0.001). The contact rate for all full closures was 6.4 times longer in dry-eye (0.045 versus 0.007, P<0.001) than normal subjects. Conclusion: Dry-eye subjects spent 4.5% of a minute with their eyes closed, while normal subjects spent 0.7% of a minute with their eyes closed. Contact time might play a role in the visual function decay associated with increased blink rates

Use of the Controlled Adverse Environment (CAE) in Clinical Research: A Review

The many internal and external factors that contribute to the pathophysiology of dry eye disease (DED) create a difficult milieu for its study and complicate its clinical diagnosis and treatment. The controlled adverse environment (CAE®) model has been developed to minimize the variability that arises from exogenous factors and to exacerbate the signs and symptoms of DED by stressing the ocular surface in a safe, standardized, controlled, and reproducible manner. By integrating sensitive, specific, and clinically relevant endpoints, the CAE has proven to be a unique and adaptable model for both identifying study-specific patient populations with modifiable signs and symptoms, and for tailoring the evaluation of interventions in clinical research studies

RGN-259 (thymosin β4) improves clinically important dry eye efficacies in comparison with prescription drugs in a dry eye model.

This study evaluated the clinical activity of RGN-259 (thymosin β4) in comparison with cyclosporine A (CsA), diquafosol (DQS), and lifitegrast (LFA) in a murine model of dry eye. The model was NOD.B10-H2b mice in a 30-40% humidified environment together with daily scopolamine hydrobromide injections for 10 days. After desiccation stress, all drugs were evaluated after 10 treatment days. RGN-259 increased tear production similar to that in the DQS- and LFA-treated mice while CsA was inactive. RGN-259 improved corneal smoothness and decreased fluorescein staining similar to that of LFA group while CsA and DQS were inactive. Corneal epithelial detachment was reduced by RGN-259, and DQS and LFA showed similar activity but the CsA was inactive. RGN-259 increased conjunctival goblet cells and mucin production comparable to that seen with CsA, while DQS and LFA were inactive. RGN-259 reduced the over-expression of inflammatory factors comparable to that with CsA and LFA, while DQS was inactive. RGN-259 increased mucin production comparable to that observed with CsA, while DQS and LFA were inactive. In conclusion, RGN-259 promoted recovery of mucins and goblet cells, improved corneal integrity, and reduced inflammation in a dry eye mouse model and was equal to or more effective than prescription treatments