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Dry eye disease (DED) affects up to one-third of the global population. Traditional therapies, including topical lubricants, have been employed with variable success in the treatment of DED. Recently, neurostimulation of the lacrimal functional unit (LFU) has emerged as a promising alternative therapy for DED. In this review, we describe the neuroanatomical and pathophysiological considerations of DED and the LFU that make neurostimulation a viable therapeutic alternative. We further detail the various neurostimulatory approaches taken thus far—from implanted stimulators to external devices to chemical neurostimulation. Existing studies reveal the strengths of the neurostimulatory approach in increasing tear volume and improving dry eye symptoms, but further studies are needed to elucidate its true potential in treatment of DED.

Impaired tear production - a common sign of keratoconjunctivitis sicca (KCS) - is associated with qualitative or quantitative tear deficiency. OTX-101 0.09% is a novel, nanomicellar formulation of cyclosporine A approved in the US for increasing tear production in patients with KCS. We present a pooled analysis of the phase 2b/3 and phase 3 studies evaluating the effect of OTX-101 on tear production in a subgroup of patients with keratoconjunctivitis sicca with severely impaired tear production (Schirmer's score5 mm in either eye at baseline).In these randomized, double-masked studies, patients instilled 1 drop OTX-101 or vehicle per eye twice daily for 84 days. Pooled efficacy endpoints included percent (%) of patients with ≥10 mm change from baseline and mean change from baseline in Schirmer's score at day 84. Pooled safety endpoints included adverse event monitoring.Subgroup analyses included 133 and 113 patients receiving OTX-101 and vehicle, respectively. Mean baseline (BL) Schirmer's score ± standard deviation was 2.7 ± 1.2 for OTX-101 and 2.5 ± 1.1 mm for vehicle (OTX-101 administered twice daily for 84 days significantly improved tear production vs vehicle in patients with severely impaired tear production, as evidenced by significantly larger proportion of patients with ≥10 mm increases from baseline and higher mean change from baseline in Schirmer's scores.

Infrared (IR) thermographic assessment of ocular surface temperature (OST) is gaining interest as an adjuvant method to evaluate the ocular surface. It is a quick, non-invasive test that causes minimal, if any, discomfort to patients. The purpose of this article was to summarize research on how OST relates to tear film parameters and dry eye disease (DED). PubMed, Google Scholar, and Scopus searches for specific terms were carried out and eligible articles reviewed. OST of the central cornea is ~34-35°C when measured as a single time-point (typically right after a blink). Dynamically, OST values decrease over time at a rate of ~ −0.01 °C/s in healthy eyes. Single time-point OST values are impacted by temperature, with positive correlations noted with both ambient (1°C↓ results in ~0.16°C↓ in OST) and body (1°C↑ results in ~0.98°C↑ in OST) temperature. Single time-point OST values are also impacted by tear parameters, with negative correlations noted with tear break-up time (TBUT; r=−0.61) and positive correlations with lipid layer thickness (~r=0.50). Dynamically, the rate of OST cooling over the interblink period correlates with various tear parameters including Schirmer’s test scores (r=−0.39), tear meniscus height (r=−0.52) and the rate of tear film break-up (r=−0.74). These data imply that OST decreases more rapidly in individuals with greater tear production, larger tear volumes, and shorter tear break-up times (faster rates of tear film break-up). There are discrepancies in relationships between OST and DED across studies, which is not surprising given that DED encompasses a number of different phenotypic presentations. However, most studies found that OST decreases at a more rapid rate in DED vs. control groups. As such, cooling rate may have utility as a screening tool in DED in combination with established point-of-care tests.

Purpose To evaluate the optical quality and tear film quality in patients with dry eye syndrome (DES) before and after using an intranasal neurostimulation device to stimulate tear production. Methods Cross-sectional review of 33 eyes in 21 patients with DES who underwent optical quality and tear film analysis as part of their routine dry eye evaluation pre- and post-neurostimulation trial in office. Optical quality was assessed by measuring the objective scattering index (OSI) and modulation transfer function (MTF). The time to blink and mean tear film OSI were used to analyze the tear film. Results Optical quality after the use of the intranasal neurostimulator improved with an average decrease (improvement) in OSI of 0.30±0.68 (P=0.015) and an average increase (improvement) in MTF of 2.12±9.2 (P=0.15). Pre-intranasal neurostimulation OSI had a positive correlation with age (Spearman's rho 0.60, p < 0.001), while MTF had a negative correlation (Spearman's rho -0.38, p = 0.03). Pre-intranasal neurostimulation OSI had a negative correlation with MTF (Spearman's rho -0.85, p < 0.001) and a positive correlation with tear film mean OSI (Spearman's rho 0.85, p

Keratoconjunctivitis sicca (KCS) is a multifactorial disease characterized by tear hyperosmolarity, inflammation, and ocular surface damage. Cyclosporine A (CsA) is used as an effective disease-modifying agent to improve the signs and symptoms of KCS by reducing inflammation, which interferes with tear production. This review provides an overview of efficacy, safety, and limitations of currently marketed topical CsA formulations-including CsA ophthalmic emulsion, cationic nanoemulsion, and aqueous nanomicelles-and highlights newer technologies for controlled ocular delivery of CsA and their clinical implications. Long available emulsion formulations of CsA are oil-based and have several limitations, including slow onset of efficacy and low intraocular penetration and bioavailability. Aqueous CsA nanomicelle carriers produce rapid improvement in objective signs of KCS such as corneal and conjunctival staining as early as 4 weeks and have acceptable safety profiles. CsA formulations using semifluorinated alkanes or polyaphrons are currently in clinical development, having recently completed Phase 2 studies. Other carriers for CsA currently in the preclinical phase include microemulsions, polymeric aqueous and lyophilized micelles, and hydrogels; these novel formulations have yet to undergo clinical trials. Formulations that improve tissue availability of CsA may be beneficial in clinical practice by providing faster onset of relief and improving patient adherence.

Purpose To determine whether reliance on eyelid margin vascularization as a diagnostic criterion for meibomian gland dysfunction (MGD) results in underdiagnosis of MGD in individuals with dark skin pigmentation. Patients and methods This cross-sectional study enrolled consecutive cornea clinic patients in Buffalo, New York. Eyelid margin vascularization was graded qualitatively from slit-lamp photos. Skin pigmentation was quantified from digital photos using red/green/blue (RGB) pixel analysis and dichotomized using the RGB median. MGD was defined as abnormal quantity or quality of meibum or increased pressure required to express meibum. Additional testing included infrared meibography, Schirmer's testing, and a dry eye questionnaire. Sensitivity of MGD diagnosis by visualization of vascularization, compared to diagnosis by expression of meibum, was estimated with and without stratification by skin pigmentation. Results Among 47 participants, 15-79 years old, meibomian gland truncation/dropout, abnormal tear production, and dry eye symptoms affected individuals of all skin pigmentations. Eyelid margin vascularization was less common in subjects with dark (n=21%) compared to light pigmentation (65%; p=0.002), although the prevalence of MGD assessed via clinical evaluation did not vary significantly between those groups. Use of eyelid margin vascularization alone was not sensitive (33%) for MGD diagnosis. The sensitivity was 17% when limited to those with dark pigmentation. Conclusion Our findings highlight the importance of gland expression and suggest limiting reliance on eyelid margin vascularization for MGD diagnosis, especially in those with dark eyelid skin pigmentation.

Masahiko Ayaki, Motoko Kawashima, Miki Uchino, Kazuo Tsubota, Kazuno Negishi Department of Ophthalmology, Keio University, Shinjuku, Tokyo, Japan Purpose: The purpose of this study was to evaluate the influence of seasons on the signs and symptoms of dry eye disease (DED). Methods: This is a cross-sectional, case-control study, and participants were non-DED subjects (n=1,916, mean age 54.4±14.4 years) and DED patients (n=684, 54.2±12.1 years) visiting six eye clinics at various practices and locations in Japan. We evaluated the signs and symptoms of DED and the seasons with the most severe results were compared to those with the least severe results in both groups. Main outcome measures were differences in the severity of the signs and symptoms of DED between the most and least severe seasons. Results: The majority of DED symptoms were most severe during spring and least severe in summer. Significant differences between these two seasons were found for irritation (P=0.001), pain (P=0.007), blurring (P=0.000), and photophobia (P=0.007) in the DED group. Superficial punctate keratopathy (P=0.001) and tear break-up time (BUT; P=0.000) results also indicated that DED was most severe in spring. In contrast, fewer patients had low Schirmer test results in spring, although this was not statistically significant (P=0.061). Conclusion: Our results demonstrated that the severity of DED is seasonal, which may explain the increase of short BUT-type DED cases observed in spring when air pollen counts are highest. Keywords: dry eye disease, seasonality, tear break-up time, cornea, ocular surface, tear production, hay fever, air pollen, allergic conjunctivitis

To determine the tear osmolarity in patients with tearing secondary to dry eye and other pathologies, and to determine the prevalence of dry eye disease among patients with tearing in an oculoplastics setting.108 eyes of 54 patients with a chief complaint of tearing were prospectively recruited. Subjects were excluded if they used eye drops or contact lenses within 2 hours of assessment, had a history of refractive surgery, an active ocular allergy, or evidence of a systemic disease which affects tear production. A full medical and ocular history was taken with a complete eye exam pertinent to dry eye. Tear osmolarity was measured using the TearLab device. A clinical diagnosis of dry eye was made based on findings, without reference to tear osmolarity.Among 86 eyes symptomatic for tearing, 32 eyes had dry eye disease (37%). Patients with dry eye had a significantly higher median tear osmolarity compared to that in patients with other diagnoses (308 mOsm/L vs. 294 mOsm/L, p 0.0001). At a cut-off of 308 mOsm/L, tear osmolarity resulted in a sensitivity of 50% and a specificity of 88% for the diagnosis of dry eye.A significant proportion of patients with tearing in an oculoplastics practice had dry eye disease. The high specificity of tear osmolarity may render it a useful tool to rule in dry eye disease and may assist the oculoplastic surgeon in more accurately determining the cause of tearing.

Pepper spray is used both by civilians and by law enforcement. Burning sensation occurs when exposed to skin, pain and temporary blindness occurs when exposed to the eyes. This study focused on the effect of pepper spray on lacrimal tear production and subsequently on corneal sensitivity in a large group after an intense exposure.Ninety-six people who were exposed to pepper spray during the Gezi park protests volunteered. Subjects were asked if they wore any protective goggles and if they irrigated their eyes after exposure. They were asked to record their symptoms regarding dry eye in a standardized questionnaire. Schirmer I and II tests were performed.Eighty-two people wore protective goggles during exposure, whereas 14 people did not have any protection. Both Schirmer results in unprotected subjects were significantly lower than that in protected subjects. Schirmer I and II results of unprotected subjects were not statistically different, whereas they were statistically different in protected subjects. Thirty-five percent of unprotected subjects and 24% of protected subjects expressed symptoms of dry eye.The active ingredient of pepper spray is oleoresin capsicum. It is randomly diffused to polymodal nerve terminals, leading to opening of non-selective cationic channels and block neuronal transmission. The lower results of both Schirmer in unprotected group emphasize the importance of a protective Google glass around the eyes during exposal, serving as a barrier minimalizing the contact of the spray with the eyes. The combination of the low results and lack of symptoms could suggest that corneal reflex lacrimation in our subjects was not abundant enough. The findings of this study could not fully represent long term findings but it could be assumed that our findings could be indicative of the sensory denervation and alterations demonstrated in studies investigating the long term effects of oleoresin capsicum.

The term “dry eye” has evolved over the past 2 decades to include both symptoms (visual complaints and dysesthesias) and signs (aqueous and evaporative deficiency) of disease. Dry eye is common in older individuals and a source of morbidity. Confusion arises, however, on what combination of symptoms and signs constitute “dry eye” and how to best individualize treatment in patients. This editorial will discuss the evolution of dry eye, discuss potential sub-categorizations for the disease, and discuss their potential implications on treatment.

The term functional nasolacrimal duct obstruction (FNLDO; watering with patent drainage) is misleading as it implies occluded drainage and solely nasolacrimal duct pathology. ‘Normal’ tear dynamics cannot be defined, comprising of a complex interplay of tear production, evaporation and drainage, with variability due to anatomical differences, variation in movements, environmental factors and age-related changes. FNLDO is due to several scenarios and therefore comprises an inhomogeneous group of patients for whom treatment should, logically, be sequential. First, medical measures to reduce inflammatory mediators include bathing the ocular surface and drainage system; next, lateral canthus elevation where lateral tear spillage is present; if medial spillage continues, dacryocystorhinostomy is performed; and last, secondary placement of a canalicular bypass tube will generally control symptoms where they persist after dacryocystorhinostomy.

An accurate measurement of tear production is clinically important in the diagnosis and monitoring of dry eye conditions. Re-examination of the results of Schirmer test indicated that the rate of tear secretion decreased with advancing age. Fluorophotometry revealed that the tear turnover rate also decreased with age. Then reappraisal was made on the clinical tests for dry eye syndrome. The non-invasive tear film breakup time (NIBUT) showed a reasonable level of accuracy with a cut-off value of 5 seconds (sensitivity 95.9% and specificity 90.8%). The concentration of lactoferrin showed an optimal level of accuracy with a cut-off value of 1.1 mg/ml (sensitivity 79.4% and specificity 78.3%). A study of the ocular surface area revealed that the decrease of ocular surface area was related to the values of NIBUT in normal subjects younger than 50 years of age. The present findings suggested that a combination of these clinical tests was needed for the diagnosis of dry eye syndrome.

Background: As in many parts of the world, the Schirmer tear test is the main test used by optometrists in Saudi Arabia for assessing adequacy of tear production. Variability of the test has been reported in different ethnic groups but not in Arabs. This paper looks at the mean and repeatability of the values obtained by the Schirmer test in a normal Arab population Method: The test was performed on the right eyes of 23 young adult Saudi male subjects at five visits over two weeks. Result: Results showed that for each subject the test values were not repeatable, varying widely over the period of evaluation. The mean value was estimated at 10.6 mm and the 95 per cent confidence limits were 7.9 and 13.3 mm. It was also established that the greater the amount of tears, the greater the variability. Conclusion: This study supports the claim that the Schirmer test is not repeatable and hence is unreliable. Therefore, caution should be exercised in employing it for clinical diagnosis. (Clin Exp Optom 1995; 78: 5: 190–193)

Cotton theread tests (CTT) were perfomed on a group of chinese living in Hong Kong (HK-Chinese) and a group of Caucasians living in the United Kingdom (UK-Caucasian). The Cotton thread was inserted into the lower conjuctival sac and the amount of wetting recorded after one minute to eye closure. The CTT was repeated for each subject at Intervals of five, 10 and 15 minutes between successive measurements on the same day to investigate the required recovery time after one CTT before the next CTT can be performed. CTT obtained five minutes after the first CTT were significantly different from the baseline value. In a second experiment, two CTT measurements were performed, 10 minutes apart, on another group of HK-Chinese. The result of both experiments show that for both HK-Chinese and UK-Caucassian, 10 minutes is a sufficient time interval for tear recovery after the CTT.

Francis Mah,1 Mark Milner,2 Samuel Yiu,3 Eric Donnenfeld,4 Taryn M Conway,5 David A Hollander51University of Pittsburgh, Pittsburgh, PA, 2The Eye Center, Hamden, CT, 3University of Southern California, Los Angeles, CA, 4Ophthalmic Consultants of Long Island and Connecticut, Rockville Centre, New York, NY, 5Allergan Inc, Irvine, CA, USABackground: Chronic dry eye disease often requires long-term therapy. Tear film alterations in the setting of dry eye may include reduced tear volume as well as an increase in inflammatory cytokines and osmolarity. Topical cyclosporine ophthalmic emulsion 0.05% (Restasis®; Allergan Inc, Irvine, CA) is indicated to increase tear production in patients with dry eye and reduced tear production presumed to be due to ocular inflammation. This study was designed to evaluate the efficacy of a second trial of topical cyclosporine in patients with dry eye who were previously considered treatment failures.Materials and methods: This multicenter (three cornea practices) retrospective chart review evaluated clinical outcomes in patients with dry eye who received a second trial of cyclosporine after a prior treatment failure, defined as prior discontinuation of topical cyclosporine after less than 12 weeks.Results: Thirty-five patients, most of whom were female (71.4%) and Caucasian (62.9%), were identified. Prior discontinuation was most commonly due to burning/stinging (60%). The median duration of second treatment was 10 months (range 1 week to 45 months). Physician education was provided in the second trial in 97.1% of cases. At initiation of the second trial of cyclosporine, 10 (28.6%) patients received courses of topical corticosteroids. Physicians reported on a questionnaire that 80% of patients achieved clinical benefit with a second trial of cyclosporine.Conclusion: A repeat trial with topical cyclosporine can achieve clinical success. Direct patient education via the physician and staff may be key to success. Proper patient education may overcome adherence issues, particularly with respect to the need for long-term treatment of chronic dry eye. This study has the usual limitations associated with a retrospective chart review, and future prospective studies are warranted.Keywords: cyclosporine, Restasis®, dry eye, tear cytokines, tear hyperosmolarity, corneal staining, keratoconjunctivitis sicca