Cecilia Chao

The role of corneal innervation in LASIK-induced neuropathic dry eye.

Almost half the patients who undergo laser in situ keratomileusis (LASIK) experience dry eye following the procedure. However, the etiology of LASIK-induced dry eye is unclear. The purpose of this review is to examine and summarize the current evidence for the etiology of LASIK-induced dry eye, with a focus on ocular surface sensitivity and corneal innervation. Evidence suggests that the alteration of corneal nerves after LASIK is the most likely cause of the subjective symptoms of LASIK-induced dry eye, even though corneal sensitivity and the clinical indicators of dry eye return to apparently normal values within a year due to the partial recovery of the corneal nerve plexus. The hypothesis is explored that dry eye symptoms following LASIK may result from abnormal sensation due to LASIK-induced corneal neuropathy. Other factors, such as alterations in conjunctival goblet cell density, might also contribute to the symptoms and signs of LASIK-induced dry eye. Inter-relationships between nerve morphology, tear neuropeptide levels and dry eye require further investigation. A better understanding of this phenomenon may result in improved management of post-LASIK dry eye.

Ocular surface sensitivity repeatability with Cochet-Bonnet esthesiometer.

Purpose To determine the repeatability of ocular surface threshold measurements using the Cochet-Bonnet esthesiometer on the same day and 3 months apart. Methods Two separate studies were conducted to determine the repeatability of ocular surface threshold measurements made on the same day (n = 20 subjects) and 3 months apart (n = 29 subjects). The Cochet-Bonnet esthesiometer was used to measure corneal and inferior conjunctival thresholds using the ascending method of limits. The pressure exerted by the Cochet-Bonnet esthesiometer was determined using an analytical balance, for both the 0.08- and 0.12-mm-diameter filaments. This calibration was then used to convert filament length measurements to pressure. Repeatability was determined using a Bland and Altman analysis. Results The pressure exerted at each filament length differed between the two filament diameters. The measured pressure also differed from values provided by the manufacturer. Repeatability of threshold measurements at the central cornea was shown to be good, with better repeatability for same-day measurements (coefficient of repeatability [CoR] = ±0.23 g/mm2) than for those 3 months apart (CoR = ±0.52 g/mm2). Threshold measurements at the inferior conjunctiva, in contrast, were poorly repeatable (CoR = ±12.78 g/mm2). Conclusions Cochet-Bonnet esthesiometry is repeatable when performed on the central cornea on the same day and 3 months apart, but this instrument is not recommended for conjunctival threshold measurements.

Focused Tortuosity Definitions Based on Expert Clinical Assessment of Corneal Subbasal Nerves.

PURPOSE We examined agreement among experts in the assessment of corneal subbasal nerve tortuosity. METHODS Images of corneal subbasal nerves were obtained from investigators at seven sites (Auckland, Boston, Linköping, Manchester, Oslo, Rostock, and Sydney) using laser-scanning in vivo confocal microscopy. A set of 30 images was assembled and ordered by increasing tortuosity by 10 expert graders from the seven sites. In a first experiment, graders assessed tortuosity without a specific definition and performed grading three times, with at least 1 week between sessions. In a second experiment, graders assessed the same image set using four focused tortuosity definitions. Intersession and intergrader repeatability for the experiments were determined using the Spearman rank correlation. RESULTS Expert graders without a specific tortuosity definition had high intersession (Spearman correlation coefficient 0.80), but poor intergrader (0.62) repeatability. Specific definitions improved intergrader repeatability to 0.79. In particular, tortuosity defined by frequent small-amplitude directional changes (short range tortuosity) or by infrequent large-amplitude directional changes (long range tortuosity), indicated largely independent measures and resulted in improved repeatability across the graders. A further refinement, grading only the most tortuous nerve in a given image, improved the average correlation of a given graders ordering of images with the group average to 0.86 to 0.90. CONCLUSIONS Definitions of tortuosity specifying short or long-range tortuosity and considering only the most tortuous nerve in an image improved the agreement in tortuosity grading among a group of expert observers. These definitions could improve accuracy and consistency in quantifying subbasal nerve tortuosity in clinical studies.

Long-term Effects of LASIK on Corneal Innervation and Tear Neuropeptides and the Associations With Dry Eye.

PURPOSE To investigate the associations between dry eye, corneal nerves, and tear neuroptides in dry eye after LASIK. METHODS A single visit cross-sectional study was performed. Twenty participants who had LASIK more than 12 months prior and 20 healthy participants were recruited. Ocular comfort, tear functions, ocular surface sensitivity, basal tear collection, and corneal nerve morphology assessments were conducted. Tear substance P and calcitonin gene-related peptide (CGRP) concentrations were determined using ELISAs. Differences in variables between groups were examined using an independent t test or Mann-Whitney U test, as appropriate. Associations between variables in the post-LASIK group were examined using a Spearmans correlation test. A P value of less than .05 was considered significant. RESULTS Central corneal nerve morphology parameters were all altered in the post-LASIK group (P < .05). Higher ocular discomfort (P = .01), tear CGRP concentration (P = .001), and conjunctival sensitivity (P < .009) were found in the post-LASIK group. There was a positive association between dry eye symptoms and superior corneal sensitivity (P = .51, P = .02) and tear substance P concentration (P = .52, P < .03). CONCLUSIONS This study provides evidence of the association between tear neuropeptides, conjunctival sensitivity, and symptoms in symptomatic patients after LASIK. The differences in nerve morphology, neuropeptide, and ocular surface sensitivity between symptomatic and asymptomatic patients after LASIK are required to better understand the mechanism of dry eye after LASIK. [J Refract Surg. 2016;32(8):518-524.].

Development of a chinese version of the ocular comfort index.

PURPOSE Dry eye is common in Asian populations, but there are limited validated instruments available to assess ocular symptoms within these populations. This study aimed to develop and assess the psychometric properties of a Chinese version of the ocular comfort index (OCI-C). METHODS The OCI was translated and back translated by 32 bilingual volunteers and a preliminary OCI-C was produced for analysis; 165 bilingual volunteers completed both the OCI and the preliminary OCI-C. The item scores for preliminary OCI-C were compared with the OCI using Cronbachs α. Repeatability of the total score of OCI-C was evaluated in a subgroup of 20 participants after a week by calculating the coefficient of repeatability (CoR) and intraclass correlation coefficient (ICC) for the OCI-C score; 322 subjects, including 81 dry eye subjects, completed the OCI-C to verify the sensitivity in dry eye diagnosis. Rasch analysis was used to estimate interval measures from ordinal Likert score and assess psychometric property of item-fit, category function, targeting of items to subjects, and person separation reliability. RESULTS Cronbachs α for all items was above 0.85. The CoR was ± 5.84 and the ICC was 0.96 (95% confidence interval 0.91-0.98). The total score of OCI-C was able to differentiate dry eye (40.0) with non-dry eye (30.2) (P < 0.0001). In the Rasch analysis model, the OCI-C showed robust psychometric properties for item-fit and category calibration: person-separation reliability: 2.47 and item reliability: 8.42. CONCLUSIONS The psychometric properties of the OCI-C are comparable with the OCI and the instrument is appropriate as a diagnostic tool and to determine the severity of dry eye in this population.

Corneal Nerve Morphology, Sensitivity, and Tear Neuropeptides in Contact Lens Wear

PURPOSE To determine tear neuropeptide levels in contact lens wearers and non-wearers, and to examine relationships with indices of corneal innervation, tear function, and ocular discomfort. METHODS A cross-sectional, single-visit, investigator-masked pilot study. Assessments included Ocular Comfort Index (OCI), central and mid-peripheral corneal nerve density and morphology (HRT-Rostock), corneal sensitivity (Cochet-Bonnet aesthesiometer), tear Substance P and calcitonin gene-related peptide (CGRP) concentration (ELISA), in situ tear osmolarity (TearLab), tear secretion (Phenol Red Thread), and noninvasive tear break-up time (NITBUT; Keeler Tearscope). Groups were compared using independent t-test or Mann-Whitney U test, and regional differences assessed using paired t-tests. Associations were analyzed using Pearson or Spearman correlation. Significance was determined at P < .05. RESULTS Twenty contact lens wearers (7M:13F, 32 ± 5 years) and 20 non-wearers (7M:13F, 31 ± 5 years) completed the study. OCI score was numerically higher in lens wearers (32.27 ± 5.33) than non-wearers (27.66 ± 9.94). Tear osmolarity was higher [298.0 (IQR 291.0-309.8) vs. 288.5 (282.3-298.3) mOsmol/L; P = .01] whereas NITBUT was lower (9.8 ± 3.4 vs. 13.8 ± 5.6 s; P = .01) in lens wearers compared with non-wearers. Tear neuropeptide concentrations were not different between groups [Substance P 4.29 ng/ml (IQR 1.57-6.05), CGRP 14.89 ng/ml (5.08-59.26)], and there were no differences in nerve morphology or ocular surface sensitivity. Higher nerve density, interconnections, and tortuosity were observed in the central cornea than mid-peripherally (P < .05). OCI score was moderately associated with nerve tortuosity (r = 0.42, P = .01). CGRP was associated with central nerve density (ρ = 0.38, P = .02), as was tear secretion (r = -0.37, P = .02). Nerve interconnections were strongly associated with corneal sensitivity (ρ = 0.64, P < .001). CONCLUSIONS Relationships were demonstrated between nerve density, tear CGRP, and corneal sensitivity. Markers of corneal neurobiology and sensory function do not appear to be altered in contact lens wear despite worse tear function (osmolarity and stability) in lens wearers. This suggests that mechanisms other than overt changes in corneal innervation regulate tear function during lens wear. The relationship between nerve tortuosity and ocular discomfort requires elucidation.

Non-invasive objective and contemporary methods for measuring ocular surface inflammation in soft contact lens wearers – A review

Contact lens wear is one of the primary risk factors for the development of ocular surface inflammatory events. The purpose of this review is to examine and summarize existing knowledge on the mechanisms of contact lens related ocular surface inflammation and the evidence for the effectiveness of current objective methods to measure ocular surface inflammation. Contact lens wear is postulated to trigger an inflammatory response on the ocular surface due to mechanical, chemical, hypoxic stress, or by the introduction of microbes and their toxins. Apart from the traditional signs of inflammation, such as swelling, oedema, redness and heat, on the ocular surface, other methods to measure ocular surface inflammation in sub-clinical levels include tear inflammatory mediator concentrations, conjunctival cell morphology, and corneal epithelial dendritic cell density and morphology. Tear inflammatory mediator concentrations are up- or down-regulated during contact lens wear, with or without the presence of associated inflammatory events. There is higher conjunctival cell metaplasia observed with contact lens wear, but changes in goblet cell density are inconclusive. Dendritic cell density is seen to increase soon after initiating soft contact lens wear. The long term effects of contact lens wear on dendritic cell migration in the cornea and conjunctiva, including the lid wiper area, require further investigation. Currently patient factors, such as age, smoking, systemic diseases and genetic profile are being studied. A better understanding of these mechanisms may facilitate the development of new management options and strategies to minimize ocular surface inflammation related to contact lens wear.

Changes in Tear Cytokine Concentrations Following Discontinuation of Soft Contact Lenses-A Pilot Study.

Purpose: This study investigated changes in selected tear cytokine concentrations (IL-1&bgr;, IL-1Ra, IL-6, IL-10, IL-12 (p70), and TNF-&agr;) after a 1-week washout from soft contact lens wear (CLW), and the repeatability of cytokine measurements using custom multiplex assays. Methods: A total of 10 subjects completed this 6-visit (immediately following contact lens removal, and after 1, 2, 3, 4, and 7 [±1] days without CLW) pilot study. Approximately 20 to 30 &mgr;L of pooled basal tears were collected from both eyes at each visit. Two custom multiplex assays were used by two operators to quantify the concentration of tear cytokines. Tear samples from subjects 1 to 6 were analyzed using the first kit by operator 1. Tear samples from subject 7 to 10 plus additional tear samples from subjects 1 to 5, which were used to determine the between-kit per operator repeatability, were analyzed using the second kit by operator 2. Linear mixed models were used to determine changes in tear cytokine concentrations over time. Between-kit per operator and within-kit per operator repeatabilities were assessed using the Bland and Altman analysis. Results: There were no significant changes in tear cytokine concentrations over a 1-week washout of CLW. More than 99% of the tear samples had detectable levels of cytokines using custom multiplex assays. Within-kit per operator repeatability was good, but between-kit per operator repeatability was poor; likely due to protein degradation, differences in operator experience, and operating procedures. Conclusion: A washout period may not be necessary when evaluating changes in tear cytokines with new contact lenses or lens care products. A well-trained operator using standardized operating procedures can produce repeatable measurements using custom multiplex assays.

Preinflammatory Signs in Established Reusable and Disposable Contact Lens Wearers

SIGNIFICANCE Established reusable contact lens (CL) wearers show higher tear inflammatory cytokine concentrations and greater conjunctival metaplasia in the region covered by standard soft CLs. The balance of proinflammatory to anti-inflammatory cytokines, but not individual tear cytokine concentrations, was associated with self-reported CL discomfort. PURPOSE Daily disposable (DD) lenses are often used to improve CL discomfort, but the effect on ocular inflammatory responses has not been fully investigated. This study aimed to compare the concentrations of tear cytokines and conjunctival cell morphology in healthy habitual DD and reusable soft CL wearers. METHODS Thirty-six established daily CL wearers, including 14 DD and 24 reusable wearers, were enrolled. Symptoms and ocular surface integrity were evaluated. The concentration of tear cytokines (interleukin 1β [IL-1β], IL-6, IL-10, IL-12(p70), IL-17A, and tumor necrosis factor α) were determined using Multiplex assays. The ratios of proinflammatory and anti-inflammatory cytokines were calculated. Impression cytology was performed on the conjunctiva, and goblet cell density and epithelial squamous metaplasia were quantified. Differences in variables by CL replacement schedules and the associations between variables were analyzed. RESULTS Reusable CL wearers had higher concentrations (in pg/mL) of IL-1β (26 ± 7 vs. 16 ± 11), IL-6 (42 ± 14 vs. 25 ± 20), IL-10 (83 ± 23 vs. 49 ± 36), IL-12(p70) (145 ± 44 vs. 91 ± 68), IL-17A (93 ± 26 vs. 54 ± 44), and tumor necrosis factor α (312 [171 to 468] vs. 189 [6 to 447]) (all P < .01) and greater conjunctival metaplasia in the region covered by CLs (0.7 [0.2 to 1.6] vs. 0.4 [0.04 to 1.2], P = .01) compared with DD wearers. There was a positive association between CL discomfort and ratios of IL-1β to IL-10 and IL-12(p70) to IL-10 (ρ = 0.42 and ρ = 0.33, P < .05). CONCLUSIONS Higher ocular inflammatory responses, as indicated by higher tear cytokine concentrations and higher conjunctival epithelial metaplasia, were found in reusable CL wearers than in DD CL wearers. The balance of proinflammatory and anti-inflammatory cytokines may be helpful to assess the inflammatory status of the eye.