CLINICAL SCIENCE
Tear Film Thickness After Treatment With Artificial Tears in Patients With Moderate Dry Eye Disease Doreen Schmidl, MD, PhD,*† Leopold Schmetterer, PhD,*† Katarzyna J. Witkowska, MD, PhD,* Angelika Unterhuber, PhD,† Valentin Aranha dos Santos, MSc,† Semira Kaya, MD,‡ Johannes Nepp, MD,§ Carina Baar, RN,* Peter Rosner, MD,* René M. Werkmeister, PhD,† and Gerhard Garhofer, MD*
Purpose: This study was designed to investigate the effect of a single-drop instillation of different lacrimal substitutes on tear film thickness (TFT) assessed with optical coherence tomography in patients with mild to moderate dry eye disease.
Methods: The study was performed in a randomized, doublemasked, controlled parallel group design. Patients received a single dose of either unpreserved trehalose 30 mg/mL and sodium hyaluronate 1.5 mg/mL (TH-SH, Thealoz Duo), unpreserved sodium hyaluronate, 0.15% (HA, Hyabak) or sodium chloride, 0.9% (NaCl, Hydrabak) eye drops. Sixty patients finished the study according to the protocol. TFT was measured with a custom-built ultrahighresolution Fourier domain optical coherence tomography system providing a resolution of 1.2 mm. Results: The mean TFT before treatment was 2.5 6 0.4 mm. Ten minutes after instillation, TFT significantly increased in the THSH group from 2.4 6 0.4 to 3.1 6 0.9 mm (P , 0.01) and in the HA group from 2.4 6 0.3 to 2.9 6 0.5 mm (P , 0.01), whereas no significant change was observed in the NaCl group (from 2.6 6 0.4 to 2.7 6 0.4 mm, P = 0.76). The increase in TFT remained statistically significant up to 240 minutes after administration of THSH. In contrast, the increase in TFT after administration of HA was only statistically significant at 10, 20, and 40 minutes after drop instillation.
Conclusions: The findings of this study indicate that single instillation of TH-SH and HA eye drops increases TFT in patients with dry eye disease. The data also indicate longer corneal residence of the TH-containing eye drops. The effect of multiple instillation
Received for publication October 15, 2014; revision received November 13, 2014; accepted November 22, 2014. Published online ahead of print February 3, 2015. From the *Department of Clinical Pharmacology, Medical University Vienna, Vienna, Austria; †Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria; ‡Department of Ophthalmology, Paracelsus University Salzburg, Salzburg, Austria; and §Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. Supported by an unrestricted grant from Laboratoires Thea, Clermont Ferrand, France. The authors have no conflicts of interest to disclose. Reprints: Gerhard Garhofer, MD, Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cornea Volume 34, Number 4, April 2015
and long-term use of artificial tears on TFT warrants further investigation. Key Words: dry eye, trehalose, hyaluronic acid, tear film thickness, optical coherence tomography (Cornea 2015;34:421–426)
D
ry eye disease (DED) is a highly prevalent condition of the ocular surface. It is defined as disturbance of the Lacrimal functional unit, an integrated system comprising the lacrimal glands, ocular surface (cornea, conjunctiva, and meibomian glands) and lids, as well as the interconnecting sensory and motor nerves.1,2 Pathophysiology of DED is complex and involves different components such as tear film instability, hyperosmolarity, and inflammation.3–6 One of the mainstays of the therapy is treatment with topical lubricants and artificial tears.7,8 However, requirements for topically applied artificial tears for the treatment of DED are high. The agent used should be safe, well tolerated, and should provide a long residence time on the ocular surface.9 Among the different agents used for the treatment of DED, hyaluronic acid (HA) has become widely used because of its good biocompatibility and its viscoelastic properties.10 It is a naturally occurring glycosaminoglycan of the extracellular matrix that has antiinflammatory properties and promotes corneal epithelial wound healing by stimulating migration, adhesion, and proliferation.11–13 Another advantage relates to its relatively long residence time on the ocular surface.14 Another approach for the treatment of DED is related to osmoprotection. Tear hyperosmolarity arises as a result of reduced tear volume and increased tear evaporation in DED.1 It triggers inflammatory processes that lead to apoptosis of epithelial and goblet cells.15 In recent years, several artificial tears entered the market aiming at osmoprotection. The concept is to protect against the adverse effects of increased tear osmolarity by using compatible solutes.16 Among these osmoprotectants, trehalose, a naturally occurring disaccharide, was marketed several years ago for the treatment of DED.17 A key point with all artificial tears is the residence time on the ocular surface. The International Dry Eye WorkShop report has mentioned optical coherence tomography (OCT) as one of the potential diagnostic tools for DED.18 We have recently introduced an ultrahigh-resolution OCT technique www.corneajrnl.com |
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Schmidl et al
using a broadband titanium:sapphire laser as light source to image the human precorneal tear film.19 In this study, we tested the hypothesis that administration of different artificial tears may increase tear film thickness (TFT) as measured with OCT in patients with DED.
MATERIALS AND METHODS Subjects This study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines of the European Union. The protocol of the study was approved by the Ethics Committee of the Medical University of Vienna. Sixty-one male and female patients with DED were included in this study. All patients gave written informed consent before inclusion. A prestudy screening was performed on each patient within the 2 weeks before the first study day. Patients had to abstain from administration of artificial tears 24 hours before the screening examination. This examination included medical history, pregnancy test in women with childbearing potential, subjective assessment of symptoms of DED using the Ocular Surface Disease Index (OSDI) questionnaire, an ophthalmic examination including visual acuity using the early treatment diabetic retinopathy study acuity charts, slitlamp biomicroscopy, and indirect funduscopy, measurement of break-up time (BUT), Schirmer I test, and measurement of intraocular pressure (IOP). Inclusion criteria for this study were age of at least 18 years, normal ophthalmic findings except DED, ametropy ,6 diopters, history of DED for at least 3 months, BUT #10 seconds or Schirmer I test #5 and $2 mm, and an OSDI #32 and $13. The eye with the more severe DED defined as the eye with the lower BUT was chosen for analysis. If BUT was identical for both eyes, the eye with the lower Schirmer I test was chosen. If Schirmer I test results were also identical for both eyes, the right eye was used for analysis. Exclusion criteria for this study were participation in a clinical trial in the 3 weeks preceding the study, symptoms of a clinically relevant illness in the 3 weeks before the first study day, presence or history of a severe medical condition as judged by the clinical investigator, intake of parasympathomimetic or antipsychotic drugs, wearing of contact lenses, glaucoma, systemic treatment with corticosteroids or topical treatment with any ophthalmic drug except artificial tears in the 4 weeks preceding the study, ocular infection or clinically significant inflammation, ocular surgery in the 3 months preceding the study, Sjögren syndrome, Stevens–Johnson syndrome, history of allergic conjunctivitis, pregnancy, and planned pregnancy or lactating.
trometamol 1.2 mg/mL, hydrochloric acid (to adjust pH 7.2) water for injections to 10 mL in ABAK system bottle. Hyabak (Laboratoires Thea, Clermont Ferrand, France)—unpreserved sodium hyaluronate (HA, 0.15%) eye drops in ABAK system bottle. Hydrabak (Laboratoires Thea, Clermont Ferrand, France)—unpreserved sodium chloride (NaCl [0.9%]), sodium dihydrogen phosphate dehydrate, disodium hydrogen phosphate dodecahydrate, water for injections in ABAK system bottle.
Study Design This study was performed in a randomized, doublemasked, active-controlled fashion using TH-SH, HA, and NaCl eye drops. Patients were randomized to 1 of the 3 study groups. In addition, patients were asked to restrain from administration of artificial tears in the 24 hours before the study day. On the study day, after baseline measurement of TFT with OCT, 1 of the 3 agents was administered. Three minutes after administration, patient’s feeling on instillation was assessed. Measurements of TFT were repeated 10, 20, 40, 60, 120, and 240 minutes after instillation. After the last measurement, the following procedures were performed: assessment of patient’s satisfaction (subjective evaluation of ocular comfort), visual acuity, BUT, Schirmer I test, measurement of IOP, and assessment of adverse events.
Methods Measurement of TFT Using OCT
In this study, the following 3 artificial tears were compared. Thealoz Duo (Laboratoires Thea, Clermont Ferrand, France)—unpreserved trehalose 30 mg/mL, sodium hyaluronate 1.5 mg/mL (TH-SH), sodium chloride 2.6 mg/mL,
A custom-built OCT system presented previously was used for TFT measurements in this study.19 As a light source, a titanium:sapphire laser (Integral OCT; Femtolasers Produktions GmbH, Vienna, Austria) with a central wavelength of 800 nm and a full width at half maximum bandwidth of 170 nm was used. This results in a theoretical axial resolution of 1.2 mm in tissue. Incident power of the probe beam onto the cornea was set to 600 mW, which is less than a tenth of the maximum permissible exposure of the eye given by ANSI and EN 60825-1.20,21 The optics and spectrometer are optimized for the broad bandwidth to ensure utilization of the full spectrum. The transverse resolution of the OCT system is 21 mm at the front surface of the cornea. The light-delivery system of the sample arm is mounted on a modified slit-lamp headrest. This is done in an effort to minimize head movements and to allow precise alignment of the probe beam onto the subject’s eye. Patients were presented an internal fixation target and were asked to blink normally during the alignment procedure that took about 10 seconds. Thereafter, patients were advised to blink once, and measurement started immediately after opening of the eyes. Three volumes with a size of 4 · 4 · 1 mm (horizontal · vertical · depth) were acquired within 3 seconds, each containing 512 · 128 · 1024 voxels. For analysis, the first volume was discarded and only the second and third volume was used. For calculation of central TFT, in each volume, the 15 horizontal frames above the central specular reflex of the probe beam at the apex of the cornea were used.
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Artificial Tears
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Tear Film Thickness and Artificial Tears
Break-Up Time Tear BUT was measured following the guidelines published in the Report of the International Dry Eye WorkShop.18 Five microliters of Minims-Fluorescein Sodium 2.0% eye drops was applied in the conjunctival sac of the eye. Patients were instructed to blink naturally several times to distribute fluorescein. Within 10 to 30 seconds after fluorescein instillation, patients were asked to stare straight ahead without blinking, until told otherwise. Slit-lamp magnification was set at ·10; the background illumination intensity was kept constant (cobalt blue light) and a Wratten 12 yellow filter was used to enhance observation of the tear film over the entire cornea. Using a stopwatch, the time between the last complete blink and first appearance of a dry spot was recorded. Once break-up of the tear film was observed, the patient was instructed to blink freely.
Schirmer I Test Schirmer I test (without anesthesia) was performed following the guidelines published in the Report of the International Dry Eye WorkShop.18 Schirmer paper strips were inserted in the unanesthetized eye over the lower lid margin, midway between the middle and outer third. The patient was then asked to close the eye. After a time of 5 minutes, wetting of the Schirmer paper was measured.
Intraocular Pressure IOP was measured with a slit lamp–mounted Goldmann applanation tonometer. Before each measurement, 1 drop of oxybuprocaine hydrochloride combined with sodium fluorescein was used for local anesthesia of the cornea.
Ocular Surface Disease Index Symptoms of dry eye were assessed using the OSDI. The questionnaire that underlies the OSDI is specifically designed for patients with DED and asks patients about the frequency of specific symptoms and their impact on visionrelated functioning.
Subjective Evaluation of Ocular Comfort and Patient Satisfaction Patient’s feelings on instillation were assessed 3 minutes after instillation, namely foreign body sensation, burning, photophobia, blurred vision, pain, and itching. After the last measurement, patients were asked about the satisfaction with the eye drops.
Data Analysis
Statistical analysis was performed as a “per protocol” analysis. TFT was used as the main outcome variable. To detect differences between treatments, a 3-way repeatedmeasures analysis of variance (ANOVA) model was applied. Planned comparisons within the ANOVA model were performed to assess differences in TFT between time points and groups. All values are presented as mean 6 SD. A P value of 0.05 or less was considered significant. For the data arising from the questionnaires, a Kruskal–Wallis ANOVA was used. All statistical analysis was performed using CSS Statistica (Statsoft, version 6.0, Tulsa, OK).
RESULTS Of the 61 patients included in this study, 60 completed the study according to the protocol (age, 42.7 6 11.6 years, mean 6 SD; 43 females and 17 males). One patient was excluded because of technical difficulties with the OCT instrument. The mean duration of DED in the whole study group was 4.7 6 3.6 years. Baseline characteristics of the study population are presented in Table 1. No significant differences were noted between the 3 study groups in any of the outcome parameters. The baseline TFT was 2.4 6 0.4 mm, 2.4 6 0.3 mm, and 2.6 6 0.4 mm in the TH-SH, HA, and NaCl groups, respectively. Administration of artificial tears significantly increased TFT in the TH-SH (P , 0.01 vs. baseline) and HA groups (P , 0.01 vs. baseline), whereas no significant change was observed in the NaCl group (P = 0.76 vs. baseline, Fig. 1). In both, the TH-SH and HA groups, the highest TFT values were reached 10 minutes after drop administration
TABLE 1. Baseline Characteristics of the Study Population Before Assignment to the 3 Groups (Trehalose Combined With Sodium Hyaluronate [TH-SH], Unpreserved Sodium Hyaluronate [HA], or Sodium Chloride [NaCl]) Age, yrs Gender (M/F) Duration DED, yrs OSDI score ETDRS, letters BUT, s Schirmer I test, mm/5 min IOP, mm Hg TFT, mm
TH-SH
HA
NaCl
P
All Groups
43.6 6 13.3 5/15 4.2 6 3.7 26.1 6 5.1 83.9 6 8.2 5.4 6 2.1 7.5 6 7.1 15.5 6 2.3 2.4 6 0.4
42.9 6 12.0 5/15 4.5 6 3.3 27.1 6 4.7 85.1 6 2.8 5.0 6 1.9 13.7 6 9.5 15.6 6 2.3 2.4 6 0.3
41.8 6 9.9 7/13 5.3 6 4.2 27.0 6 4.9 84.4 6 3.5 4.8 6 2.3 10.4 6 9.6 15.6 6 2.1 2.6 6 0.4
0.89 0.73 0.62 0.78 0.78 0.65 0.09 0.98 0.09
42.7 6 11.6 17/43 4.7 6 3.6 26.7 6 4.8 84.0 6 5.0 5.1 6 2.1 11.0 6 9.0 15.5 6 2.2 2.5 6 0.4
Values are given as mean 6 SD. ETDRS, early treatment diabetic retinopathy study.
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FIGURE 1. Relative TFT over time (n = 60) after instillation of unpreserved trehalose combined with sodium hyaluronate (TH-SH), unpreserved sodium hyaluronate (HA), or sodium chloride (NaCl). Data are presented as mean 6 SD. #Significant versus baseline for TH-SH, *Significant versus baseline for HA.
amounting to 3.1 6 0.9 mm for the TH-SH group and 2.9 6 0.5 mm for the HA group. The repeated-measures ANOVA model revealed a statistically significant difference in the time course between all 3 administered products (ANOVA, time vs. treatment P , 0.01). When compared with the preinstillation value in the planned comparison analysis, the increase in TFT of the TH-SH group remained statistically significant at 240 minutes after administration. In contrast, the increase in TFT in the HA group was only statistically significant different from baseline at 10, 20, and 40 minutes after instillation, indicating a shorter residence time on the ocular surface. All 3 groups showed a tendency toward an increase in BUT, but this effect did not reach the level of significance in either of the groups (P = 0.66 between groups, Fig. 2). Likewise, no significant effect on Schirmer I test (P = 0.81 between groups), IOP (P = 0.41 between groups), or visual acuity (P = 0.71 between groups) was observed (Table 2). There were no differences in terms of tolerability assessed immediately after instillation or patient satisfaction at the end of the study day between the 3 groups (data not shown).
DISCUSSION This study indicates significant differences between artificial tears in increasing TFT after topical administration. Whereas the product containing HA increased TFT for 40 minutes, and the product containing TH-SH increased TFT for as long as 240 minutes. The custom-built OCT system used in this study seems to be capable of detecting such differences by following a standardized protocol.19 Little is known about the ocular residence time of artificial tears on the ocular surface. Most previous studies used radioactive labeling to detect artificial tears after administration. Results obtained using quantitative gamma scintigra-
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FIGURE 2. Change in BUT over time after instillation of unpreserved trehalose combined with sodium hyaluronate (THSH), unpreserved sodium hyaluronate (HA), or sodium chloride (NaCl). Data are presented as mean 6 SD.
phy observed ocular residence times that are in the same range as those obtained in this study.14 Mean ocular surface residence times of 23.5 and 11.1 minutes were reported for 0.3% HA and 0.2% HA, respectively. A direct comparison between our data and this previous study is, however, difficult because of the different techniques used, potential differences in viscosity, which are assumed to play a role in how long the product stays on the ocular surface and differences in patient characteristics.22 Our results are also compatible with data that show that both 0.1% HA and 0.3% HA offer longer-lasting relief of symptoms than saline.23 The authors attributed this effect to a longer-lasting residence time of HA on the ocular surface, which is supported by the results of this study. Interestingly, the TH-SH-containing products used in our study increased TFT considerably longer than HA. The
TABLE 2. Changes in Schirmer I Test Scores, IOP and Visual Acuity 240 Minutes After Instillation (Trehalose Combined With Sodium Hyaluronate [TH-SH], Unpreserved Sodium Hyaluronate [HA], or Sodium Chloride [NaCl]) Schirmer I test, mm/5 min TH-SH HA NaCl IOP, mm Hg TH-SH HA NaCl ETDRS (letters) TH-SH HA NaCl
Baseline
240 Minutes
P
7.5 6 7.1 13.7 6 9.5 10.4 6 9.6
9.1 6 9.7 16.1 6 10.2 13.6 6 10.3
0.54 0.44 0.32
15.5 6 2.3 15.6 6 2.3 15.6 6 2.1
16.5 6 1.7 15.7 6 1.9 15.8 6 1.6
0.13 0.88 0.74
83.9 6 8.2 85.1 6 2.8 84.4 6 3.5
81.8 6 18.3 85.5 6 3.1 84.7 6 3.1
0.64 0.63 0.77
Values are given as mean 6 SD. ETDRS, early treatment diabetic retinopathy study.
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Cornea Volume 34, Number 4, April 2015
reason for this behavior is unclear. One speculation is that this is related to interaction of TH with lipid membranes, which involves the surrounding hydration shell.24 TH is synthesized by many organisms during prolonged periods of desiccation to protect cells from dehydration,25 a concept that also seems to function for corneal epithelial cells.26–28 In addition, TH is a compatible solute that can be taken up by the cell and does not disturb cellular macromolecules even at high concentrations, thereby acting as an osmoprotectant.17 Efficacy of trehalose has been shown in several experiments in a murine dry eye model.29,30 Clinical studies include investigation on HA hydroxyethylcellulose formulations or saline.31–33 In this study, we saw a considerably lower baseline TFT in patients with DED than previously reported for healthy subjects.19 Indeed, the values reported in this study are more than 40% lower than those observed in healthy subjects. A direct comparison of these data is difficult because we used a 3-dimensional imaging approach in this study, whereas our previous data relied only on 2-dimensional data. We believe that the present approach is preferable because it is less sensitive to eye movements. However, a study that relates TFT measured with OCT to other important biomarkers for the assessment of dry eye treatment effectiveness such as tear osmolarity and others is still missing.34 Furthermore, whether a combination of these parameters will allow us to better evaluate the clinical response to dry eye therapy in future studies is yet to be determined. Several previous studies have aimed to use OCT to characterize the effect of eye drops on TFT. As such, it has been shown that treatment with cyclosporine is associated with an increase in tear meniscus.35 In another study, topical instillation of sodium carboxymethylcellulose enabled detection of an artificial tear film appearing as a 2-layered structure on top of the epithelial surface of the cornea. It consisted of an outer band with high reflectivity and an inner band with low reflectivity.36 This phenomenon was only observed 1 to 5 minutes after administration, which is considerably earlier than measurements performed in this study. As mentioned above, the present OCT system provides a resolution of 1.2 mm in tissue, a value that is based on the full-width at half maximum of coherence function and defines the ability of the system to separate 2 structures within 1 A-scan. Changes induced by the artificial tears used in this study are, however, much smaller. Modeling of the OCT signal indicates that with a system of 1-mm resolution, changes in TFT in the order of 40 nm can be detected.37 Although this model may not reflect the present situation in all aspects, our unpublished data indicate that this is indeed the range in which such changes can be detected. All administered eye drops were well tolerated in this study, with no significant differences between groups. Likewise, there were no differences in patient satisfaction between the 3 treatment arms. None of the artificial tears had a significant effect on BUT or Schirmer I test. This is expected after single dosing, and further studies are required to clarify the effects of TH-SH combination on signs and symptoms of DED after prolonged treatment. In conclusion, the data of this study indicate that the ocular residence time of TH-SH is considerably longer than Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
Tear Film Thickness and Artificial Tears
that of HA alone. The reason for this effect is unknown and requires further investigation. REFERENCES 1. DEWS. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:75–92. 2. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 1998;17:584–589. 3. Mantelli F, Massaro-Giordano M, Macchi I, et al. The cellular mechanisms of dry eye: from pathogenesis to treatment. J Cell Physiol. 2013;228:2253–2256. 4. Sullivan BD, Whitmer D, Nichols KK, et al. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci. 2010;51:6125–6130. 5. Garrett Q, Khandekar N, Shih S, et al. Betaine stabilizes cell volume and protects against apoptosis in human corneal epithelial cells under hyperosmotic stress. Exp Eye Res. 2013;108:33–41. 6. Cher I. Fluids of the ocular surface: concepts, functions and physics. Clin Experiment Ophthalmol. 2012;40:634–643. 7. Foulks GN. Pharmacological management of dry eye in the elderly patient. Drugs Aging. 2008;25:105–118. 8. Wagh VD, Apar DU, Surana SJ. Drug delivery and pharmacotherapy for dry eye disease. Int J Pharm Pharm Sci. 2012;4:42–46. 9. Murube J, Paterson A, Murube E. Classification of artificial tears. I: composition and properties. Adv Exp Med Biol. 1998;438:693–704. 10. Rah MJ. A review of hyaluronan and its ophthalmic applications. Optometry. 2011;82:38–43. 11. Nishida T, Nakamura M, Mishima H, et al. Hyaluronan stimulates corneal epithelial migration. Exp Eye Res. 1991;53:753–758. 12. Inoue M, Katakami C. The effect of hyaluronic acid on corneal epithelial cell proliferation. Invest Ophthalmol Vis Sci. 1993;34:2313–2315. 13. Gomes JA, Amankwah R, Powell-Richards A, et al. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br J Ophthalmol. 2004;88:821–825. 14. Snibson GR, Greaves JL, Soper ND, et al. Precorneal residence times of sodium hyaluronate solutions studied by quantitative gamma scintigraphy. Eye (Lond). 1990;4:594–602. 15. Yeh S, Song XJ, Farley W, et al. Apoptosis of ocular surface cells in experimentally induced dry eye. Invest Ophthalmol Vis Sci. 2003;44:124–129. 16. Yancey PH. Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses. J Exp Biol. 2005;208:2819–2830. 17. Baudouin C, Aragona P, Messmer EM, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf. 2013;11:246–258. 18. DEWS. Methodologies to diagnose and monitor dry eye disease: report of the diagnostic methodology subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:108–152. 19. Werkmeister RM, Alex A, Kaya S, et al. Measurement of tear film thickness using ultrahigh-resolution optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54:5578–5583. 20. American National Standards Institute. American National Standard for Safe Use of Lasers. Orlando, Fl: The Laser Institute of America; 2000. ANSI Z136. 1–2000. 21. Despriet DD, Klaver CC, Witteman JC, et al. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA. 2006;296:301–309. 22. Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2011;52:2050–2064. 23. Johnson ME, Murphy PJ, Boulton M. Effectiveness of sodium hyaluronate eyedrops in the treatment of dry eye. Graefes Arch Clin Exp Ophthalmol. 2006;244:109–112. 24. Huxtable RJ. Physiological actions of taurine. Physiol Rev. 1992;72:101–163. 25. Luyckx J, Baudouin C. Trehalose: an intriguing disaccharide with potential for medical application in ophthalmology. Clin Ophthalmol. 2011;5:577–581. 26. Matsuo T. Trehalose protects corneal epithelial cells from death by drying. Br J Ophthalmol. 2001;85:610–612.
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27. Hill-Bator A, Misiuk-Hojlo M, Marycz K, et al. Trehalose-based eye drops preserve viability and functionality of cultured human corneal epithelial cells during desiccation. Biomed Res Int. 2014;2014:292139. 28. Izawa Y, Matsuo T, Uchida T, et al. Atomic force microscopic observation of trehalose-treated and dried corneal epithelial surface. Cell Preserv Technol. 2006;4:117–122. 29. Chen W, Zhang X, Liu M, et al. Trehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosis. Exp Eye Res. 2009;89:311–318. 30. Li J, Roubeix C, Wang Y, et al. Therapeutic efficacy of trehalose eye drops for treatment of murine dry eye induced by an intelligently controlled environmental system. Mol Vis. 2012;18:317–329. 31. Matsuo T. Trehalose versus hyaluronan or cellulose in eyedrops for the treatment of dry eye. Jpn J Ophthalmol. 2004;48:321–327. 32. Matsuo T, Tsuchida Y, Morimoto N. Trehalose eye drops in the treatment of dry eye syndrome. Ophthalmology. 2002;109:2024–2029.
33. Ramoth T, Hovakimyan M, Guthoff RF, et al. Characterisation of tear film dynamics after application of trehalose for treatment of dry eye [in German]. Klin Monbl Augenheilkd. 2013;230:1220–1224. 34. Benelli U, Nardi M, Posarelli C, et al. Tear osmolarity measurement using the TearLab Osmolarity system in the assessment of dry eye treatment effectiveness. Cont Lens Anterior Eye. 2010;33:61–67. 35. Wang J, Cui L, Shen M, et al. Ultra-high resolution optical coherence tomography for monitoring tear meniscus volume in dry eye after topical cyclosporine treatment. Clin Ophthalmol. 2012;6:933–938. 36. Napoli PE, Coronella F, Satta GM, et al. A novel OCT technique to measure in vivo the corneal adhesiveness for sodium carboxymethylcellulose in humans and its validity in the diagnosis of dry eye. Invest Ophthalmol Vis Sci. 2014;55:3179–3185. 37. Huang J, Clarkson E, Kupinski M, et al. Maximum-likelihood estimation in Optical Coherence Tomography in the context of the tear film dynamics. Biomed Opt Express. 2013;4:1806–1816.
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Tear Film Thickness After Treatment With Artificial Tears in Patients With Moderate Dry Eye Disease Doreen Schmidl, MD, PhD,*† Leopold Schmetterer, PhD,*† Katarzyna J. Witkowska, MD, PhD,* Angelika Unterhuber, PhD,† Valentin Aranha dos Santos, MSc,† Semira Kaya, MD,‡ Johannes Nepp, MD,§ Carina Baar, RN,* Peter Rosner, MD,* René M. Werkmeister, PhD,† and Gerhard Garhofer, MD*
Purpose: This study was designed to investigate the effect of a single-drop instillation of different lacrimal substitutes on tear film thickness (TFT) assessed with optical coherence tomography in patients with mild to moderate dry eye disease.
Methods: The study was performed in a randomized, doublemasked, controlled parallel group design. Patients received a single dose of either unpreserved trehalose 30 mg/mL and sodium hyaluronate 1.5 mg/mL (TH-SH, Thealoz Duo), unpreserved sodium hyaluronate, 0.15% (HA, Hyabak) or sodium chloride, 0.9% (NaCl, Hydrabak) eye drops. Sixty patients finished the study according to the protocol. TFT was measured with a custom-built ultrahighresolution Fourier domain optical coherence tomography system providing a resolution of 1.2 mm. Results: The mean TFT before treatment was 2.5 6 0.4 mm. Ten minutes after instillation, TFT significantly increased in the THSH group from 2.4 6 0.4 to 3.1 6 0.9 mm (P , 0.01) and in the HA group from 2.4 6 0.3 to 2.9 6 0.5 mm (P , 0.01), whereas no significant change was observed in the NaCl group (from 2.6 6 0.4 to 2.7 6 0.4 mm, P = 0.76). The increase in TFT remained statistically significant up to 240 minutes after administration of THSH. In contrast, the increase in TFT after administration of HA was only statistically significant at 10, 20, and 40 minutes after drop instillation.
Conclusions: The findings of this study indicate that single instillation of TH-SH and HA eye drops increases TFT in patients with dry eye disease. The data also indicate longer corneal residence of the TH-containing eye drops. The effect of multiple instillation
Received for publication October 15, 2014; revision received November 13, 2014; accepted November 22, 2014. Published online ahead of print February 3, 2015. From the *Department of Clinical Pharmacology, Medical University Vienna, Vienna, Austria; †Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria; ‡Department of Ophthalmology, Paracelsus University Salzburg, Salzburg, Austria; and §Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. Supported by an unrestricted grant from Laboratoires Thea, Clermont Ferrand, France. The authors have no conflicts of interest to disclose. Reprints: Gerhard Garhofer, MD, Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cornea Volume 34, Number 4, April 2015
and long-term use of artificial tears on TFT warrants further investigation. Key Words: dry eye, trehalose, hyaluronic acid, tear film thickness, optical coherence tomography (Cornea 2015;34:421–426)
D
ry eye disease (DED) is a highly prevalent condition of the ocular surface. It is defined as disturbance of the Lacrimal functional unit, an integrated system comprising the lacrimal glands, ocular surface (cornea, conjunctiva, and meibomian glands) and lids, as well as the interconnecting sensory and motor nerves.1,2 Pathophysiology of DED is complex and involves different components such as tear film instability, hyperosmolarity, and inflammation.3–6 One of the mainstays of the therapy is treatment with topical lubricants and artificial tears.7,8 However, requirements for topically applied artificial tears for the treatment of DED are high. The agent used should be safe, well tolerated, and should provide a long residence time on the ocular surface.9 Among the different agents used for the treatment of DED, hyaluronic acid (HA) has become widely used because of its good biocompatibility and its viscoelastic properties.10 It is a naturally occurring glycosaminoglycan of the extracellular matrix that has antiinflammatory properties and promotes corneal epithelial wound healing by stimulating migration, adhesion, and proliferation.11–13 Another advantage relates to its relatively long residence time on the ocular surface.14 Another approach for the treatment of DED is related to osmoprotection. Tear hyperosmolarity arises as a result of reduced tear volume and increased tear evaporation in DED.1 It triggers inflammatory processes that lead to apoptosis of epithelial and goblet cells.15 In recent years, several artificial tears entered the market aiming at osmoprotection. The concept is to protect against the adverse effects of increased tear osmolarity by using compatible solutes.16 Among these osmoprotectants, trehalose, a naturally occurring disaccharide, was marketed several years ago for the treatment of DED.17 A key point with all artificial tears is the residence time on the ocular surface. The International Dry Eye WorkShop report has mentioned optical coherence tomography (OCT) as one of the potential diagnostic tools for DED.18 We have recently introduced an ultrahigh-resolution OCT technique www.corneajrnl.com |
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using a broadband titanium:sapphire laser as light source to image the human precorneal tear film.19 In this study, we tested the hypothesis that administration of different artificial tears may increase tear film thickness (TFT) as measured with OCT in patients with DED.
MATERIALS AND METHODS Subjects This study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines of the European Union. The protocol of the study was approved by the Ethics Committee of the Medical University of Vienna. Sixty-one male and female patients with DED were included in this study. All patients gave written informed consent before inclusion. A prestudy screening was performed on each patient within the 2 weeks before the first study day. Patients had to abstain from administration of artificial tears 24 hours before the screening examination. This examination included medical history, pregnancy test in women with childbearing potential, subjective assessment of symptoms of DED using the Ocular Surface Disease Index (OSDI) questionnaire, an ophthalmic examination including visual acuity using the early treatment diabetic retinopathy study acuity charts, slitlamp biomicroscopy, and indirect funduscopy, measurement of break-up time (BUT), Schirmer I test, and measurement of intraocular pressure (IOP). Inclusion criteria for this study were age of at least 18 years, normal ophthalmic findings except DED, ametropy ,6 diopters, history of DED for at least 3 months, BUT #10 seconds or Schirmer I test #5 and $2 mm, and an OSDI #32 and $13. The eye with the more severe DED defined as the eye with the lower BUT was chosen for analysis. If BUT was identical for both eyes, the eye with the lower Schirmer I test was chosen. If Schirmer I test results were also identical for both eyes, the right eye was used for analysis. Exclusion criteria for this study were participation in a clinical trial in the 3 weeks preceding the study, symptoms of a clinically relevant illness in the 3 weeks before the first study day, presence or history of a severe medical condition as judged by the clinical investigator, intake of parasympathomimetic or antipsychotic drugs, wearing of contact lenses, glaucoma, systemic treatment with corticosteroids or topical treatment with any ophthalmic drug except artificial tears in the 4 weeks preceding the study, ocular infection or clinically significant inflammation, ocular surgery in the 3 months preceding the study, Sjögren syndrome, Stevens–Johnson syndrome, history of allergic conjunctivitis, pregnancy, and planned pregnancy or lactating.
trometamol 1.2 mg/mL, hydrochloric acid (to adjust pH 7.2) water for injections to 10 mL in ABAK system bottle. Hyabak (Laboratoires Thea, Clermont Ferrand, France)—unpreserved sodium hyaluronate (HA, 0.15%) eye drops in ABAK system bottle. Hydrabak (Laboratoires Thea, Clermont Ferrand, France)—unpreserved sodium chloride (NaCl [0.9%]), sodium dihydrogen phosphate dehydrate, disodium hydrogen phosphate dodecahydrate, water for injections in ABAK system bottle.
Study Design This study was performed in a randomized, doublemasked, active-controlled fashion using TH-SH, HA, and NaCl eye drops. Patients were randomized to 1 of the 3 study groups. In addition, patients were asked to restrain from administration of artificial tears in the 24 hours before the study day. On the study day, after baseline measurement of TFT with OCT, 1 of the 3 agents was administered. Three minutes after administration, patient’s feeling on instillation was assessed. Measurements of TFT were repeated 10, 20, 40, 60, 120, and 240 minutes after instillation. After the last measurement, the following procedures were performed: assessment of patient’s satisfaction (subjective evaluation of ocular comfort), visual acuity, BUT, Schirmer I test, measurement of IOP, and assessment of adverse events.
Methods Measurement of TFT Using OCT
In this study, the following 3 artificial tears were compared. Thealoz Duo (Laboratoires Thea, Clermont Ferrand, France)—unpreserved trehalose 30 mg/mL, sodium hyaluronate 1.5 mg/mL (TH-SH), sodium chloride 2.6 mg/mL,
A custom-built OCT system presented previously was used for TFT measurements in this study.19 As a light source, a titanium:sapphire laser (Integral OCT; Femtolasers Produktions GmbH, Vienna, Austria) with a central wavelength of 800 nm and a full width at half maximum bandwidth of 170 nm was used. This results in a theoretical axial resolution of 1.2 mm in tissue. Incident power of the probe beam onto the cornea was set to 600 mW, which is less than a tenth of the maximum permissible exposure of the eye given by ANSI and EN 60825-1.20,21 The optics and spectrometer are optimized for the broad bandwidth to ensure utilization of the full spectrum. The transverse resolution of the OCT system is 21 mm at the front surface of the cornea. The light-delivery system of the sample arm is mounted on a modified slit-lamp headrest. This is done in an effort to minimize head movements and to allow precise alignment of the probe beam onto the subject’s eye. Patients were presented an internal fixation target and were asked to blink normally during the alignment procedure that took about 10 seconds. Thereafter, patients were advised to blink once, and measurement started immediately after opening of the eyes. Three volumes with a size of 4 · 4 · 1 mm (horizontal · vertical · depth) were acquired within 3 seconds, each containing 512 · 128 · 1024 voxels. For analysis, the first volume was discarded and only the second and third volume was used. For calculation of central TFT, in each volume, the 15 horizontal frames above the central specular reflex of the probe beam at the apex of the cornea were used.
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Artificial Tears
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Tear Film Thickness and Artificial Tears
Break-Up Time Tear BUT was measured following the guidelines published in the Report of the International Dry Eye WorkShop.18 Five microliters of Minims-Fluorescein Sodium 2.0% eye drops was applied in the conjunctival sac of the eye. Patients were instructed to blink naturally several times to distribute fluorescein. Within 10 to 30 seconds after fluorescein instillation, patients were asked to stare straight ahead without blinking, until told otherwise. Slit-lamp magnification was set at ·10; the background illumination intensity was kept constant (cobalt blue light) and a Wratten 12 yellow filter was used to enhance observation of the tear film over the entire cornea. Using a stopwatch, the time between the last complete blink and first appearance of a dry spot was recorded. Once break-up of the tear film was observed, the patient was instructed to blink freely.
Schirmer I Test Schirmer I test (without anesthesia) was performed following the guidelines published in the Report of the International Dry Eye WorkShop.18 Schirmer paper strips were inserted in the unanesthetized eye over the lower lid margin, midway between the middle and outer third. The patient was then asked to close the eye. After a time of 5 minutes, wetting of the Schirmer paper was measured.
Intraocular Pressure IOP was measured with a slit lamp–mounted Goldmann applanation tonometer. Before each measurement, 1 drop of oxybuprocaine hydrochloride combined with sodium fluorescein was used for local anesthesia of the cornea.
Ocular Surface Disease Index Symptoms of dry eye were assessed using the OSDI. The questionnaire that underlies the OSDI is specifically designed for patients with DED and asks patients about the frequency of specific symptoms and their impact on visionrelated functioning.
Subjective Evaluation of Ocular Comfort and Patient Satisfaction Patient’s feelings on instillation were assessed 3 minutes after instillation, namely foreign body sensation, burning, photophobia, blurred vision, pain, and itching. After the last measurement, patients were asked about the satisfaction with the eye drops.
Data Analysis
Statistical analysis was performed as a “per protocol” analysis. TFT was used as the main outcome variable. To detect differences between treatments, a 3-way repeatedmeasures analysis of variance (ANOVA) model was applied. Planned comparisons within the ANOVA model were performed to assess differences in TFT between time points and groups. All values are presented as mean 6 SD. A P value of 0.05 or less was considered significant. For the data arising from the questionnaires, a Kruskal–Wallis ANOVA was used. All statistical analysis was performed using CSS Statistica (Statsoft, version 6.0, Tulsa, OK).
RESULTS Of the 61 patients included in this study, 60 completed the study according to the protocol (age, 42.7 6 11.6 years, mean 6 SD; 43 females and 17 males). One patient was excluded because of technical difficulties with the OCT instrument. The mean duration of DED in the whole study group was 4.7 6 3.6 years. Baseline characteristics of the study population are presented in Table 1. No significant differences were noted between the 3 study groups in any of the outcome parameters. The baseline TFT was 2.4 6 0.4 mm, 2.4 6 0.3 mm, and 2.6 6 0.4 mm in the TH-SH, HA, and NaCl groups, respectively. Administration of artificial tears significantly increased TFT in the TH-SH (P , 0.01 vs. baseline) and HA groups (P , 0.01 vs. baseline), whereas no significant change was observed in the NaCl group (P = 0.76 vs. baseline, Fig. 1). In both, the TH-SH and HA groups, the highest TFT values were reached 10 minutes after drop administration
TABLE 1. Baseline Characteristics of the Study Population Before Assignment to the 3 Groups (Trehalose Combined With Sodium Hyaluronate [TH-SH], Unpreserved Sodium Hyaluronate [HA], or Sodium Chloride [NaCl]) Age, yrs Gender (M/F) Duration DED, yrs OSDI score ETDRS, letters BUT, s Schirmer I test, mm/5 min IOP, mm Hg TFT, mm
TH-SH
HA
NaCl
P
All Groups
43.6 6 13.3 5/15 4.2 6 3.7 26.1 6 5.1 83.9 6 8.2 5.4 6 2.1 7.5 6 7.1 15.5 6 2.3 2.4 6 0.4
42.9 6 12.0 5/15 4.5 6 3.3 27.1 6 4.7 85.1 6 2.8 5.0 6 1.9 13.7 6 9.5 15.6 6 2.3 2.4 6 0.3
41.8 6 9.9 7/13 5.3 6 4.2 27.0 6 4.9 84.4 6 3.5 4.8 6 2.3 10.4 6 9.6 15.6 6 2.1 2.6 6 0.4
0.89 0.73 0.62 0.78 0.78 0.65 0.09 0.98 0.09
42.7 6 11.6 17/43 4.7 6 3.6 26.7 6 4.8 84.0 6 5.0 5.1 6 2.1 11.0 6 9.0 15.5 6 2.2 2.5 6 0.4
Values are given as mean 6 SD. ETDRS, early treatment diabetic retinopathy study.
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FIGURE 1. Relative TFT over time (n = 60) after instillation of unpreserved trehalose combined with sodium hyaluronate (TH-SH), unpreserved sodium hyaluronate (HA), or sodium chloride (NaCl). Data are presented as mean 6 SD. #Significant versus baseline for TH-SH, *Significant versus baseline for HA.
amounting to 3.1 6 0.9 mm for the TH-SH group and 2.9 6 0.5 mm for the HA group. The repeated-measures ANOVA model revealed a statistically significant difference in the time course between all 3 administered products (ANOVA, time vs. treatment P , 0.01). When compared with the preinstillation value in the planned comparison analysis, the increase in TFT of the TH-SH group remained statistically significant at 240 minutes after administration. In contrast, the increase in TFT in the HA group was only statistically significant different from baseline at 10, 20, and 40 minutes after instillation, indicating a shorter residence time on the ocular surface. All 3 groups showed a tendency toward an increase in BUT, but this effect did not reach the level of significance in either of the groups (P = 0.66 between groups, Fig. 2). Likewise, no significant effect on Schirmer I test (P = 0.81 between groups), IOP (P = 0.41 between groups), or visual acuity (P = 0.71 between groups) was observed (Table 2). There were no differences in terms of tolerability assessed immediately after instillation or patient satisfaction at the end of the study day between the 3 groups (data not shown).
DISCUSSION This study indicates significant differences between artificial tears in increasing TFT after topical administration. Whereas the product containing HA increased TFT for 40 minutes, and the product containing TH-SH increased TFT for as long as 240 minutes. The custom-built OCT system used in this study seems to be capable of detecting such differences by following a standardized protocol.19 Little is known about the ocular residence time of artificial tears on the ocular surface. Most previous studies used radioactive labeling to detect artificial tears after administration. Results obtained using quantitative gamma scintigra-
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FIGURE 2. Change in BUT over time after instillation of unpreserved trehalose combined with sodium hyaluronate (THSH), unpreserved sodium hyaluronate (HA), or sodium chloride (NaCl). Data are presented as mean 6 SD.
phy observed ocular residence times that are in the same range as those obtained in this study.14 Mean ocular surface residence times of 23.5 and 11.1 minutes were reported for 0.3% HA and 0.2% HA, respectively. A direct comparison between our data and this previous study is, however, difficult because of the different techniques used, potential differences in viscosity, which are assumed to play a role in how long the product stays on the ocular surface and differences in patient characteristics.22 Our results are also compatible with data that show that both 0.1% HA and 0.3% HA offer longer-lasting relief of symptoms than saline.23 The authors attributed this effect to a longer-lasting residence time of HA on the ocular surface, which is supported by the results of this study. Interestingly, the TH-SH-containing products used in our study increased TFT considerably longer than HA. The
TABLE 2. Changes in Schirmer I Test Scores, IOP and Visual Acuity 240 Minutes After Instillation (Trehalose Combined With Sodium Hyaluronate [TH-SH], Unpreserved Sodium Hyaluronate [HA], or Sodium Chloride [NaCl]) Schirmer I test, mm/5 min TH-SH HA NaCl IOP, mm Hg TH-SH HA NaCl ETDRS (letters) TH-SH HA NaCl
Baseline
240 Minutes
P
7.5 6 7.1 13.7 6 9.5 10.4 6 9.6
9.1 6 9.7 16.1 6 10.2 13.6 6 10.3
0.54 0.44 0.32
15.5 6 2.3 15.6 6 2.3 15.6 6 2.1
16.5 6 1.7 15.7 6 1.9 15.8 6 1.6
0.13 0.88 0.74
83.9 6 8.2 85.1 6 2.8 84.4 6 3.5
81.8 6 18.3 85.5 6 3.1 84.7 6 3.1
0.64 0.63 0.77
Values are given as mean 6 SD. ETDRS, early treatment diabetic retinopathy study.
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Cornea Volume 34, Number 4, April 2015
reason for this behavior is unclear. One speculation is that this is related to interaction of TH with lipid membranes, which involves the surrounding hydration shell.24 TH is synthesized by many organisms during prolonged periods of desiccation to protect cells from dehydration,25 a concept that also seems to function for corneal epithelial cells.26–28 In addition, TH is a compatible solute that can be taken up by the cell and does not disturb cellular macromolecules even at high concentrations, thereby acting as an osmoprotectant.17 Efficacy of trehalose has been shown in several experiments in a murine dry eye model.29,30 Clinical studies include investigation on HA hydroxyethylcellulose formulations or saline.31–33 In this study, we saw a considerably lower baseline TFT in patients with DED than previously reported for healthy subjects.19 Indeed, the values reported in this study are more than 40% lower than those observed in healthy subjects. A direct comparison of these data is difficult because we used a 3-dimensional imaging approach in this study, whereas our previous data relied only on 2-dimensional data. We believe that the present approach is preferable because it is less sensitive to eye movements. However, a study that relates TFT measured with OCT to other important biomarkers for the assessment of dry eye treatment effectiveness such as tear osmolarity and others is still missing.34 Furthermore, whether a combination of these parameters will allow us to better evaluate the clinical response to dry eye therapy in future studies is yet to be determined. Several previous studies have aimed to use OCT to characterize the effect of eye drops on TFT. As such, it has been shown that treatment with cyclosporine is associated with an increase in tear meniscus.35 In another study, topical instillation of sodium carboxymethylcellulose enabled detection of an artificial tear film appearing as a 2-layered structure on top of the epithelial surface of the cornea. It consisted of an outer band with high reflectivity and an inner band with low reflectivity.36 This phenomenon was only observed 1 to 5 minutes after administration, which is considerably earlier than measurements performed in this study. As mentioned above, the present OCT system provides a resolution of 1.2 mm in tissue, a value that is based on the full-width at half maximum of coherence function and defines the ability of the system to separate 2 structures within 1 A-scan. Changes induced by the artificial tears used in this study are, however, much smaller. Modeling of the OCT signal indicates that with a system of 1-mm resolution, changes in TFT in the order of 40 nm can be detected.37 Although this model may not reflect the present situation in all aspects, our unpublished data indicate that this is indeed the range in which such changes can be detected. All administered eye drops were well tolerated in this study, with no significant differences between groups. Likewise, there were no differences in patient satisfaction between the 3 treatment arms. None of the artificial tears had a significant effect on BUT or Schirmer I test. This is expected after single dosing, and further studies are required to clarify the effects of TH-SH combination on signs and symptoms of DED after prolonged treatment. In conclusion, the data of this study indicate that the ocular residence time of TH-SH is considerably longer than Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
Tear Film Thickness and Artificial Tears
that of HA alone. The reason for this effect is unknown and requires further investigation. REFERENCES 1. DEWS. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:75–92. 2. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 1998;17:584–589. 3. Mantelli F, Massaro-Giordano M, Macchi I, et al. The cellular mechanisms of dry eye: from pathogenesis to treatment. J Cell Physiol. 2013;228:2253–2256. 4. Sullivan BD, Whitmer D, Nichols KK, et al. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci. 2010;51:6125–6130. 5. Garrett Q, Khandekar N, Shih S, et al. Betaine stabilizes cell volume and protects against apoptosis in human corneal epithelial cells under hyperosmotic stress. Exp Eye Res. 2013;108:33–41. 6. Cher I. Fluids of the ocular surface: concepts, functions and physics. Clin Experiment Ophthalmol. 2012;40:634–643. 7. Foulks GN. Pharmacological management of dry eye in the elderly patient. Drugs Aging. 2008;25:105–118. 8. Wagh VD, Apar DU, Surana SJ. Drug delivery and pharmacotherapy for dry eye disease. Int J Pharm Pharm Sci. 2012;4:42–46. 9. Murube J, Paterson A, Murube E. Classification of artificial tears. I: composition and properties. Adv Exp Med Biol. 1998;438:693–704. 10. Rah MJ. A review of hyaluronan and its ophthalmic applications. Optometry. 2011;82:38–43. 11. Nishida T, Nakamura M, Mishima H, et al. Hyaluronan stimulates corneal epithelial migration. Exp Eye Res. 1991;53:753–758. 12. Inoue M, Katakami C. The effect of hyaluronic acid on corneal epithelial cell proliferation. Invest Ophthalmol Vis Sci. 1993;34:2313–2315. 13. Gomes JA, Amankwah R, Powell-Richards A, et al. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br J Ophthalmol. 2004;88:821–825. 14. Snibson GR, Greaves JL, Soper ND, et al. Precorneal residence times of sodium hyaluronate solutions studied by quantitative gamma scintigraphy. Eye (Lond). 1990;4:594–602. 15. Yeh S, Song XJ, Farley W, et al. Apoptosis of ocular surface cells in experimentally induced dry eye. Invest Ophthalmol Vis Sci. 2003;44:124–129. 16. Yancey PH. Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses. J Exp Biol. 2005;208:2819–2830. 17. Baudouin C, Aragona P, Messmer EM, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf. 2013;11:246–258. 18. DEWS. Methodologies to diagnose and monitor dry eye disease: report of the diagnostic methodology subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:108–152. 19. Werkmeister RM, Alex A, Kaya S, et al. Measurement of tear film thickness using ultrahigh-resolution optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54:5578–5583. 20. American National Standards Institute. American National Standard for Safe Use of Lasers. Orlando, Fl: The Laser Institute of America; 2000. ANSI Z136. 1–2000. 21. Despriet DD, Klaver CC, Witteman JC, et al. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA. 2006;296:301–309. 22. Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2011;52:2050–2064. 23. Johnson ME, Murphy PJ, Boulton M. Effectiveness of sodium hyaluronate eyedrops in the treatment of dry eye. Graefes Arch Clin Exp Ophthalmol. 2006;244:109–112. 24. Huxtable RJ. Physiological actions of taurine. Physiol Rev. 1992;72:101–163. 25. Luyckx J, Baudouin C. Trehalose: an intriguing disaccharide with potential for medical application in ophthalmology. Clin Ophthalmol. 2011;5:577–581. 26. Matsuo T. Trehalose protects corneal epithelial cells from death by drying. Br J Ophthalmol. 2001;85:610–612.
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27. Hill-Bator A, Misiuk-Hojlo M, Marycz K, et al. Trehalose-based eye drops preserve viability and functionality of cultured human corneal epithelial cells during desiccation. Biomed Res Int. 2014;2014:292139. 28. Izawa Y, Matsuo T, Uchida T, et al. Atomic force microscopic observation of trehalose-treated and dried corneal epithelial surface. Cell Preserv Technol. 2006;4:117–122. 29. Chen W, Zhang X, Liu M, et al. Trehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosis. Exp Eye Res. 2009;89:311–318. 30. Li J, Roubeix C, Wang Y, et al. Therapeutic efficacy of trehalose eye drops for treatment of murine dry eye induced by an intelligently controlled environmental system. Mol Vis. 2012;18:317–329. 31. Matsuo T. Trehalose versus hyaluronan or cellulose in eyedrops for the treatment of dry eye. Jpn J Ophthalmol. 2004;48:321–327. 32. Matsuo T, Tsuchida Y, Morimoto N. Trehalose eye drops in the treatment of dry eye syndrome. Ophthalmology. 2002;109:2024–2029.
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