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Home , Astigmatism

Special Issue Irregular Astigmatism and Higher-Order Aberrations in Eyes With Dry

Shizuka Koh1,2 1Department of Innovative Visual Science, Osaka University Graduate School of Medicine, Osaka, Japan 2Department of , Osaka University Graduate School of Medicine, Osaka, Japan

Correspondence: Shizuka Koh, De- Visual disturbances were included in the definition of dry eye disease in the 2007 Dry Eye partment of Innovative Visual Sci- Workshop report. As a result, quality of vision (QoV) in dry eye patients has received ence, Osaka University Graduate increased attention. and wavefront sensors have been used to objectively School of Medicine, Room E7, 2-2 and quantitatively evaluate optical quality, with data showing increases in irregular Yamadaoka, Suita Osaka, 565-0871, astigmatism and higher-order aberrations (HOAs) in dry eye patients. Furthermore, ocular Japan; optical characteristics are influenced by the tear film, which constantly fluctuates over time. [email protected]. Therefore, dynamic quantitative assessments of optical quality with continuous measure- Submitted: November 28, 2017 ments are essential to understanding QoV in dry eye patients. This review summarizes what is Accepted: March 12, 2018 known and what advances have been made in evaluating and understanding QoV in dry eye patients. In particular, corneal topographic and wavefront analyses, conducted both overseas Citation: Koh S. Irregular astigmatism and in Japan, are described. and higher-order aberrations in eyes with dry eye disease. Invest Ophthal- Keywords: irregular astigmatism, higher-order aberrations, dry eye, corneal topography, mol Vis Sci. 2018;59:DES36–DES40. wavefront sensor https://doi.org/10.1167/iovs.17-23500

he tear film greatly influences ocular because it is the optical quality are of particular importance for better under- T first refracting surface that light comes into contact with. standing and treating dry eye disease.4 This may seem obvious, but the influence of the tear film on optical quality and visual function has not been discussed in great detail in eyes with dry eye. This is likely because most dry RECENT PROGRESS AROUND THE WORLD eye patients have a good best-corrected , with the exception of advanced or severe cases (e.g., Sj¨ogren’s syndrome Corneal Topographic Analyses and Steven–Johnson syndrome). Visual acuity measurements Corneal topographic analyses are used to detect corneal have become the hallmark of visual function. Unfortunately, irregular astigmatism. Conventional Placido ring–based corneal these conventional assessments do not detect all aspects of topographers measure anterior corneal surface contours7 by degraded visual function. In the early 1990s, Rieger1 first analyzing reflected images of a ring projected onto the air–tear demonstrated the importance of the tear film in vision by film interface. Therefore, this system is capable of detecting comparing vision and static perimetry results in patients with tear film–related changes in corneal topography. Several studies dry eye. Thereafter, the effect of the tear film on contrast have indicated that fluctuations and irregularities in the tear 8–10 sensitivity has been the focus of investigations, as this film increase irregular astigmatism. Previous studies on eyes 11–13 subjective measurement more accurately reflects visual perfor- with dry eye have measured surface regularity index (SRI) mance.2,3 and surface asymmetry index (SAI) to better understand local The development of marked a major corneal variations. These studies showed that both SAI and SRI turning point in ophthalmology. Successful refractive outcomes were higher in dry eyes than in healthy eyes. High-speed relied on understanding quantitative quality of vision (QoV) videokeratoscopy was also recently developed to document and assess dynamic corneal topography changes associated evaluations and not just conventional visual acuity testing 14–18 results. As a result, remarkable advances in objective QoV with precorneal tear film behavior. assessments have been made, including the development of corneal topography systems and wavefront sensors. Notably, Wavefront Sensing QoV assessments are also applicable to ophthalmology fields Wavefront sensing measures the refractive status, including other than refractive surgery. Corneal topography systems and irregular astigmatism, of the eye’s whole optical system.19,20 wavefront sensors are now widely used in clinical practice to The wavefront sensor detects and quantifies irregular astigma- objectively and quantitatively assess optical quality. These tism as higher-order aberrations (HOAs). Exploding interest in measurements revealed an increase in irregular astigmatism QoV and how it relates to wavefront analyses indicates the new and have facilitated further study on how tear film behavior trend of focusing on the tear film. Wavefront sensors are relates to QoV in dry eyes.4,5 Dry eye is a multifactorial disorder sensitive enough to objectively quantify increases in HOAs that of the tear film and ocular surface that results in discomfort, occur with tear film fluctuations.21–24 visual disturbance, tear film instability, and, potentially, ocular Wavefront analyses have utilized the same technologies and surface damage.6 Therefore, advances in objectively assessing analysis methods as corneal topographic analyses. Sequential

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FIGURE 1. Representative color maps obtained using a tear film stability analysis system (TSAS). Maps from a normal subject (A) and a dry eye patient (B) are shown for comparison. Image collection began immediately after the patient was asked to blink. The time of image capture is shown in the bottom left corner of each image. Additionally, the bottom right image in each figure part shows how the surface regularity index (SRI, blue) and the surface asymmetry index (SAI, red) changed over time. Reprinted with permission from Kojima T, Ishida R, Dogru M, et al. A new noninvasive tear stability analysis system for the assessment of dry eyes. Invest Ophthalmol Vis Sci. 2004;45:1369–1374. Copyright Ó 2004 ARVO.

corneal wavefront aberration measurements (not whole-eye (i.e., TSRI and TSAI, which were derived from SRI and SAI, HOAs) were made in and compared between normal and dry respectively). They found that both TSRI and TSAI were eyes.25,26 Additionally, several Japanese studies (fully described significantly greater in dry eyes than in normal eyes (Fig. 1). below) have examined how HOAs of the whole eye change in Additionally, the insertion of punctal plugs to treat dry eye was connection with postblink changes to tear film dynamics. associated with a significant decrease in both SRI and SAI.35 These sequential wavefront measurements revealed that 27–31 dynamic tear film changes affect postblink optical quality. Wavefront Sensing Additionally, French researchers found that the progression index for corneal HOAs was correlated with subjective, patient- Interest in wavefront analysis has been growing worldwide. 36 reported visual outcomes in subjects with dry eye.29 They also Koh et al. quantified the optical impact of tear film breakup found that optical quality degradation in dry eyes is associated for the first time using a wavefront sensor from Japan. This with during driving.30 Furthermore, simul- study confirmed that physicians need to perform careful taneous evaluation of ocular HOAs and tear meniscus preoperative wavefront measurements before refractive sur- dimensions makes it possible to investigate the influence of gery to avoid the effects of tear film breakup. real-time tear film changes, including tear volume, on optical The introduction of sequential measurements of corneal quality.31 wavefront aberration allowed the postblink changes in HOA to be quantified over time.25,26 This, in turn, led to a better understanding of how the tear film influences QoV. Koh and 37–40 41 RECENT PROGRESS IN JAPAN colleagues (Koh et al., Mihashi et al., and Hirohara et al.42) specifically examined sequential ocular wavefront Corneal Topographic Analyses aberrations and the optical effect of tear film dynamics after blinking. They introduced the following quantitative indices Attention to assessing corneal irregular astigmatism induced by that describe sequential HOA change over time: the total HOA tear film changes has increased around the world, including in fluctuation index (FI) and stability index (SI). Both FI and SI are 32 Japan. Goto et al. reported an increase in SRI after sustained useful in describing time-dependent HOA changes that cannot eye opening in dry eyes, but not in normal eyes. After this be detected with a single measurement.37 FI and SI measure- study was done, tear film stability analysis system (TSAS) ments can now be performed in the clinical setting, because software was developed for the TMS-2N corneal topography the Hartmann-Shack wavefront aberrometer developed in their instrument (Tomey Technology, Nagoya, Japan). This new study was used as the prototype for the commercially available software gave the system the ability to capture serial corneal KR-1W (Topcon Corp., Tokyo, Japan). surface images once a second for 10 seconds. Using reverse- Wavefront analysis studies in Japan have played a significant engineered Placido ring–based corneal topographic map role in understanding the mechanisms underlying visual calculations, the system was able to detect subtle tear film disturbances associated with dry eye.4 Total ocular HOAs are changes from mire ring distortions. This software program also believed to be stable between blinks in normal eyes (Fig. 2A), allows tear breakup time (TMS-BUT), and the ratio of breakup but evidence shows that, even in clinically normal subjects, area to the entire color-coded area (TMS-BUA), to be calculated HOAs can change dynamically after blinking.37 Subjects with a from corneal topographic data. According to Goto et al.,33 decreased tear film BUT and dry eye symptoms, but without TMS-BUT and TMS-BUA sensitivity were both significantly ocular surface damage or tear deficiency, are designated as higher than conventional BUT sensitivity (measured with having ‘‘short BUT dry eye.’’ In these eyes, HOAs increase over fluorescein tear film staining) in normal eyes. In a subsequent time after blinking, and continue to increase during the 10- study, Goto et al.34 reported that laser in situ keratomileusis second measurement period, during which the subject does not (LASIK) significantly decreased tear film stability in the early blink (Fig. 2B).39 In contrast, subjects with ‘‘aqueous tear- postoperative period. Furthermore, Kojima et al.35 used TSAS deficient’’ dry eye showed high initial total ocular HOAs, and dry to measure tear film stability, regularity, and asymmetry indices eyes with superficial punctate keratopathy (SPK) of the central

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FIGURE 2. Representative serial ocular higher-order aberration (HOA) color maps following a blink. The simulated retinal images of the 20/20 Landolt ring are shown for clinical reference. Wavefront data were obtained at a rate of one image per second. Maps from a normal eye (A) show that optical quality is stable throughout the measurement period. However, maps from an eye with short breakup time (BUT) dry eye (B) indicate an eye with initially normal optical quality that progressively deteriorates over time as tear film stability declines. This finding explains the complaint of fluctuating vision associated with blinking in patients with short TBUT dry eye. Maps from a dry eye with superficial punctate keratopathy (SPK) in the central corneal region (C) show that simulated retinal image quality is impaired immediately after blinking and during the entire measurement period. This explains the complaint of by dry eye patients with SPK in the central corneal region. Reprinted with permission from Koh S. Mechanisms of visual disturbance in dry eye. . 2016;35:S83–S88. Copyright Ó 2016 Wolters Kluwer Health, Inc.

cornea had even higher initial HOAs (Fig. 2C).40 Interestingly, mucous secretion. The long-term use of diquafosol in eyes with dry eyes without SPK in the central corneal region had aqueous-deficient dry eye has been shown to reduce HOAs, consistently lower total HOAs, which exhibited similar changes improve tear film stability, and decrease corneal epithelial over time relative to those seen in normal eyes40 (Fig. 2 in Ref. damage.47 Diquafosol treatment also significantly improved 4). These findings were confirmed by Kaido et al.,43 who ocular HOAs in eyes with short BUT dry eye.48 Rebamipide reported that optical disturbances in the central optical zone of improved optical quality in the short BUT type; after treatment, with dry eye may affect visual performance. This is a decrease was observed in the ‘‘progressive increase pattern’’ particularly true in short BUT dry eye, which often has an of the dynamic HOAs. Eyes with short BUT dry eye showed underestimated impact. In short BUT dry eye, patients often improvement in both optical quality and tear film BUT 49 complain of severe dry eye symptoms, particularly ocular (measured with fluorescein). fatigue.44 Functional visual acuity and sequential wavefront measurements have helped physicians better understand the importance of treating short BUT dry eye.45,46 FUTURE DIRECTIONS Two unique topical pharmacologic agents for treating dry Quantifying optical quality with corneal topographic and eye are commercially available in Japan. Diquafosol ophthalmic wavefront analyses has demonstrated that both tear film solution 3% (Diquas, ophthalmic solution 3%; Santen Pharma- instability and ocular surface damage degrade QoV in dry eye ceutical Co. Ltd, Osaka, Japan) stimulates aqueous and mucous patients. Moreover, continuous corneal topographic and secretions directly on the ocular surface. Rebamipide ophthal- wavefront measurements provide detailed information about mic suspension 2% (Mucosta ophthalmic suspension UD2%; how optical quality changes with precorneal tear film changes Otsuka Pharmaceutical, Co., Ltd, Tokyo, Japan) stimulates over time. Trends in the study of optical quality have largely

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been similar between Japan and other countries. However, 13. de Paiva CS, Lindsey JL, Pflugfelder SC. Assessing the severity similar studies that have been performed outside of Japan are of sicca with videokeratoscopic indices. Ophthal- limited in that the vast majority were performed in the basic mology. 2003;110:1102–1109. science setting, whereas studies performed in the clinical 14. Nemeth´ J, Erdelyi´ B, Cs´ak´any B. Corneal topography changes setting are essential for understanding disease pathophysiolo- after a 15 second pause in blinking. J Refract Surg. gy, as well as for introducing novel diagnostic methods for 2001;27:589–592. clinical use. 15. Nemeth´ J, Erdelyi´ B, Cs´ak´any B, et al. High-speed videotopo- Interestingly, optical quality has not been shown by graphic measurement of tear film build-up time. Invest objective assessment to be correlated with subjective visual Ophthalmol Vis Sci. 2002;43:1783–1790. dry eye symptoms. Further investigation of this relationship is 16. Erdelyi´ B, Cs´ak´any B, Nemeth´ J. Spontaneous alterations of 4 required. Blinking plays an important role in providing the the corneal topographic pattern. J Cataract Refract Surg. smooth optical surface of the tear film; however, there are 2005;31:973–978. variations in blinking that arise from intrinsic and environ- 50 17. Iskander DR, Collins MJ. Applications of high-speed video- mental factors. The effects of variations in blinking (e.g., left keratoscopy. Clin Exp Optom. 2005;88:223–231. eye–right eye variations, longitudinal variations between 18. Zhu M, Collins MJ, Iskander DR. Dynamics of ocular surface examinations, and variations throughout the course of the topography. Eye. 2007;21:624–632. day) on the measurement of optical quality should be investigated in further studies. The evolution of corneal 19. Liang J, Grimm B, Goelz S, Bille JF. Objective measurement of wave aberrations of the with the use of a topographers and wavefront sensors may enable the assess- Hartmann-Shack wave-front sensor. J Opt Soc Am A. 1994;11: ment of optical quality in a simple and accurate fashion in 1949–1957. situations that simulate the activities of daily life.51 20. Maeda N. Wavefront technology in ophthalmology. Curr Opin Ophthalmol. 2001;12:294–299. Acknowledgments 21. Thibos LN, Hong X. Clinical applications of the Shack- Funding of the publication fee and administration was provided by Hartmann aberrometer. Optom Vis Sci. 1999;76:817–825. the Dry Eye Society, Tokyo, Japan. The Dry Eye Society had no role 22. Himebaugh NL, Thibos LN, Bradley A, et al. Predicting optical in the contents or writing of the manuscript. effects of tear film break up on retinal image quality using the Disclosure: S. Koh, Otsuka (R), Santen (R) Shack-Hartmann aberrometer and computational optical modeling. Adv Exp Med Biol. 2002;506:1141–1147. 23. 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