New Developments in Dry Eye Research

  • Kazuo TsubotaEmail author
  • Norihiko Yokoi


This chapter covers recent developments in dry eye research, including the relationship between dry eye and the patient’s systemic condition, and the importance of tear-film breakup. Eye drops are the standard first line of treatment for dry eye, but as dry eye is a lifestyle disease, treatment should begin with lifestyle interventions, in which patients are provided with advice on diet, computer usage, and ways to improve their mental health. Tear stability is an important aspect of dry eye, and it is useful to evaluate tear-film breakup times and patterns to provide information to help clinicians stabilize the tear film. In addition, the basis of the neuropathic pain of dry eye has been elucidated as an unstable tear film disrupts the corneal nerving. The progress in this field is expected to lead to new treatments or prevention for dry eye.


Exercise Mental health Sleep Supplements Systemic condition Tear breakup patterns Tear-film breakup time 



The authors are indebted to Synergy Vision for the English editing on this chapter.

Conflicts of Interest

Kazuo Tsubota reports consultancies and research funding received from Santen Pharmaceutical Co., Ltd., and Otsuka Pharmaceutical Co., Ltd., as well as research funding from Wakamoto Pharmaceutical Co., Ltd., Toshiba Materials, R-Tech Ueno, and Kowa Company. He holds the patent rights for the method and the apparatus used for the measurement of functional visual acuity (US patent no: 255 7470026), and is the inventor of JINS Moisture eye glasses by JINS, Inc., patent holder. In addition, he is an investor for Tissue Tech, Inc., Tear Solutions and Tsubota Laboratory, Inc. where is holds the position of CEO. Outside the submitted work, Kazuo Tsubota reports consultancies for Novaliq GmbH, Laboratoires Thea, AMO Japan K.K., Ocular Surface Research & Education Foundation, and NIDEK Co., Ltd.

Norihiko Yokoi reports personal fees from Santen Pharmaceutical Co., Ltd., and Otsuka Pharmaceutical Co., Ltd.


  1. 1.
    Belmonte C, Nichols JJ, Cox SM, Brock JA, Begley CG, Bereiter DA, et al. TFOS DEWS II pain and sensation report. Ocul Surf. 2017;15:404–37.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15:276–83.PubMedCrossRefGoogle Scholar
  3. 3.
    Willcox MDP, Argueso P, Georgiev GA, Holopainen JM, Laurie GW, Millar TJ, et al. TFOS DEWS II tear film report. Ocul Surf. 2017;15:366–403.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Lim A, Wenk MR, Tong L. Lipid-based therapy for ocular surface inflammation and disease. Trends Mol Med. 2015;21:736–48.PubMedCrossRefGoogle Scholar
  5. 5.
    Tsubota K, Toda I, Nakamori K. Poor illumination, VDTs, and desiccated eyes. Lancet. 1996;347:768–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Uchino M, Schaumberg DA, Dogru M, Uchino Y, Fukagawa K, Shimmura S, et al. Prevalence of dry eye disease among Japanese visual display terminal users. Ophthalmology. 2008;115:1982–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Nakamura S, Kinoshita S, Yokoi N, Ogawa Y, Shibuya M, Nakashima H, et al. Lacrimal hypofunction as a new mechanism of dry eye in visual display terminal users. PLoS One. 2010;5:e11119.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Kojima T, Ibrahim OM, Wakamatsu T, Tsuyama A, Ogawa J, Matsumoto Y, et al. The impact of contact lens wear and visual display terminal work on ocular surface and tear functions in office workers. Am J Ophthalmol. 2011;152:933–40e2.PubMedCrossRefGoogle Scholar
  9. 9.
    Uchino M, Nishiwaki Y, Michikawa T, Shirakawa K, Kuwahara E, Yamada M, et al. Prevalence and risk factors of dry eye disease in Japan: Koumi study. Ophthalmology. 2011;118:2361–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Dogru M, Ward SK, Wakamatsu T, Ibrahim O, Schnider C, Kojima T, et al. The effects of 2 week senofilcon-A silicone hydrogel contact lens daily wear on tear functions and ocular surface health status. Cont Lens Anterior Eye. 2011;34:77–82.PubMedCrossRefGoogle Scholar
  11. 11.
    Kojima T, Matsumoto Y, Ibrahim OM, Wakamatsu TH, Uchino M, Fukagawa K, et al. Effect of controlled adverse chamber environment exposure on tear functions in silicon hydrogel and hydrogel soft contact lens wearers. Invest Ophthalmol Vis Sci. 2011;52:8811–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Siddireddy JS, Vijay AK, Tan J, Willcox M. The eyelids and tear film in contact lens discomfort. Cont Lens Anterior Eye. 2018;41:144–53.PubMedCrossRefGoogle Scholar
  13. 13.
    Yoon SY, Bae SH, Shin YJ, Park SG, Hwang SH, Hyon JY, et al. Low serum 25-Hydroxyvitamin D levels are associated with dry eye syndrome. PLoS One. 2016;11:e0147847.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Ogawa Y, Okamoto S, Kuwana M, Mori T, Watanabe R, Nakajima T, et al. Successful treatment of dry eye in two patients with chronic graft-versus-host disease with systemic administration of FK506 and corticosteroids. Cornea. 2001;20:430–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Ono M, Takamura E, Shinozaki K, Tsumura T, Hamano T, Yagi Y, et al. Therapeutic effect of cevimeline on dry eye in patients with Sjogren’s syndrome: a randomized, double-blind clinical study. Am J Ophthalmol. 2004;138:6–17.PubMedCrossRefGoogle Scholar
  16. 16.
    Dogru M, Matsumoto Y, Yamamoto Y, Goto E, Saiki M, Shimazaki J, et al. Lactoferrin in Sjogren’s syndrome. Ophthalmology. 2007;114:2366–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Inoue S, Kawashima M, Hisamura R, Imada T, Izuta Y, Nakamura S, et al. Clinical evaluation of a royal jelly supplementation for the restoration of dry eye: a prospective randomized double blind placebo controlled study and an experimental mouse model. PLoS One. 2017;12:e0169069.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Kawashima M, Nakamura S, Izuta Y, Inoue S, Tsubota K. Dietary supplementation with a combination of lactoferrin, fish oil, and Enterococcus faecium WB2000 for treating dry eye: a rat model and human clinical study. Ocul Surf. 2016;14(2):255–63.PubMedCrossRefGoogle Scholar
  19. 19.
    Toda I, Shimazaki J, Tsubota K. Dry eye with only decreased tear break-up time is sometimes associated with allergic conjunctivitis. Ophthalmology. 1995;102:302–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Yokoi N, Georgiev GA, Kato H, Komuro A, Sonomura Y, Sotozono C, et al. Classification of fluorescein breakup patterns: a novel method of differential diagnosis for dry eye. Am J Ophthalmol. 2017;180:72–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Tsubota K. Will sitting more than six hours a day leading to an early death?[Japanese]. Tokyo: KK Best Sellers; 2013.Google Scholar
  22. 22.
    Tsubota K, Nakamori K. Dry eyes and video display terminals. N Engl J Med. 1993;328:584.PubMedCrossRefGoogle Scholar
  23. 23.
    Nakamura S, Shibuya M, Nakashima H, Imagawa T, Uehara M, Tsubota K. D-beta-hydroxybutyrate protects against corneal epithelial disorders in a rat dry eye model with jogging board. Invest Ophthalmol Vis Sci. 2005;46:2379–87.PubMedCrossRefGoogle Scholar
  24. 24.
    Kawashima M, Kawakita T, Okada N, Ogawa Y, Murat D, Nakamura S, et al. Calorie restriction: a new therapeutic intervention for age-related dry eye disease in rats. Biochem Biophys Res Commun. 2010;397(4):724–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Nakamura S, Shibuya M, Nakashima H, Hisamura R, Masuda N, Imagawa T, et al. Involvement of oxidative stress on corneal epithelial alterations in a blink-suppressed dry eye. Invest Ophthalmol Vis Sci. 2007;48:1552–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298–300.PubMedCrossRefGoogle Scholar
  27. 27.
    Imamura Y, Noda S, Hashizume K, Shinoda K, Yamaguchi M, Uchiyama S, et al. Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proc Natl Acad Sci U S A. 2006;103:11282–7.CrossRefGoogle Scholar
  28. 28.
    Yuki K, Ozawa Y, Yoshida T, Kurihara T, Hirasawa M, Ozeki N, et al. Retinal ganglion cell loss in superoxide dismutase 1 deficiency. Invest Ophthalmol Vis Sci. 2011;52:4143–50.PubMedCrossRefGoogle Scholar
  29. 29.
    Kojima T, Dogru M, Ibrahim OM, Wakamatsu TH, Ito M, Igarashi A, et al. Effects of oxidative stress on the conjunctiva in Cu, Zn-Superoxide Dismutase-1 (Sod1)-knockout mice. Invest Ophthalmol Vis Sci. 2015;56:8382–91.PubMedCrossRefGoogle Scholar
  30. 30.
    Ibrahim OM, Dogru M, Matsumoto Y, Igarashi A, Kojima T, Wakamatsu TH, et al. Oxidative stress induced age dependent meibomian gland dysfunction in cu, zn-superoxide dismutase-1 (sod1) knockout mice. PLoS One. 2014;9:e99328.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Sano K, Kawashima M, Ito A, Inaba T, Morimoto K, Watanabe M, et al. Aerobic exercise increases tear secretion in type 2 diabetic mice. Invest Ophthalmol Vis Sci. 2014;55:4287–94.PubMedCrossRefGoogle Scholar
  32. 32.
    Higuchi A, Takahashi K, Hirashima M, Kawakita T, Tsubota K. Selenoprotein P controls oxidative stress in cornea. PLoS One. 2010;5:e9911.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Higuchi A, Inoue H, Kawakita T, Ogishima T, Tsubota K. Selenium compound protects corneal epithelium against oxidative stress. PLoS One. 2012;7:e45612.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Higuchi A, Inoue H, Kaneko Y, Oonishi E, Tsubota K. Selenium-binding lactoferrin is taken into corneal epithelial cells by a receptor and prevents corneal damage in dry eye model animals. Sci Rep. 2016;6:36903.Google Scholar
  35. 35.
    Uchino M, Yokoi N, Uchino Y, Dogru M, Kawashima M, Komuro A, et al. Prevalence of dry eye disease and its risk factors in visual display terminal users: the Osaka study. Am J Ophthalmol. 2013;156:759–66e1.CrossRefGoogle Scholar
  36. 36.
    Kaido M, Uchino M, Yokoi N, Uchino Y, Dogru M, Kawashima M, et al. Dry-eye screening by using a functional visual acuity measurement system: the Osaka study. Invest Ophthalmol Vis Sci. 2014;55:3275–81.PubMedCrossRefGoogle Scholar
  37. 37.
    Kawashima M, Uchino M, Yokoi N, Uchino Y, Dogru M, Komuro A, et al. The association between dry eye disease and physical activity as well as sedentary behavior: results from the Osaka study. J Ophthalmol. 2014;2014:943786.CrossRefGoogle Scholar
  38. 38.
    Uchino M, Uchino Y, Dogru M, Kawashima M, Yokoi N, Komuro A, et al. Dry eye disease and work productivity loss in visual display users: the Osaka study. Am J Ophthalmol. 2014;157:294–300.PubMedCrossRefGoogle Scholar
  39. 39.
    Uchino Y, Uchino M, Yokoi N, Dogru M, Kawashima M, Okada N, et al. Alteration of tear mucin 5AC in office workers using visual display terminals: the Osaka study. JAMA Ophthalmol. 2014;132:985–92.PubMedCrossRefGoogle Scholar
  40. 40.
    Kawashima M, Uchino M, Yokoi N, Uchino Y, Dogru M, Komuro A, et al. Associations between subjective happiness and dry eye disease: anew perspective from the Osaka study. PLoS One. 2015;10(4):e0123299.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Kawashima M, Uchino M, Yokoi N, Uchino Y, Dogru M, Komuro A, et al. The association of sleep quality with dry eye disease: the Osaka study. Clin Ophthalmol. 2016;10:1015–21.Google Scholar
  42. 42.
    Sano K, Kawashima M, Takechi S, Mimura M, Tsubota K. Exercise program improved subjective dry eye symptoms for office workers. Clin Ophthalmol. 2018;12:307–11.CrossRefGoogle Scholar
  43. 43.
    Hirshkowitz M, Whiton K, Albert SM, Alessi C, Bruni O, DonCarlos L, et al. National Sleep Foundation’s updated sleep duration recommendations: final report. Sleep Health. 2015;1:233–43.PubMedCrossRefGoogle Scholar
  44. 44.
    Ayaki M, Kawashima M, Negishi K, Tsubota K. High prevalence of sleep and mood disorders in dry eye patients: survey of 1,000 eye clinic visitors. Neuropsychiatr Dis Treat. 2015;11:889–94.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Ayaki M, Kawashima M, Negishi K, Kishimoto T, Mimura M, Tsubota K. Sleep and mood disorders in dry eye disease and allied irritating ocular diseases. Sci Rep. 2016;6:22480.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Ayaki M, Kawashima M, Negishi K, Kishimoto T, Mimura M, Tsubota K. Sleep and mood disorders in women with dry eye disease. Sci Rep. 2016;6:35276.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Ayaki M, Toda I, Tachi N, Negishi K, Tsubota K. Preliminary report of improved sleep quality in patients with dry eye disease after initiation of topical therapy. Neuropsychiatr Dis Treat. 2016;12:329–37.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Foundation NS. 2015 Sleep in America Poll – pain and sleep. Summary of findings. Sleep Health. 2015;1:e14–e375.CrossRefGoogle Scholar
  49. 49.
    Knutson K. Sleep and pain: summary of the 2015 Sleep in America Poll. Sleep Health. 2015;1:85.PubMedCrossRefGoogle Scholar
  50. 50.
    Ozawa Y, Kawashima M, Inoue S, Inagaki E, Suzuki A, Ooe E, et al. Bilberry extract supplementation for preventing eye fatigue in video display terminal workers. J Nutr Health Aging. 2015;19:548–54.PubMedCrossRefGoogle Scholar
  51. 51.
    Conneely OM. Antiinflammatory activities of lactoferrin. J Am Coll Nutr. 2001;20:389S–95S; discussion 96S–97S.PubMedCrossRefGoogle Scholar
  52. 52.
    Legrand D, Elass E, Carpentier M, Mazurier J. Lactoferrin: a modulator of immune and inflammatory responses. Cell Mol Life Sci. 2005;62:2549–59.PubMedCrossRefGoogle Scholar
  53. 53.
    Kawashima M, Kawakita T, Inaba T, Okada N, Ito M, Shimmura S, et al. Dietary lactoferrin alleviates age-related lacrimal gland dysfunction in mice. PLoS One. 2012;7:e33148.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Heneghan C, Kiely M, Lyons J, Lucey A. The effect of berry-based food interventions on markers of cardiovascular and metabolic health: a systematic review of randomized controlled trials. Mol Nutr Food Res. 2018;62.Google Scholar
  55. 55.
    Kowalska K, Olejnik A. Current evidence on the health-beneficial effects of berry fruits in the prevention and treatment of metabolic syndrome. Curr Opin Clin Nutr Metab Care. 2016;19:446–52.PubMedCrossRefGoogle Scholar
  56. 56.
    Nakamura S, Tanaka J, Inada T, Shimoda H, Tsubota K. Delphinidin 3,4-O-diglucoside, a constituent of the maqui berry (Aristoteliachilensis) anthocyanin, restores tear secretion in a rat dry eye model. J Funct Foods. 2014;10:346–54.CrossRefGoogle Scholar
  57. 57.
    Imada T, Nakamura S, Kitamura N, Shibuya I, Tsubota K. Oral administration of royal jelly restores tear secretion capacity in rat blink-suppressed dry eye model by modulating lacrimal gland function. PLoS One. 2014;9:e106338.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Imada T, Nakamura S, Hisamura R, Izuta Y, Jin K, Ito M, et al. Serotonin hormonally regulates lacrimal gland secretory function via the serotonin type 3a receptor. Sci Rep. 2017;7(1):6965.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Iovieno N, Dalton ED, Fava M, Mischoulon D. Second-tier natural antidepressants: review and critique. J Affect Disord. 2011;130:343–57.PubMedCrossRefGoogle Scholar
  60. 60.
    Turner E, Loftis J, Blackwell A. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2006;109:325–38.CrossRefGoogle Scholar
  61. 61.
    Le Floc’h N, Otten W, Merlot E. Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids. 2011;41:1195–205.PubMedCrossRefGoogle Scholar
  62. 62.
    Kim KW, Han SB, Han ER, Woo SJ, Lee JJ, Yoon JC, et al. Association between depression and dry eye disease in an elderly population. Invest Ophthalmol Vis Sci. 2011;52:7954–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Pflugfelder SC, Tseng SC, Sanabria O, Kell H, Garcia CG, Felix C, et al. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea. 1998;17:38–56.PubMedCrossRefGoogle Scholar
  64. 64.
    Pflugfelder SC. Anti-inflammatory therapy of dry eye. Ocul Surf. 2003;1:31–6.PubMedCrossRefGoogle Scholar
  65. 65.
    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.Google Scholar
  66. 66.
    Akpek EK, Amescua G, Farid M, Garcia-Ferrer FJ, Lin A, Rhee MK, et al. Dry eye syndrome preferred practice pattern(R). Ophthalmology 2019;126:P286–P334.PubMedCrossRefGoogle Scholar
  67. 67.
    Hyon JY, Kim HM, Lee D, Chung ES, Song JS, Choi CY, et al. Korean guidelines for the diagnosis and management of dry eye: development and validation of clinical efficacy. Korean J Ophthalmol. 2014;28:197–206.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Tsubota K, Yokoi N, Shimazaki J, Watanabe H, Dogru M, Yamada M, et al. New perspectives on dry eye definition and diagnosis: a consensus report by the Asia Dry Eye Society. Ocul Surf. 2017;15:65–76.PubMedCrossRefGoogle Scholar
  69. 69.
    Kheirkhah A, Dohlman TH, Amparo F, Arnoldner MA, Jamali A, Hamrah P, et al. Effects of corneal nerve density on the response to treatment in dry eye disease. Ophthalmology. 2015;122:662–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Galor A, Levitt RC, Felix ER, Martin ER, Sarantopoulos CD. Neuropathic ocular pain: an important yet underevaluated feature of dry eye. Eye (Lond). 2015;29:301–12.CrossRefGoogle Scholar
  71. 71.
    Galor A, Moein HR, Lee C, Rodriguez A, Felix ER, Sarantopoulos KD, et al. Neuropathic pain and dry eye. Ocul Surf. 2018;16:31–44.PubMedCrossRefGoogle Scholar
  72. 72.
    Galor A, Zlotcavitch L, Walter SD, Felix ER, Feuer W, Martin ER, et al. Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain. Br J Ophthalmol. 2015;99:665–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Rosenthal P, Borsook D, Moulton EA. Oculofacial pain: corneal nerve damage leading to pain beyond the eye. Invest Ophthalmol Vis Sci. 2016;57:5285–7.CrossRefGoogle Scholar
  74. 74.
    Goyal S, Hamrah P. Understanding neuropathic corneal pain–gaps and current therapeutic approaches. Semin Ophthalmol. 2016;31:59–70.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Quallo T, Vastani N, Horridge E, Gentry C, Parra A, Moss S, et al. TRPM8 is a neuronal osmosensor that regulates eye blinking in mice. Nat Commun. 2015;6:7150.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Kaido M, Ishida R, Dogru M, Tamaoki T, Tsubota K. Efficacy of punctum plug treatment in short break-up time dry eye. Optom Vis Sci. 2008;85:758–63.PubMedCrossRefGoogle Scholar
  77. 77.
    Kaido M, Ishida R, Dogru M, Tsubota K. Visual function changes after punctal occlusion with the treatment of short BUT type of dry eye. Cornea. 2012;31:1009–13.PubMedCrossRefGoogle Scholar
  78. 78.
    Koh S, Inoue Y, Sugmimoto T, Maeda N, Nishida K. Effect of rebamipide ophthalmic suspension on optical quality in the short break-up time type of dry eye. Cornea. 2013;32:1219–23.PubMedCrossRefGoogle Scholar
  79. 79.
    Shimazaki-Den S, Iseda H, Dogru M, Shimazaki J. Effects of diquafosol sodium eye drops on tear film stability in short BUT type of dry eye. Cornea. 2013;32:1120–5.PubMedCrossRefGoogle Scholar
  80. 80.
    Kim YH, Kang YS, Lee HS, Choi W, You IC, Yoon KC. Effectiveness of combined tear film therapy in patients with evaporative dry eye with short tear film breakup time. J Ocul Pharmacol Ther. 2017;33:635–43.PubMedCrossRefGoogle Scholar
  81. 81.
    Shigeyasu C, Yamada M, Kawashima M, Suwaki K, Uchino M, Hiratsuka Y, et al. Quality of life measures and health utility values among dry eye subgroups. Health Qual Life Outcomes. 2018;16:170.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Tsubota K. Short tear film breakup time-type dry eye. Invest Ophthalmol Vis Sci. 2018;59:DES64–70.PubMedCrossRefGoogle Scholar
  83. 83.
    Kaido M, Kawashima M, Ishida R, Tsubota K. Relationship of corneal pain sensitivity with dry eye symptoms in dry eye with short tear break-up time. Invest Ophthalmol Vis Sci. 2016;57(3):914–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Goto E, Yagi Y, Matsumoto Y, Tsubota K. Impaired functional visual acuity of dry eye patients. Am J Ophthalmol. 2002;133:181–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Koh S, Maeda N, Hirohara Y, Mihashi T, Bessho K, Hori Y, et al. Serial measurements of higher-order aberrations after blinking in patients with dry eye. Invest Ophthalmol Vis Sci. 2008;49:133–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Koh S, Maeda N, Ikeda C, Asonuma S, Mitamura H, Oie Y, et al. Ocular forward light scattering and corneal backward light scattering in patients with dry eye. Invest Ophthalmol Vis Sci. 2014;55:6601–6.PubMedCrossRefGoogle Scholar
  87. 87.
    Koh S, Maeda N, Ikeda C, Asonuma S, Ogawa M, Hiraoka T, et al. The effect of ocular surface regularity on contrast sensitivity and straylight in dry eye. Invest Ophthalmol Vis Sci. 2017;58:2647–51.PubMedCrossRefGoogle Scholar
  88. 88.
    Koh S, Tung CI, Inoue Y, Jhanji V. Effects of tear film dynamics on quality of vision. Br J Ophthalmol. 2018;102:1615–20.PubMedCrossRefGoogle Scholar
  89. 89.
    Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136:318–26.PubMedCrossRefGoogle Scholar
  90. 90.
    Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch Ophthalmol. 2009;127:763–8.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kaido M, Dogru M, Ishida R, Tsubota K. Concept of functional visual acuity and its applications. Cornea. 2007;26(9 Suppl 1):S29–35.PubMedCrossRefGoogle Scholar
  92. 92.
    Koh S. Irregular astigmatism and higher-order aberrations in eyes with dry eye disease. Invest Ophthalmol Vis Sci. 2018;59(14):DES36–40.PubMedCrossRefGoogle Scholar
  93. 93.
    Kaido M, Uchino M, Kojima T, Dogru M, Tsubota K. Effects of diquafosol tetrasodium administration on visual function in short break-up time dry eye. J Ocul Pharmacol Ther. 2013;29:595–603.PubMedCrossRefGoogle Scholar
  94. 94.
    Jung HH, Kang YS, Sung MS, Yoon KC. Clinical efficacy of topical 3% diquafosol tetrasodium in short tear film break-up time dry eye. J Korean Ophthalmol Soc. 2015;56:339–44.Google Scholar
  95. 95.
    Mun Y, Kwon JW, Oh JY. Therapeutic effects of 3% diquafosol ophthalmic solution in patients with short tear film break-up time-type dry eye disease. BMC Ophthalmol. 2018;18:237.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Kaido M, Kawashima M, Shigeno Y, Yamada Y, Tsubota K. Randomized controlled study to investigate the effect of topical diquafosol tetrasodium on corneal sensitivity in short tear break-up time dry eye. Adv Ther. 2018;35:697–706.PubMedCrossRefGoogle Scholar
  97. 97.
    Kaido M, Toda I, Oobayashi T, Kawashima M, Katada Y, Tsubota K. Reducing short-wavelength blue light in dry eye patients with unstable tear film improves performance on tests of visual acuity. PLoS One. 2016;11:e0152936.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Kojima T, Ishida R, Dogru M, Goto E, Takano Y, Matsumoto Y, et al. A new noninvasive tear stability analysis system for the assessment of dry eyes. Invest Ophthalmol Vis Sci. 2004;45:1369–74.PubMedCrossRefGoogle Scholar
  99. 99.
    Koh S, Ikeda C, Takai Y, Watanabe H, Maeda N, Nishida K. Long-term results of treatment with diquafosol ophthalmic solution for aqueous-deficient dry eye. Jpn J Ophthalmol. 2013;57:440–6.PubMedCrossRefGoogle Scholar
  100. 100.
    Kinoshita S, Awamura S, Nakamichi N, Suzuki H, Oshiden K, Yokoi N, et al. A multicenter, open-label, 52-week study of 2% rebamipide (OPC-12759) ophthalmic suspension in patients with dry eye. Am J Ophthalmol. 2014;157:576–83. e1.PubMedCrossRefGoogle Scholar
  101. 101.
    Ueda K, Matsumiya W, Otsuka K, Maeda Y, Nagai T, Nakamura M. Effectiveness and relevant factors of 2% rebamipide ophthalmic suspension treatment in dry eye. BMC Ophthalmol. 2015;15:58.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Yamane M, Ogawa Y, Fukui M, Kamoi M, Saijo-Ban Y, Yaguchi S, et al. Long-term rebamipide and diquafosol in two cases of immune-mediated dry eye. Optom Vis Sci. 2015;92:S25–32.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Hori Y, Kageyama T, Sakamoto A, Shiba T, Nakamura M, Maeno T. Comparison of short-term effects of diquafosol and rebamipide on Mucin 5AC level on the rabbit ocular surface. J Ocul Pharmacol Ther. 2017;33:493–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Kobashi H, Kamiya K, Shimizu K. Randomized comparison between rebamipide ophthalmic suspension and diquafosol ophthalmic solution for dry eye after penetrating keratoplasty. J Ocul Pharmacol Ther. 2017;33:13–8.PubMedCrossRefGoogle Scholar
  105. 105.
    Lee KB, Koh KM, Kwon YA, Song SW, Kim BY, Chung JL. Changes in tear volume after 3% diquafosol treatment in patients with dry eye syndrome: an anterior segment spectral-domain optical coherence tomography study. Korean J Ophthalmol. 2017;31:306–12.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Kase S, Shinohara T, Kase M, Ishida S. Effect of topical rebamipide on goblet cells in the lid wiper of human conjunctiva. Exp Ther Med. 2017;13:3516–22.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Zhao X, Xia S, Chen Y. Comparison of the efficacy between topical diquafosol and artificial tears in the treatment of dry eye following cataract surgery: a meta-analysis of randomized controlled trials. Medicine (Baltimore). 2017;96:e8174.CrossRefGoogle Scholar
  108. 108.
    Ousler GW 3rd, Rimmer D, Smith LM, Abelson MB. Use of the controlled adverse environment (CAE) in clinical research: a review. Ophthalmol Ther. 2017;6:263–76.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Ogawa M, Dogru M, Toriyama N, Yamaguchi T, Shimazaki J, Tsubota K. Evaluation of the effect of moist chamber spectacles in patients with dry eye exposed to adverse environment conditions. Eye Contact Lens. 2018;44(6):379–83.PubMedCrossRefGoogle Scholar
  110. 110.
    Tsubota K, Yamada M. Tear evaporation from the ocular surface. Invest Ophthalmol Vis Sci. 1992;33(10):2942–50.PubMedGoogle Scholar
  111. 111.
    Liu Z. The preliminary recommendations on the name and classification of dry eye [in Chinese]. Chin J Eye Otolaryngol. 2004;3:4–5.Google Scholar
  112. 112.
    Society TCC. The consensus on clinical diagnosis and treatment of dry eye [in Chinese]. Chin J Ophthalmol. 2013;49:73–5.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Keio University School of Medicine, Department of OphthalmologyTokyoJapan
  2. 2.Kyoto Prefectural University of Medicine, Department of OphthalmologyKyotoJapan

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