Drug-Induced Ocular Surface Disorders
Özet
Drug-induced ocular surface disorders (DIOSDs) are a significant yet frequently underrecognized cause of ocular morbidity, affecting millions of patients worldwide. The ocular surface—comprising the cornea, conjunctiva, and tear film—is susceptible to damage from both topical and systemic pharmacological agents through mechanisms including direct epithelial cytotoxicity, tear film disruption, inflammatory pathway activation, and corneal neurotrophic injury. Benzalkonium chloride (BAK), the most widely used ophthalmic preservative, remains the principal causative agent in topical medication-related disease, with up to 50% of long-term users developing signs of ocular surface dysfunction. Systemic agents such as isotretinoin and dupilumab are increasingly recognized as important causes of meibomian gland dysfunction and conjunctivitis, respectively. Severe drug reactions including Stevens-Johnson syndrome may result in permanent vision-threatening sequelae. Diagnosis requires high clinical suspicion and thorough medication history, while management centers on eliminating or modifying the offending agent, transitioning to preservative-free formulations, and providing targeted ocular surface therapy. A multidisciplinary approach and patient education are essential for optimal outcomes.
İlaca bağlı oküler yüzey bozuklukları, dünya genelinde milyonlarca hastanın etkilendiği, klinik pratikte sıklıkla göz ardı edilen önemli bir morbidite kaynağıdır. Kornea, konjonktiva ve göz yaşı filminden oluşan oküler yüzey; topikal ve sistemik farmakolojik ajanlara bağlı olarak epitelyal sitotoksisite, göz yaşı filmi bozulması, inflamatuar yolakların aktivasyonu ve kornea nörotrofik hasarı gibi çeşitli mekanizmalarla zarar görebilmektedir. En yaygın kullanılan oftalmik koruyucu olan benzalkonyum klorür (BAK), topikal ilaçlara bağlı oküler yüzey hastalığının başlıca nedeni olmaya devam etmekte; uzun süreli kullanıcıların %50'sine kadarında oküler yüzey disfonksiyonu bulguları gelişmektedir. İzotretinoin ve dupilumab gibi sistemik ajanlar, sırasıyla meibomian bezi disfonksiyonu ve konjonktivit nedenleri arasında giderek daha fazla tanınmaktadır. Stevens-Johnson sendromu gibi ağır ilaç reaksiyonları kalıcı ve görmeyi tehdit eden sekellerle sonuçlanabilir. Tanı, yüksek klinik şüphe ve kapsamlı ilaç hikayesi gerektirmektedir; tedavi ise suçlu ajanın değiştirilmesi veya kesilmesi, koruyucusuz formülasyonlara geçiş ve hedefe yönelik oküler yüzey tedavisi üzerine yoğunlaşmaktadır. En iyi sonuçlar için multidisipliner yaklaşım ve hasta eğitimi çok önemlidir.
Referanslar
Fechtner, R.D., et al., Prevalence of Ocular Surface Complaints in Patients With Glaucoma Using Topical Intraocular Pressure-Lowering Medications. Cornea, 2010. 29(6): p. 618-621.DOI: 10.1097/ICO.0b013e3181c325b2.
Leung, E.W., F.A. Medeiros, and R.N. Weinreb, Prevalence of Ocular Surface Disease in Glaucoma Patients. Journal of Glaucoma, 2008. 17(5): p. 350-355.DOI: 10.1097/IJG.0b013e31815c5f4f.
Skalicky, S.E., I. Goldberg, and P. McCluskey, Ocular Surface Disease and Quality of Life in Patients With Glaucoma. American Journal of Ophthalmology, 2012. 153(1): p. 1-9.e2.DOI: 10.1016/j.ajo.2011.05.033.
Garcia-Feijoo, J. and J.R. Sampaolesi, A multicenter evaluation of ocular surface disease prevalence in patients with glaucoma. Clin Ophthalmol, 2012. 6: p. 441-6.DOI: 10.2147/opth.S29158.
Fraunfelder, F.T., F.W. Fraunfelder, and R. Edwards, Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol, 2001. 132(3): p. 299-305.DOI: 10.1016/s0002-9394(01)01024-8.
Bakker, D.S., et al., Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in patients with atopic dermatitis. Br J Dermatol, 2019. 180(5): p. 1248-1249.DOI: 10.1111/bjd.17538.
Baudouin, C., et al., Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res, 2010. 29(4): p. 312-34.DOI: 10.1016/j.preteyeres.2010.03.001.
Baudouin, C., Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol, 2008. 86(7): p. 716-26.DOI: 10.1111/j.1755-3768.2008.01250.x.
Pisella, P.J., P. Pouliquen, and C. Baudouin, Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol, 2002. 86(4): p. 418-23.DOI: 10.1136/bjo.86.4.418.
Nordmann, J.P., et al., Vision related quality of life and topical glaucoma treatment side effects. Health Qual Life Outcomes, 2003. 1: p. 75.DOI: 10.1186/1477-7525-1-75.
Tsai, J.C., et al., Compliance barriers in glaucoma: a systematic classification. J Glaucoma, 2003. 12(5): p. 393-8.DOI: 10.1097/00061198-200310000-00001.
Lavin, M.J., et al., The influence of prior therapy on the success of trabeculectomy. Arch Ophthalmol, 1990. 108(11): p. 1543-8.DOI: 10.1001/archopht.1990.01070130045027.
Broadway, D.C., et al., Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmol, 1994. 112(11): p. 1446-54.DOI: 10.1001/archopht.1994.01090230060021.
Bron, A.J., et al., TFOS DEWS II pathophysiology report. Ocul Surf, 2017. 15(3): p. 438-510.DOI: 10.1016/j.jtos.2017.05.011.
Zhang, Z., et al., Benzalkonium chloride suppresses rabbit corneal endothelium intercellular gap junction communication. PLoS One, 2014. 9(10): p. e109708.DOI: 10.1371/journal.pone.0109708.
Halder, A., et al., Aqueous humor pharmacokinetics of Benzalkonium chloride free bimatoprost formulated in tight junction modulation technology compared to Benzalkonium chloride preserved bimatoprost 0.01% ophthalmic solution in rabbit eyes. Indian Journal of Clinical and Experimental Ophthalmology, 2021. 7(2): p. 321-326.
Datta, S., et al., The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Investigative Ophthalmology & Visual Science, 2017. 58(4): p. 2406-2412.DOI: 10.1167/iovs.16-20903.
Prusek, A., et al., Assessment of the toxic effect of benzalkonium chloride on human limbal stem cells. Scientific Reports, 2025. 15(1): p. 12295.
Ayaki, M., A. Iwasawa, and Y. Inoue, Toxicity of antiglaucoma drugs with and without benzalkonium chloride to cultured human corneal endothelial cells. Clin Ophthalmol, 2010. 4: p. 1217-22.DOI: 10.2147/opth.S13708.
Pisella, P.J., et al., Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Invest Ophthalmol Vis Sci, 2004. 45(5): p. 1360-8.DOI: 10.1167/iovs.03-1067.
Steven, D.W., P. Alaghband, and K.S. Lim, Preservatives in glaucoma medication. British journal of ophthalmology, 2018. 102(11): p. 1497-1503.
Guidera, A.C., J.I. Luchs, and I.J. Udell, Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology, 2001. 108(5): p. 936-944.
Rigas, B., W. Huang, and R. Honkanen, NSAID-induced corneal melt: Clinical importance, pathogenesis, and risk mitigation. Survey of ophthalmology, 2020. 65(1): p. 1-11.
Brandt, J.D., et al., Conjunctival impression cytology in patients with glaucoma using long-term topical medication. American journal of ophthalmology, 1991. 112(3): p. 297-301.
Cvenkel, B., et al., Symptoms and signs of ocular surface disease related to topical medication in patients with glaucoma. Clinical Ophthalmology, 2015: p. 625-631.
Ban, Y., et al., Tight junction-related protein expression and distribution in human corneal epithelium. Experimental eye research, 2003. 76(6): p. 663-669.
Uematsu, M., et al., Acute corneal epithelial change after instillation of benzalkonium chloride evaluated using a newly developed in vivo corneal transepithelial electric resistance measurement method. Ophthalmic Research, 2007. 39(6): p. 308-314.
Kusano, M., et al., Evaluation of acute corneal barrier change induced by topically applied preservatives using corneal transepithelial electric resistance in vivo. Cornea, 2010. 29(1): p. 80-85.
Zhang, P., et al., Isotretinoin impairs the secretory function of meibomian gland via the PPARγ signaling pathway. Investigative Ophthalmology & Visual Science, 2022. 63(3): p. 29-29.
Düzgün, E. and E. Özkur, The effect of oral isotretinoin therapy on meibomian gland morphology and dry eye tests. J Dermatolog Treat, 2022. 33(2): p. 762-768.DOI: 10.1080/09546634.2020.1774041.
Zakrzewska, A., et al., The effect of oral isotretinoin therapy on meibomian gland characteristics in patients with acne vulgaris. Ophthalmology and therapy, 2023. 12(4): p. 2187-2197.
Moy, A., N.A. McNamara, and M.C. Lin, Effects of isotretinoin on meibomian glands. Optometry and Vision Science, 2015. 92(9): p. 925-930.
Lekskul, M., S. Thaiwat, and J. Lekvijittada, Evaluation of recovery time of tear film function and ocular surface after discontinuing oral isotretinoin treatment for acne vulgaris: Correlation between oral isotretinoin and tear film function. International Ophthalmology, 2023. 43(12): p. 4683-4688.
Gurlevik, U., F. Kemeriz, and E. Yasar, The effect of isotretinoin on meibomian glands in eyes: a pilot study. International Ophthalmology, 2022. 42(7): p. 2071-2078.
Baudouin, C., et al., Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology, 1999. 106(3): p. 556-63.DOI: 10.1016/s0161-6420(99)90116-1.
Denoyer, A., et al., CX3CL1 expression in the conjunctiva is involved in immune cell trafficking during toxic ocular surface inflammation. Mucosal Immunol, 2012. 5(6): p. 702-11.DOI: 10.1038/mi.2012.43.
Stern, M.E., C.S. Schaumburg, and S.C. Pflugfelder, Dry eye as a mucosal autoimmune disease. International reviews of immunology, 2013. 32(1): p. 19-41.
Sambursky, R., et al., Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA ophthalmology, 2013. 131(1): p. 24-28.
Bonini, S., et al., Neurotrophic keratitis. Eye, 2003. 17(8): p. 989-995.
Rosenwasser, G.O., et al., Topical anesthetic abuse. Ophthalmology, 1990. 97(8): p. 967-72.DOI: 10.1016/s0161-6420(90)32458-2.
Martone, G., et al., An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol, 2009. 147(4): p. 725-735.e1.DOI: 10.1016/j.ajo.2008.10.019.
Villani, E., et al., The Ocular Surface in Medically Controlled Glaucoma: An In Vivo Confocal Study. Invest Ophthalmol Vis Sci, 2016. 57(3): p. 1003-10.DOI: 10.1167/iovs.15-17455.
Müller, L.J., et al., Corneal nerves: structure, contents and function. Exp Eye Res, 2003. 76(5): p. 521-42.DOI: 10.1016/s0014-4835(03)00050-2.
Romero-Díaz de León, L., et al., Conjunctival and corneal sensitivity in patients under topical antiglaucoma treatment. Int Ophthalmol, 2016. 36(3): p. 299-303.DOI: 10.1007/s10792-015-0115-1.
Lin, J.C., et al., Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol, 2000. 118(8): p. 1129-32.
Sacchetti, M. and A. Lambiase, Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol, 2014. 8: p. 571-9.DOI: 10.2147/opth.S45921.
Noecker, R.J., L.A. Herrygers, and R. Anwaruddin, Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea, 2004. 23(5): p. 490-6.DOI: 10.1097/01.ico.0000116526.57227.82.
Jaenen, N., et al., Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthalmol, 2007. 17(3): p. 341-9.DOI: 10.1177/112067210701700311.
Herreras, J.M., et al., Ocular surface alteration after long-term treatment with an antiglaucomatous drug. Ophthalmology, 1992. 99(7): p. 1082-8.DOI: 10.1016/s0161-6420(92)31847-0.
Xiong, C., et al., A rabbit dry eye model induced by topical medication of a preservative benzalkonium chloride. Invest Ophthalmol Vis Sci, 2008. 49(5): p. 1850-6.DOI: 10.1167/iovs.07-0720.
Sherwood, M.B., et al., Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucomatous patients. Ophthalmology, 1989. 96(3): p. 327-35.DOI: 10.1016/s0161-6420(89)32888-0.
Wasyluk, J., et al., Ocular Surface Parameters in Glaucoma Patients Treated with Topical Prostaglandin Analogs and the Importance of Switching to Preservative-Free Eye Drops-A Systematic Review. Life (Basel), 2025. 15(12).DOI: 10.3390/life15121837.
Broadway, D.C. and L.P. Chang, Trabeculectomy, risk factors for failure and the preoperative state of the conjunctiva. J Glaucoma, 2001. 10(3): p. 237-49.DOI: 10.1097/00061198-200106000-00017.
Boimer, C. and C.M. Birt, Preservative exposure and surgical outcomes in glaucoma patients: The PESO study. J Glaucoma, 2013. 22(9): p. 730-5.DOI: 10.1097/IJG.0b013e31825af67d.
Noecker, R., Effects of common ophthalmic preservatives on ocular health. Adv Ther, 2001. 18(5): p. 205-15.DOI: 10.1007/bf02853166.
Ammar, D.A. and M.Y. Kahook, Effects of glaucoma medications and preservatives on cultured human trabecular meshwork and non-pigmented ciliary epithelial cell lines. Br J Ophthalmol, 2011. 95(10): p. 1466-9.DOI: 10.1136/bjophthalmol-2011-300012.
Liang, H., et al., Conjunctival and corneal reactions in rabbits following short- and repeated exposure to preservative-free tafluprost, commercially available latanoprost and 0.02% benzalkonium chloride. Br J Ophthalmol, 2008. 92(9): p. 1275-82.DOI: 10.1136/bjo.2008.138768.
Pellinen, P., et al., The cytotoxic effects of preserved and preservative-free prostaglandin analogs on human corneal and conjunctival epithelium in vitro and the distribution of benzalkonium chloride homologs in ocular surface tissues in vivo. Curr Eye Res, 2012. 37(2): p. 145-54.DOI: 10.3109/02713683.2011.626909.
Campolo, A., M. Crary, and P. Shannon, A review of the containers available for multi-dose preservative-free eye drops. Biomedical Journal of Scientific & Technical Research, 2022. 45(1): p. 36035-36044.
Harasymowycz, P., et al., Preserved Versus Preservative-Free Latanoprost for the Treatment of Glaucoma and Ocular Hypertension: A Post Hoc Pooled Analysis. Adv Ther, 2021. 38(6): p. 3019-3031.DOI: 10.1007/s12325-021-01731-9.
Kim, M., et al., Comparison of Efficacy and Ocular Surface Assessment Between Preserved and Preservative-Free Brimonidine/Timolol Fixed-Combination Eye Drops in Glaucoma Patients: A Parallel-Grouped, Randomized Trial. Journal of Clinical Medicine, 2025. 14(5): p. 1587.
Day, D.G., et al., Bimatoprost 0.03% preservative-free ophthalmic solution versus bimatoprost 0.03% ophthalmic solution (Lumigan) for glaucoma or ocular hypertension: a 12-week, randomised, double-masked trial. Br J Ophthalmol, 2013. 97(8): p. 989-93.DOI: 10.1136/bjophthalmol-2012-303040.
Goldberg, I., et al., Bimatoprost 0.03%/timolol 0.5% preservative-free ophthalmic solution versus bimatoprost 0.03%/timolol 0.5% ophthalmic solution (Ganfort) for glaucoma or ocular hypertension: a 12-week randomised controlled trial. Br J Ophthalmol, 2014. 98(7): p. 926-31.DOI: 10.1136/bjophthalmol-2013-304064.
Alm, A., J. Schoenfelder, and J. McDermott, A 5-year, multicenter, open-label, safety study of adjunctive latanoprost therapy for glaucoma. Arch Ophthalmol, 2004. 122(7): p. 957-65.DOI: 10.1001/archopht.122.7.957.
Hedman, K. and A. Alm, A pooled-data analysis of three randomized, double-masked, six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol. Eur J Ophthalmol, 2000. 10(2): p. 95-104.DOI: 10.1177/112067210001000201.
Rouland, J.F., et al., Efficacy and safety of preservative-free latanoprost eyedrops, compared with BAK-preserved latanoprost in patients with ocular hypertension or glaucoma. Br J Ophthalmol, 2013. 97(2): p. 196-200.DOI: 10.1136/bjophthalmol-2012-302121.
Uusitalo, H., et al., Benefits of switching from latanoprost to preservative-free tafluprost eye drops: a meta-analysis of two Phase IIIb clinical trials. Clin Ophthalmol, 2016. 10: p. 445-54.DOI: 10.2147/opth.S91402.
Konstas, A.G., et al., 24-h Efficacy of Glaucoma Treatment Options. Adv Ther, 2016. 33(4): p. 481-517.DOI: 10.1007/s12325-016-0302-0.
Van Buskirk, E.M., Adverse reactions from timolol administration. Ophthalmology, 1980. 87(5): p. 447-50.DOI: 10.1016/s0161-6420(80)35215-9.
Ishibashi, T., N. Yokoi, and S. Kinoshita, Comparison of the short-term effects on the human corneal surface of topical timolol maleate with and without benzalkonium chloride. J Glaucoma, 2003. 12(6): p. 486-90.DOI: 10.1097/00061198-200312000-00008.
Yeh, P.H., et al., Brimonidine related acute follicular conjunctivitis: Onset time and clinical presentations, a long-term follow-up. Medicine (Baltimore), 2021. 100(29): p. e26724.DOI: 10.1097/md.0000000000026724.
Blondeau, P. and J.A. Rousseau, Allergic reactions to brimonidine in patients treated for glaucoma. Can J Ophthalmol, 2002. 37(1): p. 21-6.DOI: 10.1016/s0008-4182(02)80094-1.
Watts, P. and N. Hawksworth, Delayed hypersensitivity to brimonidine tartrate 0.2% associated with high intraocular pressure. Eye (Lond), 2002. 16(2): p. 132-5.DOI: 10.1038/sj.eye.6700053.
Konisky, H., A.N. Gregory, and A. Huho, Allergic Contact Dermatitis from Brimonidine Tartrate Eye Drops: A Rare Dermatological Reaction with a “Teardrop Streak Sign”. Dermatitis, 2025. 36(3): p. 268-270.
Katz, L.J., Twelve-month evaluation of brimonidine-purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma, 2002. 11(2): p. 119-26.DOI: 10.1097/00061198-200204000-00007.
Duru, Z. and C. Ozsaygili, Preservative-free versus preserved brimonidine% 0.15 preparations in the treatment of glaucoma and ocular hypertension: short term evaluation of efficacy, safety, and potential advantages. Cutaneous and ocular toxicology, 2020. 39(1): p. 21-24.
Kucukoduk, A., et al., Cytotoxic, Apoptotic, and Oxidative Effects of Preserved and Preservative-Free Brimonidine in a Corneal Epithelial Cell Line. Journal of Ocular Pharmacology and Therapeutics, 2022. 38(8): p. 576-583.DOI: 10.1089/jop.2022.0053.
Silver, L.H., Clinical efficacy and safety of brinzolamide (Azopt), a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Brinzolamide Primary Therapy Study Group. Am J Ophthalmol, 1998. 126(3): p. 400-8.DOI: 10.1016/s0002-9394(98)00095-6.
Asrani, S., et al., Netarsudil/Latanoprost Fixed-Dose Combination for Elevated Intraocular Pressure: Three-Month Data from a Randomized Phase 3 Trial. Am J Ophthalmol, 2019. 207: p. 248-257.DOI: 10.1016/j.ajo.2019.06.016.
Gokhale, N.S. and G.K. Vemuganti, Diclofenac-induced acute corneal melt after collagen crosslinking for keratoconus. Cornea, 2010. 29(1): p. 117-9.DOI: 10.1097/ICO.0b013e3181a06c31.
Starr, C.E., et al., An algorithm for the preoperative diagnosis and treatment of ocular surface disorders. J Cataract Refract Surg, 2019. 45(5): p. 669-684.DOI: 10.1016/j.jcrs.2019.03.023.
Congdon, N.G., et al., Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg, 2001. 27(4): p. 622-31.DOI: 10.1016/s0886-3350(01)00801-x.
Petroutsos, G., et al., Corticosteroids and corneal epithelial wound healing. Br J Ophthalmol, 1982. 66(11): p. 705-8.DOI: 10.1136/bjo.66.11.705.
Knutsson, K.A., et al., Topical Corticosteroids and Fungal Keratitis: A Review of the Literature and Case Series. J Clin Med, 2021. 10(6).DOI: 10.3390/jcm10061178.
Yagci, A., et al., Topical anesthetic abuse keratopathy: a commonly overlooked health care problem. Cornea, 2011. 30(5): p. 571-5.DOI: 10.1097/ico.0b013e3182000af9.
Judge, A.J., et al., Corneal endothelial toxicity of topical anesthesia. Ophthalmology, 1997. 104(9): p. 1373-9.DOI: 10.1016/s0161-6420(97)30128-6.
Weisenthal, R.W. and R.S. Feder, 2024-2025 Basic and Clinical Science Course, Section 8: External Disease and Cornea. 2024: American Academy of Ophthalmology.
Erdem, E., et al., Topical anesthetic eye drops abuse: are we aware of the danger? Cutan Ocul Toxicol, 2013. 32(3): p. 189-93.DOI: 10.3109/15569527.2012.744758.
Egger, S.F., et al., Ocular side effects associated with 13-cis-retinoic acid therapy for acne vulgaris: clinical features, alterations of tearfilm and conjunctival flora. Acta Ophthalmol Scand, 1995. 73(4): p. 355-7.DOI: 10.1111/j.1600-0420.1995.tb00043.x.
Ruiz-Lozano, R.E., et al., Isotretinoin and the eye: A review for the dermatologist. Dermatologic Therapy, 2020. 33.
Simpson, E.L., et al., Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med, 2016. 375(24): p. 2335-2348.DOI: 10.1056/NEJMoa1610020.
Akinlade, B., et al., Conjunctivitis in dupilumab clinical trials. Br J Dermatol, 2019. 181(3): p. 459-473.DOI: 10.1111/bjd.17869.
Thyssen, J.P., et al., Incidence, prevalence, and risk of selected ocular disease in adults with atopic dermatitis. J Am Acad Dermatol, 2017. 77(2): p. 280-286.e1.DOI: 10.1016/j.jaad.2017.03.003.
Ivert, L.U., et al., Eye Complications During Dupilumab Treatment for Severe Atopic Dermatitis. Acta Derm Venereol, 2019. 99(4): p. 375-378.DOI: 10.2340/00015555-3121.
Wollenberg, A., et al., Conjunctivitis occurring in atopic dermatitis patients treated with dupilumab-clinical characteristics and treatment. J Allergy Clin Immunol Pract, 2018. 6(5): p. 1778-1780.e1.DOI: 10.1016/j.jaip.2018.01.034.
Treister, A.D., C. Kraff-Cooper, and P.A. Lio, Risk Factors for Dupilumab-Associated Conjunctivitis in Patients With Atopic Dermatitis. JAMA Dermatol, 2018. 154(10): p. 1208-1211.DOI: 10.1001/jamadermatol.2018.2690.
Nahum, Y., et al., Dupilumab-induced ocular surface disease (DIOSD) in patients with atopic dermatitis: clinical presentation, risk factors for development and outcomes of treatment with tacrolimus ointment. Br J Ophthalmol, 2020. 104(6): p. 776-779.DOI: 10.1136/bjophthalmol-2019-315010.
Popiela, M.Z., et al., Dupilumab-associated ocular surface disease: presentation, management and long-term sequelae. Eye (Lond), 2021. 35(12): p. 3277-3284.DOI: 10.1038/s41433-020-01379-9.
Agnihotri, G., K. Shi, and P.A. Lio, A Clinician's Guide to the Recognition and Management of Dupilumab-Associated Conjunctivitis. Drugs R D, 2019. 19(4): p. 311-318.DOI: 10.1007/s40268-019-00288-x.
Fu, C., et al., Ocular toxicities associated with targeted anticancer agents: an analysis of clinical data with management suggestions. Oncotarget, 2017. 8(35): p. 58709-58727.DOI: 10.18632/oncotarget.17634.
Peterson, J.L. and B.P. Ceresa, Epidermal Growth Factor Receptor Expression in the Corneal Epithelium. Cells, 2021. 10(9).DOI: 10.3390/cells10092409.
Goel, V., et al., Trichomegaly of eyelashes after treatment with erlotinib in carcinoma pancreas. Int J Trichology, 2014. 6(1): p. 23-4.DOI: 10.4103/0974-7753.136755.
Renouf, D.J., et al., Ocular toxicity of targeted therapies. J Clin Oncol, 2012. 30(26): p. 3277-86.DOI: 10.1200/jco.2011.41.5851.
Dalvin, L.A., et al., CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic Indications and Ophthalmic Side Effects. RETINA, 2018. 38(6): p. 1063-1078.DOI: 10.1097/iae.0000000000002181.
Antoun, J., C. Titah, and I. Cochereau, Ocular and orbital side-effects of checkpoint inhibitors: a review article. Current Opinion in Oncology, 2016. 28(4): p. 288-294.DOI: 10.1097/cco.0000000000000296.
Silva, C.D., et al., Lacrimal drainage system obstruction after cancer treatment: a literature review. 2022. 81: p. -.DOI: 10.37039/1982.8551.20220033.
Lochhead, J., J.F. Salmon, and A.J. Bron, Cytarabine-induced corneal toxicity. Eye (Lond), 2003. 17(5): p. 677-8.DOI: 10.1038/sj.eye.6700451.
Foutch, B.K., et al., Effects of Oral Antihistamines on Tear Volume, Tear Stability, and Intraocular Pressure. Vision (Basel), 2020. 4(2).DOI: 10.3390/vision4020032.
Katipoğlu, Z. and R.N. Abay, The relationship between dry eye disease and anticholinergic burden. Eye (Lond), 2023. 37(14): p. 2921-2925.DOI: 10.1038/s41433-023-02442-x.
Mäntyjärvi, M., K. Tuppurainen, and K. Ikäheimo, Ocular side effects of amiodarone. Surv Ophthalmol, 1998. 42(4): p. 360-6.DOI: 10.1016/s0039-6257(97)00118-5.
Fraunfelder, F.W., F.T. Fraunfelder, and B. Jensvold, Scleritis and other ocular side effects associated with pamidronate disodium. Am J Ophthalmol, 2003. 135(2): p. 219-22.DOI: 10.1016/s0002-9394(02)01840-8.
Roujeau, J.C. and R.S. Stern, Severe adverse cutaneous reactions to drugs. N Engl J Med, 1994. 331(19): p. 1272-85.DOI: 10.1056/nejm199411103311906.
Kohanim, S., et al., Acute and Chronic Ophthalmic Involvement in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis - A Comprehensive Review and Guide to Therapy. II. Ophthalmic Disease. Ocul Surf, 2016. 14(2): p. 168-88.DOI: 10.1016/j.jtos.2016.02.001.
Chung, W.H., et al., Medical genetics: a marker for Stevens-Johnson syndrome. Nature, 2004. 428(6982): p. 486.DOI: 10.1038/428486a.
Sotozono, C., et al., Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications. Ophthalmology, 2009. 116(4): p. 685-90.DOI: 10.1016/j.ophtha.2008.12.048.
Narang, P. and S. D'Souza, Chronic Ocular Sequelae of Stevens-Johnson Syndrome: Recent Advances in Understanding of Patho-Physiology and Management. Semin Ophthalmol, 2026. 41(2): p. 320-330.DOI: 10.1080/08820538.2025.2545264.
Shay, E., et al., Amniotic membrane transplantation as a new therapy for the acute ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis. Surv Ophthalmol, 2009. 54(6): p. 686-96.DOI: 10.1016/j.survophthal.2009.03.004.
Shanbhag, S.S., et al., Multidisciplinary care in Stevens-Johnson syndrome. Ther Adv Chronic Dis, 2020. 11: p. 2040622319894469.DOI: 10.1177/2040622319894469.
Pullum, K.W., M.A. Whiting, and R.J. Buckley, Scleral contact lenses: the expanding role. Cornea, 2005. 24(3): p. 269-77.DOI: 10.1097/01.ico.0000148311.94180.6b.
Fraunfelder, F.T., J.J. Sciubba, and W.D. Mathers, The role of medications in causing dry eye. J Ophthalmol, 2012. 2012: p. 285851.DOI: 10.1155/2012/285851.
Begley, C.G., et al., Characterization of ocular surface symptoms from optometric practices in North America. Cornea, 2001. 20(6): p. 610-8.DOI: 10.1097/00003226-200108000-00011.
Schiffman, R.M., et al., Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol, 2000. 118(5): p. 615-21.DOI: 10.1001/archopht.118.5.615.
Bron, A.J., V.E. Evans, and J.A. Smith, Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea, 2003. 22(7): p. 640-50.DOI: 10.1097/00003226-200310000-00008.
Tomlinson, A., et al., The international workshop on meibomian gland dysfunction: report of the diagnosis subcommittee. Invest Ophthalmol Vis Sci, 2011. 52(4): p. 2006-49.DOI: 10.1167/iovs.10-6997f.
Wolffsohn, J.S., et al., TFOS DEWS III: Diagnostic Methodology. Am J Ophthalmol, 2025. 279: p. 387-450.DOI: 10.1016/j.ajo.2025.05.033.
Bielory, L., Allergic and immunologic disorders of the eye. Part II: ocular allergy. J Allergy Clin Immunol, 2000. 106(6): p. 1019-32.DOI: 10.1067/mai.2000.111238.
Gazzard, G., et al., Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet, 2019. 393(10180): p. 1505-1516.DOI: 10.1016/s0140-6736(18)32213-x.
Huillard, O., et al., Ocular adverse events of molecularly targeted agents approved in solid tumours: a systematic review. Eur J Cancer, 2014. 50(3): p. 638-48.DOI: 10.1016/j.ejca.2013.10.016.
Jones, L., et al., TFOS DEWS III: Management and Therapy. Am J Ophthalmol, 2025. 279: p. 289-386.DOI: 10.1016/j.ajo.2025.05.039.
Prabhasawat, P., N. Tesavibul, and W. Mahawong, A randomized double-masked study of 0.05% cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction. Cornea, 2012. 31(12): p. 1386-93.DOI: 10.1097/ICO.0b013e31823cc098.
Tauber, J., et al., Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study. Ophthalmology, 2015. 122(12): p. 2423-31.DOI: 10.1016/j.ophtha.2015.08.001.
Modi, D., et al., Formulation and development of tacrolimus-gellan gum nanoformulation for treatment of dry eye disease. Colloids Surf B Biointerfaces, 2022. 211: p. 112255.DOI: 10.1016/j.colsurfb.2021.112255.
Moscovici, B.K., et al., Clinical Treatment of Dry Eye Using 0.03% Tacrolimus Eye Drops. Cornea, 2012. 31(8): p. 945-949.DOI: 10.1097/ICO.0b013e31823f8c9b.
Hussain, M., et al., Long-term use of autologous serum 50% eye drops for the treatment of dry eye disease. Cornea, 2014. 33(12): p. 1245-51.DOI: 10.1097/ico.0000000000000271.
Ervin, A.M., R. Wojciechowski, and O. Schein, Punctal occlusion for dry eye syndrome. Cochrane Database Syst Rev, 2010(9): p. Cd006775.DOI: 10.1002/14651858.CD006775.pub2.
Schornack, M.M., J. Pyle, and S.V. Patel, Scleral lenses in the management of ocular surface disease. Ophthalmology, 2014. 121(7): p. 1398-405.DOI: 10.1016/j.ophtha.2014.01.028.
Kruse, F.E., K. Rohrschneider, and H.E. Völcker, Multilayer amniotic membrane transplantation for reconstruction of deep corneal ulcers. Ophthalmology, 1999. 106(8): p. 1504-10; discussion 1511.DOI: 10.1016/s0161-6420(99)90444-x.
Medeiros, F.A., et al., Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1). Ophthalmology, 2020. 127(12): p. 1627-1641.DOI: 10.1016/j.ophtha.2020.06.018.
Yellepeddi, V.K., et al., Punctal plug: a medical device to treat dry eye syndrome and for sustained drug delivery to the eye. Drug Discov Today, 2015. 20(7): p. 884-9.DOI: 10.1016/j.drudis.2015.01.013.
Tsai, J.C., Medication adherence in glaucoma: approaches for optimizing patient compliance. Curr Opin Ophthalmol, 2006. 17(2): p. 190-5.DOI: 10.1097/01.icu.0000193078.47616.aa.
Walsh, K. and L. Jones, The use of preservatives in dry eye drops. Clin Ophthalmol, 2019. 13: p. 1409-1425.DOI: 10.2147/opth.S211611.
Zhou, L. and R.W. Beuerman, Tear analysis in ocular surface diseases. Prog Retin Eye Res, 2012. 31(6): p. 527-50.DOI: 10.1016/j.preteyeres.2012.06.002.
Bonini, S., et al., Phase II Randomized, Double-Masked, Vehicle-Controlled Trial of Recombinant Human Nerve Growth Factor for Neurotrophic Keratitis. Ophthalmology, 2018. 125(9): p. 1332-1343.DOI: 10.1016/j.ophtha.2018.02.022.
Elbaz, U., et al., Restoration of corneal sensation with regional nerve transfers and nerve grafts: a new approach to a difficult problem. JAMA Ophthalmol, 2014. 132(11): p. 1289-95.DOI: 10.1001/jamaophthalmol.2014.2316.
Vera-Duarte, G.R., et al., Neurotrophic keratopathy: General features and new therapies. Surv Ophthalmol, 2024. 69(5): p. 789-804.DOI: 10.1016/j.survophthal.2024.04.004.
Referanslar
Fechtner, R.D., et al., Prevalence of Ocular Surface Complaints in Patients With Glaucoma Using Topical Intraocular Pressure-Lowering Medications. Cornea, 2010. 29(6): p. 618-621.DOI: 10.1097/ICO.0b013e3181c325b2.
Leung, E.W., F.A. Medeiros, and R.N. Weinreb, Prevalence of Ocular Surface Disease in Glaucoma Patients. Journal of Glaucoma, 2008. 17(5): p. 350-355.DOI: 10.1097/IJG.0b013e31815c5f4f.
Skalicky, S.E., I. Goldberg, and P. McCluskey, Ocular Surface Disease and Quality of Life in Patients With Glaucoma. American Journal of Ophthalmology, 2012. 153(1): p. 1-9.e2.DOI: 10.1016/j.ajo.2011.05.033.
Garcia-Feijoo, J. and J.R. Sampaolesi, A multicenter evaluation of ocular surface disease prevalence in patients with glaucoma. Clin Ophthalmol, 2012. 6: p. 441-6.DOI: 10.2147/opth.S29158.
Fraunfelder, F.T., F.W. Fraunfelder, and R. Edwards, Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol, 2001. 132(3): p. 299-305.DOI: 10.1016/s0002-9394(01)01024-8.
Bakker, D.S., et al., Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in patients with atopic dermatitis. Br J Dermatol, 2019. 180(5): p. 1248-1249.DOI: 10.1111/bjd.17538.
Baudouin, C., et al., Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res, 2010. 29(4): p. 312-34.DOI: 10.1016/j.preteyeres.2010.03.001.
Baudouin, C., Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol, 2008. 86(7): p. 716-26.DOI: 10.1111/j.1755-3768.2008.01250.x.
Pisella, P.J., P. Pouliquen, and C. Baudouin, Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol, 2002. 86(4): p. 418-23.DOI: 10.1136/bjo.86.4.418.
Nordmann, J.P., et al., Vision related quality of life and topical glaucoma treatment side effects. Health Qual Life Outcomes, 2003. 1: p. 75.DOI: 10.1186/1477-7525-1-75.
Tsai, J.C., et al., Compliance barriers in glaucoma: a systematic classification. J Glaucoma, 2003. 12(5): p. 393-8.DOI: 10.1097/00061198-200310000-00001.
Lavin, M.J., et al., The influence of prior therapy on the success of trabeculectomy. Arch Ophthalmol, 1990. 108(11): p. 1543-8.DOI: 10.1001/archopht.1990.01070130045027.
Broadway, D.C., et al., Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmol, 1994. 112(11): p. 1446-54.DOI: 10.1001/archopht.1994.01090230060021.
Bron, A.J., et al., TFOS DEWS II pathophysiology report. Ocul Surf, 2017. 15(3): p. 438-510.DOI: 10.1016/j.jtos.2017.05.011.
Zhang, Z., et al., Benzalkonium chloride suppresses rabbit corneal endothelium intercellular gap junction communication. PLoS One, 2014. 9(10): p. e109708.DOI: 10.1371/journal.pone.0109708.
Halder, A., et al., Aqueous humor pharmacokinetics of Benzalkonium chloride free bimatoprost formulated in tight junction modulation technology compared to Benzalkonium chloride preserved bimatoprost 0.01% ophthalmic solution in rabbit eyes. Indian Journal of Clinical and Experimental Ophthalmology, 2021. 7(2): p. 321-326.
Datta, S., et al., The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Investigative Ophthalmology & Visual Science, 2017. 58(4): p. 2406-2412.DOI: 10.1167/iovs.16-20903.
Prusek, A., et al., Assessment of the toxic effect of benzalkonium chloride on human limbal stem cells. Scientific Reports, 2025. 15(1): p. 12295.
Ayaki, M., A. Iwasawa, and Y. Inoue, Toxicity of antiglaucoma drugs with and without benzalkonium chloride to cultured human corneal endothelial cells. Clin Ophthalmol, 2010. 4: p. 1217-22.DOI: 10.2147/opth.S13708.
Pisella, P.J., et al., Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Invest Ophthalmol Vis Sci, 2004. 45(5): p. 1360-8.DOI: 10.1167/iovs.03-1067.
Steven, D.W., P. Alaghband, and K.S. Lim, Preservatives in glaucoma medication. British journal of ophthalmology, 2018. 102(11): p. 1497-1503.
Guidera, A.C., J.I. Luchs, and I.J. Udell, Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology, 2001. 108(5): p. 936-944.
Rigas, B., W. Huang, and R. Honkanen, NSAID-induced corneal melt: Clinical importance, pathogenesis, and risk mitigation. Survey of ophthalmology, 2020. 65(1): p. 1-11.
Brandt, J.D., et al., Conjunctival impression cytology in patients with glaucoma using long-term topical medication. American journal of ophthalmology, 1991. 112(3): p. 297-301.
Cvenkel, B., et al., Symptoms and signs of ocular surface disease related to topical medication in patients with glaucoma. Clinical Ophthalmology, 2015: p. 625-631.
Ban, Y., et al., Tight junction-related protein expression and distribution in human corneal epithelium. Experimental eye research, 2003. 76(6): p. 663-669.
Uematsu, M., et al., Acute corneal epithelial change after instillation of benzalkonium chloride evaluated using a newly developed in vivo corneal transepithelial electric resistance measurement method. Ophthalmic Research, 2007. 39(6): p. 308-314.
Kusano, M., et al., Evaluation of acute corneal barrier change induced by topically applied preservatives using corneal transepithelial electric resistance in vivo. Cornea, 2010. 29(1): p. 80-85.
Zhang, P., et al., Isotretinoin impairs the secretory function of meibomian gland via the PPARγ signaling pathway. Investigative Ophthalmology & Visual Science, 2022. 63(3): p. 29-29.
Düzgün, E. and E. Özkur, The effect of oral isotretinoin therapy on meibomian gland morphology and dry eye tests. J Dermatolog Treat, 2022. 33(2): p. 762-768.DOI: 10.1080/09546634.2020.1774041.
Zakrzewska, A., et al., The effect of oral isotretinoin therapy on meibomian gland characteristics in patients with acne vulgaris. Ophthalmology and therapy, 2023. 12(4): p. 2187-2197.
Moy, A., N.A. McNamara, and M.C. Lin, Effects of isotretinoin on meibomian glands. Optometry and Vision Science, 2015. 92(9): p. 925-930.
Lekskul, M., S. Thaiwat, and J. Lekvijittada, Evaluation of recovery time of tear film function and ocular surface after discontinuing oral isotretinoin treatment for acne vulgaris: Correlation between oral isotretinoin and tear film function. International Ophthalmology, 2023. 43(12): p. 4683-4688.
Gurlevik, U., F. Kemeriz, and E. Yasar, The effect of isotretinoin on meibomian glands in eyes: a pilot study. International Ophthalmology, 2022. 42(7): p. 2071-2078.
Baudouin, C., et al., Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology, 1999. 106(3): p. 556-63.DOI: 10.1016/s0161-6420(99)90116-1.
Denoyer, A., et al., CX3CL1 expression in the conjunctiva is involved in immune cell trafficking during toxic ocular surface inflammation. Mucosal Immunol, 2012. 5(6): p. 702-11.DOI: 10.1038/mi.2012.43.
Stern, M.E., C.S. Schaumburg, and S.C. Pflugfelder, Dry eye as a mucosal autoimmune disease. International reviews of immunology, 2013. 32(1): p. 19-41.
Sambursky, R., et al., Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA ophthalmology, 2013. 131(1): p. 24-28.
Bonini, S., et al., Neurotrophic keratitis. Eye, 2003. 17(8): p. 989-995.
Rosenwasser, G.O., et al., Topical anesthetic abuse. Ophthalmology, 1990. 97(8): p. 967-72.DOI: 10.1016/s0161-6420(90)32458-2.
Martone, G., et al., An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol, 2009. 147(4): p. 725-735.e1.DOI: 10.1016/j.ajo.2008.10.019.
Villani, E., et al., The Ocular Surface in Medically Controlled Glaucoma: An In Vivo Confocal Study. Invest Ophthalmol Vis Sci, 2016. 57(3): p. 1003-10.DOI: 10.1167/iovs.15-17455.
Müller, L.J., et al., Corneal nerves: structure, contents and function. Exp Eye Res, 2003. 76(5): p. 521-42.DOI: 10.1016/s0014-4835(03)00050-2.
Romero-Díaz de León, L., et al., Conjunctival and corneal sensitivity in patients under topical antiglaucoma treatment. Int Ophthalmol, 2016. 36(3): p. 299-303.DOI: 10.1007/s10792-015-0115-1.
Lin, J.C., et al., Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol, 2000. 118(8): p. 1129-32.
Sacchetti, M. and A. Lambiase, Diagnosis and management of neurotrophic keratitis. Clin Ophthalmol, 2014. 8: p. 571-9.DOI: 10.2147/opth.S45921.
Noecker, R.J., L.A. Herrygers, and R. Anwaruddin, Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea, 2004. 23(5): p. 490-6.DOI: 10.1097/01.ico.0000116526.57227.82.
Jaenen, N., et al., Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthalmol, 2007. 17(3): p. 341-9.DOI: 10.1177/112067210701700311.
Herreras, J.M., et al., Ocular surface alteration after long-term treatment with an antiglaucomatous drug. Ophthalmology, 1992. 99(7): p. 1082-8.DOI: 10.1016/s0161-6420(92)31847-0.
Xiong, C., et al., A rabbit dry eye model induced by topical medication of a preservative benzalkonium chloride. Invest Ophthalmol Vis Sci, 2008. 49(5): p. 1850-6.DOI: 10.1167/iovs.07-0720.
Sherwood, M.B., et al., Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucomatous patients. Ophthalmology, 1989. 96(3): p. 327-35.DOI: 10.1016/s0161-6420(89)32888-0.
Wasyluk, J., et al., Ocular Surface Parameters in Glaucoma Patients Treated with Topical Prostaglandin Analogs and the Importance of Switching to Preservative-Free Eye Drops-A Systematic Review. Life (Basel), 2025. 15(12).DOI: 10.3390/life15121837.
Broadway, D.C. and L.P. Chang, Trabeculectomy, risk factors for failure and the preoperative state of the conjunctiva. J Glaucoma, 2001. 10(3): p. 237-49.DOI: 10.1097/00061198-200106000-00017.
Boimer, C. and C.M. Birt, Preservative exposure and surgical outcomes in glaucoma patients: The PESO study. J Glaucoma, 2013. 22(9): p. 730-5.DOI: 10.1097/IJG.0b013e31825af67d.
Noecker, R., Effects of common ophthalmic preservatives on ocular health. Adv Ther, 2001. 18(5): p. 205-15.DOI: 10.1007/bf02853166.
Ammar, D.A. and M.Y. Kahook, Effects of glaucoma medications and preservatives on cultured human trabecular meshwork and non-pigmented ciliary epithelial cell lines. Br J Ophthalmol, 2011. 95(10): p. 1466-9.DOI: 10.1136/bjophthalmol-2011-300012.
Liang, H., et al., Conjunctival and corneal reactions in rabbits following short- and repeated exposure to preservative-free tafluprost, commercially available latanoprost and 0.02% benzalkonium chloride. Br J Ophthalmol, 2008. 92(9): p. 1275-82.DOI: 10.1136/bjo.2008.138768.
Pellinen, P., et al., The cytotoxic effects of preserved and preservative-free prostaglandin analogs on human corneal and conjunctival epithelium in vitro and the distribution of benzalkonium chloride homologs in ocular surface tissues in vivo. Curr Eye Res, 2012. 37(2): p. 145-54.DOI: 10.3109/02713683.2011.626909.
Campolo, A., M. Crary, and P. Shannon, A review of the containers available for multi-dose preservative-free eye drops. Biomedical Journal of Scientific & Technical Research, 2022. 45(1): p. 36035-36044.
Harasymowycz, P., et al., Preserved Versus Preservative-Free Latanoprost for the Treatment of Glaucoma and Ocular Hypertension: A Post Hoc Pooled Analysis. Adv Ther, 2021. 38(6): p. 3019-3031.DOI: 10.1007/s12325-021-01731-9.
Kim, M., et al., Comparison of Efficacy and Ocular Surface Assessment Between Preserved and Preservative-Free Brimonidine/Timolol Fixed-Combination Eye Drops in Glaucoma Patients: A Parallel-Grouped, Randomized Trial. Journal of Clinical Medicine, 2025. 14(5): p. 1587.
Day, D.G., et al., Bimatoprost 0.03% preservative-free ophthalmic solution versus bimatoprost 0.03% ophthalmic solution (Lumigan) for glaucoma or ocular hypertension: a 12-week, randomised, double-masked trial. Br J Ophthalmol, 2013. 97(8): p. 989-93.DOI: 10.1136/bjophthalmol-2012-303040.
Goldberg, I., et al., Bimatoprost 0.03%/timolol 0.5% preservative-free ophthalmic solution versus bimatoprost 0.03%/timolol 0.5% ophthalmic solution (Ganfort) for glaucoma or ocular hypertension: a 12-week randomised controlled trial. Br J Ophthalmol, 2014. 98(7): p. 926-31.DOI: 10.1136/bjophthalmol-2013-304064.
Alm, A., J. Schoenfelder, and J. McDermott, A 5-year, multicenter, open-label, safety study of adjunctive latanoprost therapy for glaucoma. Arch Ophthalmol, 2004. 122(7): p. 957-65.DOI: 10.1001/archopht.122.7.957.
Hedman, K. and A. Alm, A pooled-data analysis of three randomized, double-masked, six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol. Eur J Ophthalmol, 2000. 10(2): p. 95-104.DOI: 10.1177/112067210001000201.
Rouland, J.F., et al., Efficacy and safety of preservative-free latanoprost eyedrops, compared with BAK-preserved latanoprost in patients with ocular hypertension or glaucoma. Br J Ophthalmol, 2013. 97(2): p. 196-200.DOI: 10.1136/bjophthalmol-2012-302121.
Uusitalo, H., et al., Benefits of switching from latanoprost to preservative-free tafluprost eye drops: a meta-analysis of two Phase IIIb clinical trials. Clin Ophthalmol, 2016. 10: p. 445-54.DOI: 10.2147/opth.S91402.
Konstas, A.G., et al., 24-h Efficacy of Glaucoma Treatment Options. Adv Ther, 2016. 33(4): p. 481-517.DOI: 10.1007/s12325-016-0302-0.
Van Buskirk, E.M., Adverse reactions from timolol administration. Ophthalmology, 1980. 87(5): p. 447-50.DOI: 10.1016/s0161-6420(80)35215-9.
Ishibashi, T., N. Yokoi, and S. Kinoshita, Comparison of the short-term effects on the human corneal surface of topical timolol maleate with and without benzalkonium chloride. J Glaucoma, 2003. 12(6): p. 486-90.DOI: 10.1097/00061198-200312000-00008.
Yeh, P.H., et al., Brimonidine related acute follicular conjunctivitis: Onset time and clinical presentations, a long-term follow-up. Medicine (Baltimore), 2021. 100(29): p. e26724.DOI: 10.1097/md.0000000000026724.
Blondeau, P. and J.A. Rousseau, Allergic reactions to brimonidine in patients treated for glaucoma. Can J Ophthalmol, 2002. 37(1): p. 21-6.DOI: 10.1016/s0008-4182(02)80094-1.
Watts, P. and N. Hawksworth, Delayed hypersensitivity to brimonidine tartrate 0.2% associated with high intraocular pressure. Eye (Lond), 2002. 16(2): p. 132-5.DOI: 10.1038/sj.eye.6700053.
Konisky, H., A.N. Gregory, and A. Huho, Allergic Contact Dermatitis from Brimonidine Tartrate Eye Drops: A Rare Dermatological Reaction with a “Teardrop Streak Sign”. Dermatitis, 2025. 36(3): p. 268-270.
Katz, L.J., Twelve-month evaluation of brimonidine-purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma, 2002. 11(2): p. 119-26.DOI: 10.1097/00061198-200204000-00007.
Duru, Z. and C. Ozsaygili, Preservative-free versus preserved brimonidine% 0.15 preparations in the treatment of glaucoma and ocular hypertension: short term evaluation of efficacy, safety, and potential advantages. Cutaneous and ocular toxicology, 2020. 39(1): p. 21-24.
Kucukoduk, A., et al., Cytotoxic, Apoptotic, and Oxidative Effects of Preserved and Preservative-Free Brimonidine in a Corneal Epithelial Cell Line. Journal of Ocular Pharmacology and Therapeutics, 2022. 38(8): p. 576-583.DOI: 10.1089/jop.2022.0053.
Silver, L.H., Clinical efficacy and safety of brinzolamide (Azopt), a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Brinzolamide Primary Therapy Study Group. Am J Ophthalmol, 1998. 126(3): p. 400-8.DOI: 10.1016/s0002-9394(98)00095-6.
Asrani, S., et al., Netarsudil/Latanoprost Fixed-Dose Combination for Elevated Intraocular Pressure: Three-Month Data from a Randomized Phase 3 Trial. Am J Ophthalmol, 2019. 207: p. 248-257.DOI: 10.1016/j.ajo.2019.06.016.
Gokhale, N.S. and G.K. Vemuganti, Diclofenac-induced acute corneal melt after collagen crosslinking for keratoconus. Cornea, 2010. 29(1): p. 117-9.DOI: 10.1097/ICO.0b013e3181a06c31.
Starr, C.E., et al., An algorithm for the preoperative diagnosis and treatment of ocular surface disorders. J Cataract Refract Surg, 2019. 45(5): p. 669-684.DOI: 10.1016/j.jcrs.2019.03.023.
Congdon, N.G., et al., Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg, 2001. 27(4): p. 622-31.DOI: 10.1016/s0886-3350(01)00801-x.
Petroutsos, G., et al., Corticosteroids and corneal epithelial wound healing. Br J Ophthalmol, 1982. 66(11): p. 705-8.DOI: 10.1136/bjo.66.11.705.
Knutsson, K.A., et al., Topical Corticosteroids and Fungal Keratitis: A Review of the Literature and Case Series. J Clin Med, 2021. 10(6).DOI: 10.3390/jcm10061178.
Yagci, A., et al., Topical anesthetic abuse keratopathy: a commonly overlooked health care problem. Cornea, 2011. 30(5): p. 571-5.DOI: 10.1097/ico.0b013e3182000af9.
Judge, A.J., et al., Corneal endothelial toxicity of topical anesthesia. Ophthalmology, 1997. 104(9): p. 1373-9.DOI: 10.1016/s0161-6420(97)30128-6.
Weisenthal, R.W. and R.S. Feder, 2024-2025 Basic and Clinical Science Course, Section 8: External Disease and Cornea. 2024: American Academy of Ophthalmology.
Erdem, E., et al., Topical anesthetic eye drops abuse: are we aware of the danger? Cutan Ocul Toxicol, 2013. 32(3): p. 189-93.DOI: 10.3109/15569527.2012.744758.
Egger, S.F., et al., Ocular side effects associated with 13-cis-retinoic acid therapy for acne vulgaris: clinical features, alterations of tearfilm and conjunctival flora. Acta Ophthalmol Scand, 1995. 73(4): p. 355-7.DOI: 10.1111/j.1600-0420.1995.tb00043.x.
Ruiz-Lozano, R.E., et al., Isotretinoin and the eye: A review for the dermatologist. Dermatologic Therapy, 2020. 33.
Simpson, E.L., et al., Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med, 2016. 375(24): p. 2335-2348.DOI: 10.1056/NEJMoa1610020.
Akinlade, B., et al., Conjunctivitis in dupilumab clinical trials. Br J Dermatol, 2019. 181(3): p. 459-473.DOI: 10.1111/bjd.17869.
Thyssen, J.P., et al., Incidence, prevalence, and risk of selected ocular disease in adults with atopic dermatitis. J Am Acad Dermatol, 2017. 77(2): p. 280-286.e1.DOI: 10.1016/j.jaad.2017.03.003.
Ivert, L.U., et al., Eye Complications During Dupilumab Treatment for Severe Atopic Dermatitis. Acta Derm Venereol, 2019. 99(4): p. 375-378.DOI: 10.2340/00015555-3121.
Wollenberg, A., et al., Conjunctivitis occurring in atopic dermatitis patients treated with dupilumab-clinical characteristics and treatment. J Allergy Clin Immunol Pract, 2018. 6(5): p. 1778-1780.e1.DOI: 10.1016/j.jaip.2018.01.034.
Treister, A.D., C. Kraff-Cooper, and P.A. Lio, Risk Factors for Dupilumab-Associated Conjunctivitis in Patients With Atopic Dermatitis. JAMA Dermatol, 2018. 154(10): p. 1208-1211.DOI: 10.1001/jamadermatol.2018.2690.
Nahum, Y., et al., Dupilumab-induced ocular surface disease (DIOSD) in patients with atopic dermatitis: clinical presentation, risk factors for development and outcomes of treatment with tacrolimus ointment. Br J Ophthalmol, 2020. 104(6): p. 776-779.DOI: 10.1136/bjophthalmol-2019-315010.
Popiela, M.Z., et al., Dupilumab-associated ocular surface disease: presentation, management and long-term sequelae. Eye (Lond), 2021. 35(12): p. 3277-3284.DOI: 10.1038/s41433-020-01379-9.
Agnihotri, G., K. Shi, and P.A. Lio, A Clinician's Guide to the Recognition and Management of Dupilumab-Associated Conjunctivitis. Drugs R D, 2019. 19(4): p. 311-318.DOI: 10.1007/s40268-019-00288-x.
Fu, C., et al., Ocular toxicities associated with targeted anticancer agents: an analysis of clinical data with management suggestions. Oncotarget, 2017. 8(35): p. 58709-58727.DOI: 10.18632/oncotarget.17634.
Peterson, J.L. and B.P. Ceresa, Epidermal Growth Factor Receptor Expression in the Corneal Epithelium. Cells, 2021. 10(9).DOI: 10.3390/cells10092409.
Goel, V., et al., Trichomegaly of eyelashes after treatment with erlotinib in carcinoma pancreas. Int J Trichology, 2014. 6(1): p. 23-4.DOI: 10.4103/0974-7753.136755.
Renouf, D.J., et al., Ocular toxicity of targeted therapies. J Clin Oncol, 2012. 30(26): p. 3277-86.DOI: 10.1200/jco.2011.41.5851.
Dalvin, L.A., et al., CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic Indications and Ophthalmic Side Effects. RETINA, 2018. 38(6): p. 1063-1078.DOI: 10.1097/iae.0000000000002181.
Antoun, J., C. Titah, and I. Cochereau, Ocular and orbital side-effects of checkpoint inhibitors: a review article. Current Opinion in Oncology, 2016. 28(4): p. 288-294.DOI: 10.1097/cco.0000000000000296.
Silva, C.D., et al., Lacrimal drainage system obstruction after cancer treatment: a literature review. 2022. 81: p. -.DOI: 10.37039/1982.8551.20220033.
Lochhead, J., J.F. Salmon, and A.J. Bron, Cytarabine-induced corneal toxicity. Eye (Lond), 2003. 17(5): p. 677-8.DOI: 10.1038/sj.eye.6700451.
Foutch, B.K., et al., Effects of Oral Antihistamines on Tear Volume, Tear Stability, and Intraocular Pressure. Vision (Basel), 2020. 4(2).DOI: 10.3390/vision4020032.
Katipoğlu, Z. and R.N. Abay, The relationship between dry eye disease and anticholinergic burden. Eye (Lond), 2023. 37(14): p. 2921-2925.DOI: 10.1038/s41433-023-02442-x.
Mäntyjärvi, M., K. Tuppurainen, and K. Ikäheimo, Ocular side effects of amiodarone. Surv Ophthalmol, 1998. 42(4): p. 360-6.DOI: 10.1016/s0039-6257(97)00118-5.
Fraunfelder, F.W., F.T. Fraunfelder, and B. Jensvold, Scleritis and other ocular side effects associated with pamidronate disodium. Am J Ophthalmol, 2003. 135(2): p. 219-22.DOI: 10.1016/s0002-9394(02)01840-8.
Roujeau, J.C. and R.S. Stern, Severe adverse cutaneous reactions to drugs. N Engl J Med, 1994. 331(19): p. 1272-85.DOI: 10.1056/nejm199411103311906.
Kohanim, S., et al., Acute and Chronic Ophthalmic Involvement in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis - A Comprehensive Review and Guide to Therapy. II. Ophthalmic Disease. Ocul Surf, 2016. 14(2): p. 168-88.DOI: 10.1016/j.jtos.2016.02.001.
Chung, W.H., et al., Medical genetics: a marker for Stevens-Johnson syndrome. Nature, 2004. 428(6982): p. 486.DOI: 10.1038/428486a.
Sotozono, C., et al., Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications. Ophthalmology, 2009. 116(4): p. 685-90.DOI: 10.1016/j.ophtha.2008.12.048.
Narang, P. and S. D'Souza, Chronic Ocular Sequelae of Stevens-Johnson Syndrome: Recent Advances in Understanding of Patho-Physiology and Management. Semin Ophthalmol, 2026. 41(2): p. 320-330.DOI: 10.1080/08820538.2025.2545264.
Shay, E., et al., Amniotic membrane transplantation as a new therapy for the acute ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis. Surv Ophthalmol, 2009. 54(6): p. 686-96.DOI: 10.1016/j.survophthal.2009.03.004.
Shanbhag, S.S., et al., Multidisciplinary care in Stevens-Johnson syndrome. Ther Adv Chronic Dis, 2020. 11: p. 2040622319894469.DOI: 10.1177/2040622319894469.
Pullum, K.W., M.A. Whiting, and R.J. Buckley, Scleral contact lenses: the expanding role. Cornea, 2005. 24(3): p. 269-77.DOI: 10.1097/01.ico.0000148311.94180.6b.
Fraunfelder, F.T., J.J. Sciubba, and W.D. Mathers, The role of medications in causing dry eye. J Ophthalmol, 2012. 2012: p. 285851.DOI: 10.1155/2012/285851.
Begley, C.G., et al., Characterization of ocular surface symptoms from optometric practices in North America. Cornea, 2001. 20(6): p. 610-8.DOI: 10.1097/00003226-200108000-00011.
Schiffman, R.M., et al., Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol, 2000. 118(5): p. 615-21.DOI: 10.1001/archopht.118.5.615.
Bron, A.J., V.E. Evans, and J.A. Smith, Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea, 2003. 22(7): p. 640-50.DOI: 10.1097/00003226-200310000-00008.
Tomlinson, A., et al., The international workshop on meibomian gland dysfunction: report of the diagnosis subcommittee. Invest Ophthalmol Vis Sci, 2011. 52(4): p. 2006-49.DOI: 10.1167/iovs.10-6997f.
Wolffsohn, J.S., et al., TFOS DEWS III: Diagnostic Methodology. Am J Ophthalmol, 2025. 279: p. 387-450.DOI: 10.1016/j.ajo.2025.05.033.
Bielory, L., Allergic and immunologic disorders of the eye. Part II: ocular allergy. J Allergy Clin Immunol, 2000. 106(6): p. 1019-32.DOI: 10.1067/mai.2000.111238.
Gazzard, G., et al., Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet, 2019. 393(10180): p. 1505-1516.DOI: 10.1016/s0140-6736(18)32213-x.
Huillard, O., et al., Ocular adverse events of molecularly targeted agents approved in solid tumours: a systematic review. Eur J Cancer, 2014. 50(3): p. 638-48.DOI: 10.1016/j.ejca.2013.10.016.
Jones, L., et al., TFOS DEWS III: Management and Therapy. Am J Ophthalmol, 2025. 279: p. 289-386.DOI: 10.1016/j.ajo.2025.05.039.
Prabhasawat, P., N. Tesavibul, and W. Mahawong, A randomized double-masked study of 0.05% cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction. Cornea, 2012. 31(12): p. 1386-93.DOI: 10.1097/ICO.0b013e31823cc098.
Tauber, J., et al., Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study. Ophthalmology, 2015. 122(12): p. 2423-31.DOI: 10.1016/j.ophtha.2015.08.001.
Modi, D., et al., Formulation and development of tacrolimus-gellan gum nanoformulation for treatment of dry eye disease. Colloids Surf B Biointerfaces, 2022. 211: p. 112255.DOI: 10.1016/j.colsurfb.2021.112255.
Moscovici, B.K., et al., Clinical Treatment of Dry Eye Using 0.03% Tacrolimus Eye Drops. Cornea, 2012. 31(8): p. 945-949.DOI: 10.1097/ICO.0b013e31823f8c9b.
Hussain, M., et al., Long-term use of autologous serum 50% eye drops for the treatment of dry eye disease. Cornea, 2014. 33(12): p. 1245-51.DOI: 10.1097/ico.0000000000000271.
Ervin, A.M., R. Wojciechowski, and O. Schein, Punctal occlusion for dry eye syndrome. Cochrane Database Syst Rev, 2010(9): p. Cd006775.DOI: 10.1002/14651858.CD006775.pub2.
Schornack, M.M., J. Pyle, and S.V. Patel, Scleral lenses in the management of ocular surface disease. Ophthalmology, 2014. 121(7): p. 1398-405.DOI: 10.1016/j.ophtha.2014.01.028.
Kruse, F.E., K. Rohrschneider, and H.E. Völcker, Multilayer amniotic membrane transplantation for reconstruction of deep corneal ulcers. Ophthalmology, 1999. 106(8): p. 1504-10; discussion 1511.DOI: 10.1016/s0161-6420(99)90444-x.
Medeiros, F.A., et al., Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1). Ophthalmology, 2020. 127(12): p. 1627-1641.DOI: 10.1016/j.ophtha.2020.06.018.
Yellepeddi, V.K., et al., Punctal plug: a medical device to treat dry eye syndrome and for sustained drug delivery to the eye. Drug Discov Today, 2015. 20(7): p. 884-9.DOI: 10.1016/j.drudis.2015.01.013.
Tsai, J.C., Medication adherence in glaucoma: approaches for optimizing patient compliance. Curr Opin Ophthalmol, 2006. 17(2): p. 190-5.DOI: 10.1097/01.icu.0000193078.47616.aa.
Walsh, K. and L. Jones, The use of preservatives in dry eye drops. Clin Ophthalmol, 2019. 13: p. 1409-1425.DOI: 10.2147/opth.S211611.
Zhou, L. and R.W. Beuerman, Tear analysis in ocular surface diseases. Prog Retin Eye Res, 2012. 31(6): p. 527-50.DOI: 10.1016/j.preteyeres.2012.06.002.
Bonini, S., et al., Phase II Randomized, Double-Masked, Vehicle-Controlled Trial of Recombinant Human Nerve Growth Factor for Neurotrophic Keratitis. Ophthalmology, 2018. 125(9): p. 1332-1343.DOI: 10.1016/j.ophtha.2018.02.022.
Elbaz, U., et al., Restoration of corneal sensation with regional nerve transfers and nerve grafts: a new approach to a difficult problem. JAMA Ophthalmol, 2014. 132(11): p. 1289-95.DOI: 10.1001/jamaophthalmol.2014.2316.
Vera-Duarte, G.R., et al., Neurotrophic keratopathy: General features and new therapies. Surv Ophthalmol, 2024. 69(5): p. 789-804.DOI: 10.1016/j.survophthal.2024.04.004.
