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Table of Contents
Year : 2021  |  Volume : 3  |  Issue : 1  |  Page : 14

High risk of intraocular pressure rise with difluprednate post collagen cross-linking for keratoconus

Department of Ophthalmology, University of Puerto Rico, San Juan, Puerto Rico

Date of Submission16-Feb-2021
Date of Acceptance01-Mar-2021
Date of Web Publication07-Apr-2021

Correspondence Address:
Dr. Sofia Ramos Bartolomei
18 Calle Tintillo, Tintillo Gardens, Guaynabo 00966
Puerto Rico
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pajo.pajo_83_21

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Purpose: To report intraocular pressure (IOP) after use of difluprednate ophthalmic solution 0.05% (Durezol®; Novartis AG, Basilea, Switzerland) post corneal cross-linking (CXL) versus prednisolone (Pred-Forte®; Allergan Inc., Irvine, CA, USA).
Methods: A retrospective single-center case series evaluation of 34 keratoconus patients ages 16-“41 (36 eyes) who underwent CXL with Avedro's KXL System® (Avedro Inc; Waltham, MA) between August 2016 and August 2017. Post-CXL, six eyes were given difluprednate and 30 were given prednisolone. IOP was recorded using Reichert model 30 pneumatonometer. Those that exhibited increased IOP at 3 days were given anti-glaucoma medications and changed to fluorometholone or loteprednol.
Results: IOP's 3 days' postoperative (24.167 ± 5.23) in the difluprednate group were significantly higher than preprocedure (16.5 ± 2.258). In the prednisolone group, 3 days postprocedure the mean IOP (14.2 ± 3.199) was not significantly higher than preoperatory IOP mean (16.8 ± 4.232). The difference between IOP 3 days' postprocedure and before was 7.667 ± 4.546 for the difluprednate group and 2.567 ± 2.648 for the prednisolone group. These were compared using an unpaired t-test (t value = 3.750 ± 1.297) with P = 0.0007.
Discussion: This study shows statistically significant difference in postoperative and preoperative IOP values after the use of difluprednate or prednisolone in young patients postCXL. Measuring the pachymetry on follow-up examinations could help see if changes in corneal thickness affect measured IOP. A controlled prospective double-blind study could confirm a greater increase in IOP following difluprednate versus prednisolone use, but due to the high risk, we do not recommend this study.

Keywords: Corneal cross-linking, intraocular pressure, keratoconus

How to cite this article:
Bartolomei SR, Román LR. High risk of intraocular pressure rise with difluprednate post collagen cross-linking for keratoconus. Pan Am J Ophthalmol 2021;3:14

How to cite this URL:
Bartolomei SR, Román LR. High risk of intraocular pressure rise with difluprednate post collagen cross-linking for keratoconus. Pan Am J Ophthalmol [serial online] 2021 [cited 2023 Mar 27];3:14. Available from: https://www.thepajo.org/text.asp?2021/3/1/14/313170

  Introduction Top

Corneal cross-linking (CXL) halts the progression of keratoconus, a bilateral progressive corneal condition leading to decreased vision secondary to irregular astigmatism and scaring.[1] It creates new collagen crosslinks resulting in shortening, thickening, and overall strengthening of the cornea.[2] Postprocedure, steroids are used. The most common, prednisolone, is known to increase the risk of glaucoma damaging the optic nerve with prolonged use.[3] Another steroid, difluprednate, requires less frequent dosing, increasing patient compliance and clearing inflammation faster, leading to decreased steroid exposure.[4] In this study, we report differences in intraocular pressure (IOP) in patients that were given difluprednate versus prednisolone after CXL.

  Methods Top

Informed consent was obtained for all patients. Inclusion criteria involved keratoconus patients who underwent Corneal CXL between August 2016 and August 2017. No patients were excluded from the study. Each participant had a comprehensive ophthalmic examination including slit-lamp examination, IOP measurement, manifest refraction, corneal pachymetry, best spectacle-corrected visual acuity (BSCVA) using the Snellen chart, and OCULUS® Pentacam (OCULUS; Wetzlar, Germany) examination. All eyes had a minimum pachymetry of 400 microns. The patients underwent the CXL procedure using the Avedro KXL System® (Avedro Inc., Waltham, MA) using riboflavin 5'-phosphate ophthalmic solution (Photrexa®; Avedro Inc., Waltham, MA) and riboflavin 5'-phosphate in 20% dextran ophthalmic solution (Photrexa®® Viscous; Avedro Inc., Waltham, MA) and their approved protocol for epithelium-off treatments.

After the procedure, a bandage contact lens was placed and patients were started on topical steroids (six in the difluprednate group and 30 in the prednisolone group) four times a day. Antibiotic drops and artificial tears were also given. Patients were evaluated at the next day (when IOP was not taken), at 3 days when the bandage contact lens was removed and at one month. By that time, most patients had already finished the steroid course a few days before; however, for those patients who had not, it was discontinued. The patients on difluprednate were given a 1 ml sample. Only one of the patients on difluprednate did not exhibit an increase in IOP at 3 days; however, this patient was given prednisolone to use after finishing the difluprednate sample and had increased IOP at the one month visit. The other patients that exhibited increased IOP at 3 days with difluprednate use were either changed to fluorometholone or loteprednol. They were also given antiglaucoma medication; in most cases, brimonidine 0.1 (Alphagan P®, Allergan, Irving CA) was used. Visual acuity, IOP, and complete slit-lamp examinations were performed in all visits. All IOP measurements were done with the same pneumatonometer Reichert Model 30.

  Results Top

Patient sex, age, and baseline IOPs for preoperative, 3 days postoperative, and 1-month postoperative are displayed in [Table 1], [Table 2], [Table 3]. The IOP recorded at 3 days postoperative in the difluprednate group were significantly higher at 3 days postprocedure (IOP mean 24.167 ± 5.23) than preprocedure (IOP mean 16.5 ± 2.258). Meanwhile in the prednisolone group at 3 days' postprocedure the mean IOP was 14.2 ± 3.199 and in preprocedure 16.8 ± 4.232. The difference between IOP at 3 days' postprocedure and IOP preprocedure was calculated for both the difluprednate and the prednisolone groups. The average difference for the difluprednate group was 7.667 ± 4.546 and for the prednisolone group, it was 2.567 ± 2.648. These means were then compared using an unpaired t-test which resulted in a t = 3.750 with a standard error of 1.297, with a two-tailed P = 0.0007, which is considered extremely statistically significant. The 95% confidence interval of the difluprednate group minus the prednisolone group mean ranges from 2.229 to 7.503.
Table 1: Patient data and baseline preoperative, 3 days and 1-month postoperative intraocular pressure (mmHg) with difluprednate use

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Table 2: Female patient data and baseline preoperative, 3 days and 1-month postoperative intraocular pressure (mmHg) with prednisolone use

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Table 3: Male patient data and baseline preoperative, 3 days and 1-month postoperative intraocular pressure (mmHg) with prednisolone use

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  Discussion Top

Keratoconus patients have highly astigmatic and usually thinned corneas making it difficult and less accurate to measure IOP with regular applanation tonometry and the pneumotonometer may be a more accurate mode to measure it.[5]

Recently (April 2016) a new treatment, Corneal CXL, has been approved in the United States to halt the progression of keratoconus. This treatment option is indicated for patients with progressive keratoconus and corneal ectasia following refractive surgery with a minimum pachymetry of 400 microns. Collagen CXL has been proven to deter the progression of this condition and is indicated for patients who have shown worsening disease within the last year.[6]

The currently approved CXL method in the US consists of removing the epithelium before the treatment is given. Recommended postoperative care includes the use of a bandage contact lens, topical antibiotic, a topical steroid for three to four weeks, and artificial tears four times a day for a month.[7]

Difluprednate is a steroid indicated for the treatment of inflammation and pain after ocular surgery and for anterior uveitis which is believed to require less dosage thus providing less exposure to steroids leading to reduced side effects.[4] Prednisolone acetate ophthalmic suspension is also a steroid that is commonly used to decrease inflammation in the eye. However, in cases of severe inflammation such as complicated eye surgery or corneal transplants prednisolone may not result adequate when used alone and may require the use of supplementary systemic steroids. In these situations, difluprednate which provides greater control of inflammation with less frequent dosing may result more adequate.[8]

There have been studies which have reported an increased incidence of elevated pressures in patients with keratoconus. It is up for debate whether the keratoconus eyes are naturally more susceptible to increased IOP caused by topical steroid use or whether the increased corneal rigidity following Corneal CXL contributes to the increased IOP.

In the 2016 Kanellopoulos et al. study, “Higher incidence of steroid-induced ocular hypertension in keratoconus,” statistically significant (P < 0.01) higher IOP was demonstrated following topical dexamethasone administration during 1 month after both combined Photorefractive Keratectomy (PRK) and Corneal CXL in patients with keratoconus and after PRK in patients with normal eyes. This shows that keratoconus eyes might be naturally more susceptible to increased IOP following steroid use, regardless of increased rigidity resulting from the CXL procedure.[9] The final outcome of the CXL is a decrease in the initial pachymetry, but in the initial days after the procedure, it may be increased due to inflammation and edema.[10] This may also explain the increased postoperative IOP observed in our study. Even though the keratoconus eyes could be inherently more susceptible to topical steroid administration perhaps corneal thickness should also be measured postoperatively to see if there is a correlation between increased corneal thickness and increased IOP after CXL initially. A thicker cornea leads to higher IOP readings on tonometry causing an overestimation of the true IOP value. Similarly, thinner corneas lead to an underestimation of the actual IO P value and thus to less than optimal management of glaucoma in these patients.[11] It has long been studied whether central corneal thickness (CCT) directly influences IOP. CCT might serve as a biomarker for structural and anatomical conditions that influence the pathogenies of increased IOP and glaucoma. As of right now little is known about the pathogenies of ectasia, distention, or dilation of the cornea, however, some studies have demonstrated the possibility of a genetic role in an abnormality of collagen CXL that leads to stromal thinning.[12],[13],[14]

The measurement of pachymetry on follow-up examinations would give more information about the change in corneal thickness after the procedure and how this would impact the IOP measured in follow-up visits. This warrants further evaluation as it could add valuable information to our findings. In addition, this report analyses a small sample size for patients treated with CXL and a small percentage of patients started on difluprednate six eyes versus 30 on prednisolone. It was also noted that patients who were changed to fluorometholone had no difference in observed haze and had similar results to those on prednisolone. This suggests using a less potent steroid could be enough in extraocular procedures such as CXL. This observation should serve as caution to avoid difluprednate in any young patient, especially if unmonitored, for conditions such as allergies or keratitis that do not have intraocular inflammation such as uveitis.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42:297-319.  Back to cited text no. 1
Mohammadpour M, Heidari Z, Hashemi H. Updates on managements for keratoconus. J Curr Ophthalmol 2017;30:110-24.  Back to cited text no. 2
Phulke S, Kaushik S, Kaur S, Pandav SS. Steroid-induced Glaucoma: An avoidable irreversible blindness. J Curr Glaucoma Pract 2017;11:67-72.  Back to cited text no. 3
Foster CS, Davanzo R, Flynn TE, McLeod K, Vogel R, Crockett RS. Durezol (Difluprednate Ophthalmic Emulsion 0.05%) compared with Pred Forte 1% ophthalmic suspension in the treatment of endogenous anterior uveitis. J Ocul Pharmacol Ther 2010;26:475-83.  Back to cited text no. 4
Duch S, Serra A, Castanera J, Abos R, Quintana M. Tonometry after laser in situ keratomileusis treatment. J Glaucoma 2001;10:261-5.  Back to cited text no. 5
Belin MW, Lim L, Rajpal RK, Hafezi F, Gomes JA, Cochener B. Corneal cross-linking: Current USA Status: Report from the cornea society. Cornea 2018;37:1218-25.  Back to cited text no. 6
Jouve L, Borderie V, Temstet C, Labbé A, Trinh L, Sandali O, et al. Le crosslinking du collagène dans le kératocône [Corneal collagen crosslinking in keratoconus]. J Fr Ophtalmol 2015;38:445-62.  Back to cited text no. 7
Loftsson T, Stefánsson E. Cyclodextrins in eye drop formulations: Enhanced topical delivery of corticosteroids to the eye. Acta Ophthalmol Scand 2002;80:144-50.  Back to cited text no. 8
Kanellopoulos AJ, Cruz EM, Ang RE, Asimellis G. Higher incidence of steroid-induced ocular hypertension in keratoconus. Eye Vis (Lond) 2016;3:4.  Back to cited text no. 9
Waszczykowska A, Jurowski P. Two-year accelerated corneal cross-linking outcome in patients with progressive keratoconus. Biomed Res Int 2015;2015:325157.  Back to cited text no. 10
Amit A, Gaurav K, Vikas A, Ashok K, Harpreet AS, Shivani A. Evaluation of intraocular pressure and corneal thickness in individuals at high altitude area (10000 ft above sea level). Rom J Ophthalmol 2019;63:217-21.  Back to cited text no. 11
Li X, Yang H, Rabinowitz YS. Longitudinal study of keratoconus progression. Exp Eye Res 2007;85:502-7.  Back to cited text no. 12
Edwards M, McGhee CN, Dean S. The genetics of keratoconus. Clin Exp Ophthalmol 2001;29:345-51.  Back to cited text no. 13
Bykhovskaya Y, Rabinowitz YS. Update on the genetics of keratoconus. Exp Eye Res. 2021 Jan;202:108398. doi: 10.1016/j.exer.2020.108398. Epub 2020 Dec 13.  Back to cited text no. 14


  [Table 1], [Table 2], [Table 3]


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