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 Table of Contents  
Year : 2013  |  Volume : 106  |  Issue : 3  |  Page : 168-171

Possible changes in intraocular pressure measurements after corneal collagen cross-linking with riboflavin and ultraviolet A in eyes with keratoconus

1 Department of Ophthalmology, Lecturer of Ophthalmology, Cairo University Hospital, Cairo, Egypt
2 Researcher of Ophthalmology, Research Institute of Ophthalmology (RIO), Giza, Egypt

Date of Submission11-Oct-2013
Date of Acceptance30-Oct-2013
Date of Web Publication28-Feb-2014

Correspondence Address:
Iman M Eissa
6 Othman-Diplomats-Towers, Othman Buildings, Korniche Al Maadi, Floor 6, Appt. 62, Maadi 11431, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2090-0686.127378

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The aim of the study was to determine the possible effect of corneal collagen cross-linking (CXL) with riboflavin and ultraviolet A on intraocular pressure (IOP) measurements using Goldmann applanation tonometry (GAT) in eyes with keratoconus.
The study was designed as a prospective case series and conducted in Al Haram Eye Center and RCC Hospital, Giza, Egypt.
Materials and methods
This noncomparative study measured IOP using GAT before CXL and at 3, 6, and 12 months after CXL.
The study evaluated 49 eyes (40 patients). There was a statistically significant increase in the measured IOP at 3, 6, and 12 months after CXL (P<0.001). The mean preoperative IOP was 11.2 mmHg (1.29 SD), whereas the mean postoperative IOP was 12.24 mmHg (1.13 SD) at 3 months, 12.37 mmHg (1.13 SD) at 6 months, and 12.55 mmHg (1.12 SD) at 12 months. We also found a direct correlation between preoperative central corneal thickness and IOP measurements at postoperative examinations. However, postoperative IOP measurements were not correlated with patient age, sex, or preoperative keratometric readings.
After riboflavin-ultraviolet A CXL in eyes with keratoconus, there was a significant increase in IOP measured using GAT, which was probably caused by an increase in corneal rigidity and not a true increase.

Keywords: Collagen cross-linking, intraocular pressure, keratoconus, corneal rigidity, riboflavin, ultraviolet A, applanation tonometry

How to cite this article:
Eissa IM, El-Husseiny MA, Ismail A. Possible changes in intraocular pressure measurements after corneal collagen cross-linking with riboflavin and ultraviolet A in eyes with keratoconus. J Egypt Ophthalmol Soc 2013;106:168-71

How to cite this URL:
Eissa IM, El-Husseiny MA, Ismail A. Possible changes in intraocular pressure measurements after corneal collagen cross-linking with riboflavin and ultraviolet A in eyes with keratoconus. J Egypt Ophthalmol Soc [serial online] 2013 [cited 2023 Jan 31];106:168-71. Available from: http://www.jeos.eg.net/text.asp?2013/106/3/168/127378

  Introduction Top

Keratoconus is an asymmetric, bilateral, progressive ectasia of the cornea that affects approximately one in 2000 people [1],[2]. Compared with normal corneas, the mechanical stability of keratoconic corneas is decreased because of increased pepsin digestion and fewer collagen cross-links [3].

Current 'conventional' treatment options for keratoconus include both rigid gas permeable contact lenses and penetrating keratoplasty. Unfortunately, neither of these options treats the underlying cause of ectasia. Corneal collagen cross-linking (CXL), however, is a relatively recent procedure that was proven to slow down, stabilize, or even possibly reverse the progression of corneal ectasia in patients with keratoconus [4].

First studied in a series of time-response and dose-response assays on rabbit and porcupine eyes, researchers found a 70-300% increase in corneal rigidity after CXL [4],[5],[6],[7]. The first few CXL procedures on keratoconic human patients, however, dates only as far back as 1998. In fact, the first clinical application of CXL was used to treat corneal melt [8].

In 2003, research showed that CXL appeared to halt the progression of keratectasia [5]. Subsequent studies with limited follow-up data also supported these findings [9],[10]. In addition, a controlled, prospective study of the effect of CXL on keratectasia patients, which was completed in early 2009, showed that the corneal shape appears to undergo a process of regularization, evoluting toward a more 'normal' shape during the first year after treatment [11].

Results of several recent studies indicate that CXL results in corneal stiffening [12]. In a recent in-vitro study on human corneas, an overestimation of true intraocular pressure (IOP) was found as a result of CXL induced by riboflavin and ultraviolet A (UVA) [13]. To our knowledge, there is one clinical study in the literature [14] that directly evaluates the effect of CXL with riboflavin and UVA on IOP measurements by performing Goldmann applanation tonometry (GAT).

A standard CXL procedure begins with the administration of a topical anesthetic, followed by debridement of the central 7-9 mm of the cornea to allow a uniform diffusion of riboflavin into the stroma [5]. Next, 0.1% riboflavin, suspended in a 20% solution of dextran T500, is applied and allowed to permeate the cornea before UVA irradiation.

Riboflavin is reapplied every 5 min during a 30-min irradiation period. Following treatment, a topical antibiotic ointment is applied until corneal re-epithelialization is achieved [5]. Bandage soft contact lenses can be used for pain management and/or to enhance healing.

UVA irradiation has a toxic effect on cell viability and can cause keratocyte and corneal endothelial cell destruction or death, as well as possible lens and retinal damage [5],[15],[16].

In addition, it is suggested that CXL treatment be restricted to the anterior 250-350 μm of the stroma. Thus, CXL is not recommended in patients whose corneas are thinner than 400 μm [16]. Because 85-90% of UVA radiation is absorbed in the anterior 400 μm of the cornea, the procedure should spare the patient's deeper corneal structures, crystalline lens, and retina [15].

To protect the corneal endothelium and deeper ocular structures, the currently used treatment parameters are set; hence, the anterior 250-350 μm of the corneal stroma is treated. Accordingly, the current inclusion criteria require a minimum stromal thickness (without the corneal epithelium) of 400 μm, including a safety margin [16].

  Aim of study Top

The aim of this study was to evaluate the effect of riboflavin-UVA CXL on GAT readings in grade two keratoconus patients with a normal preoperative IOP and no history of glaucoma, diabetes, or other local eye disease. The correlation between preoperative and postoperative IOP measurements and preoperative corneal pachymetry was also evaluated.

  Patients and methods Top

Inclusion criteria and protocol

This prospective clinical study enrolled 49 eyes of 40 patients with keratoconus, who underwent corneal CXL induced by riboflavin and UVA in one or both eyes. All patients were examined using slit lamp biomicroscopy, and the IOP was measured by performing GAT. Fundus examination was performed in all patients using indirect ophthalmoscopy, and any patient suffering from coexisting retinal disease was excluded from the study. All patients were between 16 and 32 years of age. None of them was diabetic, nor did they have a local eye disease other than keratoconus. The clinical diagnosis of keratoconus was based mainly on corneal topography data (using Pentacam rotating Scheimpflug camera) and clinical signs such as Fleischer rings, Vogt striae, stromal thinning, and conical protrusion of the cornea.

After being informed about the nature of the study, before their participation all patients gave informed consent in accordance with the guidelines in the Declaration of Helsinki. Data obtained from the patient records included age and sex, preoperative and postoperative IOP measurements determined with GAT, keratometry (K) readings (Pentacam), central corneal thickness (CCT) using a Pentacam rotating Scheimpflug camera, and slit lamp biomicroscopy and fundus examination findings.

Surgical procedure

Corneal CXL was performed under sterile conditions. The patient's eye was topically anesthetized with benoxinate hydrochloride 0.4% eyedrops (Benox; Eipico). A 7.5-8.0-mm-diameter section of corneal epithelium (including the cone) was mechanically removed with a spatula, and sterile riboflavin 0.1% solution was instilled every 2 min for 30 min. UVA irradiation was performed using the commercially available UVA system (UV-X; IROC AG, Zurich, Switzerland). Irradiation was performed for 30 min, corresponding to a dose of 5.4 J/cm 2 . During treatment, riboflavin 0.1% solution was applied every 2-3 min to saturate the cornea. At the end of the procedure, a silicone-hydrogel bandage contact lens was applied until full re-epithelialization had occurred, which was typically after 4 days from surgery.


Tonometry measurements were recorded using GAT with sterile sodium fluorescein strips. The same tonometer (Haag- Streit AG) was used throughout the study. Tonometry measurements were taken at the center of the cornea (before and after CXL). Corneal topography, CCT, and K readings (Pentacam) were examined and recorded by a masked observer. The K measurements were actual K readings in the flat axis and steep axis. The GAT measurements, CCT, and K measurements before surgery as well as IOP measurements at 3, 6, and 12 months postoperatively were included in the statistical analysis.

Statistical analysis

The mean preoperative IOP was 11.2±1.29 mmHg, whereas the mean postoperative IOP values were 12.24 mmHg (1.13 SD) at 3 months, 12.37 mmHg (1.13 SD) at 6 months, and 12.55 mmHg (1.12 SD) at 12 months. An a-priori two-tailed paired t-test power calculation showed that a total sample size of at least 25 patients was required to achieve a power of 0.95. Results were presented as mean ± SD.

Analysis of variance was used to compare IOP measurements before and after CXL. Correlation analysis was used to test the influence of variables (e.g. patient age and sex, preoperative corneal pachymetry, preoperative K readings) on the postoperative changes in IOP measurements.

A P-value of less than 0.05 was considered statistically significant.

A one-way Kolmogorov-Smirnov test was used to examine the normality of the data.

  Results Top

The study enrolled 49 eyes of 40 patients with a mean age of 22.4 ± 3.1 years (range 16-32 years). The apices of the patients' cones were mostly inferior (38 eyes); the rest (11 eyes) were central. No intraoperative or postoperative complications occurred. There was a statistically significant increase in IOP measurements at 3, 6, and 12 months [Figure 1] after CXL when compared with the preoperative IOP (P = 0.000).
Figure 1:

Click here to view

The mean IOP measurement was 11.2±1.29 mmHg before CXL, whereas it was 12.24 mmHg at 3 months, 12.37 mmHg at 6 months, and 12.55 mmHg at 12 months after operation. There was no statistically significant change in IOP between the 3- and 6-month postoperative measurements (P = 0.341), nor between the 6- and 12-month postoperative measurements (P = 0.499). However, a statistically significant difference in IOP was noticed between the 3- and 12-month postoperative measurements (P = 0.011).

A strong positive correlation [Figure 2] was found between preoperative CCT and preoperative IOP readings (P = 0.000, r = 0.789) as well as IOP readings at 3, 6, and 12 months (P = 0.000, r = 0.652), which means that the higher the preoperative pachymetric reading the higher the preoperative and postoperative IOP readings. However, we found no statistically significant correlation between postoperative IOP measurements and patient age (P = 0.433), sex (P = 0.227), or preoperative K readings (P = 0.071).
Figure 2:

Click here to view

  Discussion Top

Collagen CXL with riboflavin and UVA is a rather new surgical technique used in the treatment of keratoconus. The treatment is based on the activation of photosensitizer riboflavin by UVA, which produces oxygen radicals that induce the formation of strong chemical bonds between the collagen fibrils and thus increases corneal stiffness [17]. Several studies [5,6] report corneal stiffening after riboflavin-UVA CXL to treat keratoconus. The corneal stiffening might be correlated with an increase in corneal and ocular rigidity. Ocular rigidity is a measurable physical parameter of the eye that expresses the elastic properties of the globe. In 1937, Friedenwald [18] described the coefficient of ocular rigidity as a 'measure of the resistance, which the eye exerts to distending forces'. Results in a recent in-vitro study [13] indicated that riboflavin-UVA CXL in human corneas results in overestimation of true IOP, in the range of 1.8-3.1 mmHg depending on the tonometer type (GAT, dynamic contour tonometry, Tono-Pen XL). Nevertheless, this overestimation was considerably smaller than the magnitude of overestimation expected from theoretic calculations [19], despite a reported increase in corneal rigidity after CXL in human corneas of up to 330% [6]. This result might be because of the maximum stiffening effect of CXL in the anterior corneal stroma [6],[15]. In another recent study [20], it was found that CXL with a dialdehyde agent in human corneas led to significant increase in wave velocity and transcorneal IOP measurements, despite a constant intravitreal pressure.

In our study, there was a statistically significant increase in measured IOP using GAT after CXL with riboflavin and UVA at 3, 6, and 12 months, postoperatively.

Biomechanical alterations and corneal rigidity increments are probably related to IOP changes after CXL. The change in IOP readings at 3, 6, and 12 months was positively correlated with preoperative CCT; yet, it was not correlated with patient age, sex, or preoperative K readings. Ehlers et al. [21] reported that applanation tonometry provided accurate IOP measurements only when the CCT was 520 mm, whereas thinner and thicker corneas gave false lower readings and false higher readings, respectively.

Nevertheless, in our study, neither CCT nor K readings changed after CXL. Although we believe that alterations in corneal rigidity and elasticity by CXL may induce an overestimation of IOP, we cannot exclude the possibility that the 'true' IOP increased after CXL. This possibility could be verified through a real-time measurement of the IOP using an invasive method. Thus, the preoperative IOP levels (used as baseline IOP) should be taken into account in patients treated with CXL, especially if glaucoma is suspected.

There are some limitations to this study. The change in IOP may have been a response to aqueous humor dynamics to the surgery (decrease in outflow from the effect on the trabecular meshwork), or the CXL procedure may have had an unknown effect on IOP readings. Moreover, this was a noncomparative study with no control group. Finally, the IOP measurements were performed using only GAT, without the use of other tonometer devices (e.g. dynamic contour).

  Conclusion Top

In conclusion, after CXL with riboflavin and UVA in eyes with keratoconus, there was a significant increase in IOP measured using GAT. The increase was probably the result of an increase in corneal rigidity. The increase in corneal rigidity led to an increase in measurement and not to a true increase in IOP.

  Acknowledgements Top

Conflicts of interest

There are no conflicts of interest.

  References Top

1.Kennedy RH, Bourne WM, Dyer JA .A 48-year clinical and epidemiological study of keratoconus. Am J Ophthalmol 1986; 101:267-273.  Back to cited text no. 1
2.Rabinowitz YS Keratoconus. Surv Ophthalmol 1998; 42:297-319.  Back to cited text no. 2
3.Andreassen T, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res 1980; 31:435-441.  Back to cited text no. 3
4.Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res 1998; 66:97-103.  Back to cited text no. 4
5.Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135:620-627.  Back to cited text no. 5
6.Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced crosslinking. J Cataract Refract Surg 2003; 29:1780-1785.  Back to cited text no. 6
7.Wollensak G, Spoerl E, Seiler T. Treatment of keratoconus by collagen cross linking. Ophthalmologe 2003; 100:44-49.  Back to cited text no. 7
8.Scnitzler E, Sporl E, Seiler T. Crosslinking of the corneal collagen by UV radiation with riboflavin for the mode of treatment melting ulcer of the cornea, first results of four patients. Klin Monbl Augenheilkd 2000; 217:190-193.  Back to cited text no. 8
9.Caporossi A, Baiocchi S, Mazzotta C. Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of the corneal collagen; preliminary refractive results in an Italian study. J Cataract Refract Surg 2006; 32:837-845.  Back to cited text no. 9
10.Wittig-Silva C. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus; preliminary results. J Refract Surg 2008; 24:S720-S725.  Back to cited text no. 10
11.Koller T, Iseli HP, Hafezi F. Scheimpflug imaging of corneas after collagen cross-linking. Cornea 2009; 28:510-515.  Back to cited text no. 11
12.Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008; 34:796-801.  Back to cited text no. 12
13.Romppainen T, Bachmann LM, Kaufmann C, Kniestedt C, Mrochen M, Thiel MA. Effect of riboflavin-UVA-induced collagen cross-linking on intraocular pressure measurement. Invest Ophthalmol Vis Sci 2007; 48:5494-5498.  Back to cited text no. 13
14.GD Kymionis, MA Grentzelos, GA Kounis, DM Portaliou. Intraocular pressure measurements after corneal collagen crosslinking with riboflavin and ultraviolet A in eyes with keratoconus. J Cataract Refract Surg 2010; 36:1724-1727.  Back to cited text no. 14
15.Kohlhaas M, Spoerl E, Schilde T. Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet a light. J Cataract Refract Surg 2006; 32:279-283.  Back to cited text no. 15
16.Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA riboflavin cross-linking of the cornea. Cornea 2007; 26:385-389.  Back to cited text no. 16
17.Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006; 17:356-360.  Back to cited text no. 17
18.Friedenwald JS Contribution to the theory and practice of tonometry. Am J Ophthalmol 1937; 20:985-1024.  Back to cited text no. 18
19.Liu J, Roberts CJ. Influence of corneal biomechanical properties on intraocular pressure measurement; quantitative analysis. J Cataract Refract Surg 2005; 31:146-155.  Back to cited text no. 19
20.Dupps WJ Jr, Netto MV, Herekar S, Krueger RR. Surface wave elastometry of the cornea in porcine and human donor eyes. J Refract Surg 2007; 23:66-75.  Back to cited text no. 20
21.Ehlers N, Bramsen T, Sperling S. Applanation tonometry and central corneal thickness. Acta Ophthalmol (Copenh) 1975; 53:34-43.  Back to cited text no. 21


  [Figure 1], [Figure 2]


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