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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 107  |  Issue : 4  |  Page : 226-231

Analysis of 2-year corneal cross-linking results in keratoconus patients


Department of Ophthalmology, Sohag University Hospital, Sohag University, Sohag, Egypt

Date of Submission07-May-2014
Date of Acceptance20-Sep-2014
Date of Web Publication24-Feb-2015

Correspondence Address:
Mohammed I Hafez
MD, Department of Ophthalmology, Sohag University Hospital, Sohag University, Arab Mahrous, Mohamed Mousa Street, Sohag city, 82524 Sohag
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2090-0686.150659

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  Abstract 

Purpose
To analyze the results of 2 years of corneal collagen cross-linking (CXL) for the treatment of keratoconus and to detect the efficiency of this procedure.
Design
This was a retrospective noncomparative study.
Patients and methods
A total of 58 eyes of 40 keratoconus patients were subjected to CXL. Epithelium-off CXL was the only procedure performed for all cases. The preoperative and postoperative measures included uncorrected visual acuity, best-corrected visual acuity (BCVA), fundus examination, slit-lamp examination, pachymetry, keratometry, refractometry, and corneal topography. All eyes included in this study were followed up at 1, 3, 6, 12, and 24 postoperative months. All preoperative and postoperative data of all eyes were collected, revised, and analyzed.
Results
This study showed that uncorrected visual acuity improved by at least one line in 70.7% of the eyes in the study, but remained stable in 22.4% of the eyes in the study. BCVA improved by at least one line in 53.4% of the eyes in the study, but remained stable in 36.2% of the eyes in the study. Astigmatism remained stable in 86.2% of the eyes in the study and decreased by a mean of 1.20 D in 13.8% of the eyes in the study. The average keratometry (K) decreased by more than 1 D in 74.1% of the eyes in the study, but remained stable in 13.7% of the eyes in the study. The maximum K value decreased by a mean of 2.47 D in 55.1% of the eyes in the study, but remained stable in 38% of the eyes in the study. The K value of the apex decreased by a mean of 2.73 D in 65.5% of the eyes in the study, but remained stable in 25.9% of the eyes in the study.
Conclusion
This study proved that corneal cross-linking is beneficial both as a visual-preserving and as a visual-improving procedure. K readings are the main indicator of the success or the failure of the procedure. Central corneal thickness can be an indicator of improvement; there is a reciprocal relationship between the central corneal thickness and the BCVA. The best chance is for patients with corneal thickness more than 400 μm. It is advised that the refractive surgeon should store the riboflavin in the refrigerator from +4°C to +8°C and discard it immediately after surgery. The use of steroid from the first postoperative day was helpful. Most postoperative visual improvements resulted from a decrease in myopia, whereas there was no remarkable improvement in astigmatism.

Keywords: Cross-linking, epithelium-off, keratoconus, long-term results, myopic correction


How to cite this article:
Hafez MI. Analysis of 2-year corneal cross-linking results in keratoconus patients. J Egypt Ophthalmol Soc 2014;107:226-31

How to cite this URL:
Hafez MI. Analysis of 2-year corneal cross-linking results in keratoconus patients. J Egypt Ophthalmol Soc [serial online] 2014 [cited 2017 Oct 21];107:226-31. Available from: http://www.jeos.eg.net/text.asp?2014/107/4/226/150659


  Introduction Top


Corneal collagen cross-linking (CXL) is the first surgical procedure that appears to halt the progression of corneal ectatic disorders such as keratoconus and postoperative corneal ectasia after refractive surgery. CXL offers a treatment for corneal disease for which there are no options to address the underlying disorder [1].

The overall very positive clinical outcome and the low complication rates of CXL have been reported by a growing number of studies and, especially considering the lack of any alternative disease-modifying treatment at present, standardized CXL should be seriously considered in all patients with progressive keratoconus [2].

CXL treatment of progressive keratoconus using the photosensitizer riboflavin and ultraviolet-A light was introduced by Willensak et al. [3] on the basis of the early in-vitro investigations by Spoerl et al. [4] on porcine corneas, similar to a previous work carried out on collagen gels, screening various chemical and physical cross-linking treatments for tissue strengthening [5].

The cross-linking approach was chosen because a decrease in the tensile strength of keratoconus corneas by about 36% had been described. The new treatment allowed for biomechanical stiffening of the human cornea by up to 300% and a significant increase in its biochemical resistance to collagenase digestion. CXL has proven to be clinically successful and has entered mainstream use worldwide. New applications beyond ectatic corneal disease are also being tested [6],[7].

Keratoconus is characterized by the development of a noninflammatory ectasia of the axial or periaxial region of the cornea and is usually bilateral. Its incidence in the general population is reported to be about one in 2000 [8]. Incidences of one in 600 to one in 420 seem more in keeping with the current diagnostic capacity [9]. Because of the young age of the patients, keratoconus often has a significant negative effect on the quality of life [10].

The cross-linking effect is not distributed homogenously over the corneal depth. The stiffening effect is concentrated in the anterior 200-300 μm of the cornea because of the high absorption of ultraviolet light in this area [6].

Riboflavin, also known as vitamin B 2 , is poorly soluble in water; thus, the more soluble riboflavin-5-phosphate form is commonly utilized. For the standard cross-linking protocol, an isotonic 0.1% riboflavin solution was formulated by mixing 10 mg riboflavin-5-phosphate in 10 ml of a dextran-T-500 20% solution [3].


  Patients and methods Top


This retrospective nonrandomized open-label study with consecutive recruitment involved patients who fulfilled the inclusion criteria of keratoconus grade I or II, corneal thickness of 400 μm or more, no previous refractive surgery, no corneal scarring, and non pregnant or nursing women.

The surgical procedure

Every patient was subjected to epithelium-off CXL. Pilocarpine 2% was instilled as one drop every 10 min for 30 min before surgery to minimize the exposure of the lens and retina to UV rays . Topical anesthesia was instilled in the form of benoxinate hydrochloride as one drop every 5 min for 30 min before surgery. Marking of the eye was performed with double check. Skin disinfection was performed using povidone iodine 10% to soak the skin.

The device used in this study was Xlink; Opto, Australia [Figure 1]a (Optos plc, Scotland, United Kingdom). Its parameters were T (time): 30 min D (dose): 5.371 J/cm 3 , P (power): 1.50 mW, and I (intensity): 2.984 mW/cm 3 .
Figure 1: The preoperative preparation; (a) the device: Xlink; Opto, (b) riboflavin phosphate 0.127 g (Ricrolin; Sooft).

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Riboflavin phosphate 0.127 g (Ricrolin; Sooft) was used, which was equivalent to 0.1% basic riboflavin (OFTA high-tech, SOOFT Italia, Rome, Italy). Riboflavin was kept in the refrigerator at +4°C to +8°C and discarded immediately after surgery [Figure 1]b.

A zone marker of 8 mm was used to mark the corneal area to be de-epithelized [Figure 2]a.The epithelium was removed using a blunt-tipped spatula [Figure 2]b. Sodium hyaluronate (Provisc, Alcon) was applied on the limbus all around to retain riboflavin on the cornea [Figure 2]c. The lights were turned off so that the composition and efficacy of riboflavin were not affected by the room light [Figure 2]d. The riboflavin was instilled every 3 min for 30 min until the corneal stroma was saturated with riboflavin.
Figure 2: The operative procedure; (a) an 8 mm zone marker was used to mark the corneal area to be de-epithelized, (b) the epithelium was removed using a blunt-tipped spatula, (c) a sodium hyaluronate (Provisc; Alcon) ring was used to retain riboflavin on the cornea, (d) the riboflavin was instilled (while the light was turned off), (e) the riboflavin-saturated cornea was exposed to ultraviolet-A rays.

Click here to view


Corneal irradiation with ultraviolet-A was performed for 30 min by dropping the riboflavin every 3 min [Figure 2]e. Irrigation of the eye was performed. A soft Contact lens was applied onto the cornea. Eye drops were instilled at the end of surgery in the form of antibiotic eye drops (gatifloxacin 0.3%), steroid eye drops (prednisolone acetate 1%), and cyclopentolate. Finally, the eye was covered by an eye patch.

Postoperative antibiotic eye drops (gatifloxacin 0.3%) were used hourly during the first 24 h, and then four times daily. Steroid eye drops (prednisolone acetate 1%) were used three times daily from the first postoperative day. Topical gel was used twice daily. Systemic vitamin A and vitamin C were used twice daily. Systemic analgesic and anti inflammatory drugs were also used. The treatment usually lasted 7-10 days postoperatively.

The patient was followed up daily in the first week until re-epithelization of the cornea took place. During this follow-up, the patient was examined by a slit-lamp to detect corneal re-epithelization and haziness. Then, the patient was followed up at the first, third, sixth, 12th, and 24th months postoperatively.

In most cases, re-epithelization occurred in the first 48 h, and then the contact lens and eye patch were removed. The patient was instructed to wear sun glasses for 2 weeks.


  Results Top


Fifty-eight eyes of 40 patients were subjected to epithelium-off CXL in Sohag University Hospital. All eyes were followed up for at least 24 months. This study reports these results.

The mean age of the patients was 16.9 ± 6.35 years (range 12-39 years). Meanwhile, the mean follow-up duration was 23.05 ± 1.55 months (range 24-30 months).

For visual acuity, the uncorrected visual acuity improved by at least one line in 70.7% (41/58) of the eyes in the study, remained stable in 22.4% (13/58) of the eyes in the study, and decreased by one line in 6.9% (4/58) of the eyes in the study. Meanwhile, the best-corrected visual acuity (BCVA) improved by at least one line in 53.4% (31/58) of the eyes in the study, remained stable in 36.2% (21/58) of the eyes in the study (P = 0.006), and decreased by only one line in 10.3% of the eyes in the study (6/58).

The average keratometry (K) decreased by more than 1 D in 74.1% (43/58) of the eyes in the study, remained stable in 13.7% (8/58) of the eyes in the study, and decreased within 1 D in 12.2% (7/58) of the eyes in the study. Meanwhile, the maximum K value decreased by a mean of 2.47 D in 55.1% (32/58) of the eyes in the study, remained stable (within ± 0.50 D) in 38% (22/58) of the eyes in the study, and increased by 1.00 D in 6.9% (4/58) of the eyes in the study. Furthermore, the K value of the apex decreased by a mean of 2.73 D in 65.5% (38/58) of the eyes in the study, remained stable (within ± 0.50 D) in 25.9% (15/58) of the eyes in the study, and increased by 1.00 D in 8.6% (5/58) of the eyes in the study.

Astigmatism remained stable (within ± 0.50 D) in 86.2% (50/58) of the eyes in the study and decreased by a mean of 1.20 D 13.8% in (8/58) of the eyes in the study.

Analysis of the corneal wave front indicated that the coma component showed a very significant reduction at 24 months after CXL. Meanwhile, there were no significant variations in the follow-up period in spherical and higher-order aberrations.

It is important to report examples of the preoperative and postoperative patient state: [Table 1] and [Table 2].
Table 1: Example A shows the preoperative and postoperative data of one eye

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Table 2: Example B shows the preoperative and postoperative data of another eye

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  Discussion Top


This study reports on a long-term postoperative follow-up period over 2 years. To my knowledge, this is the first report of its kind. This study, like other studies from Europe, Asia, and India, shows that CXL with riboflavin is effective in stopping the progression of keratoconus by 'freezing' the cornea [3],[9],[11],[12].

The standard CXL protocol is the first conservative treatment that successfully halts the progression of keratoconus and postoperative corneal ectasia in most cases. CXL has been in use for more than a decade with a low complication rate. A good safety profile has been documented [7]. The success of cross-linking treatment in keratoconus is not surprising because a significantly reduced tensile strength has been measured biomechanically in keratoconus [5].

This study showed that the postoperative change in the keratometry at the apex of the cone (K apex) showed a mean decrease of 2.73 D at 6 months and continued reduce at 24 months. Currently available published and unpublished data have shown that CXL is significantly safer than corneal transplantation, the ultimate alternative for advanced ectatic corneal disease not amenable to less invasive therapies. In fact, there is a good likelihood that CXL will become the standard of care for the treatment of keratoconus and ectasia after refractive surgery [1].

Raiskup-Wolf et al. [11], who followed up patients up to 6 years and reported on a larger cohort of patients, concluded that the improvement in vision after cross-linking is caused by a decrease in astigmatism and corneal curvature as well as by topographical homogenization of the cornea as a result of the increased rigidity in the cross-linked cornea. In addition, the fitting of contact lenses is improved. This leads to an increase in both the unaided visual acuity and BCVA through improvement in corneal symmetry indices after cross-linking [11].

As with all surgical procedures, patient selection is critical to enhance success. On the basis of current knowledge and treatment efficacy, to justify a treatment where the main goal is to halt progression, CXL in adults should be reserved for patients with progressive ectatic disorders with documented progression [1].

Furthermore, Caporossi et al. [9] reported in human eyes that refractive results showed a reduction of about 2.5 D in the mean spherical equivalent, topographically confirmed by the reduction in mean K. Results of surface aberrometric analysis showed an improvement in morphologic symmetry with a significant reduction in coma aberrations [9].

Another possible explanation for cross-linking success, especially in terms of keratoconus stabilization, is the new more compact collagen lamellar structure after corneal cross-linking as reported in recent studies by Wollensak and Redl [13] and Mazzotta et al. [14]. It is important to note that in this cohort of patients, we did not encounter any complications.

Raiskup-Wolf et al. [11] had two patients in their series who needed repeat treatment with cross-linking. However, these patients had acute exacerbation of neurodermatitis. They also reported the longest series of patients followed from three to 6 years after treatment. Thus, it is important to cross-link corneas with progressive keratoconus as early as possible. In 2007, Chan et al. [15] reported the possibility of combining the cross-linking procedure with procedures such as intracorneal ring implantation and topography-guided photorefractive keratectomy.

This study showed that in most cases, there was no remarkable improvement in corneal astigmatism whereas the basic improvement was in a decrease in corneal curvature and a decrease in the myopic element of keratoconus. This may be because of the fact that corneal cross-linking affects all meridians symmetrically. In contrast to other studies, [11],[16], we observed no remarkable improvement in corneal astigmatism. In addition, most patients had regular astigmatism and not irregular astigmatism. This may be attributed to strict patient selection according to keratoconus grade I and II with corneal pachymetry of 400 μm or more.

The results in this study led the author to formulate the following hypothesis:

The CXL leads to corneal rigidity, which usually affects the anterior 200-300 μm [4],[17],[18] of the cornea. However, the central corneal thickness decreases, whereas the peripheral corneal thickness increases, which raises many questions.

This hypothesis (CXL Hammered Cornea Hypothesis) explains that the central cornea is under two antagonistic forces:

(1) Pull-back force (posterior force):

This force pulls the central cornea backwards (posteriorly) by the action of increased peripheral corneal rigidity and thickness, leading to decreased corneal curvature (K readings), thus improving the visual acuity.

(2) Push-forward force (anterior force):

This force pushes the central cornea forwards (anteriorly) by the action of intraocular pressure (IOP), which is most at the central cornea representing the mean IOP vector from the anterior capsule of the crystalline lens directed toward the posterior corneal surface. This leads to maximal accumulation of aqueous, with the forward direction of aqueous currents placing continuous pressure on the posterior corneal surface.

The final result of these two forces is that the posterior corneal surface is inbetween two hammers:

  1. Rigidity of the anterior cornea with continuous pulling-back force of the peripheral thickened cornea.
  2. Continuous pushing-forward force of IOP.


Thus, thinning of central cornea mainly occurs in the central posterior cornea.

This study showed that in most cases, there was no remarkable improvement in the corneal astigmatism whereas the basic improvement was a decrease in corneal curvature, thus decreasing the myopic element of keratoconus. This may be because of the fact that corneal cross-linking affects all meridians symmetrically.

Another hypothesis (CXL Optical Gain Hypothesis) derived from this study that needs to be proved or refuted by further studies is as follows:

The optical effect after CXL is a decrease in the K readings resulting from:

  1. Decrease in corneal curvature leads to an increase in the radius of curvature and a decrease in the K readings.
  2. Decreased central corneal thickness results in a decrease in the refractive index of the cornea (bulk loss), leading to a decrease in K readings.


This combined optical effects of the CXL resulted in a marked decrease in myopia of up to 4 Din this study.


  Conclusion Top


This study proved that corneal cross-linking is beneficial both as a visual-preserving and as a visual-improving procedure. K readings are the main indicator of the success or the failure of the procedure. Central corneal thickness can be an indicator of improvement; there is a reciprocal relationship between the central corneal thickness and the BCVA. The best chance is for patients with corneal thickness more than 400 μm. It is advised that the refractive surgeon should store the riboflavin in the refrigerator from +4°C to +8°C and discard it immediately after surgery. The use of steroid from the first postoperative day was helpful. Most of the postoperative visual improvement resulted from a decrease in myopia, whereas there was no remarkable improvement in astigmatism.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Hafezi F, Bradley J, Doyle R. Corneal collagen cross-linking. SLACK Incorporated 2013; 5 :41-44.  Back to cited text no. 1
    
2.
Hafezi F, Bradley J, Kohlhaas M. Corneal collagen cross-linking. SLACK Incorporated 2013; 10 :67-73.  Back to cited text no. 2
    
3.
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. 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.
Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res 1980; 31 :435-441.  Back to cited text no. 5
[PUBMED]    
6.
Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg 2003; 29 :1780-1785.  Back to cited text no. 6
    
7.
Spoerl E, Mrochen M, Sliney D, et al. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007; 26 :385-389.  Back to cited text no. 7
    
8.
Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998; 42 :297-319.  Back to cited text no. 8
    
9.
Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study. J Cataract Refract Surg 2006; 32 :837-845.  Back to cited text no. 9
    
10.
Kymes SM, Walline JJ, Zadnik K, Gordon MO. Quality of life in keratoconus: The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study Group. Am J Ophthalmol 2004; 138 :527-535.  Back to cited text no. 10
    
11.
Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen cross-linking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cat Refract Surg 2008; 34 :796-801.  Back to cited text no. 11
    
12.
Saini JS, Saroha V, Singh P, Sukhija JS, Jain AK. Keratoconus in Asian eyes at a tertiary eye care facility. Clin Exp Optom 2004; 87 : 97-101.  Back to cited text no. 12
    
13.
Wollensak G, Redl B. Gel eletrophoretic analysis of corneal collagen after photodynamic cross-linking treatment. Cornea 2008; 27 :353-356.  Back to cited text no. 13
    
14.
Mazzotta C, Traversi C, Baiocchi S, Caporossi O, Bovone C, Sparano MC, et al. Corneal healing after riboflavin ultraviolet-A collagen cross-linking determined by confocal laser scanning microscopy in vivo: early and late modifications. Am J Ophthalmol 2008; 146 : 527-533.  Back to cited text no. 14
    
15.
Chan CC, Sharma M, Wachler BS. Effect of inferior-segment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg 2007; 33 :75-80.  Back to cited text no. 15
    
16.
Agrawal VB. Corneal collagen cross-linking with riboflavin and ultraviolet - a light for keratoconus: results in Indian eyes. Indian J Ophthalmol 2009; 57 :111-114.  Back to cited text no. 16
    
17.
Kasper M, Sporl E, Huhle M, et al. Artificial stiffening of the cornea by induction of intrastromal cross-links. Ophthalmologe 1997; 94 :902-906.  Back to cited text no. 17
    
18.
Kohlhaas M, Spoerl E, Schilde T, Unger G, Wittig C, Pillunat LE. 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. 18
    


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