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ORIGINAL ARTICLE
Year : 2019  |  Volume : 20  |  Issue : 2  |  Page : 47-54

Evaluation of corneal and lens density changes after cross-linking in keratoconus


Department of Ophthalmology, Menoufia University, Shebin El-Kom, Menoufia Governorate, Egypt

Date of Submission22-Oct-2018
Date of Acceptance25-Dec-2018
Date of Web Publication24-Jul-2019

Correspondence Address:
Lamyaa S Soliman
Department of Ophthalmology, Menoufia University, Shebin El-Kom 32511, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/DJO.DJO_53_18

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  Abstract 


Background Corneal cross-linking (CXL) is an important modality for keratoconus therapy. Lens and corneal density are reported to change in keratoconus and with CXL. However, these changes are not well studied.
Aim The aim of this study was to evaluate the changes in corneal and lens density in patients with keratoconus after corneal CXL.
Patients and methods This is a prospective case series study that was conducted in a private Eye Laser Center, Menoufia Governorate, Egypt. The study consisted of patients with bilateral clinical keratoconus whose age ranging between 15 and 40 years with clear lenses. Bilateral minimum corneal thickness of 400 µm, measured with Pentacam, was essential. All study patients were examined preoperatively and 1, 3, and 6 months postoperatively. Ophthalmic examination included uncorrected distance visual acuity, corrected distance visual acuity, and manifest refraction as well as corneal thickness, thinnest location, maximal keratometric reading (Kmax), and corneal and lens densitometry measured by Pentacam.
Results The preoperative mean corneal density on the axis 0–180 was 17.3±1.8, which changed to 20.7±2.01 after 6 months postoperatively (P=0.001). Although the preoperative mean corneal density on the axis of 90–270 was 17.4±2.06, it changed to 19.9±2.4 after 6 months postoperatively (P=0.04). No significant changes were encountered in lens density after CXL.
Conclusion Corneal CXL significantly increased the corneal but not the lens density. This increase was maximal after 1 month and gradually returned toward the baseline. CXL is considered as a safe procedure for the lens.

Keywords: corneal density, cross-linking, keratoconus, lens density


How to cite this article:
Soliman LS, Abdel-Aziz MS, Zaky MA, Marey HM. Evaluation of corneal and lens density changes after cross-linking in keratoconus. Delta J Ophthalmol 2019;20:47-54

How to cite this URL:
Soliman LS, Abdel-Aziz MS, Zaky MA, Marey HM. Evaluation of corneal and lens density changes after cross-linking in keratoconus. Delta J Ophthalmol [serial online] 2019 [cited 2019 Sep 23];20:47-54. Available from: http://www.djo.eg.net/text.asp?2019/20/2/47/263413




  Introduction Top


Keratoconus (KC) is a bilateral, progressive, noninflammatory disease of the cornea which often leads to high myopia and astigmatism, with an estimated prevalence of approximately one in 2000 and an incidence between 50 and 230 per 100 000 per year. It is a multifactorial disease with an unknown exact etiology which impairs the acuity and quality of vision secondary to thinning in and protrusion of the cornea that ultimately affects both eyes [1].

In its early stages, KC can be managed conservatively via spectacles or rigid contact lenses. In more advanced stages, surgical treatment with deep lamellar keratoplasty and penetrating keratoplasty should be considered. However, potential complications and technical needs run the race for an alternative [2],[3].

Corneal collagen cross-linking (CXL) is a relatively new technique to decrease the progression of KC and other corneal ectatic disorders such as post-laser in-situ keratomileusis ectasia [4]. CXL decreases corneal steepness and improves topographic indices, thus leading to improvement in uncorrected and best-corrected visual acuities, as the cornea is exposed to ultraviolet-A (UVA) after riboflavin (vitamin B2) is administered topically. The result of the exposure is the formation of free oxygen radicals that cause mechanical stiffness of the corneal stroma owing to the formation of chemical bonds within the stroma. The resulting compaction of the collagen lamellae leads to thinning of the cornea [5].

Corneal stromal haze is common after CXL. This is related to the corneal stromal changes occurring after CXL. This can be detected clinically and graded subjectively at the slit lamp, or measured objectively using Scheimpflug imaging densitometry [6].

The aim of this study was to assess the changes in corneal and lens density after CXL in patients with KC.


  Patients and methods Top


This was a prospective case series study including all patients with KC undergoing CXL. All study procedures were carried out and approved by the Ethical Committee of Menoufia Faculty of Medicine and in accordance with the declaration of Helsinki. Participant’s names were kept on a password-protected database and linked only with a study identification number for this research. All participants in this study received a detailed explanation about the aim, objectives, and methodology of the study before enrollment. The principal investigator was responsible for obtaining the participants’ approval and written informed consent.

Patients with clinical bilateral KC whose age ranged between 15 and 40 years with clear lenses were included in the study. Bilateral minimum corneal thickness of 400 µm, measured by Pentacam (WaveLight Oculyzer; WaveLight GmbH, Erlangen, Germany), was essential for inclusion in the study. Maximum keratometry of 60 D in each eye was required. Any patient with ocular surface disorders or any other eye pathology other than KC was excluded.

All study patients were examined preoperatively and 1, 3 and 6 months postoperatively. Ophthalmic examination included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA) in decimal units, and manifest refraction in diopters (D). Corneal thickness and thinnest location in micrometers as well as maximal keratometric reading (Kmax) and corneal and lens densitometry were measured with Pentacam. The Pentacam Scheimpflug system (WaveLight Oculyzer; WaveLight GmbH, Erlangen, Germany) was used before and after the procedure to measure objectively the corneal and lens densitometry values. The Scheimpflug system quantifies the density of the cornea and the lens on a scale from 0 to 100. Peak densitometry values were at the nearest axis 90–270 and its perpendicular axis 0–180.

Corneal CXL procedure was carried out by the same surgeon (M.S.A.) to minimize bias. The procedure began by instilling a topical anesthetic agent. The epithelium was mechanically scraped within the central 7.0-mm diameter area. Riboflavin (0.1% solution, 10 mg riboflavin 5-phosphate; Medio-Haus Medizinprodukte GmbH, Neudorf, Germany) in 10 ml dextran 20% solution was applied every 3 min for 30 min until the stroma was completely saturated and aqueous was stained yellow. UVA irradiation was performed using UVA system (CCL-365 vario; Peschke Meditrade GmbH, Zurich, Switzerland), giving surface irradiance of 5.4 J/cm2 surface dose after 10 min. During treatment, riboflavin solution was applied every 3 min to ensure saturation, and a balanced salt solution was applied every 5 min to moisten the cornea. At the end of the procedure, a drop of topical antibiotic was instilled, and a bandage contact lens was applied.


  Results Top


Thirty-six eyes of 18 patients were included, comprising six males and 12 females. The mean age was 24.4±3.9 years ([Table 1]).
Table 1 Demographic features of the study population

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The mean UDVA and CDVA (decimal units) preoperatively were 0.4±0.1 and 0.5±0.006, respectively. It changed after 1 month postoperatively to 0.35±0.2 and 0.4±0.1, respectively (P=0.5 and 0.6, respectively); after 3 months to 0.38±0.2 and 0.55±0.1, respectively (P=0.3 and 0.2, respectively); and after 6 months to 0.45±0.3 and 0.6±0.2, respectively (P=0.1). The preoperative mean spherical equivalent was −5.75±0.7 D and changed to −6.25±1.1 D after 1 month postoperatively (P=0.3), to −5.8±0.4 D after 3 months postoperatively (P=0.3), and to −5.5±0.6 D after 6 months, postoperatively (P=0.4). [Table 2] shows the mean UDVA, CDVA, and spherical equivalent at 1, 3, and 6 months postoperatively.
Table 2 Absolute values of preoperative and postoperative outcomes

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The preoperative mean Kmax was 50.2±2.01 D and changed to 48.7±1.8 D after 1 month, postoperatively (P=0.001), to 49.5±1.9 D after 3 months postoperatively (P=0.001), and to 50.1±1.9 D after 6 months postoperatively (P=0.2). [Table 2] shows the mean Kmax at 1, 3, and 6 months after CXL.

The preoperative mean corneal thinnest location thickness was 466±23.8 μm and decreased to 426.5±20.7 μm after 1 month postoperatively (P=0.001), to 446.1±16.2 μm after 3 months postoperatively (P=0.01), and to 462±15.6 μm after 6 months postoperatively (P=0.3). [Table 2] and [Figure 1] shows the mean corneal thinnest location thickness at 1, 3, and 6 months after CXL.
Figure 1 Thinnest location change from baseline.

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The preoperative mean corneal density on the axis 0–180 was 17.3±1.8 and changed to 26.9±2.6 after 1 month postoperatively (P=0.001), to 22.6±2.3 after 3 months postoperatively (P=0.001), and became 20.7±2.01 after 6 months postoperatively (P=0.001). The preoperative mean corneal density on the axis 90–270 was 17.4±2.06 and changed to 28.9±3.1 after 1 month postoperatively (P=0.001), to 22.6±2.4 after 3 months postoperatively (P=0.001) and became 19.9±2.4 after 6 months postoperatively (P=0.04). [Figure 2] and [Table 2] show the mean corneal density at 1, 3, and 6 months after CXL.
Figure 2 Changes in corneal density over the study duration.

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The preoperative mean lens density on the axis 0–180 was 12.9±2.3 and became 12.9±2.3 after 1 month postoperatively (P=0.7), and 13±2.4 after 3 months postoperatively (P=0.4), and became 13.2±2.4 after 6 months postoperatively (P=0.8). The preoperative mean lens density on the axis 90–270 was 13.2±2.3 and changed to 13.6±2.3 after 1 month postoperatively (P=0.03), to 13.6±2.6 after 3 months postoperatively (P=0.2), and became 13.1±2.3 after 6 months postoperatively (P=0.8). [Figure 3] and [Table 2] show the mean lens density at 1, 3, and 6 months after CXL.
Figure 3 Mean lens density.

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Pearson’s correlation was conducted between thinnest location and Kmax as well as corneal and lens density. No significant correlations were encountered between the study variables. [Table 3] illustrates the correlation for all these variables. To extend the reliability of obtained results, the value of the change from baseline was calculated for each variable. At 6 months, Kmax has been reduced with a mean value of −0.1 D, whereas the thinnest location has decreased with a value of 20 μm. Corneal density has increased with a mean value of 3.3 and 2.6 at 180° and 90°, respectively, at 6 months. The lens density has also increased with 0.3 at 180° whereas it has decreased by −0.1 at axis of 90°. [Table 4] illustrates all values of change from baseline to 1, 3, and 6 months postoperatively. [Figure 4] and [Figure 5] demonstrate the change in corneal and lens density, respectively.
Table 3 Pearson’s correlation for all variables

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Table 4 Changes of postoperative values at 1, 3, and 6 months from baseline

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Figure 4 Change value in corneal density from baseline.

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Figure 5 Change value in lens density from baseline.

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  Discussion Top


Transient corneal haze is a common adverse effect of corneal CXL. This reaction is related to the healing process after treatment and is commonly graded subjectively by slit-lamp examination, which may not detect mild changes between follow-up visits. This is considered a transient consequence of the histological changes induced by the alteration of the CXL structure of the stroma [7]. Moreover, Raiskup et al. [7] reported a greater tendency toward stromal haze in patients with more advanced KC.

Haze formation is a concern after CXL, as it can potentially limit the benefits of the treatment by diminishing the transparency of the cornea, thus limiting the potential visual acuity achievable by means of subsequent treatments or contact lens fitting [7],[8].

Several studies tried to explain the possible changes and mechanisms leading to corneal CXL-associated haze. Mazzotta et al. [9] investigated corneal ultrastructural changes in KC eyes undergoing CXL using in-vivo confocal microscopy. They found that the corneal stroma was invaded by activated keratocytes that have alterations in their crystalline proteins, leading to an increased scattering of light and a possible increase in the haze [9]. Wollensak et al. [10] described an increase in the spacing between stromal collagen fibrils and an increase in the individual fibril diameter after CXL. This is another possible factor that can lead to postoperative corneal haze.

In this study, there was a significant reduction in central corneal thickness at 1 month postoperatively coinciding with the maximum corneal haze. This was followed by a gradual return to a near baseline level coinciding with the decrease of haze. These concomitant changes in central corneal thickness and corneal haze support a suggestion that changes in corneal stromal lamellar spacing and arrangement (compactness of the corneal stroma) may increase light scattering, thus leading to corneal haze.

Regarding the thinnest location, the mean thickness decreased markedly at 1 month postoperatively by 39.5 μm. It increased gradually to reach a near baseline level at 6 months postoperatively. This corneal thinning was correlated inversely with corneal densitometry values at 1 month (r=−0.25). This is in agreement with a previous report on transient thinning of the cornea with ultrasound pachymetry after CXL treatment [11]. Changes in the corneal thickness seem to reflect a compactness of the corneal stroma. This corneal thinning was correlated inversely with corneal densitometry values at 1 month (r=−0.65). In addition, CDVA was correlated inversely with corneal densitometry at 1 month (r=−0.72). Similarly, it was reported by Helaly and Osman [12] that the mean corneal thickness decreased markedly at 1 month postoperatively by 51 μm. It increased gradually to reach a near baseline level at 12 months postoperatively.

Regarding corneal densitometry, there was a significant increase in the corneal stromal haze, peaking at 1 month postoperatively. Then, there was a gradual reduction of the corneal haze as measured objectively using Pentacam densitometry. At 6 months postoperatively, the values of corneal densitometry did not reach the baseline levels. The mean corneal densitometry remained higher than the baseline level, with an increase of 2.5. Our findings are consistent with those found in the KC subgroup of the study conducted by Greenstein et al. [11], where the baseline mean corneal densitometry was 14.60±2.10. There was a statistically significant increase in the mean densitometry between baseline and 1 month (22.9±4.7). Then, it was followed by decreased corneal densitometry at 3, 6, and 12 months. They reported that despite the fact that the mean densitometry decreased significantly between 6 and 12 months postoperatively, it remained elevated compared with baseline values (P<0.001). This course of increased postoperative haze at 1 month was followed by a gradual decrease; however, it did not return to the baseline level at 1 year [11]. This was similar to what was reported by Gutiérrez et al. [13] in their study, despite the fact that they reported higher corneal densitometry values. This may be attributed to the higher baseline corneal stromal haze in their series resulting from more advanced KC. Clinical evaluation of the stromal haze followed a similar course, peaking at 1 month postoperatively, and then decreasing gradually. At 12 months postoperatively, it was higher than the baseline level (0.62±0.55 vs. 0.31±0.70), with an increase of 0.31 (P<0.001). This course also agreed with that reported by Helaly and Osman [12], where the mean Scheimpflug corneal densitometry at baseline was 16.30±1.90. At 1 month postoperatively, the corneal densitometry increased to 28.81±4.33. At 1 month, there was a statistically significant increase in the clinical haze by 1.40 (P<0.001). Between 6 and 12 months postoperatively, there was a decrease in the corneal densitometry values by 4.78, which was statistically significant (P<0.001). At 12 months postoperatively, the corneal densitometry did not return to baseline levels [12]. It is worth mentioning that in this study, Scheimpflug imaging detected corneal densitometry changes in cases with absent clinical haze.

Regarding lens densitometry, in this study, we found that exposure of the crystalline lens to UVA and triplet state of riboflavin during CXL did not significantly affect lens density measured with a Scheimpflug camera. The mean of the preoperative lens density was 13.05, whereas the mean value after 6 months was 13.1, with a statistically insignificant difference. This is in accordance with the results of a study performed by Vinciguerra et al. [14] who studied 12 eyes with a 36-month follow-up and evaluated a 1.2-mm-diameter cylindrical-shaped central section of the lens. The authors did not find any deterioration of the crystalline lens transparency or permanent negative adverse effects on the cornea and endothelium. Grewal et al. [5] also reported no change in crystalline lens density 12 months after CXL in 102 patients. Another study showed that there was a noticeable difference in the mean lens density as reported by Baradaran-Rafii et al. [15], where the mean lens density in the CXL group was 6.68±0.58% at baseline and 6.77±0.53% at the last visit (P=0.352). The corresponding values of the control group were 6.53±0.27 and 6.39±0.31%, respectively (P=0.213). However, there was no significant difference between the study groups at baseline or 6 months later (P=0.96).

One more point to discuss is the axis of density to be measured. Almost all prior studies evaluated corneal and lens density using the steepest meridian. In this study, density was evaluated at the two main axes: 0–180 and 90–270. We hypothesize that such method is more reliable to evaluate the changes in the whole cornea and/or lens rather than to rely on one meridian. This may partially explain the discrepancy between our results and other studies.

This noticeable difference in the mean density values may be explained by the inherent variations encountered with age, sex, and race as well as different method of examination. To expand this point, Baradaran-Rafii et al. [15] evaluated the density of the anterior capsule and anterior cortex of the lens, as these areas are more prone to riboflavin-free radicals and UVA irradiation during CXL, whereas this study considered the peak or the maximal densitometry values aiming to highlight how CXL may affect the density values of the whole lens.

In summary, we observed no signs of cataractogenesis or any change in the mean lens density following epi-off CXL for progressive KC with short-term follow-up using Pentacam. According to in-vitro studies, although there may be some oxidative stress in the crystalline lens during CXL, it may not be significant enough to be measured by a Scheimpflug camera.


  Conclusion Top


Corneal CXL significantly increased the corneal but not the lens density. This increase was maximal after 1 month and then gradually returned toward the baseline. CXL is considered as a safe procedure for the lens. However, longer follow-up is required for better assessment of the long-term safety.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sinjab M. Quick guide to the management of keratoconus. Berlin, Germany: Springer Science & Business Media; 2012. pp. 118–120.  Back to cited text no. 1
    
2.
Arnalich-Montiel F, Alió Del Barrio JL, Alió JL. Corneal surgery in keratoconus: which type, which technique, which outcomes? Eye Vis 2016; 3:2–14.  Back to cited text no. 2
    
3.
Keane M, Coster D, Ziaei M, Williams K. Deep anterior lamellar keratoplasty versus penetrating keratoplasty for treating keratoconus. Cochrane Database Syst Rev 2014; 7:CD009700.  Back to cited text no. 3
    
4.
Koller T, Pajic B, Vinciguerra P, Seiler T. Flattening of the cornea after collagen crosslinking for keratoconus. J Cataract Refract Surg 2011; 37:1488–1492.  Back to cited text no. 4
    
5.
Grewal DS, Brar GS, Jain R, Sood V, Singla M, Grewal SPS. Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus. J Cataract Refract Surg 2009; 35:425–432.  Back to cited text no. 5
    
6.
Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg 2010; 36:2105–2114.  Back to cited text no. 6
    
7.
Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg 2009; 25:S824–S828.  Back to cited text no. 7
    
8.
Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg 2009; 25:S812–S818.  Back to cited text no. 8
    
9.
Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation. Clin Experiment Ophthalmol 2007; 35:580–582.  Back to cited text no. 9
    
10.
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. 10
    
11.
Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg 2011; 37:691–700.  Back to cited text no. 11
    
12.
Helaly H, Osman I. Corneal and lens densitometry after corneal collagen cross-linking for keratoconus. J Egypt Ophthalmol Soc 2014; 107:248–252.  Back to cited text no. 12
  [Full text]  
13.
Gutiérrez R, Lopez I, Villa-Collar C, González-Méijome JM. Corneal transparency after cross-linking for keratoconus: 1-year follow-up. J Refract Surg 2012; 28:781–786.  Back to cited text no. 13
    
14.
Vinciguerra P, Camesasca FI, Romano MR. Corneal crosslinking and lens opacity. Ophthalmology 2011; 118:2519.e1–2591.e2.  Back to cited text no. 14
    
15.
Baradaran-Rafii A, Amiri M, Mohaghegh S, Zarei-Ghanavati M. Lens densitometry after corneal cross-linking in patients with keratoconus using a Scheimpflug camera. J Ophthalmic Vis Res 2015; 10:118–122.  Back to cited text no. 15
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