Menoufia Medical Journal

ORIGINAL ARTICLE
Year
: 2016  |  Volume : 29  |  Issue : 3  |  Page : 616--622

Evaluation of combined corneal cross-linking with LASIK in risky patients


Abdel Rahman E Sarhan1, Ghada Z Elabedin1, Wesam S Elsayed2,  
1 Ophthalmology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Al-Fardous Eye and Dental Hospital, Zagazig, Egypt

Correspondence Address:
Wesam S Elsayed
Zagazig, Sharkia, 44511
Egypt

Abstract

Objective The aim of this study was to evaluate the efficacy and safety of ultraviolet A irradiation cross-linking on completion of laser-assisted in-situ keratomileusis (LASIK) in risky patients to avoid post-LASIK ectasia. Background Patients with thinner-than-normal corneas, irregular corneal astigmatism, asymmetry on corneal topography, against-the-rule astigmatism, or steeper-than-normal corneas have higher risk of development of post-LASIK ectasia which need improvement in surgical interference. Materials and methods Forty-eight eyes of 30 myopic patients presented for LASIK at Al-Fardous Eye and Dental Hospital, Zagazig, Egypt, between September 2013 and August 2014. The study group comprised risky patients with corneal thickness of at least 480 μm and postoperative residual stromal thickness of at least 300 μm. After reflecting the flap, 0.1% riboflavin sodium phosphate solution was applied on the bare stromal bed and left to be soaked in for 60 s, and then the patient was positioned with the ultraviolet light (typically 365-370 μm). Results The study proved that there was an improvement in mean spherical error from −4.05 ± 1.19 preoperatively to −0.98 ± 0.12 on the second day postoperatively, and it improved to −0.59 ± 0.49, −0.49 ± 0.39, and −0.39 ± 0.36 at 1, 3, and 6 months postoperatively, respectively. These results showed a statistically highly significant difference (P < 0.001). Visual acuity improved from 0.828 ± 0.33 best-corrected visual acuity preoperatively to 0.881 ± 0.11, 0.894 ± 0.21, 0.9 ± 0.22, and 0.913 ± 0.22 at second day postoperatively, and 1, 3, and 6 months postoperatively, respectively. However, the improvement did not show a statistically significant difference (P > 0.05) because we compared the results with the preoperative best-corrected visual acuity. Conclusion Application of riboflavin with ultraviolet after LASIK in risky patients improves refractive errors (spherical and cylindrical errors) and prevents post-LASIK corneal ectasia.



How to cite this article:
Sarhan AE, Elabedin GZ, Elsayed WS. Evaluation of combined corneal cross-linking with LASIK in risky patients.Menoufia Med J 2016;29:616-622


How to cite this URL:
Sarhan AE, Elabedin GZ, Elsayed WS. Evaluation of combined corneal cross-linking with LASIK in risky patients. Menoufia Med J [serial online] 2016 [cited 2020 Apr 10 ];29:616-622
Available from: http://www.mmj.eg.net/text.asp?2016/29/3/616/198742


Full Text

 Introduction



Corneal ectasia is a serious vision-threatening complication of laser-assisted in-situ keratomileusis (LASIK) [1] . It is associated with progressive corneal steepening, an increase in myopia and astigmatism, and a decrease in uncorrected visual acuity. These cases can be managed with lamellar or penetrating keratoplasty that involves surgical removal of diseased or damaged cornea from the host and replacement with a full-thickness donor cornea; however, minimally invasive techniques are also possible [2] . These options include rigid gas-permeable contact lenses, intrastromal corneal ring segments (Intacs) [3] , and corneal cross-linking with ultraviolet radiation and riboflavin treatment [4] .

Corneal collagen cross-linking (CXL) based on the combined use of the photosensitizer riboflavin and ultraviolet A (UVA) light of 370 nm was introduced by Wollensak et al. [5] from Germany. CXL is the only available treatment directed at the underlying pathology in keratoconic cornea, which stromal biomechanical and structural instability is leading to progressive ectasia. Cross-linking of collagen refers to the ability of collagen fibrils to form strong chemical bonds with adjacent fibrils creating an increase in the biomechanical rigidity of human cornea by about 300%. The cross-linking effect is maximal only in the anterior stroma. CXL is currently under investigation to determine whether it can slow, stabilize, or even possibly reverse the progression of corneal ectasia in patients with keratoconus [6] .

For prophylactic use, virtually any patient can be treated with cross-linking to reduce the chance of future development of post-LASIK ectasia, especially patients with thinner-than-normal corneas, irregular corneal astigmatism, asymmetry on corneal topography, against-the-rule astigmatism, or steeper-than-normal corneas [5] .

The aim of this work was to evaluate the efficacy and safety of UVA irradiation cross-linking on completion of LASIK in risky patients to avoid post-LASIK ectasia.

 Materials and methods



After written consent was obtained, 48 eyes of 30 LASIK patients were recruited in the study. Their ages ranged from 18 to 38 years. They had myopia of less than −10.00 D, with or without myopic astigmatism. They had low corneal thickness greater than 480 μm with enough residual stromal thickness not less than 300 μm.

Preoperative assessment

All patients were subjected to uncorrected visual acuity evaluation, determination of best-corrected visual acuity (BCVA) with cycloplegic refraction, keratometry, corneal topography, pachymetry using pentacam, slit-lamp biomicroscopy, and fundus examination.

Operative procedure

After patients' preparation, all procedures were performed on Schwind Amaris system (SCHWIND eye-tech-solutions, Kleinostheim, Germany), markings were made on corneal edge, and a suction ring was placed to minimize decentration. Thereafter, a 90 μm LASIK flap was created with mechanical microkeratome. LASIK ablation was then applied. Afterward, a drop of 0.1% riboflavin sodium phosphate solution was placed on the bare stromal bed and left to be soaked in for 60 s. Special care was taken not to allow the riboflavin solution to come into contact with the already folded LASIK flap. After the 60-s riboflavin soak, the LASIK flap was reflected into place, copiously irrigated, following flap repositioning, the surface was kept moist with a drop of ofloxacin solution, and irradiated with 3 mW/cm 2 ultraviolet light of average wavelength 370 nm, for 15 min. A bandage contact lens was placed on the ocular surface and removed the next day.

Postoperative assessment

All patients were subjected to the following on the next postoperative day, and 1, 3, and 6 months postoperatively: visual acuity, refraction, slit-lamp examination, and pentacam (keratometry, corneal topography, and pachymetry).

 Results



This study was performed on 48 eyes of 30 myopic patients during the period from September 2013 to August 2014. The age of the studied group ranged between 21 and 36 years, with a mean of 24.9 years. As regards sex, more than half of them were female (60%). About two-third of cases had affection in both eyes (60%). The spherical error of cases ranged from −1.75 to −7.0 D (mean = −4.05 D) and cylinder error ranged between −0.5 and −2.5 D (mean=−1.297 D); corneal thickness ranged between 480 and 547 μm (mean = 498.2 μm) and posterior elevation ranged between 0 and 13 (mean = 5.625). K1 and K2 ranged between 40 and 46 and between 41 and 49, with a mean of 42.9 and 44.4, respectively. Finally, visual acuity ranged from 0.05 to 1, with a mean of 0.84 ([Table 1]).{Table 1}

In this study, there were statistically significant differences between preoperative findings and findings after 1, 3, and 6 months postoperatively in spherical error, cylinder error, corneal thickness, and K1 and K2 , but there were no statistically significant differences in both posterior elevation and visual acuity (P > 0.05) ([Figure 1] and [Figure 2],).{Figure 1}{Figure 2}

There was an improvement in mean spherical error from −4.05 ± 1.19 preoperatively to −0.98 ± 0.12 on the second day postoperatively and it improved to −0.59 ± 0.49, −0.49 ± 0.39, and −0.39 ± 0.36 at 1, 3, and 6 months postoperatively, respectively. These results showed a statistically highly significant difference (P < 0.001). There was also improvement in the cylindrical error from −1.3 ± 0.8 preoperatively to −0.9 ± 0.23 on the second day postoperatively, and it improved to −0.75 ± 0.32, −0.67 ± 0.33, and −0.7 ± 0.22 at 1, 3, and 6 months postoperatively. These results showed a statistically highly significant difference (P < 0.001). The study also showed improvement in visual acuity from 0.828 ± 0.33 BCVA preoperatively to 0.881 ± 0.11, 0.894 ± 0.21, 0.9 ± 0.22, and 0.913 ± 0.22 on second day and 1, 3, and 6 months postoperatively, respectively. However, the improvement did not show a statistically significant difference (P > 0.05) because we compared the results with the preoperative BCVA ([Figure 3]). This study also found that K1 decreased from 42.91 ± 2.01 D preoperatively to 39.65 ± 2.91 D on the second day, and then the operation flattened to 39.61 ± 2.74, 39.65 ± 2.73, and 39.48 ± 2.68 D at 1, 3, and 6 months postoperatively, respectively, and preoperative K2 was 44.37 ± 2.29 D and flattened to 41.06 ± 3.22, 40.56 ± 3.12, 40.54 ± 2.82, and 40.43 ± 2.78 D on the second day, and 1, 3, and 6 months postoperatively, respectively. This result showed a mean flattening of the cornea on the second postoperative day of 3.26 D and a mean flattening of 3.43 D at the end of the follow-up period ([Figure 4]). The study showed a statistically highly significant difference (P < 0.001). There was also evidence of a reduction in posterior elevation from 5.625 ± 4.76 μm preoperatively to 4.925 ± 6.73, 4.375 ± 6.73, 5.438 ± 4.82, and 4.813 ± 4.97 μm on the second day, 1 month, 3 months, and 6 months postoperatively, respectively ([Figure 5]). The study did not show a statistically significant difference (P < 0.55). The corneal thickness showed a reduction from 498.19 ± 15.1 μm preoperatively to 439.9 ± 15.9, 428.1 ± 27.4, 428.2 ± 27.4, and 434.2 ± 4.97 μm on the second day, 1 month, 3 months, and 6 months, postoperatively, respectively ([Figure 6]). The study showed a statistically highly significant difference (P < 0.001) ([Table 2]).{Figure 3}{Figure 4}{Figure 5}{Figure 6}{Table 2}

 Discussion



In 2012, the results of a year's follow-up following simultaneous CXL with topography-guided Photo Refractive Keratectomy (PRK), including 22 eyes of 15 patients with low-grade keratoconus, demonstrated that this protocol appeared safe and efficient, with safety and efficacy indices of 1.6 and 0.4, respectively [7] .

The objective of this study was to evaluate the efficacy and safety of UVA irradiation cross-linking on completion of LASIK in risky patients to avoid post-LASIK ectasia. We hope that more patients with visual impairment due to the corneal ecstatic disorders can benefit from it.

Patients in our study had an age range from 21 to 36 years, with a mean ± SD of 24.9 ± 4.9 years. This is similar to other studies such as that of Kanellopoulos et al. [8] , who selected patients with range from 19 to 39 years, with a mean of 27.5 ± 6.1 years. However, their preoperative central corneal thickness ranged from 474 to 595 μm with a mean of 545.96 ± 33.93 μm, whereas our patients' corneal thickness ranged from 480 to 547 μm, with a mean of 498.19 ± 15.14 μm.

In this study, we carried out LASIK correction of myopic patients with the application of CXL in the protocol mentioned before in patients and methods. The study proved that there was an improvement in mean spherical error from −4.05 ± 1.19 preoperatively to −0.98 ± 0.12 on the second day postoperatively and it improved to −0.59 ± 0.49, −0.49 ± 0.39, and −0.39 ± 0.36 at 1, 3, and 6 months postoperatively, respectively. These results showed a statistically highly significant difference (P < 0.001).

There was also improvement in the cylindrical error from −1.3 ± 0.8 preoperatively to −0.9 ± 0.23 on the second day postoperatively, and it improved to −0.75 ± 0.32, −0.67 ± 0.33, and −0.7 ± 0.22 at 1, 3, and 6 months postoperatively. These results showed a statistically highly significant difference (P < 0.001).

The study also showed improvement in visual acuity from 0.828 ± 0.33 BCVA preoperatively to 0.881 ± 0.11, 0.894 ± 0.21, 0.9 ± 0.22 and 0.913 ± 0.22 on second day, and 1, 3, and 6 months postoperatively, respectively. However, the improvement did not show a statistically significant difference (P > 0.05) because we compared the results with the preoperative BCVA.

In 2011, Kymionis et al. [9] reported that a simultaneous combination operation may also be used to treat corneal ectasia after LASIK. The uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) of the patient described by Kymionis and colleagues showed significant improvements from 20/100 to 20/40 and from 20/40 to 20/25, respectively. In the research of Kanellopoulos and Binder, 27 of 32 eyes had an improvement in UDVA and CDVA of 20/45 or better (2.25 log MAR) at last follow-up [10] .

In 2013, a study including 17 patients (34 eyes) who underwent PRK followed by CXL versus CXL alone suggested that the combined procedure was better in reducing corneal aberrations and stabilizing progressive keratoconus. The changes in UDVA were from 0.63 ± 0.36 to 0.19 ± 0.17 log MAR and from 0.59 ± 0.29 to 0.52 ± 0.29 log MAR, respectively [11] . Furthermore, a self-reported quality-of-life comparison showed improvements in the quality of life with simultaneous CXL with topography-guided PRK, over those reported with CXL alone [10] .

Kanellopoulos [12] has successfully treated corneal blindness from severe corneal scarring with the Athens Protocol. The treated cornea improved translucency and was topographically stable, with CDVA increasing from 20/100 to 20/40. This method may provide an effective alternative to existing surgical options, such as keratoplasty, for patients with severe corneal scarring.

Kampik et al. [13] reported that the microkeratome and laser parameters for LASIK need adjusting after CXL due to the influence of the cornea stiffening effect. The in-vitro animal study conducted to investigate the influence of CXL on LASIK concluded that CXL reduced the amount of refractive change after LASIK for myopia and increased flap thickness.

In a study by Celik et al. [14] , four patients underwent LASIK with concurrent accelerated CXL in one eye and LASIK only in the fellow eye to treat myopia or myopic astigmatism. During the surgery, 0.1% riboflavin solution was instilled into the corneal bed for 1.5 min while the flap remained open, and UVA exposure was performed for 3 min at a power of 30 mW/cm 2 after flap closure. The attempted correction (SE) ranged from −5.00 to −8.50 D in the LASIK-CXL group and from −3.00 to −7.25 in the LASIK-only group. The LASIK-CXL group had a UDVA and manifest refraction equal to or better than those in the LASIK-only group [15] .

Concurrent surgery appeared to be a promising modality for future applications to prevent corneal ectasia after LASIK treatment [14] . Tamayo reported a similar work in a letter to the editor. The riboflavin instillation and irradiation times were 60 and 75 s at 30 mW/cm 2 , respectively, and the UDVA and manifest refraction SE postoperatively were improved to 20/18 and 0.49, respectively [16] .

A similar study reported on 43 patients treated with femtosecond laser flap and the WaveLight excimer platform with a UVA irradiation power of 10 mW/cm 2 for 3 min [17] . This method appeared to be a safe and effective adjunctive treatment for refractive regression and potential ectasia. The mean UCVA changed from 0.2 to 1.2, BCVA from 1.1 to 1.2, SE from −7.5 to −0.2 D, and keratometry from 44.5 to 38 D. None of the cases developed signs of ectasia or significant regression during a mean follow-up duration of 3.5 years [15] . Kanellopoulos [17] said that this application could be viewed as a 'prophylactic customization of the biomechanical behavior of corneal collagen'.

A further investigation of a combined operation using topography-guided LASIK and the same UVA parameter applied in a contralateral eye study of 34 consecutive patients reached the same conclusion [18] . Eyes that underwent CXL demonstrated a mean regression from treatment of +0.22 ± 0.31 D, whereas eyes that did not undergo CXL showed a greater regression of +0.72 ± 0.19 D at 2 years postoperatively.

In a study that reported the long-term outcomes, safety, stability, and efficacy of a pilot series of simultaneous LASIK and CXL with an illumination of 3 mW/cm 2 for 15 min, the average SE was + 3.4 D after 4 years [19] ; the authors suggested that this technique may be promising for ameliorating hyperopic regression.

This study also found that keratometry decreased from 42.91 ± 2.01 D (K1 ) preoperatively to 39.65 ± 2.91 D on the second day postoperatively and flattened to 39.61 ± 2.74, 39.65 ± 2.73, and 39.48 ± 2.68 D at 1, 3, and 6 months postoperatively, respectively, and preoperative K2 was 44.37 ± 2.29 D and flattened to 41.06 ± 3.22, 40.56 ± 3.12, 40.54 ± 2.82, and 40.43 ± 2.78 D on the second day and 1, 3, and 6 months postoperatively, respectively. This result showed a mean flattening of the cornea on the second postoperative day of 3.26 D and a mean flattening of 3.43 D at the end of the follow-up period. The study showed a statistically highly significant difference (P < 0.001).

This coincides with the study by Kanellopoulos [20] , who stated that K1 decreased from 44.5 D preoperatively to 42.96 D postoperatively and K2 flattened from 45.3 D preoperatively to 43.96 D postoperatively, with a mean flattening of the cornea of 2.3 D in the first week postoperatively and 1.44 D after 6 months. Moreover, similar to our results, Kanellopoulos et al. [8] found that K1 reading decreased from 43.94 D preoperatively to 37.64, 37.69, 37.66, and 37.67 D at 1, 3, 6, and 12 months postoperatively, whereas K2 decreased from 45.17 D to 38.32, 38.35, 38.36, and 38.37 D at 1, 3, 6, and 12 months postoperatively.

Our study showed a reduction in corneal thickness from 498.19 ± 15.1 μm preoperatively to 439.9 ± 15.9, 428.1 ± 27.4, 428.2 ± 27.4, and 434.2 ± 4.97 μm on the second day, 1 month, 3 months, and 6 months postoperatively, respectively, with a reduction of 58.29, 70.09, 69.99, and 63.99 μm on the second day and 1, 3, and 6 months postoperatively, respectively. The study shows a statistically highly significant difference (P < 0.001).

These results are similar to the study by Kanellopoulos [20] , who reported corneal thinning of 44 μm at 1 month postoperatively, and then it increased to 48 μm at 5 months postoperatively. The decrease in thickness in his study is lower than that in our results because his patients had mild myopia. Similar to our results in 65 eyes treated with LASIK with CXL, Kanellopoulos et al. [8] reported a mean preoperative corneal thickness of 545.96 ± 33.93 μm that reduced to 438.11 ± 28.35 μm after 1-year follow-up.

Recently, this type of concurrent operation has mostly been applied to myopic patients to decrease the incidence of corneal ectasia after LASIK and to improve the quality of sporting activities after LASIK. Obviously, the effect of different irradiation parameters of UVA should be compared further [21] .

The formation of liner haze in posterior stroma or nodular epithelial hyperplasia has been reported for patients who have undergone topography-guided PRK followed by immediate CXL [22] . The authors thought that this was probably caused by an inflammatory stimulus triggered by the combined operation.

Almost all of the reports identified had used topography-guided PRK in combined operations; the laser ablation profile was more suitable for keratoconus patients because of highly irregular astigmatism. In terms of the sequence, PRK followed by CXL seems better because removing the cross-linked stiffer anterior cornea possibly minimizes the benefit of CXL if CXL is followed by PRK. However, the long-term effects and safety of removing the Bowman layer with laser ablation have not been established and may potentially lead to rapid deterioration and eventual corneal transplantation [15] .

The limitations of this study are the low number of patients and the shorter follow-up period. More studies are needed in a large scale of patients for better evaluation and with a prolonged follow-up period up to 2 years.

 Conclusion



LASIK combined with a prophylactic CXL intervention appears to provide predictability as well as refractive and keratometric stability. The data reported in this study provide evidence of the safety and efficacy of this approach. The adjuvant CXL procedure adds enhanced corneal biomechanical stability. High-myopic and younger age LASIK cases may require biomechanical re-enforcement, as means of reducing the incidence and degree of future myopic regression and/or the potential ectasia risk.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Randleman JB. Post-laser in-situ keratomileusis ectasia: current understanding and future directions. Curr Opin Ophthalmol 2006; 17 :406-412.
2 MK Nassar, AE Sarhan, MF El-Sawey, AI Alsherbiny. Assessment and evaluation of visual acuity, indications, and complications after penetrating keratoplasty. Menoufia Med J 2014; 27 :234-238.
3 Kymionis GD, Tsiklis NS, Pallikaris AI. Long-term follow-up of Intacs for post-LASIK corneal ectasia. Ophthalmology 2006; 113 :1909-1917.
4 Kymionis GD, Kontadakis GA, Kounis GA, Portaliou DM, Karavitaki AE, Magarakis M, et al. Simultaneous topography-guided PRK followed by corneal collagen cross-linking for keratoconus. J Refract Surg 2009; 25 :S807-S811.
5 Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003; 135 :620-627.
6 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.
7 Tuwairqi WS, Sinjab MM. Safety and efficacy of simultaneous corneal collagen cross-linking with topography-guided PRK in managing low-grade keratoconus: 1-year follow-up. J Refract Surg 2012; 28 :341-345.
8 Kanellopoulos AJ, Asimellis G, Karabatsas C. Comparison of prophylactic higher fluence corneal cross-linking to control, in myopic LASIK, one year results. Clin Ophthalmol 2014; 8 :2373-2381.
9 Kymionis GD, Portaliou DM, Diakonis VF, Karavitaki AE, Panagopoulou SI, JankovIi MR, et al. Management of post laser in situ keratomileusis ectasia with simultaneous topography guided photorefractive keratectomy and collagen cross-linking. Open Ophthalmol J 2011; 5 :11-13.
10Labiris G, Giarmoukakis A, Sideroudi H, Gkika M, Fanariotis M, Kozobolis V. Impact of keratoconus, cross-linking and cross-linking combined with photorefractive keratectomy on self-reported quality of life. Cornea 2012; 31 :734-739.
11Alessio G, L'abbate M, Sborgia C, La Tegola MG. Photorefractive keratectomy followed by cross-linking versus cross-linking alone for management of progressive keratoconus: two-year follow-up. Am J Ophthalmol 2013; 155 :54-65.
12Kanellopoulos AJ. The management of cornea blindness from severe corneal scarring, with the Athens Protocol (transepithelial topography-guided PRK therapeutic remodeling, combined with same-day, collagen cross-linking). Clin Ophthalmol 2012; 6 :87-90.
13Kampik D, Ralla B, Keller S, Hirschberg M, Friedl P, Geerling G. Influence of corneal collagen crosslinking with riboflavin and ultraviolet-a irradiation on Excimer laser surgery. Invest Ophthalmol Vis Sci 2010; 51 :3929-3934.
14Celik HU, Alagöz N, Yildirim Y, Agca A, Marshall J, Demirok A, et al. Accelerated corneal crosslinking concurrent with laser in situ keratomileusis. J Cataract Refract Surg 2012; 38 :1424-1431.
15Li N, Peng XJ, Fan ZJ. Progress of corneal collagen cross-linking combined with refractive surgery. Int J Ophthalmol 2014; 7 :157-162.
16Tamayo GE. Predictable visual outcomes with accelerated corneal cross-linking concurrent with laser in situ keratomileusis. J Cataract Refract Surg 2012; 38 :2206.
17Kanellopoulos AJ. Long-term safety and efficacy follow-up of prophylactic higher fluence collagen cross-linking in high myopic laser-assisted in situ keratomileusis. Clin Ophthalmol 2012; 6 :1125-1130.
18Kanellopoulos AJ, Kahn J. Topography-guided hyperopic LASIK with and without high irradiance collagen cross-linking: initial comparative clinical findings in a contralateral eye study of 34 consecutive patients. J Refract Surg 2012; 28(Suppl) :837-840.
19Aslanides IM, Mukherjee AN. Adjuvant corneal crosslinking to prevent hyperopic LASIK regression. Clin Ophthalmol. 2013; 7 :637-641.
20Kanellopoulos AJ. Novel myopic refractive correction with transepithelial very high-fluence collagen cross-linking applied in a customized pattern: early clinical results of a feasibility study. Clin Ophthalmol 2014; 8 :697-702.
21Li X, Wang Z, Cao Q, Hu L, Tian F, Dai H. Pentacam could be a useful tool for evaluating and qualifying the anterior chamber morphology Int J Clin Exp Med 2014; 7 :1878-1882.
22Bogoni A, Salerno LC, Ghanem VC, Ghanem RC. Nodular epithelial hyperplasia after photorefractive keratectomy followed by corneal collagen cross-linking. Case Rep Ophthalmol Med 2013; 2013 :953267.