https://orcid.org/0000-0002-7211-0343
Figures
Abstract
Purpose
This study performs comparative assessment of the results of different types of two-stage surgical treatment in patients with keratoconus, including combination of corneal collagen cross-linking with intrastromal corneal ring segments followed by topography-guided photorefractive keratectomy.
Materials and methods
Prospective review of 101 patients (101 eyes) with keratoconus was performed. Patients underwent corneal collagen cross-linking (32 patients), intrastromal corneal ring segments (48 patients), and a combination of these two procedures (21 patients). Transepithelial topography-guided photorefractive keratectomy was performed as the second stage of treatment in all patients with obtained stable refractive results at 8 months after first stage. Main outcome measures were visual acuity (uncorrected distance and corrected distance) and corneal topographic indices.
Results
Comparison of the studied parameters after first stage surgical treatment between non-combined CXL and combined groups demonstrated a statistically significant difference for uncorrected distance visual acuity, corrected distance visual acuity, and cylindrical refraction values (p<0.05). We observed significant improvement of visual acuity and key corneal topographic indices after topography-guided photorefractive keratectomy in all study groups (p<0.05). In 50 (49.5%) patients customized excimer laser ablation gave the possibility of full spherical and cylindrical corrections. Ten eyes (10%) had delayed epithelial healing, no corneal stromal opacities developed.
Conclusions
This study shows that combined two-stage surgical treatment of keratoconus, consisting of intrastromal corneal ring segment implantation with corneal collagen cross-linking followed by topography-guided photorefractive keratectomy, is clinically more effective to prevent keratectasia progression and increase visual acuity than the use of non-combined two-stage techniques.
Citation: Maharramov PM, Aghayeva FA (2022) Evaluation of the effectiveness of combined staged surgical treatment in patients with keratoconus. PLoS ONE 17(3): e0264030. https://doi.org/10.1371/journal.pone.0264030
Editor: Rajiv R. Mohan, University of Missouri-Columbia, UNITED STATES
Received: October 5, 2021; Accepted: January 31, 2022; Published: March 7, 2022
Copyright: © 2022 Maharramov, Aghayeva. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Keratoconus is a progressive bilateral pathology of cornea, which is manifested by its thinning and protrusion that lead to astigmatism and deterioration of vision [1]. Different treatment options, such as spectacles and contact lenses [2], intrastromal corneal ring segments (ICRS) [3–7], keratoplasty (penetrating and deep anterior lamellar), corneal collagen cross-linking (CXL) [8–11] with topography-guided customized excimer laser ablation treatment—photorefractive keratectomy (PRK) [12–21], and combinations of the above-mentioned methods [16,21–23] with the application of novel ray-tracing excimer laser customization [24] could be used in patients with keratoconus, depending on its severity and grade. All treatment methods are reported to be effective and safe. This conclusion is based on the comparative analysis of such pre- and postoperative parameters, as visual acuity, refraction and corneal topographic indices. Several reports about the combination of CXL, ICRS, and topography-guided PRK (TG-PRK) were published [25]. The authors considered several combinations of different treatment methods, including phototherapeutic keratectomy (PTK) and implantation of phakic intraocular lenses [16,21]. It is supposed that corneal surgery in keratoconus should both provide prevention of the progression of pathology and also an improvement in vision [26]. An analytical review of literature indicates that the use of only CXL for the treatment of keratoconus has almost no effect on functional parameters, while effectively stops the disease progression, due to the cross-linking of corneal collagen with riboflavin and an increase in corneal biomechanics and strength [13]. The combination of CXL with PRK has a double effect: an increase in corneal stability and a significant improvement in visual acuity [12–21], but reported data is still controversial. Egyptian scientists presented the effectiveness of combination of CXL with PRK in correction of the refractive status in seventy-nine eyes of 46 patients with 18 months of follow-up. However, longer-term postoperative complications and a high rate of postoperative disease progression made confirmation of the safety and stability of the procedure challenging [12]. Interesting data about the clinical efficacy of the combination of ICRS with CXL in the treatment of keratoconus was presented by different researchers [4–7,23]. A more extended and detailed review of the protocols for the combined use of CXL (CXL plus) with different other treatment modalities demonstrates that further studies are required to determine the most effective treatment strategy [23]. Therefore, we decided to compare the results of different types of two-stage surgical treatment in patients with keratoconus, including combination of CXL with ICRS followed by TG-PRK.
Materials and methods
We performed a prospective clinical study including 101 patients (101 eyes) with keratoconus who underwent two-stage surgical management at the National Centre of Ophthalmology named after academician Zarifa Aliyeva, Baku, Azerbaijan. Mean age of the patients was 20.1±8.4 years, 53 were males and 48 females. The occupations of treated patients included office workers (42 patients), oil workers (20 patients), doctors (15 patients), and other (24 patients). The study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the National Centre of Ophthalmology named after academician Zarifa Aliyeva, Baku, Azerbaijan.
As the first stage of treatment, 32 patients (32 eyes) underwent only CXL (CXL group), 48 patients (48 eyes) underwent only ICRS (ICRS group) and 21 patients with keratoconus stage II–III in accordance with Amsler-Krumeich classification, underwent a combination of CXL and ICRS (first ICRS, after 24 hours CXL, ICRS+CXL group) from January 2017 to January 2018. Decision to select and include patients into one of the abovementioned three groups was made on a clinical basis (keratoconus stage and topographic parameters) and informed written consent was obtained in all patients. Transepithelial TG-PRK was performed as the second stage of treatment in all patients with obtained stable refractive results at 8 months after first stage.
Surgical technique was standard. KeraRing ICRS (Mediphacos, Belo Horizonte, Brazil) was implanted into corneal intrastromal tunnels with the inside and outside diameters 4.4 mm and 5.6 mm, respectively, created by means of the 200 kHz femtosecond laser FS200 (Alcon WaveLight®, USA). The ring was implanted in the thinnest part of the cornea at a depth of 90 μm from the endothelium.
To perform CXL under topical anaesthesia, corneal deepithelialization was carried out with the use of a special scraper within the boundaries of the treatment zone of 7 mm, marked with a special trephine. Then 0.1% riboflavin solution (Riboflavin Medio Cross) was applied on the cornea every 5 minutes for 30 minutes to increase the absorption of ultraviolet-A light (UVA) radiation and exposure to UVA itself with a wavelength of 365 nm, radiation energy of 3.0 mW/cm2 and light spot diameter of 7.0 mm (UVX-1000, IROCAG, Switzerland) in six steps of 5 minutes each was performed. A soft bandage contact lens was applied at the end of surgery. During transepithelial TG-PRK 50 μm thick corneal epithelium was removed by PTK under topical anaesthesia, then ablation of the stroma was performed by PRK. The planned maximal topographic stromal ablation depth did not exceed 50 μm after epithelium removal.
All patients were examined before surgery and at 1, 3, 6, 8 months after every surgical procedure during first and the second stage treatment (mean follow-up period was 16.2±1.8 months; minimal follow-up of patients in all groups was 14 months). The ophthalmic examination included measurement of uncorrected distance and corrected distance visual acuity (UDVA and CDVA), autorefractometry (TOMEY RC-5000, Japan), noncontact tonometry (TOMEY FT-1000, Japan), biomicroscopy (Tomey TSL 5000, Tomey, Japan), Pentacam corneal tomography (Oculus Wetzlar, Germany), Wavelight Oculyzer (ALCON, USA), WaveLight® Topolyzer® VARIO (ALCON, USA), anterior segment OCT (Cirrus HD-OCT 5000, Zeiss, Germany), ultrasound pachymetry, and funduscopy.
Statistical analysis:
Statistical analysis was conducted using analysis methods of quantitative and qualitative characteristics (descriptive statistics, one-factor and two-factor variance analysis, two sample t-test with different variances) with the use of an appropriate software package Microsoft Excel-2010 [27]. Continuous data are presented as mean ± standard deviation and chi-square test was used to compare pre- and postoperative parameters.
Results
The preoperative corneal thickness was at least 400 μm at the thinnest corneal location in all patients. Data on visual acuity and corneal topography before surgery and 6 months after CXL, ICRS and ICRS with CXL are shown in Table 1. There were no statistically significant differences in preoperative visual acuity and corneal indices between groups. Presented data indicate that visual acuity and key corneal topographic indices changed noticeably at 6 months after all three types of first stage surgical treatment, thus confirming the achievement of the expected effect (p<0.05). The clinical results after combination of CXL with ICRS are comparatively better than in CXL non-combined group; the differences for UDVA, CDVA, and cylindrical refraction values (p<0.05) between these groups were statistically significant. Clinical parameters before TG-PRK (8 months after first stage) and 6 months after ТG-PRK are presented in Table 2.
These data confirm statistically significant improvement of visual acuity and key topographic indices of cornea after TG-PRK in all studied groups (p<0.05) (Figs 1–3). Several parameters, such as UDVA, cylindrical refraction, spherical equivalent, and IVA, were better in patients underwent previous combination of CXL and ICRS. In 50 (49.5%) patients TG-PRK gave the possibility of full spherical and cylindrical corrections. No intraoperative complications were observed in all groups of patients. Ten eyes (10%) had delayed epithelial healing, no corneal stromal opacities developed.
Pentacam sagittal curvature (front) and elevation (front) maps in patient from CXL+TG-PRK group: a. initial keratometric maps; b. keratometric maps after CXL; c. keratometric maps after CXL+TG-PRK. CXL = corneal collagen cross-linking; TG-PRK = topography-guided photorefractive keratectomy.
Pentacam sagittal curvature (front) and elevation (front) maps in patient from ICRS+TG-PRK group: a. initial keratometric maps; b. keratometric maps after ICRS; c. keratometric maps after ICRS+TG-PRK. ICRS = intrastromal corneal ring segments; TG-PRK = topography-guided photorefractive keratectomy.
Pentacam sagittal curvature (front) and elevation (front) maps in patient from ICRS+CXL+TG-PRK group: a. initial keratometric maps; b. keratometric maps after ICRS+CXL; c. keratometric maps after ICRS+CXL+TG-PRK. ICRS = intrastromal corneal ring segments; CXL = corneal collagen cross-linking; TG-PRK = topography-guided photorefractive keratectomy.
Discussion
All of the modern surgical methods for the treatment of keratoconus have been developed considering its pathogenesis. Crosslinking is a photopolymerization of stromal collagen fibers of the cornea, caused by the combined effect of a photosensitizing substance (riboflavin or vitamin B2) and UVA exposure. The results of studies on the use of CXL show that the procedure is highly effective with a significant improvement of keratometric indices and a detectable increase of visual acuity at 12 months after surgery [8–11]. Our study demonstrates statistically significant increase in UDVA and CDVA, and a reduction of steep axis keratometry of the anterior surface. Furthermore, statistically significant changes of such keratometric indices as ICV, IVA, KI, SRI, SAI were revealed.
A huge number of published works are devoted to the investigation of the efficacy and safety of combined methods in the treatment of keratoconus [1,5,6,12,16,28]. Coshkunseven et al. reported an efficacy and safety of combined treatment, including posterior chamber toric phakic Visian ICL implantation after Keraring ICRS implantation followed by CXL in a three-step procedure in 14 keratoconic eyes with extreme myopia and astigmatism [16]. These works present mainly the results of combined treatment and there are just a few studies comparing the efficacy of various types of combined treatment [7,23]. Hosny et al. presented the comparative results of two variations of combined surgical treatment in keratoconus, including different CXL types: a combination of intra-tunnel CXL with ICRS implantation and a combination of epithelium-off CXL with ICRS in 20 eyes. Simultaneous intra-tunnel CXL with implantation of ICRS showed early visual rehabilitation due to the absence of epithelial defect [5]. Our observation gave possibility to compare efficacy of the independent application of CXL or ICRS with the use of their combination. We have found no statistically significant differences in clinical parameters between ICRS+CXL and ICRS groups, while a greater improvement of visual acuity and decrease in cylindrical refraction value in combined group compared with CXL group was revealed.
The treatment of keratoconus in mild and moderate stages with the use of combination of the CXL, PRK and PTK has been well documented. Kanellopoulos showed safety and long-term efficacy of the partial TG-PRK in conjunction with CXL (Athens Protocol) up to 3 years postoperatively in the treatment of two hundred thirty-one keratoconic cases [29] and at 10 years follow-up of one hundred thirty-four eyes with keratoconus [30]. Our study confirms that an application of TG-PRK in patients of all three groups provides further statistically significant improvement of visual acuity and key keratotopographic indices.
PRK-CXL combined refractive surgery treatment is considered to cause only several undesirable mild complications and identified as effective in slowing or arresting the progression of keratoconus [31]. Despite a plenty of publications on keratoconus treatment, there is still a debate, whether cross-linking and topographic ablation procedures should be performed simultaneously, sequentially and in what order [32,33]. In accordance with the results of Bardan et al., the use of CXL followed by sequential PRK provides a greater improvement in CDVA, SE, and refractive astigmatism [32]. It is well-known, that CXL causes thinning, due to an active increase of the degree of covalent bonding between and within collagen type I and proteoglycans and subsequent compaction of the collagen layers and cornea might not be suitable for further excimer laser ablation from a safety point of view [34]. Therefore, CXL performed after PRK is supposed to be safer. As the main purpose of our proposed treatment modality was to prevent keratectasia progression and stabilize corneal topography at first, we performed CXL as the first stage treatment in our keratoconic patients. TG-PRK was applied as an attempt to correct spherical and cylindrical errors in keratoconus only at already suitable stabilized cornea at 8 months after first stage. This approach gave the possibility of full spherical and cylindrical correction in almost half of our patients, better mean UDVA and CDVA values were achieved in ICRS+CXL+TG-PRK and CXL+TG-PRK/ ICRS+CXL+TG-PRK groups, respectively. One of the explanations could be that the majority of our patients were diagnosed with the II-III stage of keratoconus in accordance with Amsler-Krumeich classification, and preoperative corneal thickness was at least 400 μm at the thinnest corneal location in all patients.
One of the strengths of our study is that we compared not only the results of a combined keratoconus treatment method (CXL and ICRS) with non-combined options [1,5,7,12], but also different types of two-stage surgical treatment of keratoconus with the use of transepithelial TG-PRK. CXL and ICRS, as well as a combined version (CXL+ICRS) followed by TG-PRK are more clinically effective than methods without use of TG-PRK. By taking into account the confirmed greater efficacy of combined treatment CXL+ICRS, its staged use with TG-PRK is supposed to be the most optimal option in the treatment of keratoconus: CXL+ICRS as the first stage and TG-PRK as the second stage. These study results are considered to be reliable to prove the efficacy and safety of proposed keratoconus treatment strategy in terms of treated patients’ quantity and number of analysed clinical parameters.
Thus, our data demonstrate that different options of two-stage treatment modality are effective and safe to stabilize ectasia and improve corneal regularity in eyes with mild to moderate keratoconus, so can improve quality of life in these patients. Combined two-stage (with 8-month interval) surgical treatment in patients with keratoconus, consisting of ICRS implantation with CXL followed by TG-PRK, is more effective to prevent keratectasia progression and increase visual acuity than the use of non-combined two-stage methods.
References
- 1. Andreanos KD, Hashemi K, Petrelli M, Droutsas K, Georgalas I, Kymionis GD. Keratoconus Treatment Algorithm. Ophthalmol Ther. 2017;6(2):245–262. pmid:28755306
- 2. Lim L, Lim EWL. Current perspectives in the management of keratoconus with contact lenses. Eye (Lond). 2020;34(12):2175–2196. pmid:32641797
- 3. Ayar O, Muftuoglu O, Akdemir MO, Ozmen MC. Results of ethanol-assisted epithelium-on corneal cross-linking with and without intrastromal corneal ring implantation. Int Ophthalmol. 2019;39(3):651–9. pmid:29429144
- 4. Gordillo CH, Grandin JC, Zaldivar R, Zaldivar R, Lotfi AC. Efficacy of intrastromal corneal ring segments combined with flash collagen cross-linking in keratoconus. Cornea. 2017;36(2):144–7. pmid:28060059
- 5. Hosny M, Nour M, Azzam S, Salem M, El-Mayah E. Simultaneous intratunnel cross-linking with intrastromal corneal ring segment implantation versus simultaneous epithelium-off cross-linking with intrastromal corneal ring segment implantation for keratoconus management. Clin Ophthalmol. 2018;12:147–152. pmid:29398901
- 6. Nattis A, Donnenfeld ED, Rosenberg E, Perry HD. Visual and keratometric outcomes of keratoconus patients after sequential corneal crosslinking and topography-guided surface ablation: early United States experience. J Cataract Refract Surg. 2018;44:1003–11. pmid:30037699
- 7. Sharma IP, Bakshi R, Chaudhry M. Corneal collagen cross-linking with and without simultaneous intrastromal corneal ring segment implantation: One-year pilot study. Eur J Ophthalmol. 2021;31(1):61–68. pmid:31707858
- 8. Hersh PS, Stulting RD, Muller D, Durrie DS, RajpalRK. United States Crosslinking Study Group United States. Multicenter Clinical Trial of Corneal Colla-gen Crosslinking for Keratoconus Treatment. Ophthalmology. 2017;124(9):1259–70. pmid:28495149
- 9. Kymionis GD, Grentzelos MA, Liakopoulos DA, Paraskevopoulos TA, Klados NE, Tsoulnaras KI, et al. Long-term follow-up of corneal collagen cross-linking for keratoconus—the Cretan study. Cornea. 2014;33(10):1071–9. pmid:25170581
- 10. Raiskup F, Theuring A, Pillunat LE, Spoerl E. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg. 2015;41(1):41–6. pmid:25532633
- 11. Wittig-Silva C, Chan E, Islam FMA, Wu T, Whiting M, Snibson GR. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology. 2014;121:812–21. pmid:24393351
- 12. Iqbal M, Elmassry A, Tawfik A, Elgharieb ME, El Deen Al Nahrawy OM, Soliman AH, et al. Evaluation of the Effectiveness of Cross-Linking Combined with Photorefractive Keratectomy for Treatment of Keratoconus. Cornea. 2018;37(9):1143–1150. pmid:29952798
- 13. Al-Mohaimeed MM. Combined corneal CXL and photorefractive keratectomy for treatment of keratoconus: a review. Int J Ophthalmol. 2019;12(12):1929–1938. pmid:31850179
- 14. Zhu AY, Jun AS, Soiberman US. Combined Protocols for Corneal Collagen Cross-Linking with Photorefractive Surgery for Refractive Management of Keratoconus: Update on Techniques and Review of Literature. Ophthalmol Ther. 2019;8(Suppl 1):15–31. pmid:31605317
- 15. Ohana O, Kaiserman I, Domniz Y, Cohen E, Franco O, Sela T, et al. Outcomes of simultaneous photorefractive keratectomy and collagen crosslinking. Can J Ophthalmol. 2018;53(5):523–8. pmid:30340722
- 16. Couskunseven E. Combined treatment for keratoconus. Ophthalmology Times Europe. 2011 Aug 1 [Cited 2011 August 1];7(6):1045–1047. Available from: http://www.oteurope.com/ophthalmologytimeseurope/content/printCon.
- 17. Iqbal M, Elmassry A, Tawfik A, Elgharieb M, Nagy K, Soliman A, et al. Standard cross-linking versus photorefractive keratectomy combined with accelerated cross-linking for keratoconus management: a comparative study. Acta Ophthalmol. 2019; 97(4):e623–31. pmid:30499232
- 18. Gore DM, Leucci MT, Anand V, Fernandez-Vega Cueto L, Arba Mosquera S, Allan BD. Combined wavefront-guided transepithelial photorefractive keratectomy and corneal crosslinking for visual rehabilitation in moderate keratoconus. J Cataract Refract Surg. 2018;44(5):571–580. pmid:29891154
- 19. Kanellopoulos AJ. Management of progressive keratoconus with partial topography-guided PRK combined with refractive, customized CXL—a novel technique: the enhanced Athens protocol. Clin Ophthalmol. 2019;13:581–8. pmid:31040638
- 20. Moraes RLB, Ghanem RC, Ghanem VC, Santhiago MR. Haze and visual acuity loss after sequential photorefractive keratectomy and corneal cross-linking for keratoconus. J Refract Surg. 2019;35(2):109–14. pmid:30742225
- 21. Grentzelos MA, Kounis GA, Diakonis VF, Siganos CS, Tsilimbaris MK, Pallikaris IG, et al. Combined transepithelial phototherapeutic keratectomy and conventional photorefractive keratectomy followed simultaneously by corneal crosslinking for keratoconus: Cretan protocol plus. J Cataract Refract Surg. 2017;43:1257–62. pmid:29120711
- 22. Kim KH, Mian SI. Refractive approaches to visual rehabilitation in patients with keratoconus. Curr Opin Ophthalmol. 2020;31(4):261–267. pmid:32487813
- 23. Zhu W, Han Y, Cui C, Xu W, Wang X, Dou X, et al. Corneal collagen crosslinking combined with phototherapeutic keratectomy and photorefractive keratectomy for corneal ectasia after laser in situ keratomileusis. Ophthalmic Res. 2018;59:135–41. pmid:29339637
- 24. Kanellopoulos AJ. Keratoconus Management With Customized Photorefractive Keratectomy by Artificial Intelligence Ray-Tracing Optimization Combined With Higher Fluence Corneal Crosslinking: The Ray-Tracing Athens Protocol. Cornea. 2021 Sep 1;40(9):1181–1187. pmid:34050067
- 25. Rocha G, Ibrahim T, Gulliver E, Lewis K. Combined phototherapeutic keratectomy, intracorneal ring segment implantation, and corneal collagen cross-linking in keratoconus management. Cornea. 2019;38(10):1233–8. pmid:31335530
- 26. 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. pmid:26783544
- 27.
Stenton G. Medical-biological statistics [Mediko-biologicheskaia statistika]. Moskva: Izd. Praktika [Moscow: Practice Press]; 1999. Russian.
- 28. Karmel M, Hersh PS, Lin DTC, Rabinowitz YS, Trattler WS. Keratoconus: consider combination therapy. Clinical update. Cornea. 2013 [Cited 2013 March];31–33. Available from: https://www.aao.org/assets/dede14a6-4e5f-4335-8009-c99da14027d4/635570315230 230000/march-2013-clinical-update-cornea-pdf
- 29. Kanellopoulos AJ, Asimellis G. Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol). J Refract Surg. 2014;30(2):88–93. pmid:24763473
- 30. Kanellopoulos AJ. Ten-Year Outcomes of Progressive Keratoconus Management With the Athens Protocol (Topography-Guided Partial-Refraction PRK Combined With CXL). J Refract Surg. 2019;35(8):478–483. pmid:31393985
- 31. Ezzeldin M, Filev F, Steinberg J, Frings A. Excimer laser treatment combined with riboflavin ultraviolet-A (UVA) collagen crosslinking (CXL) in keratoconus: a literature review. Int Ophthalmol. 2020;40(9):2403–2412. pmid:32361861
- 32. Bardan AS, Lee H, Nanavaty MA. Outcomes of Simultaneous and Sequential Cross-linking With Excimer Laser Surface Ablation in Keratoconus. J Refract Surg. 2018 1;34(10):690–696. pmid:30296330
- 33. Ramamurthy S, Soundarya B, Sachdev GS. Topography-guided treatment in regular and irregular corneas. Indian J Ophthalmol. 2020;68(12):2699–2704. pmid:33229645
- 34. Saad S, Saad R, Jouve L, Kallel S, Trinh L, Goemaere I, et al. Corneal crosslinking in keratoconus management. J Fr Ophtalmol. 2020;43(10):1078–1095. pmid:32972759