Journal of Refractive Surgery

Review 

Corneal Collagen Cross-linking (CXL) Combined With Refractive Procedures for the Treatment of Corneal Ectatic Disorders: CXL Plus

George D. Kymionis, MD, PhD; Michael A. Grentzelos, MD; Dimitra M. Portaliou, MD; Vardhaman P. Kankariya, MD; J. Bradley Randleman, MD

Abstract

PURPOSE:

To discuss current combined corneal collagen cross-linking (CXL) and refractive surgical techniques (herein termed “CXL plus”) for the treatment of corneal ectatic disorders to improve functional visual acuity in addition to corneal stability from CXL alone.

METHODS:

Literature review.

RESULTS:

Efficacious combined treatments with CXL include: photorefractive keratectomy, transepithelial phototherapeutic keratectomy, intrastromal corneal ring segments implantation, phakic intraocular lens implantation, and multiple combined procedures. Some uncertainty remains as to the optimal strategies for each patient. A decision tree is proposed to facilitate optimal patient management.

CONCLUSIONS:

With multiple adjuvant techniques, CXL plus is likely to benefit many patients with corneal ectatic disorders. The appropriate combined procedure will depend on multiple factors, such as refraction, corneal thickness, and degree of irregular astigmatism.

[ J Refract Surg. 2014;30(8):566–576.]

From Vardinoyiannion Eye Institute of Crete, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece (GDK, MAG, DMP, VPK); Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, Florida (GDK, DMP); and the Department of Ophthalmology, Emory Eye Center, Emory University School of Medicine, Atlanta, Georgia (JBR).

Supported in part by the special research account of the University of Crete and an unrestricted departmental Emory University grant from Research to Prevent Blindness, Inc.

The authors have no financial or proprietary interest in the materials presented herein.

Dr. Randleman did not participate in the editorial review of this manuscript.

AUTHOR CONTRIBUTIONS

Study concept and design (GDK, JBR); data collection (MAG, DMP, VPK); analysis and interpretation of data (JBR); drafting of the manuscript (GDK, MAG, DMP, VPK, JBR); critical revision of the manuscript (GDK, MAG, JBR); supervision (GDK)

Correspondence: George D. Kymionis, MD, PhD, University of Crete, Faculty of Medicine, Vardinoyiannion Eye Institute of Crete, 71003 Heraklion, Crete, Greece. E-mail: kymionis@med.uoc.gr

Received: January 02, 2014
Accepted: June 02, 2014
Posted Online: August 05, 2014

Abstract

PURPOSE:

To discuss current combined corneal collagen cross-linking (CXL) and refractive surgical techniques (herein termed “CXL plus”) for the treatment of corneal ectatic disorders to improve functional visual acuity in addition to corneal stability from CXL alone.

METHODS:

Literature review.

RESULTS:

Efficacious combined treatments with CXL include: photorefractive keratectomy, transepithelial phototherapeutic keratectomy, intrastromal corneal ring segments implantation, phakic intraocular lens implantation, and multiple combined procedures. Some uncertainty remains as to the optimal strategies for each patient. A decision tree is proposed to facilitate optimal patient management.

CONCLUSIONS:

With multiple adjuvant techniques, CXL plus is likely to benefit many patients with corneal ectatic disorders. The appropriate combined procedure will depend on multiple factors, such as refraction, corneal thickness, and degree of irregular astigmatism.

[ J Refract Surg. 2014;30(8):566–576.]

From Vardinoyiannion Eye Institute of Crete, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece (GDK, MAG, DMP, VPK); Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, Florida (GDK, DMP); and the Department of Ophthalmology, Emory Eye Center, Emory University School of Medicine, Atlanta, Georgia (JBR).

Supported in part by the special research account of the University of Crete and an unrestricted departmental Emory University grant from Research to Prevent Blindness, Inc.

The authors have no financial or proprietary interest in the materials presented herein.

Dr. Randleman did not participate in the editorial review of this manuscript.

AUTHOR CONTRIBUTIONS

Study concept and design (GDK, JBR); data collection (MAG, DMP, VPK); analysis and interpretation of data (JBR); drafting of the manuscript (GDK, MAG, DMP, VPK, JBR); critical revision of the manuscript (GDK, MAG, JBR); supervision (GDK)

Correspondence: George D. Kymionis, MD, PhD, University of Crete, Faculty of Medicine, Vardinoyiannion Eye Institute of Crete, 71003 Heraklion, Crete, Greece. E-mail: kymionis@med.uoc.gr

Received: January 02, 2014
Accepted: June 02, 2014
Posted Online: August 05, 2014

Corneal collagen cross-linking (CXL) is a minimally invasive procedure used for the stabilization of corneal ectatic disorders such as keratoconus, pellucid marginal corneal degeneration, and postoperative corneal ectasia. 1–6 The use of riboflavin (ie, vitamin B2) in conjunction with ultraviolet-A irradiation increases corneal resistance and inhibits progression of the ectatic disorder. 1–6

Visual rehabilitation for ectatic corneas requires addressing three concerns: halting the ectatic process, decreasing corneal curvature irregularity, and minimizing the residual refractive error. 7 CXL treatment can restore corneal tectonic integrity to increase the biomechanical rigidity and inhibit the progression of the ectatic disorder. After the first study in 2003 by Wollensak et al., 1 several other studies reported promising results regarding CXL treatment; several ocular parameters have been shown to improve after CXL due to the stiffening effect and corneal curvature regularization. 8–13 Nevertheless, in many cases, patients cannot achieve a visual acuity sufficient to provide them functional vision after CXL without the use of rigid gas permeable contact lenses due to significant residual irregularity and refractive error.

Several adjuvant therapies in combination with CXL treatment (CXL plus) have been proposed to develop a combined technique that can treat patients diagnosed as having keratectasia and offer them stability together with improved functional vision. 14 The term “CXL plus,” introduced in 2011, refers to the several combined refractive procedures studied to enhance the CXL result. 14

Evidence exists for the use of the following complements to the CXL procedure: photorefractive keratectomy (PRK), transepithelial phototherapeutic keratectomy (PTK), intrastromal corneal ring segments (ICRS) implantation, phakic intraocular lens (PIOL) implantation, and multiple techniques combined with CXL.

The current study evaluates and compares the literature on the varying combination treatment strategies and presents a decision tree to facilitate optimal patient management.

PRK and CXL

Topography-guided PRK in combination with CXL was the first combined CXL treatment performed with the use of excimer laser ablation and many iterations of this design have followed ( Table 1 ). 15–27 Reported variations in technique have included timing of procedures (simultaneous or sequential), maximal recommended ablation depth, and the use of mitomycin C.

Outcomes With Combined PRK and CXL

Table 1:

Outcomes With Combined PRK and CXL

Initially, Kanellopoulos and Binder presented a patient diagnosed as having keratoconus who underwent topography-guided PRK 1 year after CXL and showed significant clinical improvement. 15 Then, simultaneous topography-guided PRK followed by CXL was reported as an alternative option for optimizing the outcome of CXL in the treatment of keratoconus. 16,17 Kymionis et al. described a patient with pellucid marginal corneal degeneration who underwent simultaneous topography-guided PRK followed by CXL and showed significant visual and topographic improvement. 16 In a prospective study by Kymionis et al., patients with keratoconus treated with simultaneous topography-guided PRK followed by CXL showed significant improvement in all parameters evaluated: spherical equivalent, defocus, uncorrected and corrected distance visual acuity, and keratometric values. 17 In a comparative study, Kanellopoulos showed that same-day simultaneous topography-guided PRK followed by CXL is more effective than sequential CXL with delayed (6 months or more) PRK in the visual rehabilitation of keratoconus. 18 Several studies followed and confirmed the safety and/or efficacy of the simultaneous topography-guided PRK followed by CXL in patients with keratoconus and corneal ectasia after LASIK; long-term stability of this combined procedure has also been demonstrated. 19–27 Recently, Kymionis et al. reported that simultaneous conventional PRK and CXL could be an effective and safe treatment for the management of pellucid marginal corneal degeneration. 28

The major considerations in planning this combined procedure are ablation depth and postoperative corneal thickness; varying recommendations have been proposed, based mainly on maximal ablation depth and residual corneal thickness. Kymionis et al. recommended PRK treatment planning based on the patient’s corneal thickness. 16,17,21,23,28 Treatment modifications (eg, attempted correction, ablation zone, and percentage of customization in case of topography-guided PRK) were based on preoperative corneal pachymetry, corrected distance visual acuity, and manifest refraction to arrive at a recommended maximum ablation depth of 50 μm. 16,17,21,23,28 Kanellopoulos et al. recommended a maximum ablation depth of 50 μm in their cases, but a corneal thickness of no less than 350 μm after PRK. 15,18,19,22 Stojanovic et al. recommended a maximum ablation depth of 60 μm and a minimal postoperative corneal thickness of 400 μm. 20 Tuwairqi and Sinjab limited the ablation depth to achieve ±1.00 diopter of emmetropia and keep approximately 400 μm of stroma before proceeding with CXL, taking into account that the thickness of corneal epithelium is normally 50 μm. 24 Lin et al. reported that the refractive treatment was limited by a minimal residual stromal depth of 300 μm and maximum stromal ablation depth of 80 μm. 25 Alessio et al. planned an ablation stromal depth between 18 and 49 μm (mean: 31.1 ± 0.9 μm) in their study. 26 In any case, corneal thickness plays a significant role in the planning of the combined PRK-CXL procedure. Moreover, thin corneas limit the possibility of tissue removal by PRK and therefore this combined procedure may not be performed in advanced cases of keratoconus.

Regarding mitomycin C use after laser ablation during PRK, Kanellopoulos et al. used mitomycin C 0.02% for 20 seconds after laser ablation in their cases. 15,18,19,22 Kymionis et al. did not use mitomycin C and considered that cross-linking of the ablated stroma offers the advantage of depopulating keratocytes in the anterior stroma, which could reduce the possibility of haze formation. 16,17,21,23,28 Tuwairqi and Sinjab used mitomycin C 0.02% after excimer laser ablation for 30 seconds in all cases. 24

Transepithelial PTK and CXL

According to the Dresden protocol, the epithelium must be removed prior to CXL treatment to permit the penetration of riboflavin solution into the corneal stroma and ensure adequate corneal saturation with riboflavin. 1 Mechanical or alcohol-assisted epithelial debridement during CXL can be replaced with excimer laser transepithelial PTK removal to enhance the postoperative outcome ( Table 2 ). 29–32 The aim of transepithelial PTK is epithelial removal and anterior corneal stromal smoothing to decrease the keratoconic irregular astigmatism.

Outcomes With Combined t-PTK and CXL

Table 2:

Outcomes With Combined t-PTK and CXL

Kymionis et al. described a patient with keratoconus who demonstrated significant visual and topographic improvement after transepithelial PTK epithelial removal during CXL treatment. 29 In a comparative case series, Kymionis et al. showed that epithelial removal using transepithelial PTK during CXL (Cretan protocol) results in better visual and refractive outcomes in comparison with mechanical epithelial removal. 30,31 In a similarly designed comparative but retrospective study, transepithelial PTK removal during CXL was superior to CXL with mechanical epithelial removal. 32 Explanation of why transepithelial PTK-CXL results in better outcomes in comparison with mechanical epithelial removal during CXL has been given in both relevant studies. 30,32 It is well known that the epithelium does not form a uniform layer of thickness over the stroma, but is thinner usually in the region of the cone in patients with keratoconus or postoperative ectasia. 33–37 Therefore, transepithelial PTK may result in epithelial removal in some areas, whereas in others it may include epithelial, Bowman’s layer, and partial stromal removal regularizing the corneal surface. 30,32,38 In patients with keratoconus, transepithelial PTK uses the patients’ own epithelium as a masking agent, allowing excimer laser ablation to remove corneal epithelium along with corneal stromal tissue on the apex of the cone to regularize the anterior corneal surface. 30

CXL and ICRS Implantation

ICRS implantation has been proven beneficial in keratoconus and corneal ectasia after LASIK because it can result in topographic and visual rehabilitation without interfering with patients’ visual axes. 39–46 Despite the promising results, ICRS likely does not halt the progression, especially in young patients. Therefore, CXL in addition to ICRS use offers a “plus” in the biomechanical stability of the ectatic cornea. Reported variations in technique have included the number of segments implanted, location of segments, timing of channel creation, use of multiple segments of different styles, and timing of ICRS and CXL. Although there is limited literature on large samples and long-term results regarding this combined treatment, we report the already published studies ( Table 3 ).

Outcomes With Combined CXL and ICRS Implantation

Table 3:

Outcomes With Combined CXL and ICRS Implantation

In a study by Chan et al., 47 inferior Intacs segments (Addition Technology, Lombard, IL) insertion alone and with the addition of CXL were compared to evaluate the synergic effect of the combined procedure in patients with keratoconus. Intacs with the CXL group resulted in better keratoconus improvement than Intacs insertion alone. Coskunseven et al. published a comparative study of two sequences in patients with keratoconus: CXL followed by ICRS versus ICRS followed by CXL. 48 ICRS implantation followed by CXL resulted in greater improvement of keratoconus. 48

El-Raggal evaluated the creation of a femtosecond laser-mediated channel for the insertion of ICRS 6 months after CXL in patients with keratoconus. 49 The author concluded that although femtosecond laser channel creation can be performed safely after CXL, it is advised to perform it before or simultaneously with CXL to avoid increase in energy use, difficult dissection, and postoperative corneal haze formation. 49 In contrast, Henriquez et al. reported that Ferrara ICRS implantation (Ferrara Ophthalmics Ltda, Belo Horizonte, Brazil) after CXL is a safe and efficacious treatment option. 50

Renesto et al. reported on the refractive and topographic outcomes 24 months after CXL, and insertion of ICRS in keratoconic eyes; ICRS insertion, with or without prior CXL, showed no difference between groups in terms of refractive, topographic, pachymetric, and corneal biomechanical results. 51

El Awady et al. reported CXL has an additive effect after KeraRing implantation (Mediphacos, Belo Horizonte, Brazil) and may be considered as an enhancement/stabilizing procedure. 52 El-Raggal reported that even though combined femtosecond-assisted KeraRing insertion and CXL can be performed safely in one or two sessions, the same-session procedure appears to be more effective regarding the improvement in the corneal shape. 53 Comparable results were observed by Saelens et al. after same-day Ferrara ICRS implantation and CXL. 54

A same-day combined ICRS-CXL procedure, without epithelial removal, was investigated by Kilic et al. 55 Similarly, a separate study demonstrated that transepithelial CXL has an additive effect on Intacs implantation in keratoconic eyes. 56 A case of bilateral transepithelial CXL after Intacs SK implantation in a patient with ectasia after LASIK was also described. 57 Results showed improvement in visual acuity and manifest refraction in both studies. 56,57

Alió et al. reported the results in two groups of patients with keratoconus who previously underwent KeraRing segments implantation using an Intralase femtosecond laser (Abbott Medical Optics, Santa Ana, CA) and 3 to 12 months later underwent CXL either by using the standard epithelial removal protocol or by creating an intrastromal pocket for riboflavin delivery. 58 There were no statistically significant differences between the two groups in any of the parameters measured. 58

Recently, Lam et al. reported another case of corneal ectasia after LASIK, which showed stabilization of the ectatic disorder and vision improvement after femtosecond laser-assisted ICRS implantation followed by CXL. 59

CXL and PIOL Implantation

Three types of PIOL are currently available for intraocular refractive correction: angle supported, iris fixated, and posterior chamber. 60 PIOL implantation in addition to CXL is another alternative combined treatment of keratoconus performed to optimize the CXL outcome ( Table 4 ).

Outcomes With Combined CXL and PIOL Implantation

Table 4:

Outcomes With Combined CXL and PIOL Implantation

The combination of CXL and toric PIOL (toric Visian ICL; STAAR Surgical, Monrovia, CA) implantation was first reported in 2011 as a two-step approach for treatment of progressive keratoconus and high myopic astigmatism in a 29-year-old woman. 61 Three months postoperatively, uncorrected distance visual acuity improved from counting fingers to 20/40 and corrected distance visual acuity improved from 20/100 to 20/30. 61 Kurian et al. 62 and Fadlallah et al. 63 also consequently reported the results of CXL followed by toric Visian ICL implantation in eyes with progressive keratoconus, demonstrating optimum efficacy, safety, and stability of visual and refractive outcomes.

Implantation of the foldable iris-claw PIOL (Artiflex; Ophtec BV, Groningen, The Netherlands) following CXL is another possible option to improve visual rehabilitation in keratoconic eyes. Izquierdo et al. implanted the Artiflex 6 months after CXL, resulting in significant improvement in visual acuity, keratometry, and refractive error. 64 Güell et al. reported long-term outcomes of combined CXL and toric iris-claw PIOL (Artiflex or Artisan; Ophtec BV) implantation, concluding that this combined procedure effectively and safely corrected myopic astigmatism in progressive and mild keratoconus. 65 Uncorrected distance visual acuity was 20/40 or better in 16 eyes (94%) postoperatively. 65 No eye lost lines of corrected distance visual acuity and no significant decrease in central endothelial cell count occurred ( P > .05) was noted. 65

Multiple Techniques Combined with CXL

To optimize the results of CXL, more than one technique has been proposed to be combined with CXL in two or more steps ( Table 5 ). Reported procedure combinations include:

  1. CXL with PRK and ICRS implantation

  2. CXL with PRK and PIOL implantation

  3. CXL with ICRS and PIOL implantation

  4. CXL with transepithelial PTK and ICRS implantation

Outcomes With Multiple Techniques Combined With CXL

Table 5:

Outcomes With Multiple Techniques Combined With CXL

Kymionis et al. presented a patient with pellucid marginal corneal degeneration who had PRK followed by CXL 12 months after ICRS implantation and showed significant improvement in uncorrected and corrected distance visual acuity and significant flattening of the keratometry values. 66 Kanellopoulos and Skouteris reported the management of secondary ectasia due to forceps injury at childbirth with combined topography-guided PRK and CXL and subsequent PIOL implantation. 67 Iovieno et al. reported significant improvement in visual acuity, refraction, keratometry, and total aberrations after ICRS implantation followed by same-day topography-guided PRK and CXL. 68 Kremer et al. reported significant improvement of visual acuity and keratometric values after simultaneous wavefront-guided PRK and CXL in a series of patients with moderate keratoconus who previously underwent ICRS implantation. 69

Coskunseven et al. reported results after combined transepithelial topography-guided PRK after KeraRing ICRS implantation followed by CXL in a three-step procedure. 70 In another study, Coskunseven et al. reported collagen copolymer toric PIOL implantation for residual myopic astigmatism after ICRS implantation and CXL in a three-stage procedure for keratoconus. 71 Recently, in an attempt to further enhance the CXL result, Yeung et al. investigated and showed the efficacy of transepithelial PTK followed by a single inferior ICRS implantation and CXL as a same-day triple procedure. 72

Controversies for Combined Techniques

Simultaneous Versus Sequential PRK and CXL

The first approach of sequential CXL followed by PRK by Kanellopoulos and Binder had some limitations. 15 First, this approach has limited efficacy because the cross-linked corneas may have a different ablation rate from that of normal corneas; this could lead to unpredictable results. Moreover, there is an increased possibility of haze formation after PRK. Finally, probably the most significant limitation of this approach was the removal of the stiffened cross-linked corneal tissue by PRK that could decrease or even reverse the possible effects of CXL. These aspects led to the consideration that the best option for optimizing the outcome of CXL in the treatment of keratoconus was simultaneous PRK followed by CXL. In his comparative study, Kanellopoulos confirmed this consideration, showing that same-day simultaneous topography-guided PRK followed by CXL is more effective than sequential CXL with delayed (6 months or more) PRK in the visual rehabilitation of keratoconus. 18 The main advantage of simultaneous PRK followed by CXL is that laser ablation does not interfere with the already cross-linked part of the cornea. Nevertheless, this remains an area for future study.

Optimal Epithelial Removal Technique During CXL

Two comparative studies have shown that epithelial removal using transepithelial PTK during CXL seems to be a better option in comparison with mechanical epithelial removal because it results in better visual and refractive outcomes. 30,32 It seems that transepithelial PTK during CXL could be performed in many cases of CXL for better visual and refractive outcomes, especially in cases in which PRK before CXL cannot be performed due to low corneal thickness. However, a larger patient series with a longer follow-up is needed to confirm the outcomes of combined transepithelial PTK-CXL.

Order of Combined Procedures

ICRS Implantation and CXL. The main goal of CXL is to stabilize the ectatic cornea and arrest the progression of the ectatic disorder. ICRS implantation is used to flatten the central corneal curvature while maintaining the biomechanical status in the underlying corneal stroma. Therefore, pretreatment with ICRS implantation would re-shape and flatten the cornea and subsequent CXL would stabilize the newly shaped cornea. In accordance with this consideration, the comparative study by Coskunseven et al., which is the only comparative study to date, showed that ICRS implantation followed by CXL resulted in greater improvement of keratoconus in comparison with CXL followed by ICRS implantation. 48 The findings of the study suggested that although each treatment step flat-tens the cornea, a stiffer cornea that has been treated by CXL decreases the flattening effect of ICRS implantation, thus restricting its effect and decreasing the maximum flattening potential. 48 Therefore, to achieve the maximum overall effect, ICRS implantation should be better performed first to reshape the cornea and CXL treatment applied afterward to further flatten the cornea and stabilize corneal disorder.

PIOL Implantation and CXL. CXL plus PIOL implantation is performed as a two-step approach: CXL is performed first to stabilize keratoconus followed by toric PIOL implantation once stability of manifest refraction and topography is achieved (typically after 6 to 12 months of CXL).

Limitations for this Review

An apparent problem of this literature review is the great disparity of data presented in the studies analyzed. The scope of this review is to list the available information regarding combined CXL treatments; the heterogeneity of the methods presented (eg, prospective, retrospective, randomized, nonrandomized studies, etc.) is not further analyzed, but is clearly stated in the tables. The conclusions drawn by certain studies (ie, prospective randomized trials) might be of greater importance than others (ie, case reports). Moreover, the number of patients included and the follow-up period can play an important role in the evaluation of the outcome measures of a published study.

Another limitation is that long-term data of CXL alone show a continuous visual, refractive, and topographic improvement even several years after treatment, whereas the combined CXL techniques’ follow-up period was relatively shorter. Therefore, the addition of adjuvant techniques in CXL treatment interacts unpredictably with the continuation of improvement from CXL alone.

CXL Plus Decision Tree

Figure 1 shows a proposed treatment algorithm (decision tree) that could be used for patient management after keratoconus diagnosis. Currently, simultaneous PRK followed by CXL seems to be the most effective approach for optimum results in the treatment of patients with keratoconus because it is capable of offering them functional visual improvement with stabilization of the ectatic disorder. Combined ICRS and CXL can also provide significant outcome improvement as compared to separate application of either technique. Moreover, PIOL implantation in addition to CXL can be an effective alternative combined treatment of keratoconus because it provides a solution for the two principal problems of high refractive error and progression of the disease.

Proposed treatment algorithm (decision tree) for patient management after keratoconus diagnosis. Decisions are made considering the stability or progression of keratoconus and the functional vision. VA = visual acuity; RGP-CL = rigid gas permeable contact lens; DALK = deep anterior lamellar keratoplasty; PKP = penetrating keratoplasty; CXL = corneal collagen cross-linking; t-PTK = transepithelial phototherapeutic keratectomy; PRK = photorefractive keratectomy; ICRS = intrastromal corneal ring segments; PIOL = phakic intraocular lens

Figure 1.

Proposed treatment algorithm (decision tree) for patient management after keratoconus diagnosis. Decisions are made considering the stability or progression of keratoconus and the functional vision. VA = visual acuity; RGP-CL = rigid gas permeable contact lens; DALK = deep anterior lamellar keratoplasty; PKP = penetrating keratoplasty; CXL = corneal collagen cross-linking; t-PTK = transepithelial phototherapeutic keratectomy; PRK = photorefractive keratectomy; ICRS = intrastromal corneal ring segments; PIOL = phakic intraocular lens

Conclusion

CXL alone is effective in halting the progression of keratoconus, but the improvement in visual acuity that studies have confirmed is usually not sufficient for functional vision and better quality of life. Combined CXL treatments (CXL plus) seem to be the way for optimization of the CXL result in the treatment of corneal ectatic disorders. 14 Whatever the adjuvant technique, it seems that CXL plus may be the way of the future for appropriate candidates, a combined procedure that might represent an actual treatment for most of the cases of corneal ectatic disorders.

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Outcomes With Combined PRK and CXL

AuthorStudy DesignEyesSurgical ProceduresFollow-upOutcomesRemarks
Kanellopoulos & Binder 15Case report1CXL followed by topography-guided PRK 12 months later18 monthsSignificant clinical improvement and stabilityNo complications
Kymionis et al. 16Case report2Simultaneous topography-guided PRK and CXL12 monthsSignificant visual (UDVA and CDVA) and topographic improvementNo complications
Kymionis et al. 17Pilot study14Simultaneous topography-guided PRK followed by CXL10.69 ± 5.95 months (range: 3 to 16 months)Significant improvement in UDVA, CDVA, SE, defocus, and keratometry readingsNo complications
Kanellopoulos 18Retrospective study127 (sequential), 198 (simultaneous)Sequential (⩾ 6 months after CXL) and simultaneous topography-guided PRK followed by CXL36 ± 18 months (range: 24 to 68 months)Simultaneous group did better in all fields evaluated (UDVA, CDVA, keratometry, SE, and corneal haze)Significant haze in 19 eyes (17 of sequential and 2 of simultaneous group)
Krueger & Kanellopoulos 19Case report2Simultaneous topography-guided PRK and CXL36 and 30 monthsReduction of spherocylindrical refraction and visual function improvementNo complications
Stojanovic et al. 20Case series12Topography-guided custom ablation followed by CXL12 monthsVisual, refractive, and topographic improvementNo complications
Kymionis et al. 21Case report1Simultaneous topography-guided PRK and CXL12 monthsVisual (UDVA and CDVA) and topographic improvementNo complications
Kanellopoulos & Binder 22Case series32Simultaneous topography-guided partial transepithelial PRK and CXL27 months (range: 6 to 59 months)27 of 32 eyes had visual (UDVA and CDVA) improvement2 of 32 eyes had corneal progression, corneal haze grade 2 in 2 of 32 eyes
Kymionis et al. 23Prospective case series31Simultaneous topography-guided PRK followed by CXL19.53 ± 3.97 months (range: 12 to 25 months)Significant improvement in UDVA, CDVA, SE, and keratometry readings16 of 31 eyes showed posterior linear stromal haze
Tuwairqi & Sinjab 24Prospective, nonrandomized, noncontrolled study22Simultaneous topography-guided PRK and CXL12 monthsSignificant improvement in all study parameters (UDVA, CDVA, sphere, SE, manifest and topographic astigmatism, and keratometry)No complications
Lin et al. 25Retrospective, nonrandomized, consecutive series72 (keratoconus), 17 (postoperative LASIK ectasia)Simultaneous topography-guided PRK and CXL12 monthsVisual and topographic improvement2 eyes had sufficient haze, 1 eye had herpetic keratitis, 2 eyes had PKP, 2 eyes had re-treatment
Alessio et al. 26Prospective, nonrandomized, clinical trial17 (PRK and CXL), 17 (CXL)Transepithelial topography-guided PRK and CXL/CXL24 monthsPRK-CXL provided better UDVA/CDVA and lower SE, spherical/cylindrical power, and keratometric values than CXLNo ocular adverse events
Kanellopoulos & Asimellis 27Case series231Simultaneous topography-guided PRK and CXL36 monthsVisual (UDVA and CDVA) and topographic improvementNo complications
Kymionis et al. 28Case series8Simultaneous conventional PRK and CXL12 monthsImprovement of UDVA, SE, and corneal astigmatismNo complications

Outcomes With Combined t-PTK and CXL

AuthorDesignEyesSurgical ProceduresFollow-upOutcomesRemarks
Kymionis et al. 29Case report1t-PTK followed by CXL6 monthsVisual and topographic improvementNo complications
Kymionis et al. 30Prospective, comparative38t-PTK (group 1) and mechanical epithelial debridement (group 2) during CXL12 monthsUDVA, CDVA, steep keratometry, and corneal astigmatism improved significantly in patients with t-PTK epithelial removal during CXLNo complications
Kapasi et al. 32Retrospective, comparative34t-PTK during CXL (t-PTK group) and mechanical epithelial removal during CXL (mechanical group)1 monthCXL with laser epithelial removal resulted in significantly better change in SE and astigmatism compared to CXL with mechanical epithelial removalNo complications

Outcomes With Combined CXL and ICRS Implantation

AuthorDesignEyesSurgical ProceduresFollow-upOutcomesRemarks
Chan et al. 47Retrospective, comparative12/13Intacs alone/Intacs and CXL102 ± 39 days/97 ± 38 daysIntacs with CXL showed significantly greater reduction in cylinder, steep, and average keratometry, and topographic lower-upper ratioNo complications
Coskunseven et al. 48Prospective, comparative, and randomized48CXL followed by ICRS/ICRS followed by CXL (mean: 7 ± 2 months)13 ± 1 monthsICRS followed by CXL showed an overall higher increase of CDVA and decrease of the manifest cylinder and mean keratometry values8 eyes had slight subepithelial and stromal edema with stromal opacities, which disappeared within 3 months
El-Raggal 49Comparative5 (1.5 mJ), 5 (1.6 mJ), 5 (1.7 mJ),Femtosecond-mediated channel creation using 1.5, 1.6, and 1.7 mJ power setting for ICRS insertion 6 months after CXL6 monthsFemtosecond laser channel creation can be performed after CXL; the laser power must be modified. Channel dissection and ICRS implantation should be performed before or concurrent with CXLCorneal haze resolved in all eyes within 6 weeks
Henriquez et al. 50Prospective9CXL followed by Ferrara ICRS 6 months later6 monthsSignificant visual improvement, reductions in SE, and keratometry readingsNo complications
Renesto et al. 51Randomized clinical trial 2 groups19/20Riboflavin only and ICRS with 3-month delay/CXL and ICRS 3 months later24 monthsNo significant difference was identified between groups in UDVA, CDVA, SE, and spherical or cylindrical componentsNo complications
El Awady et al. 52Prospective21KeraRing implantation followed by CXL at least 3 months later5.67 ± 1.89 monthsAll outcome measurements (UDVA, CDVA, SE, cylinder, and keratometry readings) were improved after KeraRing implantation and showed further improvement after CXLNo complications
El-Raggal 53Prospective, comparative9/7KeraRing insertion followed by CXL with a 6-month interval/2 step same day procedure12 monthsNo significant differences in UDVA, CDVA, refractive error; keratometric values showed greater reduction in the same day groupNo complications
Saelens et al. 54Case series7Same-day Ferrara ICRS implantation and CXL12 monthsSE decreased significantly and keratometry values showed improvementInferior ring had to be removed in 1 patient 5 months postoperatively because of implant migration
Kilic et al. 55Case series131Same-day combined ICRS-CXL procedure, no epithelial removal7.07 ± 4.66 months (range: 1 to 25 months)Refractive and keratometric measurements were improved in all casesNo complications
Ertan et al. 56Case series25ICRS followed by transepithelial CXL, 3.98 month interval3 monthsTransepithelial CXL after Intacs resulted in an additional improvement in UDVA, CDVA, sphere, cylinder, and keratometryNo complications
Kamburoglu & Ertan 57Case report2CXL (1 month right eye, 1 day left eye) after Intacs SK implantation8 monthsImprovement in visual acuity and decrease in manifest refraction and keratometric valuesNo complications
Alió et al. 58Retrospective, comparative, nonrandomized16 (classic group), 11 (pocket group)ICRS followed by CXL (3 to 12 months later) either with epithelial debridement (classic group) or intrastromal pocket for riboflavin delivery (pocket group)12 monthsNo statistically significant differences between the 2 groups in any of the parameters measured (UDVA, CDVA, sphere, cylinder, and keratometry values, corneal aberrations, and corneal pachymetry)Significant corneal haze was observed in all cases in the early postoperative period, which resolved over time
Lam et al. 59Case report1ICRS and CXL7 monthsImprovement in refractive and keratometric valuesNo complications

Outcomes With Combined CXL and PIOL Implantation

AuthorDesignEyesType of PIOLInterval Between PIOL and CXLFollow-upOutcomesRemarks
Kymionis et al. 61Case report1Toric PICL12 months3 monthsImprovement in UDVA and CDVANo complications
Kurian et al. 62Prospective, case series5PICL11.4 ± 7.7 months6 monthsSignificant visual and refractive improvement2 eyes also received ICRS
Fadlallah et al. 63Retrospective16Toric PICL6 months6 monthsSignificant visual and refractive improvementNo complications
Izquierdo et al. 64Prospective11Iris claw PIOL (Artiflex)6 months6 monthsSignificant visual and refractive improvementNo complications
Güell et al. 65Case series17Toric iris-claw PIOL (Artiflex or Artisan)3.9 ± 0.7 months (range: 3.1 to 5.5 months)36.9 ± 15.0 months (range: 14 to 58 months)Significant visual and refractive improvementNo complications

Outcomes With Multiple Techniques Combined With CXL

AuthorDesignEyesCombined ProcedureOrder of ProceduresFollow-upMain OutcomesRemarks
Kymionis et al. 66Case report1ICRS, PRK, and CXLPRK followed by CXL 12 months after ICRS implantation9 monthsImprovement in vision (UDVA and CDVA) and keratometric valuesNo complications
Kanellopoulos & Skouteris 67Case report1PRK, CXL, and PIOLTopography-guided PRK and CXL and subsequent (1 year later) PIOL implantation36 monthsImprovement in vision and keratometric valuesNo complications
Iovieno et al. 68Case report5ICRS, PRK, and CXLICRS implantation followed by same-day PRK and CXL6 monthsImprovement in UDVA, CDVA, SE, keratometry values, and total aberrationsNo complications
Kremer et al. 69Case series45ICRS, PRK, and CXLICRS implantation followed by (6 months later) simultaneous wavefront-guided PRK and CXL12 monthsSignificant improvement in UDVA, CDVA, and keratometry values; no patient lost any line of CDVA; no ECD changesMild haze in 11.1% of treated eyes, epithelial hyperplasia in 4 of 45 eyes
Coskunseven et al. 70Prospective16ICRS, CXL, and PRKICRS implantation followed by CXL (after 6 months) and transepithelial topography-guided PRK (6 months after CXL)6 monthsAll of the parameters analyzed (UDVA, CDVA, SE, and keratometry values) showed significant improvement; no eye lost any line of CDVANo complications
Coskunseven et al. 71Case series14ICRS, CXL, and PIOLICRS implantation followed by CXL (⩾ 6 months) and then toric PIOL implantation (⩾ 6 months)12 monthsSignificant improvement in UDVA and CDVA in keratoconic eyes with high refractive errorNo complications
Yeung et al. 72Retrospective case series16t-PTK, ICRS, and CXLSame-day t-PTK followed by single ICRS implantation and CXL6.9 ± 4.6 monthsSignificant improvement in UDVA, CDVA, and mean and steep keratometry valuesNo complications

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