Keratoconus is a bilateral, progressive, non-inflammatory, and often asymmetric disease of the cornea that causes complex refractive errors such as high and typically irregular astigmatism, high ametropia, and anisometropia. Surgical treatment options include corneal cross-linking (CXL),1 implantation of intracorneal ring segments (ICRS),2 deep lamellar or penetrating keratoplasty, photorefractive keratectomy,3 and implantation of phakic intraocular lenses such as the intraocular contact lens (ICL).4 Due to the complexity of the refractive error, a one-step treatment is usually not sufficient to correct the visual disability.5,6
Previous studies have shown that a combination of ICRS implantation, CXL, and toric ICL implantation was safe and effective in the treatment of keratoconus.6 However, the number of eyes included was relatively small, and corneal wavefront measurements were not performed. We therefore evaluated the staged use of ICRS implantation, CXL, and toric ICL implantation in a larger number of eyes and in the setting of our group of refractive laser centers in Germany. In addition, we looked at the changes of corneal shape using indices derived from corneal topography and corneal wavefront analysis.7
Patients and Methods
We included a consecutive series of 31 eyes (24 patients) treated between May 2014 and May 2016 (14 men and 10 women, mean age: 32.2 ± 8.1 years, range: 18 to 46 years). Six eyes had post–laser in situ keratomileusis (LASIK) ectasia and 25 eyes had keratoconus. All eyes were treated in our clinic in Hamburg, Germany. The time interval was 4 to 6 weeks between ICRS implantation and CXL and 6 to 8 months between CXL and toric ICL implantation. Informed consent was obtained prior to surgery.
Inclusion criteria were moderate to severe keratoconus or ectasia (stage II or III of the Amsler–Krumeich classification) and intolerance to rigid gas-permeable contact lenses. Exclusion criteria were central corneal thickness of less than 400 µm, history of keratitis and other corneal or intraocular surgeries, and incomplete follow-up.
We evaluated uncorrected (UDVA) and corrected (CDVA) distance visual acuity, objective refraction (ARK-700; Nidek, Gamagori, Japan) and manifest refraction, and corneal tomography (Pentacam; Oculus Optikgeräte GmbH, Wetzlar, Germany). We used the following indices derived from the Pentacam measurements: index of surface variance, index of vertical asymmetry, keratoconus index, central keratoconus index, index of height asymmetry, and index of height decentration. We also analyzed corneal wavefront parameters. Root mean square values of the corneal higher order aberrations (HOAs), with analysis up to the 7th order of the corneal HOAs by expanding the set of Zernike mode, were calculated from Pentacam measurements. All examinations were performed preoperatively, 4 to 6 weeks after ICRS implantation, 6 to 8 months after CXL, and 12 months after ICL implantation.
ICRS (Ferrara Ring; Mediphacos, Inc., Belo Horizonte, Brazil) implantation was performed under topical anesthesia with proparacaine hydrochloride 0.5% eye drops (Bausch & Lomb Pharmaceuticals, Tampa, FL). All intrastromal pockets were created using a femtosecond laser (IntraLase FS 150-kHz; Abbott Medical Optics, Abbott Park, IL) at an average depth of 70% of the thinnest area of the midperipheral cornea, assuming a minimum depth of 100 µm of corneal tissue thickness under the ring. The docking ring of the laser was centered on the pupillary axis. The incision was made in the midperipheral cornea at an axis that allowed insertion of the thickest segment of the rings in the steepest area of the cornea. A bandage contact lens (Acuvue Oasys; Johnson & Johnson Vision Care, Inc., Jacksonville, FL) was placed on the cornea at the end of the procedure and removed on the first day after the procedure. Postoperatively, patients received dexamethasone, neomycin sulfate, and polymyxin-B-sulfate eye drops (IsoptoMax; Novartis Pharma GmbH, Freiburg, Germany) five times daily for 2 weeks.
Four to six weeks after ICRS implantation, CXL was performed as described by Wollensak et al.1 CXL methods are described in Table 1. The eye was topically anesthetized with proparacaine hydrochloride 0.5% eye drops. After positioning the patient under the operating microscope, an eyelid speculum was inserted and the central 9-mm corneal epithelium was removed with a blunt spatula, and riboflavin (0.1% in 20% dextran T500 solution) was instilled topically every 5 minutes for 30 minutes. Riboflavin absorption throughout the corneal stroma and anterior chamber was confirmed by slit-lamp examination. The cornea was then aligned and exposed to an ultraviolet-A wavelength of 370 nm at an irradiance of 3 mW/cm2 for 30 minutes (CCL-365 system; PESCHKE Trade CCL-VARIO Cross-linking; Swissmed, Gdansk, Poland). A bandage contact lens was placed on the cornea at the end of the procedure for 5 days. Postoperatively, patients received ofloxacin drops four times daily for 5 days and unpreserved artificial tears (Hylo-Comod; Ursapharm GmbH, Saarbruecken, Germany) hourly until contact lens removal. After contact lens removal, patients received 0.1% fluorometholone drops (Efflumidex; Allergan, Inc., Center Valley, PA) five times daily for 5 weeks, then twice daily for 3 weeks, and once a day for 3 weeks.
A toric ICL (STAAR Surgical, Nidau, Switzerland) was implanted under topical anesthesia 6 to 8 months after CXL, as described by Abdelmassih et al.6 Calculation was based on manifest refraction using the maximum amount of astigmatism accepted by the patient using the software provided by the manufacturer (STAAR Surgical). Emmetropia was selected as the target refraction. The appropriate ICL size was determined based on the horizontal white-to-white distance measured manually with a caliper and the Oculus Pentacam, and the anterior chamber depth measured with the Oculus Pentacam. A minor clinical adjustment of anterior chamber depth was performed by subtracting no more than 0.2 mm whenever corneal anterior bulging was advanced. The chosen axis of astigmatism was always the axis obtained by manifest refraction. The planned axis of the ICL was marked by the surgeon with the patient upright to control cyclotorsion. A 2.75-mm clear corneal tunnel incision was performed in the horizontal temporal meridian (regardless of the astigmatism axis). The anterior chamber was filled with sodium hyaluronate 1% (Healon; Johnson & Johnson Vision Care, Santa Ana, CA), and the ICL was implanted. After alignment of the ICL at the intended axis, the viscoelastic material was removed by irrigation/aspiration. Postoperatively, dexamethasone and neomycin sulfate polymyxin-B-sulfate drops were used four times daily for 10 days, and nepafenac drops (Nevanac; Alcon Novartis Europharm Limited, Camberley, United Kingdom) were used three times daily for 4 weeks.
SPSS for Windows software (version 20.0; SPSS, Inc., Chicago, IL) was used for data management and analyses. Descriptive statistics were presented as mean and standard deviation for continuous variables. The Wilcoxon signed-ranked-sum test was used to compare the different continuous parameters. A P value of less than .05 was considered to be statistically significant.
Visual Acuity, Refraction, and Keratometry
Results after each step of the three-step procedure, compared to baseline, are presented using the standard graphs for reporting astigmatism outcomes after refractive surgery (Figure 1).8 Compared to baseline, decimal UDVA increased significantly from 0.13 before surgery to 0.69 after ICL implantation (Table 2). Decimal CDVA also showed a significant increase compared to baseline: from 0.56 ± 0.24 before surgery to 0.65 ± 0.21 after ICRS implantation (P = .043), to 0.72 ± 0.20 after CXL (P = .028), and to 0.80 ± 0.18 after ICL implantation (P = .009) (Table 2). Figure 1 reflects the significant increase in CDVA, especially at the higher acuity levels, and the significant decrease of astigmatism after each of the three surgical procedures. Figure A (available in the online version of this article) shows a double-angle plot of refractive astigmatism before surgery and after each step. The greatest change of refractive astigmatism, compared to baseline, was observed after ICL implantation.
Nine standard graphs for reporting astigmatism outcomes of refractive surgery. Results shown after each step compared to preoperative values: after implantation of intracorneal ring segments (post-ICRS), corneal cross-linking (post-CXL), and implantation of intraocular contact lenses (post-ICL). UDVA = uncorrected distance visual acuity; CDVA = corrected distance visual acuity; SEQ = spherical equivalent; D = diopters
Visual Acuity, Refraction and Keratometry Before and After Three-Step Surgery for Keratoconus
Double-angle plot of refractive astigmatism before and after three-step surgery for keratoconus: (A) preoperative values; (B) values after implantation of intracorneal ring segments (post-ICRS); (C) values after corneal cross-linking (post-CXL); and (D) values after implantation of intraocular contact lenses (post-ICL). D = diopters
Corneal Topography and Corneal Wavefront
The mean values of the corneal indices derived from Pentacam measurements are shown in Table 3. The index of surface variance, index of vertical asymmetry, keratoconus index, and index of height decentration improved significantly after surgery, indicating a more regular and centered corneal topography. The main reason for improvement was ICRS implantation, because these indices improved significantly after ICRS implantation but did not further improve after ICL implantation.
Topometric Indices Before Surgery, After Implantation of ICRS, and After ICL Implantation
The values of corneal wavefront changes derived from Pentacam measurements are shown in Table 4. HOAs, spherical aberration, and coma decreased significantly after the three-step procedure compared to baseline. The main factor in this decrease was ICRS implantation, because HOAs, spherical aberration, and coma decreased significantly after ICRS implantation, whereas there was no significant change in corneal wavefront parameters after CXL and ICL implantation (Table 4).
Corneal Wavefront Changes After Each Step of the Three-Step Surgical Treatment
In 3 eyes, migration of one ICRS occurred. The incision was sutured in one of these eyes; in the other 2 eyes, one segment had to be exchanged for a larger one to resolve this complication. Another 3 eyes developed clinically significant haze (2+) after CXL, which resolved by the 6-month follow-up visit with topical steroid treatment. No other intraoperative or postoperative complications occurred.
Regarding safety, at the last follow-up visit, 61% of eyes had gained two or more lines of CDVA, 15% gained one line, and 24% remained unchanged. None lost any lines (Figure 1).
Previous studies indicated that the three-step ICRS–CXL–ICL procedure was effective and safe to correct high residual refractive error and improve visual acuity in patients with moderate to severe keratoconus with up to 2 years of follow-up.6,9 The number of eyes included was small; 11 eyes reached 6 months of follow-up and 16 eyes reached 24 months of follow-up only. In our study, 31 eyes of 24 patients were treated with the three-step procedure, and all had 12 months of follow-up. Regarding post-LASIK ectasia, it was also shown that a combination of ICRS and CXL is safe and effective.10
We found a significant improvement in UDVA and CDVA (Table 2 and Figure 1), a significant reduction of refractive astigmatism (Figures 1–2), and a significant improvement in topographic corneal indices (Table 3) and corneal wavefront parameters (Table 4). Our results confirm the findings of these studies.6,9,10 The three surgical steps complement each other to improve vision. ICRS implantation leads to improved UDVA and CDVA in keratoconic eyes (Table 2). This is due to a more regular corneal center, as indicated by the significant improvement in corneal regularity indices (Table 3) and corneal wavefront parameters (Table 4). CXL stabilizes and presumably also regularizes the cornea, adding to an improved corneal shape, but differences were not statistically significant (Table 4). The positive effect of both ICRS and CXL alone is not controversial, but the additive effect is. One study suggested that CXL has an additive effect on ICRS implantation in keratoconic eyes and may be considered as an enhancement and stabilizing method because CXL after ICRS further improved CDVA, but follow-up was short (2 months after CXL).11 Our results did not show an additive effect because corneal wavefront parameters did not change significantly after CXL compared to values after ICRS implantation (Table 4).
The first two steps (ICRS implantation and CXL) regularize the cornea, as indicated by the significant improvement of the corneal topographic indices (Table 3). The third component (ICL implantation) targets manifest refraction, especially refractive astigmatism, to improve both UDVA and CDVA. Typically, toric ICLs have to be used because most eyes show high astigmatism. Earlier studies showed that ICL after CXL or after ICRS and CXL resulted in a predictable correction of spherical and cylindrical refractive errors.6,9,12 Our results confirm these reports on a larger number of eyes.
The three-step procedure described here seems to be a safe and effective treatment of moderate to severe keratoconus and post-LASIK ectasia, improving visual acuity and corneal surface regularity.
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620–627. doi:10.1016/S0002-9394(02)02220-1 [CrossRef]
- Kymionis GD, Siganos CS, Tsiklis NS, et al. Long-term follow-up of Intacs in keratoconus. Am J Ophthalmol. 2007;143(2):236–244. doi:10.1016/j.ajo.2006.10.041 [CrossRef]
- 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(9):S812–S818. doi:10.3928/1081597X-20090813-10 [CrossRef]
- Kamiya K, Shimizu K, Kobashi H, et al. Clinical outcomes of posterior chamber toric phakic intraocular lens implantation for the correction of high myopic astigmatism in eyes with keratoconus: 6-month follow-up. Graefes Arch Clin Exp Ophthalmol. 2011;249(7):1073–1080. doi:10.1007/s00417-010-1540-5 [CrossRef]
- Fadlallah A, Dirani A, El Rami H, Cherfane G, Jarade E. Safety and visual outcome of Visian toric ICL implantation after corneal collagen cross-linking in keratoconus. J Refract Surg. 2013;29(2):84–89. doi:10.3928/1081597X-20130117-01 [CrossRef]
- Abdelmassih Y, El-Khoury S, Chelala E, Slim E, Cherfan CG, Jarade E. Toric ICL implantation after sequential intracorneal ring segments implantation and corneal cross-linking in keratoconus: 2-year follow-up. J Refract Surg. 2017;33(9):610–616. doi:10.3928/1081597X-20170621-02 [CrossRef]
- Greenstein SA, Fry KL, Hersh PS. Corneal topography indices after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37(7):1282–1290. doi:10.1016/j.jcrs.2011.01.029 [CrossRef]
- Reinstein DZ, Archer TJ, Randleman JB. JRS standard for reporting astigmatism outcomes of refractive surgery. J Refract Surg. 2014;30(10):654–659. doi:10.3928/1081597X-20140903-01 [CrossRef]
- Dirani A, Fadlallah A, Khoueir Z, Antoun J, Cherfan G, Jarade E. Visian toric ICL implantation after intracorneal ring segments implantation and corneal collagen crosslinking in keratoconus. Eur J Ophthalmol. 2014;24(3):338–344. doi:10.5301/ejo.5000384 [CrossRef]
- Kamburoglu G, Ertan A. Intacs implantation with sequential collagen cross-linking treatment in postoperative LASIK ectasia. J Refract Surg. 2008;24(7):S726–S729. doi:10.3928/1081597X-20080901-16 [CrossRef]
- Ertan A, Karacal H, Kamburoglu G. Refractive and topographic results of transepithelial cross-linking treatment in eyes with Intacs. Cornea. 2009;28(7):719–723. doi:10.1097/ICO.0b013e318191b83d [CrossRef]
- Shafik Shaheen M, El-Kateb M, El-Samadouny MA, Zaghloul H. Evaluation of a toric implantable collamer lens after corneal collagen crosslinking in treatment of early-stage keratoconus: 3-year follow-up. Cornea. 2014;33(5):475–480. doi:10.1097/ICO.0000000000000094 [CrossRef]
|Parameter||Variable (Alternate Examples)|
|Treatment target||Keratoconus (ectasia)|
|Fluence (total) (J/cm2)||5.4|
|Soak time and interval (minutes)||30(q2)|
|Treatment time (minutes)||30|
|Chromophore carrier||20% dextran (others)|
|Chromophore osmolarity||Iso-osmolar (hypo-osmolar)|
|Light source||PESCHKE Trade CCL-VARIO Cross-linking; Swissmed, Gdansk, Poland|
|Irradiation mode (interval)||Continuous|
|Protocol modifications||Contact lens-assisted|
|Protocol abbreviation in manuscript||S-CXL(3*30) (standard)|
Visual Acuity, Refraction and Keratometry Before and After Three-Step Surgery for Keratoconusa
|UDVA (decimal)||0.13 ± 0.17||0.19 ± 0.20b||0.24 ± 0.23b||0.69 ± 0.18b,c,d|
|CDVA (decimal)||0.56 ± 0.24||0.65 ± 0.21b||0.72 ± 0.20b,c||0.80 ± 0.18b,c,d|
|Sphere (D)||−2.76 ± 5.26||−1.53 ± 3.25b||−1.53 ± 3.25b||0.24 ± 0.72b,c,d|
|Cylinder (D)||−4.93 ± 2.21||−3.36 ± 1.90b||−3.14 ± 1.71b||−0.63 ± 0.67b,c,d|
|Spherical equivalent (D)||−5.23 ± 5.55||−3.21 ± 3.35b||−3.13 ± 3.32b||−0.08 ± 0.72b|
|K (steep) (D)||49.20 ± 4.21||49.15 ± 3.75b||48.89 ± 3.40b||47.23 ± 3.89b|
|K (flat) (D)||45.06 ± 3.71||45.91 ± 3.35||44.39 ± 3.47b||43.44 ± 3.57b|
|K (average) (D)||46.90 ± 3.86||48.48 ± 4.16b||47.08 ± 4.66b||45.22 ± 3.51b|
|CCT (µm)||457 ± 47||472 ± 57||458 ± 52||463 ± 52|
Topometric Indices Before Surgery, After Implantation of ICRS, and After ICL Implantationa
|Preoperative||85 ± 3 (23 to 138)||0.90 ± 0.39 (0.16 to 1.68)||1.22 ± 0.11 (1.05 to 1.43)||1.06 ± 0.06 (0.96 to 1.22)||29 ± 24 (0 to 80)||0.12 ± 0.07 (0.02 to 0.40)|
|After ICRS||71 ± 30 (16 to 131)||0.79 ± 0.38 (0.19 to 1.78)||1.17 ± 0.12 (0.93 to 1.40)||1.05 ± 0.05 (0.97 to 1.20)||28 ± 23 (0.2 to 99)||0.09 ± 0.05 (0.01 to 0.18)|
|Pb||< .05||< .05||< .05||NS||NS||< .05|
|After ICL||64 ± 27 (16 to 120)||0.63 ± 0.28 (0.14 to 1.17)||1.15 ± 0.10 (1.00 to 1.35)||1.06 ± 0.06 (0.97 to 1.21)||30 ± 25 (0.3 to 98)||0.07 ± 0.04 (0.005 to 0.17)|
|Pc||< .05||< .05||< .05||NS||NS||< .05|
Corneal Wavefront Changes After Each Step of the Three-Step Surgical Treatmenta
|Parameter||HOAs||SA||Coma (Vertical)||Coma (Horizontal)||Trefoil (Vertical)||Trefoil (Horizontal)|
|Preoperative||4.59 ± 1.83 (1.34 to 8.53)||−0.57 ± 1.78 (−4.43 to 3.57)||−3.62 ± 1.74 (−6.99 to −0.18)||−0.22 ±1.32 (−2.26 to 2.47)||0.21 ± 0.76 (−1.58 to 2.33)||0.01 ± 0.49 (−0.96 to 1.36)|
|After ICRS||4.06 ± 1.77 (1.06 to 7.99)||0.32 ± 1.57 (−2.72 to 4.50)||−2.87 ± 1.96 (−7.41 to 0.57)||0.22 ± 1.04 (−2.46 to 2.59)||0.15 ± 0.98 (−0.98 to 3.38)||−0.14 ± 0.58 (−1.68 to 1.06)|
|After CXL||3.80 ± 1.83 (1.50 to 7.40)||0.10 ± 1.68 (−3.34 to 2.32)||−2.55 ± 2.15 (−6.94 to 0.27)||0.44 ± 0.78 (−1.36 to 1.53)||−0.05 ± 0.60 (−0.95 to 0.91)||0.02 ± 0.81 (−1.63 to 1.19)|
|After ICL||3.78 ± 1.58 (1.62 to 7.82)||0.40 ± 1.50 (−2.53 to 3.32)||−2.49 ± 1.71 (−6.34 to 0.20)||0.29 ± 1.05 (−1.92 to 1.89)||0.17 ± 0.83 (−1.24 to 2.67)||−0.17 ± 0.98 (−2.46 to 1.56)|
|Pb||< .05||< .05||< .05||< .05||NS||NS|
|Pe||< .05||< .05||< .05||< .05||NS||NS|