Keratoconus is a progressive, non-inflammatory, and mostly bilateral disease with steepening and thinning of the cornea and, thus, irregular astigmatism.1 The pathogenesis of keratoconus is unclear. Genetic factors,2 eye rubbing,3,4 and subclinical inflammation5 have been considered. For more than 30 years, it has been known that keratoconus is associated with weakening of the biomechanics of the diseased cornea6,7 and even only localized reduction of the elastic modulus leading to the typical tomography of the keratoconic cornea.8
Corneal cross-linking (CXL) tries to reverse this softening effect by inducing new chemical bonds within the extracellular matrix.9 The clinically accepted procedure includes ultraviolet light and riboflavin as a photomediator and results in halting keratoconus progression in more than 90% of the cases10 with a low rate of complications.11 In a minority of treated eyes, corneal flattening occurs as a side effect12,13 within the first years after CXL, stabilizing after 1 to 3 years.14,15
In this series, we present 3 cases with continuous flattening of the cornea during follow-up of up to 12 years after CXL.
Between 2005 and 2007, 433 eyes with documented progressive keratoconus were treated with CXL at the Institut für Refraktive und Ophthalmo-Chirurgie (IROC, Zürich, Switzerland) and the Silmalaser Eye Clinic (Tallinn, Estonia). Inclusion criteria for the current study were a follow-up period of 10 years or more, no additional corneal operations such as additional CXL or refractive surgeries, and no complications of CXL such as scarring or infection. At that time, the CXL procedure was performed according to the Dresden protocol. This included epithelial removal, application of 0.1% riboflavin diluted in aqueous 20% dextran for 30 minutes, and continuous ultraviolet-A irradiation with an irradiance of 3 mW/cm2 for 30 minutes resulting in a radiant exposure of 5.4 J/cm2. Corneal tomography measurements were obtained by a rotating Scheimpflug camera (Pentacam HR; Oculus Optikgeräte, Wetzlar, Germany) and Placido system (Topolyzer; WaveLight, Erlangen, Germany). Manifest refraction was determined using the fogging technique. We selected average keratometry (Kmean) (average of steep and flat keratometry of the central 3-mm zone), and the maximum of the posterior float (reference: best fit sphere, within a diameter of 8 mm) as parameters characterizing the remodeling process. In total, 45 eyes met the inclusion criteria and 3 eyes (6.7%) of 3 patients showed continued flattening.
A 24-year-old man was referred in the summer of 2005 with bilateral progressive keratoconus and CDVA (with spectacles) in the right eye of 1.0 (20/20 Snellen) with a refraction of −2.00 −1.50 × 160°. The right eye underwent CXL in December 2005 according to the standard Dresden protocol. The surgery and the early postoperative follow-up were uneventful. The cornea was clear without any opacity after 1 year postoperatively.
After CXL, the progression of keratoconus was halted and the keratometry values decreased continuously during 12 postoperative years (Figure 1). Kmean decreased from 44.5 D preoperatively to 39.6 D in 2017. Surprisingly, the reduction of Kmean was nearly linear, indicating a constant process over time (Figure 2). The maximum of the posterior float decreased from 23 μm in 2006 to 15 μm in 2014; after 2014 a maximum could not be identified any more. The spherical equivalent of the refraction changed from −2.75 D in 2005 to +2.00 D in 2017 and the refractive astigmatism remained constant at ±0.5 D. CDVA (with spectacles) fluctuated between 1.2 and 1.0 (20/16 and 20/20 Snellen) in both eyes over the years with no trend. Corneal pachymetry at the thinnest point was 430 μm prior to CXL, increased to 445 μm within the first postoperative year, and remained stable until 2017. A similar linear evolution was found in the fellow eye, but the amount of flattening was less than 3 D.
Corneal topographies 1, 4, 7, and 10 years after corneal cross-linking (case 1).
Temporal evolution of average keratometry (Kmean) after corneal cross-linking (CXL) of all 3 cases (yellow: case 1; black: case 2; red: case 3). The decreases of Kmean are linear indicating a process without apparent end. D = diopters
A 47-year-old woman presented in 2007 with bilateral keratoconus and CDVA (with spectacles) in the left eye of 0.32 (20/63 Snellen) with a refraction of −6.50 −5.00 × 145°. The left eye underwent CXL in 2007 using the standard Dresden protocol. The surgery was uneventful, but a postoperative central stromal haze occurred that resolved within 2 years.
After CXL, the progression of keratoconus stopped and the keratometry values decreased continuously during 10 postoperative years (Figure 3). Kmean decreased from 49.0 D in 2007 to 40.1 D in 2017 (Figure 2) and the maximum posterior float decreased from 31 μm in 2007 to 18 μm in 2014; after 2014 a maximum could not be identified anymore. The spherical equivalent of the refraction changed from −9.00 D in 2007 to +1.00 D in 2017 with a refractive astigmatism change from −5.0 to −3.0 D. CDVA (with spectacles) fluctuated between 0.2 and 0.5 (20/100 to 20/40 Snellen) without trend. Corneal pachymetry decreased from 432 μm prior to CXL to 320 μm in 2017.
Corneal topographies 1, 4, 7, and 10 years after corneal cross-linking (case 2).
A 29-year-old man with bilateral keratoconus had been followed up at IROC since 2004. Because of documented progression, the left eye underwent CXL in 2006 using the standard Dresden protocol including swelling with hypotonic riboflavin solution because of an intraoperative thinnest corneal pachymetry of 340 μm. The operation was uneventful. The cornea developed the typical stromal haze during the first postoperative year but was clear at any time after.
Kmean showed a reduction of 7.5 D (Figure 2). The temporal evolution of axial curvature maps is depicted in Figure 4 for this case. The posterior float remained constant between 100 and 120 μm throughout the follow-up of 12 years. The keratometric astigmatism decreased from 2.9 D in 2007 to 0.1 D in 2017. The patient was visually rehabilitated by rigid contact lenses with 1.0 (20/20 Snellen) until he became intolerant in 2010. To maintain visual rehabilitation, a toric phakic intraocular lens (Artiflex; Ophtec, Groningen, Netherlands) was implanted through a scleral tunnel. From 2010 to 2017, the spherical equivalent of the manifest refraction changed from −1.75 to +0.75 D. Thinnest corneal pachymetry reduced from 340 to 290 μm during this time.
Corneal topographies 1, 4, 7, and 10 years after corneal cross-linking (CXL) (case 3).
Flattening of the cornea after CXL indicating remodeling of the stroma has been reported before.10,16 Even the first article reporting clinical results of CXL for keratoconus described a flattening of up to 2 D within 22 months after CXL.17 Prospective studies report a flattening of 1 D and more within 1 year after standard CXL in up to 40% of the eyes treated.12,13 Long-term follow-up revealed continuous flattening of approximately 2.5 D during the first 3 postoperative years followed by a phase of stability.15
The cases presented here differ substantially from the standard long-term behavior of corneas treated with CXL. The flattening process persisted longer than 3 years for up to 12 years. In all 3 eyes, the refraction changed from moderate myopia to hyperopia. These cases are also different from eyes experiencing strong flattening due to stromal scarring18 because none of the corneas showed stromal opacity other than transient stromal haze after CXL. In an anecdotal report, Kymionis et al.19 described a case with constant flattening during a course of 5 years that was paralleled by a significant thinning of the cornea by almost 50%. This corneal thinning was associated with scar formation in the posterior cornea. Two of our cases (case 2 and 3) showed a thinning of the cornea of 25% and 15%, respectively, in the absence of corneal opacification. The remaining third case showed neither thinning nor scarring.
In contrast, Santhiago et al.20 described 2 cases with an intense flattening of up to 14 D in the absence of stromal scars or substantial corneal thinning within the first postoperative year. Although the amount of flattening is similar, the time frame differs substantially from 1 to 10 years in the cases presented here.
The surprising aspect of the flattening presented here is that the flattening rate remained almost constant for 10 years with no sign of asymptotic decline. In the first years, the patients experienced the flattening as a beneficial effect as myopia was reduced and emmetropia achieved. The constant flattening rate indicates that this process may continue and produce progressive hyperopia. The nature of this process is unknown, but typical explanations such as scarring (none of the eyes showed persistent stromal scars) or peripheral steepening with consecutive central flattening (after radial keratotomy) do not apply here. A central tissue defect resulting in central flattening might explain some of the effect, but an amount of tissue reduction according to Munnerlyn's formula21 is not observed. In addition, after entering the hyperopic domain we consider continuous flattening a complication of CXL. The prevalence of 6.7% may be overestimated because the reference group of follow-up visits after 10 years is biased. Long-term results in prospective trials may provide a more reliable rate of the complication “continued flattening after CXL.”
- Horner JF. [Zur Behandlung des Keratoconus]. Klin Monbl Augenheilkd. 1869;5:24–26.
- Valgaeren H, Koppen C, Van Camp G. A new perspective on the genetics of keratoconus: why have we not been more successful?Ophthalmic Genet. 2018;39:158–174. doi:10.1080/13816810.2017.1393831 [CrossRef]
- Krachmer JH. Eye rubbing can cause keratoconus. Cornea. 2004;23:539–540. doi:10.1097/01.ico.0000137168.24883.3e [CrossRef]
- Sugar J, Macsai MS. What causes keratoconus?Cornea. 2012;31:716–719. doi:10.1097/ICO.0b013e31823f8c72 [CrossRef]
- Galvis V, Sherwin T, Tello A, Merayo J, Barrera R, Acera A. Keratoconus: an inflammatory disorder?Eye (Lond). 2015;29:843–859. doi:10.1038/eye.2015.63 [CrossRef]
- Edmund C. Corneal elasticity and ocular rigidity in normal and keratoconic eyes. Acta Ophthalmol (Copenh). 1988;66:134–140. doi:10.1111/j.1755-3768.1988.tb04000.x [CrossRef]
- Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res. 1980;31:435–441. doi:10.1016/S0014-4835(80)80027-3 [CrossRef]
- Roberts CJ, Dupps WJ Jr, . Biomechanics of corneal ectasia and biomechanical treatments. J Cataract Refract Surg. 2014;40:991–998. doi:10.1016/j.jcrs.2014.04.013 [CrossRef]
- Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res. 1998;66:97–103. doi:10.1006/exer.1997.0410 [CrossRef]
- Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg. 2009;35:1358–1362. doi:10.1016/j.jcrs.2009.03.035 [CrossRef]
- Seiler TG, Schmidinger G, Fischinger I, Koller T, Seiler T. Complications of corneal cross-linking [article in German]. Ophthalmologe. 2013;110:639–644. doi:10.1007/s00347-012-2682-0 [CrossRef]
- Koller T, Pajic B, Vinciguerra P, Seiler T. Flattening of the cornea after collagen crosslinking for keratoconus. J Cataract Refract Surg. 2011;37:1488–1492. doi:10.1016/j.jcrs.2011.03.041 [CrossRef]
- Seiler TG, Fischinger I, Koller T, Zapp D, Freuh BE, Seiler T. Customized corneal cross-linking: one-year results. Am J Ophthalmol. 2016;166:14–21. doi:10.1016/j.ajo.2016.02.029 [CrossRef]
- O'Brart DP, Patel P, Lascaratos G, et al. Corneal cross-linking to halt the progression of keratoconus and corneal ectasia: seven-year follow-up. Am J Ophthalmol. 2015;160:1154–1163. doi:10.1016/j.ajo.2015.08.023 [CrossRef]
- Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen cross-linking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008;34:796–801. doi:10.1016/j.jcrs.2007.12.039 [CrossRef]
- Hersh PS, Stulting RD, Muller D, et al. United States Multi-center Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment. Ophthalmology. 2017;124:1259–1270. doi:10.1016/j.ophtha.2017.03.052 [CrossRef]
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620–627. doi:10.1016/S0002-9394(02)02220-1 [CrossRef]
- Hafezi F, Koller T, Vinciguerra P, Seiler T. Marked remodelling of the anterior corneal surface following collagen cross-linking with riboflavin and UVA. Br J Ophthalmol. 2011;95:1171–1172. doi:10.1136/bjo.2010.184978 [CrossRef]
- Kymionis GD, Tsoulnaras KI, Liakopoulos DA, Paraskevopolous TA, Kouropaki AT, Tsilimarbis MK. Corneal flattening and thinning after corneal cross-linking: single-case report with 5-year follow-up. Cornea. 2015;34:704–706. doi:10.1097/ICO.0000000000000424 [CrossRef]
- Santhiago MR, Giacomin NT, Medeiros CS, Smadja D, Bechara SJ. Intense early flattening after corneal collagen cross-linking. J Refract Surg. 2015;31:419–422. doi:10.3928/1081597X-20150521-09 [CrossRef]
- Munnerlyn CR, Koons SJ, Marshall J. Photorefractive keratectomy: a technique for laser refractive surgery. J Cataract Refract Surg. 1988;14:46–52. doi:10.1016/S0886-3350(88)80063-4 [CrossRef]