Abstract
Purpose
To present the case of a patient that underwent corneal crosslinking for progressive keratoconus and 18 months later revealed clinically significant corneal stromal haze.
Observations
A 20-year-old male presented with progressive visual loss OU for the past few years. His corrected distance visual acuity (CDVA) OD was 20/30 (−2.75 -1.75 @55) and OS 20/30 (−0.50 -1.75@110). Corneal topography revealed keratoconus OU and the patient underwent corneal crosslinking according to the Dresden Protocol. The postoperative regimen included combined tobramycin and dexamethasone qid along with lubrication until epithelium healed and then fluorometholone qid with weekly tapering. At 3 months postoperatively, his topography was stable and his corrected distance visual acuity (CDVA) was 20/25 OU. On slit lamp examination, only clinically insignificant stromal haze was observed. At 18 months postoperatively, the patient reported vision deterioration. On examination his CDVA was 20/25 in right eye, and 20/40 in his left eye. Deep stromal haze was revealed in his central cornea, more dense in his left eye. Corneal topography was stable and the CDVA loss was attributed to the notable deep stromal haze. The patient was treated with dexamethasone qid with biweekly tapering. 18 months after corneal crosslinking, the patient demonstrated clinically significant stromal haze, most prominent OS. He was treated with dexamethasone qid. One month later his CDVA OS gradually improved to 20/25, and stromal haze was still noted but less dense.
Conclusions and importance
Late-onset deep corneal haze is a possible complication of corneal crosslinking in keratoconic patients.
Keywords: Corneal haze, Corneal crosslinking, Keratoconus
1. Introduction
Corneal Cross-linking (CXL) is becoming an increasingly popular technique for the treatment of corneal ectatic disorders.1, 2, 3, 4 However, although the technique has been proven to be effective, the stabilization of cornea ectasia, occurring after CXL, is accompanied by changes in microscopic structure and properties of the cornea.5, 6, 7, 8
According to corneal confocal microscopy studies, there is an immediate keratocyte desertion after CXL, followed by repopulation by activated keratocytes as early as 2 months postoperatively.9,10 It is possible that these activated keratocytes contribute to the development of CXL-associated corneal haze. Other factors that may contribute to CXL-associated corneal haze include stromal swelling pressure changes,11 proteoglycan-collagen interactions,12 and glycosaminoglycan hydration.13 Greenstein et al. studied the natural history of corneal haze after CXL and found that corneal haze has a peak at 1 month after CXL, reaches a plateau between 1 and 3 months, begins to clear 3–6 months after the procedure, and continues to decrease between 6 months and 1-year post-CXL.5
Herein, we report a case of late-onset deep corneal haze, which developed 18 months after CXL in a young patient with keratoconus and significantly affected vision. The case was documented with corneal confocal microscopy and treated successfully with topical steroids.
2. Case report
A 20-year old male presented to our clinic with progressive visual loss OU for the past few years. The patient had no past medical history. His previous ophthalmic history included use of spectacles for myopia and astigmatism bilaterally.
His corrected distance visual acuity (CDVA) at presentation was 20/30 (manifest refraction, MR: −2.75 -1.75 @55) in the right eye and 20/30 (MR: −0.50 -1.75@110) in the left eye. Slit lamp examination of anterior and posterior segment revealed no remarkable findings. Corneal topography and pachymetry revealed keratoconus bilaterally (Fig. 1).
Fig. 1.
Corneal topography. Keratoconus bilaterally.
Taking into consideration the young age of the patient and the self-reported visual acuity decline over the past years, we decided to perform CXL, in order to halt the progression of keratoconus. The procedure was uncomplicated. It was performed according to the Dresden Protocol bilaterally.7
The postoperative regimen included combined tobramycin and dexamethasone qid along with lubricant eye drops until epithelium healed and then fluorometholone qid with weekly tapering. At 3 and 6 months postoperatively, his topography was stable and his corrected distance visual acuity (CDVA) was 20/25 OU. On slit lamp examination, only trace stromal haze was observed.
At 18 months postoperatively, the patient reported vision deterioration. On examination his CDVA was 20/25 in right eye, and 20/40 in his left eye. Deep stromal haze was observed in his central cornea, more prominent in his left eye. Corneal topography was stable and the CDVA loss was attributed to the notable deep haze (Fig. 2). Corneal confocal microscopy revealed activated keratocytes and linear hyperreflective structures in the posterior stroma (Fig. 3).
Fig. 2.
Slit-lamp photos of the left eye. Deep stromal haze.
Fig. 3.
Corneal confocal microscopy. Activated keratocytes and linear hyperreflective structures in the posterior stroma.
The patient was treated with dexamethasone qid with biweekly tapering. One month later his CDVA OS gradually improved to 20/25, and stromal haze was still noted but less dense (Fig. 4).
Fig. 4.
Slit-lamp photos of left eye after treatment. Stromal haze but less dense.
3. Discussion
In this report we present a case of a young patient, who developed visually significant stromal haze after CXL in the late postoperative period. Contrary to our case, early onset clinically non-significant corneal haze is very common after CXL and considered by some authors to be part of the natural history of the condition after the procedure.7,14
In a study by Greenstein et al., haze was measured by both Scheimpflug densitometry and slit-lamp assessment and it was found to increase postoperatively. The rise peaked at 1 month and reached its plateau between 1 and 3 months. Consequently, between 3 and 6 months, the cornea began to clear and there was a significant decrease in CXL-associated corneal haze. From 6 months to 1 year postoperatively, there continued to be a decrease in haze measurements.5 A few other studies also revealed a similar clinical appearance of post-CXL haze, however, nearly all cases of this corneal haze were clinically insignificant.7,15,16
As far as late-onset corneal haze after CXL, Omary R et al. reported a case of a clinically significant corneal haze that appeared 11 months after CXL and persisted with only slow and incomplete clearing with topical steroid treatment.14 In our patient, clinically significant corneal haze appeared in the late postoperative period, 18 months after CXL, and treated successfully with topical steroids.
According to a study by Koppen et al., clinically significant corneal haze appears in about 8.6% of eyes after CXL,15 and it may persist for over a year after treatment.16 Authors suggest that advanced keratoconus should be considered at higher risk of haze development after CXL due to low corneal thickness and high corneal curvature.17
The haze after CXL differs from the haze after PRK in stromal depth. Whereas haze after PRK is strictly subepithelial, haze after CXL extends into the stroma, on average equal to an absolute depth of 300 μm. Additionally, clinical characteristics of haze differ between procedures, since haze after CXL is compiled by hyper-reflective structures and dust-like changes in the mid-stroma, whereas haze after PRK has a more reticulated subepithelial appearance.3 The haze may be associated with the depth of CXL into the stroma as well as the amount of keratocyte loss.13,18,19 Typically, late permanent scarring should be differentiated from the early postoperative temporary haze which is often paracentral and compatible with good visual results.4 It may not be actually related to CXL itself but rather to the ongoing disease process and corneal remodeling.16
In conclusion, this case demonstrates that late-onset, clinically significant, deep corneal haze is a possible complication of CXL in patients with keratoconus. A few cases have been described after PRK and lasek,20 but to our knowledge, there is only one other case report that presented this complication after CXL in a patient with keratoconus. More evidence-based research is needed in order to clarify and confirm the mechanism of such late-onset corneal haze.
Acknowledgements and disclosures
Funding: No funding or grant support
Conflicts of interest: The following authors have no financial disclosures: V.P, L.K., I.C., G.K., E.P.
Authorship: All authors attest that they meet the current ICMJE criteria for Authorship.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2019.02.008.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
References
- 1.Iseli H.P., Thiel M.A., Hafezi F., Kampmeier J., Seiler T. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea. 2008;27(5):590–594. doi: 10.1097/ICO.0b013e318169d698. [DOI] [PubMed] [Google Scholar]
- 2.Spörl E., Huhle M., Kasper M., Seiler T. Artificial stiffening of the cornea by induction of intrastromal cross-links. Ophthalmologe. 1997;94(12):902–906. doi: 10.1007/s003470050219. [DOI] [PubMed] [Google Scholar]
- 3.Chan C.C., Sharma M., Wachler B.S. Effect of inferior-segment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg. 2007;33(1):75–80. doi: 10.1016/j.jcrs.2006.09.012. [DOI] [PubMed] [Google Scholar]
- 4.Chatzis N., Hafezi F. Progression of keratoconus and efficacy of pediatric corneal collagen cross-linking in children and adolescents. J Refract Surg. 2012;28(11):753–758. doi: 10.3928/1081597X-20121011-01. [DOI] [PubMed] [Google Scholar]
- 5.Greenstein S.A., Fry K.L., Bhatt J., Hersh P.S. Natural history of corneal haze after collagen crosslinking for keratoconus and cornealectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg. 2010;36:2105–2114. doi: 10.1016/j.jcrs.2010.06.067. [DOI] [PubMed] [Google Scholar]
- 6.Greenstein S.A., Shah V.P., Fry K.L. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37:691–700. doi: 10.1016/j.jcrs.2010.10.052. [DOI] [PubMed] [Google Scholar]
- 7.Alhayek A., Lu P.R. Corneal collagen crosslinking in keratoconus and other eye disease. Int J Ophthalmol. 2015;8:407–418. doi: 10.3980/j.issn.2222-3959.2015.02.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kontadakis G.A., Ginis H., Karyotakis N. In vitro effect of corneal collagen cross-linking on corneal hydration properties and stiffness. Graefes Arch Clin Exp Ophthalmol. 2013;251(2):543–547. doi: 10.1007/s00417-012-2082-9. [DOI] [PubMed] [Google Scholar]
- 9.Kontadakis G.A., Kankariya V.P., Tsoulnaras K., Pallikaris A.I., Plaka A., Kymionis G.D. Long-term comparison of simultaneous topography-guided photorefractive keratectomy followed by corneal cross-linking versus corneal cross-linking alone. Ophthalmology. 2016;123(5):974–983. doi: 10.1016/j.ophtha.2016.01.010. [DOI] [PubMed] [Google Scholar]
- 10.Kymionis G.D., Diakonis V.F., Kalyvianaki M. One-year follow-up of corneal confocal microscopy after corneal cross-linking in patients with post laser in situ keratosmileusis ectasia and keratoconus. Am J Ophthalmol. 2009;147(5):774–778. doi: 10.1016/j.ajo.2008.11.017. [DOI] [PubMed] [Google Scholar]
- 11.Dohlman C.H., Hedbys B.O., Mishima S. The swelling pressure of the corneal stroma. Invest Ophthalmol. 1962;1:158–162. [PubMed] [Google Scholar]
- 12.Michelacci Y.M. Collagens and proteoglycans of the corneal extracellular matrix. Braz J Med Biol Res. 2003;36(8):1037–1046. doi: 10.1590/s0100-879x2003000800009. [DOI] [PubMed] [Google Scholar]
- 13.Wollensak G., Aurich H., Pham D.T., Wirbelauer C. Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A. J Cataract Refract Surg. 2007;33(3):516–521. doi: 10.1016/j.jcrs.2006.11.015. [DOI] [PubMed] [Google Scholar]
- 14.Omary R., Shehadeh-Mashor R. Late onset of persistent, deep stromal haze after corneal cross-linking in a patient with keratoconus. Can J Ophthalmol. 2017 Apr;52(2):e81–e83. doi: 10.1016/j.jcjo.2016.10.014. [DOI] [PubMed] [Google Scholar]
- 15.Koppen C., Vryghem J.C., Gobin L., Tassignon M.J. Keratitis and corneal scarring after UVA/riboflavin cross-linking for keratoconus. J Refract Surg. 2009;25(9):S819–S823. doi: 10.3928/1081597X-20090813-11. [DOI] [PubMed] [Google Scholar]
- 16.Dhawan S., Rao K., Natrajan S. Complications of corneal collagen cross-linking. J Ophthalmol. 2011;2011:869015. doi: 10.1155/2011/869015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Raiskup F., Hoyer A., Spoerl E. Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg. 2009;25(9):S824–S828. doi: 10.3928/1081597X-20090813-12. [DOI] [PubMed] [Google Scholar]
- 18.Hafezi F., Kanellopoulos J., Wiltfang R., Seiler T. Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2007;33(12):2035–2040. doi: 10.1016/j.jcrs.2007.07.028. [DOI] [PubMed] [Google Scholar]
- 19.Vinciguerra P., Albè E., Trazza S. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology. 2009;116(3):369–378. doi: 10.1016/j.ophtha.2008.09.048. [DOI] [PubMed] [Google Scholar]
- 20.Qazi M.A., Johnson T.W., Pepose J.S. Development of late onset subepithelial corneal haze after laser-assisted subepithelial keratectomy with prophylactic intraoperative mitomycin-C: case report and literature review. J Cataract Refract Surg. 2006;32:1573–1578. doi: 10.1016/j.jcrs.2006.04.027. [DOI] [PubMed] [Google Scholar]
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