Skip to main content

Corneal densitometry after accelerated corneal collagen cross-linking in progressive keratoconus

Abstract

Purpose

To analyze changes in corneal densitometry 3 months after accelerated corneal collagen cross-linking (CXL) measured with Scheimpflug tomography.

Methods

In this study we reviewed charts and anterior segment data of patients who had undergone accelerated pulsed epithelium-off CXL (30 mW/cm2 for 4 min, 8 min total radiation time) for treatment of progressive keratoconus in the Department of Ophthalmology, Goethe University, Frankfurt, Germany. Visual, topographic, pachymetric and densitometric data were extracted before surgery and at the 3-month follow-up. Corneal densitometry measurements from different corneal layers and zones obtained using Scheimpflug tomography (Pentacam HR, Oculus).

Results

The study investigated 12 eyes of 12 patients. The anterior (120 μm) stromal layer within the 0.0 to 2.0 mm and 2.0 to 6.0 mm concentric zones showed a significant elevation of mean densitometry 3 months post-surgery (P = 0.045; P = 0.015) compared to baseline. A mean stromal demarcation line was apparent at a depth of 203.00 μm ± 13.53 (SD). After accelerated CXL, no change in mean corrected distance visual acuity (LogMAR) was observed but a thinning of the cornea measured by a significant reduction in central pachymetry (μm).

Conclusion

Accelerated CXL results in an increase in corneal densitometry, particularly in the anterior stromal layer within the two central concentric zones (0.0 to 2.0 mm and 2.0 to 6.0 mm) of the cornea at 3 months postoperatively. The changes in corneal densitometry of the anterior stromal layer did not correlate with postoperative visual acuity or central pachymetry.

This is a preview of subscription content, access via your institution.

Fig. 1

Scheimpflug densitometry measured in gray-scale-units (GSU) at different concentric zones (0.0 to 2.0; 2.0 to 6.0; 6.0 to 10.0; 10.0 to 12.0 mm) and stromal depths of the cornea (anterior stromal layer (120 μm), posterior stromal layer (60 μm), middle stromal layer between these two layers). The standardized Scheimpflug densitometry is expressed in gray-scale-units (GSUs), which defines backward light scatter on a scale of 0 (minimum scatter; maximum transparency) to 100 (maximum scatter; minimum transparency)

Fig. 2
Fig. 3

Abbreviations

BSS:

Balanced salt solution

CDVA:

Corrected distance visual acuity

CXL:

Corneal collagen cross-linking

D:

Diopter

GSU:

Grayscale unit

LogMAR:

Logarithm of the minimum angle of resolution

OCT:

Optical coherence tomography

UDVA:

Uncorrected distance visual acuity

UV-A:

Ultraviolet-A

References

  1. Sykakis E, Karim R, Evans JR, Bunce C, Amissah-Arthur KN, Patwary S, McDonnell PJ, Hamada S (2015) Corneal collagen cross-linking for treating keratoconus. The Cochrane database of systematic reviews (3):Cd010621. https://doi.org/10.1002/14651858.cd010621.pub2

  2. Raiskup F, Lenk J, Herber R, Gatzioufas Z, Sporl E (2017) Therapeutic options in keratoconus. Klin Monbl Augenheilkd. https://doi.org/10.1055/s-0043-111797

    Article  PubMed  Google Scholar 

  3. Raiskup F, Velika V, Vesela M, Sporl E (2015) Cross-linking in keratoconus: “Epi-off” or “Epi-on”? Klin Monbl Augenheilkd 232(12):1392–1396. https://doi.org/10.1055/s-0035-1546155

    Article  CAS  PubMed  Google Scholar 

  4. Wollensak G, Spoerl E, Seiler T (2003) Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 135(5):620–627

    Article  CAS  PubMed  Google Scholar 

  5. Wernli J, Schumacher S, Spoerl E, Mrochen M (2013) The efficacy of corneal cross-linking shows a sudden decrease with very high intensity UV light and short treatment time. Invest Ophthalmol Vis Sci 54(2):1176–1180. https://doi.org/10.1167/iovs.12-11409

    Article  PubMed  Google Scholar 

  6. Zygoura V, Alio del Barrio J, Gatzioufas Z, Saw V, Raiskup F (2015) Evaluation of corneal stromal demarcation line depth following standard and a modified-accelerated collagen cross-linking protocol. Am J Ophthalmol 159(1):211–212. https://doi.org/10.1016/j.ajo.2014.10.018

    Article  PubMed  Google Scholar 

  7. Kymionis GD, Tsoulnaras KI, Grentzelos MA, Liakopoulos DA, Tsakalis NG, Blazaki SV, Paraskevopoulos TA, Tsilimbaris MK (2014) Evaluation of corneal stromal demarcation line depth following standard and a modified-accelerated collagen cross-linking protocol. Am J Ophthalmol 158(4):671

    Article  PubMed  Google Scholar 

  8. Webb JN, Su JP, Scarcelli G (2017) Mechanical outcome of accelerated corneal crosslinking evaluated by Brillouin microscopy. J Cataract Refract Surg 43(11):1458–1463. https://doi.org/10.1016/j.jcrs.2017.07.037

    Article  PubMed  PubMed Central  Google Scholar 

  9. Males JJ, Viswanathan D (2018) Comparative study of long-term outcomes of accelerated and conventional collagen crosslinking for progressive keratoconus. Eye 32(1):32–38. https://doi.org/10.1038/eye.2017.296

    Article  CAS  PubMed  Google Scholar 

  10. Woo JH, Iyer JV, Lim L, Hla MH, Mehta JS, Chan CM, Tan DT (2017) Conventional versus accelerated collagen cross-linking for keratoconus: a comparison of visual, refractive, topographic and biomechanical outcomes. Open Ophthalmol J 11:262–272. https://doi.org/10.2174/1874364101711010262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Raiskup F, Theuring A, Pillunat LE, Spoerl E (2015) Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: 10-year results. J Cataract Refract Surg 41(1):41–46. https://doi.org/10.1016/j.jcrs.2014.09.033

    Article  PubMed  Google Scholar 

  12. Kohlhaas M, Spoerl E, Schilde T, Unger G, Wittig C, Pillunat LE (2006) Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light. J Cataract Refract Surg 32(2):279–283. https://doi.org/10.1016/j.jcrs.2005.12.092

    Article  PubMed  Google Scholar 

  13. Baumeister M, Klaproth OK, Gehmlich J, Buhren J, Kohnen T (2009) Changes in corneal first-surface wavefront aberration after corneal collagen cross-linking in keratoconus. Klin Monbl Augenheilkd 226(9):752–756. https://doi.org/10.1055/s-0028-1109627

    Article  CAS  PubMed  Google Scholar 

  14. Koller T, Pajic B, Vinciguerra P, Seiler T (2011) Flattening of the cornea after collagen crosslinking for keratoconus. J Cataract Refract Surg 37(8):1488–1492. https://doi.org/10.1016/j.jcrs.2011.03.041

    Article  PubMed  Google Scholar 

  15. Asri D, Touboul D, Fournie P, Malet F, Garra C, Gallois A, Malecaze F, Colin J (2011) Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French national reference center for keratoconus. J Cataract Refract Surg 37(12):2137–2143. https://doi.org/10.1016/j.jcrs.2011.08.026

    Article  PubMed  Google Scholar 

  16. Seiler TG, Schmidinger G, Fischinger I, Koller T, Seiler T (2013) Complications of corneal cross-linking. Ophthalmologe 110(7):639–644. https://doi.org/10.1007/s00347-012-2682-0

    Article  CAS  PubMed  Google Scholar 

  17. Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A (2007) Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation. Clinical Exp Ophthalmol 35(6):580–582. https://doi.org/10.1111/j.1442-9071.2007.01536.x

    Article  Google Scholar 

  18. Raiskup F, Hoyer A, Spoerl E (2009) Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg 25(9):S824–S828. https://doi.org/10.3928/1081597x-20090813-12

    Article  PubMed  Google Scholar 

  19. Greenstein SA, Fry KL, Bhatt J, Hersh PS (2010) Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: scheimpflug and biomicroscopic analysis. J Cataract Refract Surg 36(12):2105–2114. https://doi.org/10.1016/j.jcrs.2010.06.067

    Article  PubMed  Google Scholar 

  20. Lopes B, Ramos I, Ambrosio R Jr (2014) Corneal densitometry in keratoconus. Cornea 33(12):1282–1286. https://doi.org/10.1097/ico.0000000000000266

    Article  PubMed  Google Scholar 

  21. Pircher N, Pachala M, Prager F, Pieh S, Schmidinger G (2015) Changes in straylight and densitometry values after corneal collagen crosslinking. J Cataract Refract Surg 41(5):1038–1043. https://doi.org/10.1016/j.jcrs.2014.07.043

    Article  PubMed  Google Scholar 

  22. Kohnen T, Neuhann T, Knorz MC (2014) Evaluation and quality assurance of refractive surgical interventions by the German Ophthalmology Society and the German Professional Association of Ophthalmologists (status 2014). Klin Monbl Augenheilkd 231(6):642–650. https://doi.org/10.1055/s-0034-1368481

    Article  CAS  PubMed  Google Scholar 

  23. Accelerated cross-linking with Pulsed illumination (2013). Clinical Update & Research News Volume 3(1): 1–4

  24. Wollensak G, Wilsch M, Spoerl E, Seiler T (2004) Collagen fiber diameter in the rabbit cornea after collagen crosslinking by riboflavin/UVA. Cornea 23(5):503–507

    Article  PubMed  Google Scholar 

  25. Wollensak G, Spoerl E, Wilsch M, Seiler T (2004) Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 23(1):43–49

    Article  PubMed  Google Scholar 

  26. Wilson SE, Kim WJ (1998) Keratocyte apoptosis: implications on corneal wound healing, tissue organization, and disease. Invest Ophthalmol Vis Sci 39(2):220–226

    CAS  PubMed  Google Scholar 

  27. Vinciguerra P, Albe E, Trazza S, Rosetta P, Vinciguerra R, Seiler T, Epstein D (2009) Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology 116(3):369–378. https://doi.org/10.1016/j.ophtha.2008.09.048

    Article  PubMed  Google Scholar 

  28. Netto MV, Mohan RR, Ambrosio R Jr, Hutcheon AE, Zieske JD, Wilson SE (2005) Wound healing in the cornea: a review of refractive surgery complications and new prospects for therapy. Cornea 24(5):509–522

    Article  PubMed  Google Scholar 

  29. Kim BZ, Jordan CA, McGhee CNJ, Patel DV (2016) Natural history of corneal haze after corneal collagen crosslinking in keratoconus using Scheimpflug analysis. J Cataract Refract Surg 42(7):1053–1059. https://doi.org/10.1016/j.jcrs.2016.04.019

    Article  PubMed  Google Scholar 

  30. Steven P, Hovakimyan M, Guthoff RF, Huttmann G, Stachs O (2010) Imaging corneal crosslinking by autofluorescence 2-photon microscopy, second harmonic generation, and fluorescence lifetime measurements. J Cataract Refract Surg 36(12):2150–2159. https://doi.org/10.1016/j.jcrs.2010.06.068

    Article  PubMed  Google Scholar 

  31. Kamaev P, Friedman MD, Sherr E, Muller D (2012) Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci 53(4):2360–2367. https://doi.org/10.1167/iovs.11-9385

    Article  PubMed  Google Scholar 

  32. Marshall J HP, Muller D (2013) Corneal collagen cross-linking; past, present, future [ebook]

  33. Koller T, Schumacher S, Fankhauser F 2nd, Seiler T (2013) Riboflavin/ultraviolet a crosslinking of the paracentral cornea. Cornea 32(2):165–168. https://doi.org/10.1097/ICO.0b013e318269059b

    Article  PubMed  Google Scholar 

  34. Moramarco A, Iovieno A, Sartori A, Fontana L (2015) Corneal stromal demarcation line after accelerated crosslinking using continuous and pulsed light. J Cataract Refract Surg 41(11):2546–2551. https://doi.org/10.1016/j.jcrs.2015.04.033

    Article  PubMed  Google Scholar 

  35. Moineau N, Sauvan L, Benichou J, Ho Wang Yin G, Hoffart L (2017) High-irradiance accelerated corneal collagen crosslinking for the treatment of keratoconus: a retrospective study. J Fr Ophtalmol 40(4):319–328. https://doi.org/10.1016/j.jfo.2016.11.014

    Article  CAS  PubMed  Google Scholar 

  36. Toker E, Cerman E, Ozcan DO, Seferoglu OB (2017) Efficacy of different accelerated corneal crosslinking protocols for progressive keratoconus. J Cataract Refract Surg 43(8):1089–1099. https://doi.org/10.1016/j.jcrs.2017.05.036

    Article  PubMed  Google Scholar 

  37. Mita M, Waring GOt, Tomita M (2014) High-irradiance accelerated collagen crosslinking for the treatment of keratoconus: six-month results. J Cataract Refract Surg 40(6):1032–1040. https://doi.org/10.1016/j.jcrs.2013.12.014

    Article  PubMed  Google Scholar 

  38. Greenstein SA, Shah VP, Fry KL, Hersh PS (2011) Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: 1-year results. J Cataract Refract Surg 37(4):691–700. https://doi.org/10.1016/j.jcrs.2010.10.052

    Article  PubMed  Google Scholar 

  39. Koller T, Iseli HP, Hafezi F, Vinciguerra P, Seiler T (2009) Scheimpflug imaging of corneas after collagen cross-linking. Cornea 28(5):510–515. https://doi.org/10.1097/ICO.0b013e3181915943

    Article  PubMed  Google Scholar 

  40. Grewal DS, Brar GS, Jain R, Sood V, Singla M, Grewal SP (2009) Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus: 1-year analysis using Scheimpflug imaging. J Cataract Refract Surg 35(3):425–432. https://doi.org/10.1016/j.jcrs.2008.11.046

    Article  PubMed  Google Scholar 

  41. Vinciguerra P, Albe E, Romano MR, Sabato L, Trazza S (2012) Stromal opacity after cross-linking. J Refract Surg 28(3):165. https://doi.org/10.3928/1081597x-20120301-04

    Article  PubMed  Google Scholar 

  42. Seiler T, Hafezi F (2006) Corneal cross-linking-induced stromal demarcation line. Cornea 25(9):1057–1059. https://doi.org/10.1097/01.ico.0000225720.38748.58

    Article  PubMed  Google Scholar 

  43. Bottos KM, Dreyfuss JL, Regatieri CV, Lima-Filho AA, Schor P, Nader HB, Chamon W (2008) Immunofluorescence confocal microscopy of porcine corneas following collagen cross-linking treatment with riboflavin and ultraviolet A. J Refract Surg 24(7):S715–719

    Article  Google Scholar 

  44. Wollensak G, Aurich H, Pham DT, Wirbelauer C (2007) Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A. J Cataract Refract Surg 33(3):516–521. https://doi.org/10.1016/j.jcrs.2006.11.015

    Article  PubMed  Google Scholar 

  45. Dohlman CH, Hedbys BO, Mishima S (1962) The swelling pressure of the corneal stroma. Investig Ophthalmol 1:158–162

    CAS  Google Scholar 

  46. Wollensak G, Iomdina E, Dittert DD, Herbst H (2007) Wound healing in the rabbit cornea after corneal collagen cross-linking with riboflavin and UVA. Cornea 26(5):600–605. https://doi.org/10.1097/ICO.0b013e318041f073

    Article  PubMed  Google Scholar 

  47. Mazzotta C, Traversi C, Baiocchi S, Caporossi O, Bovone C, Sparano MC, Balestrazzi A, Caporossi A (2008) Corneal healing after riboflavin ultraviolet-A collagen cross-linking determined by confocal laser scanning microscopy in vivo: early and late modifications. Am J Ophthalmol 146(4):527–533. https://doi.org/10.1016/j.ajo.2008.05.042

    Article  CAS  PubMed  Google Scholar 

  48. Mazzotta C, Baiocchi S, Caporossi O, Buccoliero D, Casprini F, Caporossi A, Balestrazzi A (2008) Confocal microscopy identification of keratoconus associated with posterior polymorphous corneal dystrophy. J Cataract Refract Surg 34(2):318–321. https://doi.org/10.1016/j.jcrs.2007.09.028

    Article  PubMed  Google Scholar 

  49. Michelacci YM (2003) Collagens and proteoglycans of the corneal extracellular matrix. Braz J Med Biol Res 36(8):1037–1046

    Article  CAS  PubMed  Google Scholar 

  50. Koc M, Uzel MM, Tekin K, Kosekahya P, Ozulken K, Yilmazbas P (2016) Effect of preoperative factors on visual acuity, corneal flattening, and corneal haze after accelerated corneal crosslinking. J Cataract Refract Surg 42(10):1483–1489. https://doi.org/10.1016/j.jcrs.2016.08.017

    Article  PubMed  Google Scholar 

  51. Wollensak G, Hammer T, Herrmann CI (2008) Haze or calcific band keratopathy after crosslinking treatment? Ophthalmologe 105(9):864–865. https://doi.org/10.1007/s00347-008-1831-y

    Article  CAS  PubMed  Google Scholar 

  52. Corbett MC, Prydal JI, Verma S, Oliver KM, Pande M, Marshall J (1996) An in vivo investigation of the structures responsible for corneal haze after photorefractive keratectomy and their effect on visual function. Ophthalmology 103(9):1366–1380

    Article  CAS  PubMed  Google Scholar 

  53. Shetty R, Agrawal A, Deshmukh R, Kaweri L, Rao HL, Nagaraja H, Jayadev C (2017) Effect of post crosslinking haze on the repeatability of Scheimpflug-based and slit-scanning imaging devices. Indian J Ophthalmol 65(4):305–310. https://doi.org/10.4103/ijo.IJO_690_16

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Myriam Böhm: none; Mehdi Shajari: Oculus; Matthias Remy: Avedro Inc.: Travel has been funded; Thomas Kohnen receives grant support from Hoya, J&J Vision (Abbott), Novartis (Alcon), Oculentis, Oculus, Schwind, and Zeiss; and is a consultant to Geuder, J&J Vision (Abbott), Novartis (Alcon), Oculus, Santen, Schwind, STAAR, TearLab, Thea Pharma, Thieme Compliance, Ziemer, and Zeiss.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thomas Kohnen.

Ethics declarations

Conflict of interest

Myriam Böhm and Mehdi Shajari declare that they have no conflict of interest. Matthias Remy has received a travel honorarium from Avedro (Waltham, MA 02451, USA).

Human and animal rights

This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

No informed consent was obtained from patients since this was a retrospective study and data were anonymized. This is in accordance with the ethical vote obtained from the local ethics committee.

Additional information

Thomas Kohnen has received research grants from Hoya Surgical Optics GmbH (Frankfurt, Germany); J&J Vision (Abbott Medical Optics, Inc. [Santa Ana, CA, USA]); Novartis (Alcon Laboratories, Inc. [Fort Worth, TX, USA]); Oculentis GmbH (Berlin, Germany); Oculus Optikgerate GmbH (Wetzlar, Germany); Schwind Eye-Tech Solutions GmbH (Kleinostheim, Germany); and Carl Zeiss Meditec AG (Jena, Germany); and is a consultant to Geuder AG (Heidelberg, Germany); J&J Vision (Abbott Medical Optics, Inc. [Santa Ana, CA, USA]); Novartis (Alcon Laboratories, Inc. [Fort Worth, TX, USA]); Oculus Optikgeräte GmbH (Wetzlar, Germany); Santen GmbH, (Munich, Germany); Schwind Eye-Tech Solutions GmbH (Kleinostheim, Germany); STAAR Surgical AG (Nidau, Switzerland); TearLab Corp (San Diego, CA, USA); Thea Pharma GmbH (Berlin, Germany); Thieme Compliance GmbH (Erlangen, Germany); Ziemer Ophthalmology GmbH (Emmendingen, Germany); and Carl Zeiss Meditec AG (Jena, Germany).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Böhm, M., Shajari, M., Remy, M. et al. Corneal densitometry after accelerated corneal collagen cross-linking in progressive keratoconus. Int Ophthalmol 39, 765–775 (2019). https://doi.org/10.1007/s10792-018-0876-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10792-018-0876-4

Keywords

  • Corneal collagen cross-linking
  • Densitometry
  • Scheimpflug tomography
  • Keratoconus