Anterior segment optical coherence tomography evaluation of early corneal changes following corneal collagen cross-linking for progressive keratoconus
Medical hypothesis, discovery & innovation in optometry,
Vol. 7 No. 2 (2026),
24 July 2026
,
Page 50-57
https://doi.org/10.51329/mehdioptometry245
Abstract
Background: Keratoconus is a progressive corneal ectatic disorder characterized by stromal thinning, corneal protrusion, and progressive visual impairment. Corneal collagen cross-linking (CXL) is an established treatment for halting disease progression by enhancing corneal biomechanical stability. This study evaluated early corneal structural and functional changes following accelerated epithelium-off CXL in eyes with progressive keratoconus using anterior segment optical coherence tomography (AS-OCT). Specifically, epithelial thickness and central corneal thickness (CCT) were assessed one month after treatment and correlated with stromal demarcation line depth.Methods: In this prospective study, eyes with progressive keratoconus underwent accelerated epithelium-off CXL. All participants underwent comprehensive ophthalmic examination before treatment and one month postoperatively. Assessments included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), intraocular pressure (IOP), corneal tomographic parameters, CCT, epithelial thickness, and AS-OCT measurement of stromal demarcation line depth.
Results: Thirty eyes of 15 patients with progressive keratoconus underwent accelerated epithelium-off CXL. Mean (standard deviation) age of participants was 26.5 (4.5) years (range 19–35), and 53.3% (n = 8) were female. At one month, modest but statistically significant improvements were observed in both UDVA and CDVA (both P < 0.05). A slight but statistically significant reduction in IOP was also observed (P < 0.05). Keratometric parameters yielded modest but significant reductions following treatment (all P < 0.05), consistent with early corneal flattening. Significant decreases were observed in both CCT and epithelial thickness (both P < 0.05). The median (interquartile range) stromal demarcation line depth measured by AS-OCT was 214.5 (171.0–274.3) micrometre, with 143–322 micrometre value ranges. Demarcation line depth showed significant positive correlations with both preoperative CCT (rho = 0.368, P = 0.045) and postoperative CCT (rho = 0.433, P = 0.017), whereas no significant associations were observed with preoperative (rho = -0.197, P = 0.298) or postoperative (rho = -0.093, P = 0.625) epithelial thickness.
Conclusions: Accelerated epithelium-off CXL was associated with early corneal structural changes, including reductions in CCT and epithelial thickness, accompanied by mild corneal flattening and modest improvements in visual acuity. Stromal demarcation line depth was positively correlated with CCT, suggesting an association between corneal thickness and treatment penetration. AS-OCT provided detailed, non-invasive assessment of postoperative demarcation line depth and may serve as a useful tool for monitoring early response to CXL. Further studies with larger sample sizes, longer follow-up periods, and multicenter recruitment are warranted to validate these findings in our population.
Keywords:
- keratoconus
- corneal collagen cross-linking
- epithelium-off corneal cross-linking
- anterior eye segments
- optical coherence tomography
- corneal topographies
- visual acuities
- intraocular pressures
- corneal thickness measurement
References
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10. Antonios R, Dirani A, Fadlallah A, Chelala E, Hamadeh A, Jarade E. Acute Corneal Hydrops 3 Years after Intra-corneal Ring Segments and Corneal Collagen Cross-linking. Middle East Afr J Ophthalmol. 2016 Jan-Mar;23(1):156-9. doi: 10.4103/0974-9233.171826. PMID: 26957859; PMCID: PMC4759898.
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12. Doors M, Tahzib NG, Eggink FA, Berendschot TT, Webers CA, Nuijts RM. Use of anterior segment optical coherence tomography to study corneal changes after collagen cross-linking. Am J Ophthalmol. 2009 Dec;148(6):844-51.e2. doi: 10.1016/j.ajo.2009.06.031. Epub 2009 Sep 24. PMID: 19781685.
13. Li Y, Gokul A, McGhee C, Ziaei M. Repeatability of corneal and epithelial thickness measurements with anterior segment optical coherence tomography in keratoconus. PLoS One. 2021 Jun 18;16(6):e0248350. doi: 10.1371/journal.pone.0248350. PMID: 34143790; PMCID: PMC8213071.
14. Nishida T, Kojima T, Kataoka T, Isogai N, Yoshida Y, Nakamura T. Evaluation of the Relationship Between the Changes in the Corneal Biomechanical Properties and Changes in the Anterior Segment OCT Parameters Following Customized Corneal Cross-Linking. Clin Ophthalmol. 2022 Jun 9;16:1909-1923. doi: 10.2147/OPTH.S361836. PMID: 35711971; PMCID: PMC9192785.
15. Spadea L, Tonti E, Vingolo EM. Corneal stromal demarcation line after collagen cross-linking in corneal ectatic diseases: a review of the literature. Clin Ophthalmol. 2016 Sep 19;10:1803-1810. doi: 10.2147/OPTH.S117372. PMID: 27695286; PMCID: PMC5034907.
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17. Barakat A, Elmassry A, Othman I, El-Kateb M. Evaluating corneal changes after corneal collagen cross-linking in keratoconus by optical coherence tomography. Delta Journal of Ophthalmology. 2022 Jul 1;23(3):149-56. doi: 10.4103/djo_12_22.
18. Zare MA, Mazloumi M, Farajipour H, Hoseini B, Fallah MR, Mahrjerdi HZ, Abtahi MA, Abtahi SH. Effects of Corneal Collagen Crosslinking on Confocal Microscopic Findings and Tear Indices in Patients with Progressive Keratoconus. Int J Prev Med. 2016 Dec 23;7:132. doi: 10.4103/2008-7802.196527. PMID: 28123695; PMCID: PMC5209947.
19. Kamiya K, Ishii R, Shimizu K, Igarashi A. Evaluation of corneal elevation, pachymetry and keratometry in keratoconic eyes with respect to the stage of Amsler-Krumeich classification. Br J Ophthalmol. 2014 Apr;98(4):459-63. doi: 10.1136/bjophthalmol-2013-304132. Epub 2014 Jan 23. PMID: 24457362.
20. Mazzotta C, Gagliano C, Borroni D, De Lossada CR, Vinciguerra R, Zagari M, Alessio G, D'Oria F. Crosslinking for post refractive surgery ectasia: application and clinical outcomes. Graefes Arch Clin Exp Ophthalmol. 2025 Dec;263(12):3461-3470. doi: 10.1007/s00417-025-06968-6. Epub 2025 Sep 23. Erratum in: Graefes Arch Clin Exp Ophthalmol. 2026 Jan;264(1):295-296. doi: 10.1007/s00417-025-07027-w. PMID: 40986049.
21. Elbaz U, Shen C, Lichtinger A, Zauberman NA, Goldich Y, Chan CC, Slomovic AR, Rootman DS. Accelerated (9-mW/cm2) corneal collagen crosslinking for keratoconus-A 1-year follow-up. Cornea. 2014 Aug;33(8):769-73. doi: 10.1097/ICO.0000000000000154. PMID: 24937167.
22. Ting DSJ, Rana-Rahman R, Chen Y, Bell D, Danjoux JP, Morgan SJ, Ghosh S, Baylis O. Effectiveness and safety of accelerated (9?mW/cm2) corneal collagen cross-linking for progressive keratoconus: a 24-month follow-up. Eye (Lond). 2019 May;33(5):812-818. doi: 10.1038/s41433-018-0323-9. Epub 2019 Jan 4. PMID: 30610230; PMCID: PMC6707229.
23. Ng AL, Chan TC, Cheng AC. Conventional versus accelerated corneal collagen cross-linking in the treatment of keratoconus. Clin Exp Ophthalmol. 2016 Jan-Feb;44(1):8-14. doi: 10.1111/ceo.12571. Epub 2015 Jul 22. PMID: 26140309.
24. Kirgiz A, Eliacik M, Yildirim Y. Different accelerated corneal collagen cross-linking treatment modalities in progressive keratoconus. Eye Vis (Lond). 2019 Jun 3;6:16. doi: 10.1186/s40662-019-0141-6. PMID: 31172016; PMCID: PMC6545739.
25. Tomita M, Mita M, Huseynova T. Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg. 2014 Jun;40(6):1013-20. doi: 10.1016/j.jcrs.2013.12.012. PMID: 24857442.
26. Kymionis GD, Tsoulnaras KI, Grentzelos MA, Liakopoulos DA, Tsakalis NG, Blazaki SV, Paraskevopoulos TA, Tsilimbaris MK. Evaluation of corneal stromal demarcation line depth following standard and a modified-accelerated collagen cross-linking protocol. Am J Ophthalmol. 2014 Oct;158(4):671-675.e1. doi: 10.1016/j.ajo.2014.07.005. Epub 2014 Jul 15. PMID: 25034113.
27. Bouheraoua N, Jouve L, El Sanharawi M, Sandali O, Temstet C, Loriaut P, Basli E, Borderie V, Laroche L. Optical coherence tomography and confocal microscopy following three different protocols of corneal collagen-crosslinking in keratoconus. Invest Ophthalmol Vis Sci. 2014 Oct 28;55(11):7601-9. doi: 10.1167/iovs.14-15662. PMID: 25352122.
28. Qureshi M, Watson SL, Kandel H. Pulsed corneal crosslinking in the treatment of Keratoconus: a systematic review and meta-analysis. Graefes Arch Clin Exp Ophthalmol. 2025 Mar;263(3):589-601. doi: 10.1007/s00417-024-06622-7. Epub 2024 Aug 31. PMID: 39215849; PMCID: PMC11953132.
29. Ozgurhan EB, Akcay BI, Kurt T, Yildirim Y, Demirok A. Accelerated Corneal Collagen Cross-Linking in Thin Keratoconic Corneas. J Refract Surg. 2015 Jun;31(6):386-90. doi: 10.3928/1081597X-20150521-11. PMID: 26046705.
30. Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011 Apr;37(4):691-700. doi: 10.1016/j.jcrs.2010.10.052. PMID: 21420594.
31. Shajari M, Kolb CM, Agha B, Steinwender G, Müller M, Herrmann E, Schmack I, Mayer WJ, Kohnen T. Comparison of standard and accelerated corneal cross-linking for the treatment of keratoconus: a meta-analysis. Acta Ophthalmol. 2019 Feb;97(1):e22-e35. doi: 10.1111/aos.13814. Epub 2018 May 31. PMID: 29855152.
2. Romero-Jiménez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: a review. Cont Lens Anterior Eye. 2010 Aug;33(4):157-66; quiz 205. doi: 10.1016/j.clae.2010.04.006. PMID: 20537579.
3. Vazirani J, Basu S. Keratoconus: current perspectives. Clin Ophthalmol. 2013;7:2019-30. doi: 10.2147/OPTH.S50119. Epub 2013 Oct 14. PMID: 24143069; PMCID: PMC3798205.
4. Javadi MA, Mohammad-Rabei H, Feizi S, Daryabari SH. Visual Outcomes of Successful versus Failed Big-Bubble Deep Anterior Lamellar Keratoplasty for Keratoconus. J Ophthalmic Vis Res. 2016 Jan-Mar;11(1):32-6. doi: 10.4103/2008-322X.180711. PMID: 27195082; PMCID: PMC4860984.
5. Gore DM, Shortt AJ, Allan BD. New clinical pathways for keratoconus. Eye (Lond). 2013 Mar;27(3):329-39. doi: 10.1038/eye.2012.257. Epub 2012 Dec 21. PMID: 23258309; PMCID: PMC3597866.
6. Vohra V, Tuteja S, Gurnani B, Chawla H. Collagen Cross Linking for Keratoconus. 2023 Jun 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. PMID: 32965942.
7. Papachristoforou N, Ueno A, Ledwos K, Bartu? J, Nowi?ska A, Karska-Basta I. A Review of Keratoconus Cross-Linking Treatment Methods. J Clin Med. 2025 Mar 3;14(5):1702. doi: 10.3390/jcm14051702. PMID: 40095727; PMCID: PMC11899953.
8. Raiskup F, Spoerl E. Corneal crosslinking with riboflavin and ultraviolet A. Part II. Clinical indications and results. Ocul Surf. 2013 Apr;11(2):93-108. doi: 10.1016/j.jtos.2013.01.003. Epub 2013 Jan 28. PMID: 23583044.
9. Wu D, Lim DK, Lim BXH, Wong N, Hafezi F, Manotosh R, Lim CHL. Corneal Cross-Linking: The Evolution of Treatment for Corneal Diseases. Front Pharmacol. 2021 Jul 19;12:686630. doi: 10.3389/fphar.2021.686630. PMID: 34349648; PMCID: PMC8326410.
10. Antonios R, Dirani A, Fadlallah A, Chelala E, Hamadeh A, Jarade E. Acute Corneal Hydrops 3 Years after Intra-corneal Ring Segments and Corneal Collagen Cross-linking. Middle East Afr J Ophthalmol. 2016 Jan-Mar;23(1):156-9. doi: 10.4103/0974-9233.171826. PMID: 26957859; PMCID: PMC4759898.
11. Sachdev GS, Sachdev M. Recent advances in corneal collagen cross-linking. Indian J Ophthalmol. 2017 Sep;65(9):787-796. doi: 10.4103/ijo.IJO_648_17. PMID: 28905820; PMCID: PMC5621259.
12. Doors M, Tahzib NG, Eggink FA, Berendschot TT, Webers CA, Nuijts RM. Use of anterior segment optical coherence tomography to study corneal changes after collagen cross-linking. Am J Ophthalmol. 2009 Dec;148(6):844-51.e2. doi: 10.1016/j.ajo.2009.06.031. Epub 2009 Sep 24. PMID: 19781685.
13. Li Y, Gokul A, McGhee C, Ziaei M. Repeatability of corneal and epithelial thickness measurements with anterior segment optical coherence tomography in keratoconus. PLoS One. 2021 Jun 18;16(6):e0248350. doi: 10.1371/journal.pone.0248350. PMID: 34143790; PMCID: PMC8213071.
14. Nishida T, Kojima T, Kataoka T, Isogai N, Yoshida Y, Nakamura T. Evaluation of the Relationship Between the Changes in the Corneal Biomechanical Properties and Changes in the Anterior Segment OCT Parameters Following Customized Corneal Cross-Linking. Clin Ophthalmol. 2022 Jun 9;16:1909-1923. doi: 10.2147/OPTH.S361836. PMID: 35711971; PMCID: PMC9192785.
15. Spadea L, Tonti E, Vingolo EM. Corneal stromal demarcation line after collagen cross-linking in corneal ectatic diseases: a review of the literature. Clin Ophthalmol. 2016 Sep 19;10:1803-1810. doi: 10.2147/OPTH.S117372. PMID: 27695286; PMCID: PMC5034907.
16. Yam JC, Chan CW, Cheng AC. Corneal collagen cross-linking demarcation line depth assessed by Visante OCT After CXL for keratoconus and corneal ectasia. J Refract Surg. 2012 Jul;28(7):475-81. doi: 10.3928/1081597X-20120615-03. PMID: 22767165.
17. Barakat A, Elmassry A, Othman I, El-Kateb M. Evaluating corneal changes after corneal collagen cross-linking in keratoconus by optical coherence tomography. Delta Journal of Ophthalmology. 2022 Jul 1;23(3):149-56. doi: 10.4103/djo_12_22.
18. Zare MA, Mazloumi M, Farajipour H, Hoseini B, Fallah MR, Mahrjerdi HZ, Abtahi MA, Abtahi SH. Effects of Corneal Collagen Crosslinking on Confocal Microscopic Findings and Tear Indices in Patients with Progressive Keratoconus. Int J Prev Med. 2016 Dec 23;7:132. doi: 10.4103/2008-7802.196527. PMID: 28123695; PMCID: PMC5209947.
19. Kamiya K, Ishii R, Shimizu K, Igarashi A. Evaluation of corneal elevation, pachymetry and keratometry in keratoconic eyes with respect to the stage of Amsler-Krumeich classification. Br J Ophthalmol. 2014 Apr;98(4):459-63. doi: 10.1136/bjophthalmol-2013-304132. Epub 2014 Jan 23. PMID: 24457362.
20. Mazzotta C, Gagliano C, Borroni D, De Lossada CR, Vinciguerra R, Zagari M, Alessio G, D'Oria F. Crosslinking for post refractive surgery ectasia: application and clinical outcomes. Graefes Arch Clin Exp Ophthalmol. 2025 Dec;263(12):3461-3470. doi: 10.1007/s00417-025-06968-6. Epub 2025 Sep 23. Erratum in: Graefes Arch Clin Exp Ophthalmol. 2026 Jan;264(1):295-296. doi: 10.1007/s00417-025-07027-w. PMID: 40986049.
21. Elbaz U, Shen C, Lichtinger A, Zauberman NA, Goldich Y, Chan CC, Slomovic AR, Rootman DS. Accelerated (9-mW/cm2) corneal collagen crosslinking for keratoconus-A 1-year follow-up. Cornea. 2014 Aug;33(8):769-73. doi: 10.1097/ICO.0000000000000154. PMID: 24937167.
22. Ting DSJ, Rana-Rahman R, Chen Y, Bell D, Danjoux JP, Morgan SJ, Ghosh S, Baylis O. Effectiveness and safety of accelerated (9?mW/cm2) corneal collagen cross-linking for progressive keratoconus: a 24-month follow-up. Eye (Lond). 2019 May;33(5):812-818. doi: 10.1038/s41433-018-0323-9. Epub 2019 Jan 4. PMID: 30610230; PMCID: PMC6707229.
23. Ng AL, Chan TC, Cheng AC. Conventional versus accelerated corneal collagen cross-linking in the treatment of keratoconus. Clin Exp Ophthalmol. 2016 Jan-Feb;44(1):8-14. doi: 10.1111/ceo.12571. Epub 2015 Jul 22. PMID: 26140309.
24. Kirgiz A, Eliacik M, Yildirim Y. Different accelerated corneal collagen cross-linking treatment modalities in progressive keratoconus. Eye Vis (Lond). 2019 Jun 3;6:16. doi: 10.1186/s40662-019-0141-6. PMID: 31172016; PMCID: PMC6545739.
25. Tomita M, Mita M, Huseynova T. Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg. 2014 Jun;40(6):1013-20. doi: 10.1016/j.jcrs.2013.12.012. PMID: 24857442.
26. Kymionis GD, Tsoulnaras KI, Grentzelos MA, Liakopoulos DA, Tsakalis NG, Blazaki SV, Paraskevopoulos TA, Tsilimbaris MK. Evaluation of corneal stromal demarcation line depth following standard and a modified-accelerated collagen cross-linking protocol. Am J Ophthalmol. 2014 Oct;158(4):671-675.e1. doi: 10.1016/j.ajo.2014.07.005. Epub 2014 Jul 15. PMID: 25034113.
27. Bouheraoua N, Jouve L, El Sanharawi M, Sandali O, Temstet C, Loriaut P, Basli E, Borderie V, Laroche L. Optical coherence tomography and confocal microscopy following three different protocols of corneal collagen-crosslinking in keratoconus. Invest Ophthalmol Vis Sci. 2014 Oct 28;55(11):7601-9. doi: 10.1167/iovs.14-15662. PMID: 25352122.
28. Qureshi M, Watson SL, Kandel H. Pulsed corneal crosslinking in the treatment of Keratoconus: a systematic review and meta-analysis. Graefes Arch Clin Exp Ophthalmol. 2025 Mar;263(3):589-601. doi: 10.1007/s00417-024-06622-7. Epub 2024 Aug 31. PMID: 39215849; PMCID: PMC11953132.
29. Ozgurhan EB, Akcay BI, Kurt T, Yildirim Y, Demirok A. Accelerated Corneal Collagen Cross-Linking in Thin Keratoconic Corneas. J Refract Surg. 2015 Jun;31(6):386-90. doi: 10.3928/1081597X-20150521-11. PMID: 26046705.
30. Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011 Apr;37(4):691-700. doi: 10.1016/j.jcrs.2010.10.052. PMID: 21420594.
31. Shajari M, Kolb CM, Agha B, Steinwender G, Müller M, Herrmann E, Schmack I, Mayer WJ, Kohnen T. Comparison of standard and accelerated corneal cross-linking for the treatment of keratoconus: a meta-analysis. Acta Ophthalmol. 2019 Feb;97(1):e22-e35. doi: 10.1111/aos.13814. Epub 2018 May 31. PMID: 29855152.
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