Six-month longitudinal analysis of visual, tomographic, and densitometric changes after corneal collagen cross-linking in keratoconus
Medical hypothesis, discovery & innovation in optometry,
Vol. 6 No. 3 (2025),
21 November 2025
,
Page 92-103
https://doi.org/10.51329/mehdioptometry228
Abstract
Background: Keratoconus is a progressive corneal ectasia commonly treated with corneal collagen cross-linking (CXL) to halt further progression. Although transient anterior stromal haze frequently develops after CXL, its impact on visual recovery remains unclear. This study aimed to examine the correlation between postoperative changes in corneal densitometry, visual acuity, topography, and pachymetry in eyes with keratoconus undergoing CXL.Methods: This retrospective study included eyes with progressive keratoconus undergoing epithelium-off accelerated CXL. Pre- and postoperative assessments included measuring corrected distance visual acuity (CDVA), manifest refraction, and slit-lamp biomicroscopy examination, along with Pentacam HR imaging. Densitometry was quantified across three stromal depths and four annular zones. Follow-up evaluations were performed at day 1, week 1, and months 1, 3, and 6 post-CXL.
Results: Twenty-four eyes from 24 patients with progressive keratoconus (median age, 21.9 years; 79.2% male) were evaluated over a six-month period following CXL. At six months, significant improvements were observed in CDVA, accompanied by reductions in flat keratometry, central corneal thickness, and thinnest pachymetry (all P < 0.05). Corneal densitometry increased significantly at one month and partially regressed by six months across all stromal depths and within all concentric annular zones from 0.0–2.0 mm to 6.0–10.0 mm and their corresponding total values (all P < 0.05). Baseline anterior 0.0–2.0 mm densitometry demonstrated a significant inverse correlation with CDVA (r = –0.50, P < 0.05). At one month, CDVA correlated inversely with densitometry in the anterior (r = –0.47, P = 0.003) and mid-stromal (r = –0.58, P = 0.006) depths of the 0.0–2.0 mm zone, and with anterior densitometry in the 2.0–6.0 mm zone (r = –0.45, P = 0.045). By six months, no significant correlations were found between CDVA or absolute keratometric parameters and densitometry at any depth, zone, or total value (all P > 0.05), indicating stabilization of both visual and structural recovery.
Conclusions: Accelerated epithelium-off CXL yielded significant visual and structural improvements in progressive keratoconus over six months. Corneal densitometry followed a characteristic postoperative pattern, with an early peak at one month followed by partial regression. Early stromal backscatter increases were significantly correlated with visual acuity, but these relationships diminished by six months, consistent with recovery of corneal clarity and vision. Longer-term studies are warranted to clarify the prognostic utility of densitometry for visual and tomographic outcomes after CXL.
Keywords:
- keratoconus
- pellucid marginal degeneration
- densitometries
- light scattering
- corneas
- corneal stromas
- corneal topographies
- vitamin B2
- riboflavin
- epithelium-off CXL
References
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8. Gore DM, Leucci MT, Koay SY, Kopsachilis N, Nicolae MN, Malandrakis MI, Anand V, Allan BD. Accelerated Pulsed High-Fluence Corneal Cross-Linking for Progressive Keratoconus. Am J Ophthalmol. 2021 Jan;221:9-16. doi: 10.1016/j.ajo.2020.08.021. Epub 2020 Aug 18. PMID: 32818448.
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.
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11. Ça?layan M, Öncül H, Alakus MF, Dag U. Corneal and lens densitometry with Pentacam HR in children with vernal keratoconjunctivitis. Clin Exp Optom. 2021 Mar;104(2):156-161. doi: 10.1111/cxo.13144. PMID: 32945010.
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14. Alnawaiseh M, Rosentreter A, Böhm MR, Eveslage M, Eter N, Zumhagen L. Accelerated (18 mW/cm²) Corneal Collagen Cross-Linking for Progressive Keratoconus. Cornea. 2015 Nov;34(11):1427-31. doi: 10.1097/ICO.0000000000000578. PMID: 26356752.
15. Kim BZ, Jordan CA, McGhee CN, Patel DV. Natural history of corneal haze after corneal collagen crosslinking in keratoconus using Scheimpflug analysis. J Cataract Refract Surg. 2016 Jul;42(7):1053-9. doi: 10.1016/j.jcrs.2016.04.019. PMID: 27492105.
16. Koc M, Uzel MM, Tekin K, Kosekahya P, Ozulken K, Yilmazbas P. Effect of preoperative factors on visual acuity, corneal flattening, and corneal haze after accelerated corneal crosslinking. J Cataract Refract Surg. 2016 Oct;42(10):1483-1489. doi: 10.1016/j.jcrs.2016.08.017. PMID: 27839604.
17. Ziaei M, Gokul A, Vellara H, Patel D, McGhee CNJ. Prospective two year study of changes in corneal density following transepithelial pulsed, epithelium-off continuous and epithelium-off pulsed, corneal crosslinking for keratoconus. Cont Lens Anterior Eye. 2020 Oct;43(5):458-464. doi: 10.1016/j.clae.2020.03.004. Epub 2020 Mar 22. PMID: 32209301.
18. Hafezi F, Kling S, Gilardoni F, Hafezi N, Hillen M, Abrishamchi R, Gomes JAP, Mazzotta C, Randleman JB, Torres-Netto EA. Individualized Corneal Cross-linking With Riboflavin and UV-A in Ultrathin Corneas: The Sub400 Protocol. Am J Ophthalmol. 2021 Apr;224:133-142. doi: 10.1016/j.ajo.2020.12.011. Epub 2021 Jan 30. PMID: 33340508.
19. Chan TCY, Chan JCK, Wang YM, Rapuano CJ. Survival Analysis of Corneal Densitometry After Collagen Cross-Linking for Progressive Keratoconus. Cornea. 2018 Nov;37(11):1449-1456. doi: 10.1097/ICO.0000000000001686. PMID: 29985795.
20. Kamaev P, Friedman MD, Sherr E, Muller D. Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci. 2012 Apr 30;53(4):2360-7. doi: 10.1167/iovs.11-9385. PMID: 22427580.
21. Seiler TG, Komninou MA, Nambiar MH, Schuerch K, Frueh BE, Büchler P. Oxygen Kinetics During Corneal Cross-linking With and Without Supplementary Oxygen. Am J Ophthalmol. 2021 Mar;223:368-376. doi: 10.1016/j.ajo.2020.11.001. Epub 2020 Nov 21. PMID: 33227242.
22. Gupta B, Malhotra C, Dhar S, Abhyapal K, Jain AK, Gupta A. Corneal densitometry changes post-CXL for keratoconus: Comparative evaluation of epithelium-off, contact lens-assisted, and transepithelial techniques. Indian J Ophthalmol. 2025 Jan 1;73(1):102-109. doi: 10.4103/IJO.IJO_485_24. Epub 2024 Sep 10. PMID: 39257083; PMCID: PMC11831942.
23. Li Y, Lu Y, Du K, Yin Y, Hu T, Fu Y, Xiang A, Fu Q, Wu X, Wen D. Comparison of Efficacy and Safety Between Standard, Accelerated Epithelium-Off and Transepithelial Corneal Collagen Crosslinking in Pediatric Keratoconus: A Meta-Analysis. Front Med (Lausanne). 2022 Mar 17;9:787167. doi: 10.3389/fmed.2022.787167. PMID: 35372437; PMCID: PMC8968048.
24. Omar IAN, Zein HA. Accelerated Epithelium-Off Corneal Collagen Cross-Linking For Keratoconus: 12-Month Results. Clin Ophthalmol. 2019 Dec 4;13:2385-2394. doi: 10.2147/OPTH.S232118. PMID: 31824132; PMCID: PMC6900281.
25. Schumacher S, Oeftiger L, Mrochen M. Equivalence of biomechanical changes induced by rapid and standard corneal cross-linking, using riboflavin and ultraviolet radiation. Invest Ophthalmol Vis Sci. 2011 Nov 25;52(12):9048-52. doi: 10.1167/iovs.11-7818. PMID: 22025568.
26. Csorba A, Kránitz K, Dormán P, Popper-Sachetti A, Kiss H, Szalai I, Nagy ZZ. Factors influencing haze formation and corneal flattening, and the impact of haze on visual acuity after conventional collagen cross-linking: a 12-month retrospective study. BMC Ophthalmol. 2021 Aug 23;21(1):306. doi: 10.1186/s12886-021-02066-3. PMID: 34425775; PMCID: PMC8381497.
27. Shetty R, Rajiv Kumar N, Pahuja N, Deshmukh R, Vunnava K, Abilash VG, Sinha Roy A, Ghosh A. Outcomes of Corneal Cross-Linking Correlate With Cone-Specific Lysyl Oxidase Expression in Patients With Keratoconus. Cornea. 2018 Mar;37(3):369-374. doi: 10.1097/ICO.0000000000001478. PMID: 29215396.
2. Spoerl E, Wollensak G, Dittert DD, Seiler T. Thermomechanical behavior of collagen-cross-linked porcine cornea. Ophthalmologica. 2004 Mar-Apr;218(2):136-40. doi: 10.1159/000076150. PMID: 15004504.
3. 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.
4. Gustafsson I, Bizios D, Ivarsen A, Hjortdal JØ. The intra- and inter-day repeatability of corneal densitometry measurements in subjects with keratoconus and in healthy controls. Sci Rep. 2023 Apr 5;13(1):5566. doi: 10.1038/s41598-023-32822-y. PMID: 37019974; PMCID: PMC10076276.
5. Mathews PM, De Rojas JO, Rapuano PB, Zemsky CJ, Florakis GJ, Trokel SL, Suh LH. Correlation of Scheimpflug densitometry changes with clinical outcomes after corneal crosslinking. J Cataract Refract Surg. 2018 Aug;44(8):993-1002. doi: 10.1016/j.jcrs.2018.05.016. PMID: 30115299.
6. Antonios R, Fattah MA, Maalouf F, Abiad B, Awwad ST. Central Corneal Thickness After Cross-linking Using High-Definition Optical Coherence Tomography, Ultrasound, and Dual Scheimpflug Tomography: A Comparative Study Over One Year. Am J Ophthalmol. 2016 Jul;167:38-47. doi: 10.1016/j.ajo.2016.04.004. Epub 2016 Apr 13. PMID: 27084001.
7. Bahar TS, ?ahin V, Ayaz Y, Ünal M. Long-Term Outcomes in Crosslinking Therapy for Patients with Progressive Keratoconus. Diagnostics (Basel). 2025 Mar 5;15(5):626. doi: 10.3390/diagnostics15050626. PMID: 40075873; PMCID: PMC11898512.
8. Gore DM, Leucci MT, Koay SY, Kopsachilis N, Nicolae MN, Malandrakis MI, Anand V, Allan BD. Accelerated Pulsed High-Fluence Corneal Cross-Linking for Progressive Keratoconus. Am J Ophthalmol. 2021 Jan;221:9-16. doi: 10.1016/j.ajo.2020.08.021. Epub 2020 Aug 18. PMID: 32818448.
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. Stock RA, Brustollin G, Mergener RA, Bonamigo EL. Efficacy of Standard and Accelerated (10 Minutes) Corneal Crosslinking in Keratoconus Stabilization. Clin Ophthalmol. 2020 Jun 24;14:1735-1740. doi: 10.2147/OPTH.S258205. PMID: 32612348; PMCID: PMC7322134.
11. Ça?layan M, Öncül H, Alakus MF, Dag U. Corneal and lens densitometry with Pentacam HR in children with vernal keratoconjunctivitis. Clin Exp Optom. 2021 Mar;104(2):156-161. doi: 10.1111/cxo.13144. PMID: 32945010.
12. Pircher N, Pachala M, Prager F, Pieh S, Schmidinger G. Changes in straylight and densitometry values after corneal collagen crosslinking. J Cataract Refract Surg. 2015 May;41(5):1038-43. doi: 10.1016/j.jcrs.2014.07.043. Epub 2015 May 5. PMID: 25953473.
13. Coskun C, Çelik G, Zeki Fikret C, Çomçal? S, Evren Kemer Ö. Evaluation of corneal densitometry values with Pentacam in cases of ocular hypertension and pseudoexfoliative glaucoma. Photodiagnosis Photodyn Ther. 2024 Apr;46:103988. doi: 10.1016/j.pdpdt.2024.103988. Epub 2024 Feb 16. PMID: 38368915.
14. Alnawaiseh M, Rosentreter A, Böhm MR, Eveslage M, Eter N, Zumhagen L. Accelerated (18 mW/cm²) Corneal Collagen Cross-Linking for Progressive Keratoconus. Cornea. 2015 Nov;34(11):1427-31. doi: 10.1097/ICO.0000000000000578. PMID: 26356752.
15. Kim BZ, Jordan CA, McGhee CN, Patel DV. Natural history of corneal haze after corneal collagen crosslinking in keratoconus using Scheimpflug analysis. J Cataract Refract Surg. 2016 Jul;42(7):1053-9. doi: 10.1016/j.jcrs.2016.04.019. PMID: 27492105.
16. Koc M, Uzel MM, Tekin K, Kosekahya P, Ozulken K, Yilmazbas P. Effect of preoperative factors on visual acuity, corneal flattening, and corneal haze after accelerated corneal crosslinking. J Cataract Refract Surg. 2016 Oct;42(10):1483-1489. doi: 10.1016/j.jcrs.2016.08.017. PMID: 27839604.
17. Ziaei M, Gokul A, Vellara H, Patel D, McGhee CNJ. Prospective two year study of changes in corneal density following transepithelial pulsed, epithelium-off continuous and epithelium-off pulsed, corneal crosslinking for keratoconus. Cont Lens Anterior Eye. 2020 Oct;43(5):458-464. doi: 10.1016/j.clae.2020.03.004. Epub 2020 Mar 22. PMID: 32209301.
18. Hafezi F, Kling S, Gilardoni F, Hafezi N, Hillen M, Abrishamchi R, Gomes JAP, Mazzotta C, Randleman JB, Torres-Netto EA. Individualized Corneal Cross-linking With Riboflavin and UV-A in Ultrathin Corneas: The Sub400 Protocol. Am J Ophthalmol. 2021 Apr;224:133-142. doi: 10.1016/j.ajo.2020.12.011. Epub 2021 Jan 30. PMID: 33340508.
19. Chan TCY, Chan JCK, Wang YM, Rapuano CJ. Survival Analysis of Corneal Densitometry After Collagen Cross-Linking for Progressive Keratoconus. Cornea. 2018 Nov;37(11):1449-1456. doi: 10.1097/ICO.0000000000001686. PMID: 29985795.
20. Kamaev P, Friedman MD, Sherr E, Muller D. Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci. 2012 Apr 30;53(4):2360-7. doi: 10.1167/iovs.11-9385. PMID: 22427580.
21. Seiler TG, Komninou MA, Nambiar MH, Schuerch K, Frueh BE, Büchler P. Oxygen Kinetics During Corneal Cross-linking With and Without Supplementary Oxygen. Am J Ophthalmol. 2021 Mar;223:368-376. doi: 10.1016/j.ajo.2020.11.001. Epub 2020 Nov 21. PMID: 33227242.
22. Gupta B, Malhotra C, Dhar S, Abhyapal K, Jain AK, Gupta A. Corneal densitometry changes post-CXL for keratoconus: Comparative evaluation of epithelium-off, contact lens-assisted, and transepithelial techniques. Indian J Ophthalmol. 2025 Jan 1;73(1):102-109. doi: 10.4103/IJO.IJO_485_24. Epub 2024 Sep 10. PMID: 39257083; PMCID: PMC11831942.
23. Li Y, Lu Y, Du K, Yin Y, Hu T, Fu Y, Xiang A, Fu Q, Wu X, Wen D. Comparison of Efficacy and Safety Between Standard, Accelerated Epithelium-Off and Transepithelial Corneal Collagen Crosslinking in Pediatric Keratoconus: A Meta-Analysis. Front Med (Lausanne). 2022 Mar 17;9:787167. doi: 10.3389/fmed.2022.787167. PMID: 35372437; PMCID: PMC8968048.
24. Omar IAN, Zein HA. Accelerated Epithelium-Off Corneal Collagen Cross-Linking For Keratoconus: 12-Month Results. Clin Ophthalmol. 2019 Dec 4;13:2385-2394. doi: 10.2147/OPTH.S232118. PMID: 31824132; PMCID: PMC6900281.
25. Schumacher S, Oeftiger L, Mrochen M. Equivalence of biomechanical changes induced by rapid and standard corneal cross-linking, using riboflavin and ultraviolet radiation. Invest Ophthalmol Vis Sci. 2011 Nov 25;52(12):9048-52. doi: 10.1167/iovs.11-7818. PMID: 22025568.
26. Csorba A, Kránitz K, Dormán P, Popper-Sachetti A, Kiss H, Szalai I, Nagy ZZ. Factors influencing haze formation and corneal flattening, and the impact of haze on visual acuity after conventional collagen cross-linking: a 12-month retrospective study. BMC Ophthalmol. 2021 Aug 23;21(1):306. doi: 10.1186/s12886-021-02066-3. PMID: 34425775; PMCID: PMC8381497.
27. Shetty R, Rajiv Kumar N, Pahuja N, Deshmukh R, Vunnava K, Abilash VG, Sinha Roy A, Ghosh A. Outcomes of Corneal Cross-Linking Correlate With Cone-Specific Lysyl Oxidase Expression in Patients With Keratoconus. Cornea. 2018 Mar;37(3):369-374. doi: 10.1097/ICO.0000000000001478. PMID: 29215396.
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