October 2018
Volume 59, Issue 12
Open Access
Letters to the Editor  |   October 2018
Influencing Factors Relating the Demarcation Line Depth and Efficacy of Corneal Crosslinking
Author Affiliations & Notes
  • Jui-teng Lin
    New Vision, Inc., Taipei, Taiwan.
Investigative Ophthalmology & Visual Science October 2018, Vol.59, 5125-5126. doi:10.1167/iovs.18-25244
  • Views
  • PDF
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Jui-teng Lin; Influencing Factors Relating the Demarcation Line Depth and Efficacy of Corneal Crosslinking. Invest. Ophthalmol. Vis. Sci. 2018;59(12):5125-5126. doi: 10.1167/iovs.18-25244.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
The recent article of Spadea et al.1,2 and Toker et al.3 evaluated the efficacy of accelerated corneal crosslinking (AXL) under different treatment protocols, and the relationship between CXL efficacy and the demarcation line (DL) depth based on available measured data.1,2 The sudden-drop of DL depth at high intensity (>45 mW/cm2) has the similar feature as the AXL efficacy reported by Wernli et al.4 However, it is clinically unclear whether DL depth is proportional to the crosslink depth or the CXL efficacy.13 Moreover, controversial results of AXL efficacy were reported due to inconsistent protocols which were not optimized. To improve the efficacy of AXL, Lin proposed a new protocol called riboflavin (Rf) concentration-controlled method (CCM),5 in which extra Rf drops are applied to the cornea, at every crosslink time (T*), during the UV exposure, having a frequency defined as Fdrop = N − 1, with N = 0.365 [I0/C0]0.5. This formula provides the optimal protocol that higher intensity (I0) and/or lower Rf concentration (C0) requires larger Fdrop to compensate its faster Rf depletion, and lower steady-state efficacy, comparing to the low-intensity Dresden protocol. 
This correspondence intends to further analyze the clinically measured DL depth via the key influencing factors of CXL, including Rf concentration profile (pre- and intraoperatively),6 Rf initial diffusion depth, UV light effective dose, epithelial absorption (for epi-on case), and most importantly, the administration protocols of Rf during CXL, governed by Fdrop and the waiting period after each Rf drop.5 The measured DL-depth of various protocols will be analyzed and compared to a combined-efficacy formula.5,7 
The measured DL depth may be compared to a combined type-I CXL efficacy given by57 c-Ceff = 1-exp (−4R), with R = (62/t') [C0F(z)/I03]0.5, where F(z) = 1–0.5z/D, is the Rf initial concentration profile defined by a diffusion depth (D); and the resupply Rf drops every t' − minutes. R is the efficacy ratio between the noncontrolled Dresden protocol and the optimal protocol (via CCM) having R = 1.0, and c-Ceff = 0.98, for all range of UV intensity I0 = 3 to 60 mW/cm2
Figures 1 and 2 show that the DL depth (based on measured data1,2) follows the similar decreasing-trend as the calculated CXL efficacy in AXL. Figure 2 shows the theoretical curves (1, 2, 3, 4) calculated from the combined efficacy (c-Ceff) formula,5,6 with time of resupply Rf drops t' = (4, 2, 1, 0.5) minutes. The measured DL-depth (z*) and theorized efficacy are compared to conclude the following features: 
  1.  
    In Figure 1, curve B for extended dose (6.2 J/cm2) has a larger z* than curve A (dose of 5.4 J/cm2). It is also predicted by Lin's formula for crosslink depth5 which is proportional to light dose, rather than light intensity. Modern protocol has also suggested to use a higher dose of 7.2 J/cm2, replacing the Dresden 5.4 J/cm2 (operation manual of KXL, Avedro Inc.).
  2.  
    Epi-on is less efficient than epi-off due to limited diffusion depth (D) and the extra absorption of the epithelium; and epi-on CXL with iontophoresis has a larger z* due to improved diffusion depth (D), comparing data 1 and data 2 of Figure 1. This feature is also shown in Lin's efficacy-formula,7 where higher D has higher value of F(z) = F(z) = 1 − 0.5z/D and leads to higher efficacy.
  3.  
    Curve 2 of Figure 2 represents the conventional protocol having resupply the Rf drops every 4 minutes. Therefore, it has the similar profile as curve A of Figure 1. This feature indicates that CXL efficacy is proportionally related to the DL depth. The recent article of Spadea et al.2 also concluded that the depth of DL is an indirect measurement of CXL penetration within the stroma, although “the deeper, the better” requires further clinical long-term studies.
  4.  
    Both CXL efficacy and DL depth have a cutoff maximum intensity, under the noncontrolled Dresden protocol, as reported by Wernli et al.4 It should be noted that the theoretical curve 4 (with controlled t' = 0.5 minute, or Fdrop = 3 to 4) gives the optimal efficacy comparable to CCM.5
  5.  
    In contrast to the conventional belief (by Hafezi and Kling et al.) that oxygen-mediated type-II plays the critical role of CXL, Kamaev et al.8 kinetic model showed that CXL is predominated by type-I, while oxygen (or type-II) only plays a limited and transient role. Lin's 3-pathway model9 showed mathematical details of the role of oxygen, supporting the claim of Kamaev et al.8 In addition, a recent clinical study of Lombardo et al.10 showed a simple-exponential kinetic of RF concentration also implied that, in ambient environment (with approximately 21% partial pressure of oxygen), nonoxygen-mediated type-I mechanism is predominant.
  6.  
    The conventional Dresden protocol, extra Rf drops (with a frequency Fdrop = 10–15) instilled during the UV exposure. This too-often Fdrop will reduce the effective dose and CXL efficacy. Some modern protocols propose not to apply any extra Rf drops (with Fdrop = 0), however, has less efficacy than that of optimal CCM5 which requires Fdrop = 3 to 5 for high intensity AXL (18–50 mW/cm2).
  7.  
    Extension of exposure time (or dose) in AXL may increase the crosslink depth (z) and improve the efficacy governed a crosslinked stroma volume7 = depth × strength. Higher Rf concentration (C0) achieves higher efficacy, predicted by c-Ceff formula,7 was also clinically reported by O'Brart et al.11 Therefore, new clinical studies of DL-depth for a wider range of C0 = 0.1% to 0.3%, and under the CCM protocol might lead to a breakthrough of the AXL efficacy and justify the accuracy of CCM for optimal efficacy.
Figure 1
 
Measured DL-depth in CXL under conventional dose 5.4 J/cm2 (curve A) and extended dose 6.2 J/cm2 (curve B). Also shown are the epi-on cases with (data 1) and without (data 2) iontophoresis.2
Figure 1
 
Measured DL-depth in CXL under conventional dose 5.4 J/cm2 (curve A) and extended dose 6.2 J/cm2 (curve B). Also shown are the epi-on cases with (data 1) and without (data 2) iontophoresis.2
Figure 2
 
Theoretical CXL efficacy versus UV light intensity for resupply of Rf drops at various time, t' = (4, 2, 1, 0.5) minutes, for curves (1, 2, 3, 4).
Figure 2
 
Theoretical CXL efficacy versus UV light intensity for resupply of Rf drops at various time, t' = (4, 2, 1, 0.5) minutes, for curves (1, 2, 3, 4).
Acknowledgments
Disclosure: J. Lin, New Vision, Inc. (F, E, S) 
References
Spadea L, Genova LD, Tonti E. Corneal stromal demarcation line after 4 protocols of corneal crosslinking in keratoconus determined with anterior segment optical coherence tomography. J Cataract Refract Surg. 2018; 44: 596–602.
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; 10: 1803–1810.
Toker E, Cerman E, Oscan DO, Seferoglu OB. Efficacy of different accelerated corneal crosslinking protocols for progressive keratoconus. J Cataract Refract Surg. 2017; 43: 1089–1099.
Wernli J, Schumacher S, Spoer E, Mrochen M. The efficacy of corneal cross-linking shows a sudden decrease with very high intensity UV light and short treatment time. Invest Ophthalmol Vis Sci. 2013; 54: 1176–1180.
Lin JT. A proposed concentration-controlled new protocol for optimal corneal crosslinking efficacy in the anterior stroma. Invest Ophthalmol Vis Sci. 2018; 59: 431–432.
Lin JT, Cheng DC. Modeling the efficacy profiles of UV-light activated corneal collagen crosslinking. PLoS One. 2017; 12: e0175002.
Lin JT. The role of riboflavin concentration and oxygen in the efficacy and depth of corneal crosslinking. Invest Ophthalmol Vis Sci. 2018; 59: 4449–4450.
Kamaev P, Friedman SE, Muller D. Cornea photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci. 2012; 53: 2360–2367.
Lin JT. Efficacy S-formula and kinetics of oxygen-mediated (type-II) and non-oxygen-mediated (type-I) corneal cross-linking. Ophthalmology Res. 2018; 8: 1–11.
Lombardo G, Villlan V, Micali N, et al. Non-invasive optical method for real-time assessment of intracorneal riboflavin concentration and efficacy of corneal cross-linking. J Biophotonics. 2018; 11: e201800028.
O'Brart NAL, O'Brart DPS, Aldahlawi, et al. An investigation of the effects of riboflavin concentration on the efficacy of corneal cross-linking using an enzymatic resistance model in porcine corneas. Invest Ophthalmol Vis Sci. 2018; 59: 1058–1065.
Figure 1
 
Measured DL-depth in CXL under conventional dose 5.4 J/cm2 (curve A) and extended dose 6.2 J/cm2 (curve B). Also shown are the epi-on cases with (data 1) and without (data 2) iontophoresis.2
Figure 1
 
Measured DL-depth in CXL under conventional dose 5.4 J/cm2 (curve A) and extended dose 6.2 J/cm2 (curve B). Also shown are the epi-on cases with (data 1) and without (data 2) iontophoresis.2
Figure 2
 
Theoretical CXL efficacy versus UV light intensity for resupply of Rf drops at various time, t' = (4, 2, 1, 0.5) minutes, for curves (1, 2, 3, 4).
Figure 2
 
Theoretical CXL efficacy versus UV light intensity for resupply of Rf drops at various time, t' = (4, 2, 1, 0.5) minutes, for curves (1, 2, 3, 4).
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×