Influencing Factors Relating the Demarcation Line Depth and Efficacy of Corneal Crosslinking

Abstract

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/cm 2) 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. 1-3 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 ¼ N-1, with N ¼ 0.365 [I 0 /C 0 ] 0.5. This formula provides the optimal protocol that higher intensity (I 0) and/or lower Rf concentration (C 0) 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 DLdepth 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 by 5-7 c-Ceff ¼ 1-exp (-4R), with R ¼ (62/t') [C 0 F(z)/I 0 3 ] 0.5 , where F(z) ¼ 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 ¼ 1.0, and c-Ceff ¼ 0.98, for all range of UV intensity I 0 ¼ 3 to 60 mW/ cm 2 .

Critical Analysis of Corneal Cross-linking (Part-I): Formulas for Efficacy, Safety Dose, Minimum Thickness, Demarcation Line Depth and the Role of Oxygen

“…However, for type-I steady state, DLD is a decreasing function of light intensity, as demonstrated by type-I formula, Eq. (10), in consistent with measured data [35,36].…”

“…Fig. 5 summarizes the measured data for various conditions [35][36][37][38][39][40][41][42][43][44][45][46], showing that DLD is a decreasing function of light intensity, as also demonstrated by our type-I formula, Eq. (10).…”

“…Measured DLD in CXL under conventional dose 5.4 J/ cm 2 (curve A) and extended dose (curve B). Also shown are the epi-on cases with (data 1) and without (data 2)iontophoresis[35]…”

Critical Analysis of Corneal Cross-linking (Part-II): Resolving the Controversial Issues (Theory versus Measurements)

“…The standard Dresden (SD) protocol was proposed (in 2003) by Wollensak et al [3], in which a UVA light intensity of 3.0 mW/cm 2 was applied to the cornea for an irradiation time of 30 minutes, such that a light fluence (dose) of 5.4 J/cm 2 was delivered to the cornea. To shorten the irradiation time of the SD protocol, accelerated CXL was also developed [4,5], based on Bunsen and Roscoe law [6], leading to the AC protocol given by light intensity of I= (3,9,18,30,45) mW/cm 2 , with the associated irradiation time is inverse proportional to the light intensity given by t= (30,10,5,3,2) minutes, such that the total dose applied to the cornea is fixed at 5.4 J/cm 2 [1]. In the past 18 years (2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020), over 1,000 articles were published on the clinical aspects of CXL.…”

“…In the past 18 years (2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020), over 1,000 articles were published on the clinical aspects of CXL. In comparison, only about 20 articles were published regarding the basic kinetics and/or the theory of CXL , in which over 75% was published by Lin et al [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. With the lack of indepth fundamental studies and lack of conclusive theoretical predictions, the following controversial (clinical/theoretical) issues remained to be resolved [15,22]:…”