Since the first publication reporting outcomes of corneal cross-linking (CXL) in 2003,1 the peer reviewed literature on this topic has expanded exponentially, with studies reporting outcomes, variations in protocols in terms of fluence, time, epithelial integrity, chromophores, and multiple indications for cross-linking procedures.2
A foreseeable but unfortunate consequence of this rapid expansion has been the tremendous variability in nomenclature and raw data reported. This variability limits direct comparison between various studies. When attending ophthalmic meetings or perusing the literature, one could easily come across a variety of “accelerated” protocols that all have the same name but have different treatment variables, less familiar terms such as “flash” or “rapid” protocols, or individually named protocols that may sound attractive but connote little in terms of their processes or parameters. The authors of this editorial have all written articles using some of these terms and abbreviations in attempts to communicate unique aspects of their studies; through this process we have separately realized the gross limitations of the nomenclature commonly in use today.
As our understanding of the cross-linking process evolves, so should our nomenclature and reporting. In this editorial, we outline the reasons why simple names and abbreviations, although attractive, have limited utility in reporting CXL protocols and why we therefore need more robust reporting in a clear, reproducible, readily identifiable manner.
CXL is Corneal Cross-Linking
There remains a gap in our knowledge of what exactly happens at the time of CXL; however, in 2011, Zhang et al.3 demonstrated that the actual cross-links are not formed between and within the collagen fibers, but rather between the amino terminals of the collagen side chains and the proteoglycans of the extracellular matrix. This is a fundamental difference, rendering the term “collagen cross-linking” incorrect and misleading. Therefore, we encourage elimination of the “collagen cross-linking” terminology moving forward and in the Journal of Refractive Surgery will limit the use of CXL as an abbreviation for the more accurate term “corneal cross-linking.”
The Spectrum of CXL Indications
CXL was initially used to treat progressive keratoconus1 and soon after was applied for corneal ectasia after LASIK.4 A variety of indications have since been proposed, including treatment of non-progressive keratoconus, cross-linking combined with excimer laser ablation for patients with keratoconus, prophylactic use of cross-linking in combination with surface ablation or LASIK, and cross-linking to treat infectious keratitis, among others. It is important to clarify the indications for use to appropriately frame the discussion and outcomes achieved for any individual protocol.
For general terminology, we recommend the following: CXL for corneal ectasias; CXL-Plus for corneal ectasia management in combination with refractive treatments with a primary therapeutic target5; photo-activated chromophores for keratitis (PACK-CXL) for infectious keratitis6; and prophylactic CXL for cross-linking in combination with corneal refractive surgery in non-ectatic patients with a primary refractive target. By defining these terms, we are not advocating for specific indications, merely working to clarify the discussions surrounding them.
CXL Protocols: The Standard Protocol and its Variations
Wollensak et al.1 first reported their protocol in 2003, using 3 mW fluence for 30 minutes to achieve a total irradiance of 5.4 mJ/cm2. This original protocol has been termed the “Dresden” or “standard” protocol for obvious reasons. Although both terms have merit, neither are descriptive and neither readily connote meaning in isolation nor when comparing this original protocol to the multiple variations in use today.
Most protocols that have reduced total treatment time have simply been termed “accelerated.” Although it is true that these variations share the commonality of shorter duration, they often differ in many other important respects, including total irradiance7 and efficacy,8,9 among others. Thus, the term “accelerated” by itself lacks sufficient specificity and poorly connotes the intricacies of the protocols being described.
We now know about the importance of many factors in the cross-linking process, some of which were poorly understood at the advent of the procedure. These include oxygen and its depletion during the procedure,10 the barrier effect of the epithelium,11 the formulation of riboflavin used,12 the impact of total stromal corneal thickness on procedure efficacy, the riboflavin delivery process,13 and the impact of varying treatment time and fluence,7,8 to name but a few. Because all of these factors must be clear when reporting the study methods, how could one reasonably use a simple abbreviation for a protocol and still provide clarity on its fundamental components?14
The CXL Methods Table
To facilitate communication and provide consistent, readily accessible protocol details for the reader, we are now recommending using a standardized “CXL Methods” table for every article reporting on CXL methodology and will require this moving forward for CXL articles published in the Journal of Refractive Surgery (Table 1). The contents of this table likely will evolve over time as additional important points to clarify are identified, and authors are encouraged to include more information as they identify important factors that are missing. The last row of the table includes room for the authors' abbreviation of their protocol to facilitate writing the article. We encourage the authors to use an abbreviation that is as descriptive as possible, but currently do not have specific recommendations on how best to do this. One option is to list the basic parameters in the abbreviation subscript. For instance, the standard protocol with 3 mW treatment for 30 minutes could be listed as S-CXL(3*30), whereas an accelerated protocol using 10 mW for 9 minutes could be A-CXL(10*9). These still leave out critical details but convey more information than the S-CXL and A-CXL abbreviations currently in use.
In clarifying and standardizing some terminology, we hope to provide necessary structure to the growing field of CXL and give readers and investigators easy access to critical protocol details in a consistent, reproducible manner.
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620. doi:10.1016/S0002-9394(02)02220-1 [CrossRef]
- Randleman JB, Khandelwal SS, Hafezi F. Corneal cross-linking. Surv Ophthalmol. 2015;60:509–523. doi:10.1016/j.survophthal.2015.04.002 [CrossRef]
- Zhang Y, Conrad AH, Conrad GW. Effects of ultraviolet-A and riboflavin on the interaction of collagen and proteoglycans during corneal cross-linking. J Biol Chem. 2011;286:13011–22. doi:10.1074/jbc.M110.169813 [CrossRef]
- Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2007;33:2035. doi:10.1016/j.jcrs.2007.07.028 [CrossRef]
- Kymionis GD, Grentzelos MA, Portaliou DM, Kankariya VP, Randleman JB. Corneal collagen cross-linking (CXL) combined with refractive procedures: CXL plus. J Refract Surg. 2014;30:566–576. doi:10.3928/1081597X-20140711-10 [CrossRef]
- Hafezi F, Randleman JB. PACK-CXL: defining CXL for infectious keratitis. J Refract Surg. 2014;30:438. doi:10.3928/1081597X-20140609-01 [CrossRef]
- Kymionis GD, Tsoulnaras KI, Liakopoulos DA, Skatharoudi CA, Grentzelos MA, Tsakalis NG. Corneal stromal demarcation line depth following standard and a modified high intensity corneal cross-linking protocol. J Refract Surg. 2016;32:218–222. doi:10.3928/1081597X-20160216-01 [CrossRef]
- Hammer A, Richoz O, Mosquera S, Tabibian D, Hoogewoud F, Hafezi F. Corneal biomechanical properties at different corneal collagen cross-linking (CXL) irradiances. Invest Ophthalmol Vis Sci. 2014;55:2881–2884. doi:10.1167/iovs.13-13748 [CrossRef]
- Hashemian H, Jabbarvand M, Khodaparast M, Ameli K. Evaluation of corneal changes after conventional versus accelerated corneal cross-linking: a randomized controlled trial. J Refract Surg. 2014;30:837–842. doi:10.3928/1081597X-20141117-02 [CrossRef]
- Richoz O, Hammer A, Tabibian D, Gatzioufas Z, Hafezi F. The biomechanical effect of corneal collagen cross-linking (CXL) with riboflavin and UV-A is oxygen dependent. Transl Vis Sci Technol. 2013;2:6. doi:10.1167/tvst.2.7.6 [CrossRef]
- Cruzat A, Shukla A, Arafat S, et al. Ex vivo study of transepithelial corneal cross-linking. J Refract Surg. 2017;33:171–177. doi:10.3928/1081597X-20161206-04 [CrossRef]
- Ehmke T, Seiler TG, Fischinger I, Ripken T, Heisterkamp A, Frueh BE. Comparison of corneal riboflavin gradients using dextran and HPMC solutions. J Refract Surg. 2016;32:798–802. doi:10.3928/1081597X-20160920-03 [CrossRef]
- Vinciguerra P, Romano V, Rosetta P, et al. Transepithelial iontophoresis versus standard corneal collagen cross-linking: 1-year results of a prospective clinical study. J Refract Surg. 2016;32:672–678. doi:10.3928/1081597X-20160629-02 [CrossRef]
- Santhiago MR. Accelerated corneal cross-linking: we must acquire knowledge as fast. J Refract Surg. 2016;32:362–36-3 doi:10.3928/1081597X-20160519-01 [CrossRef]
|Parameter||Variable (EXAMPLES)||Alternative Examples|
|Treatment target||Ectasia||Infectious keratitis, therapeutic refractive, prophylaxis, others|
|Fluence (total) (mJ/cm2)||5.4||7.2, 2.7, others|
|Soak time and interval (minutes)||30(q2)||10(q2), 20(q5), others|
|Intensity (mW)||3||5, 10, 14, 18, 30, others|
|Treatment time (minutes)||30||10, 9, 5, 4, 3, others|
|Epithelium status||Off||On, partial removal, iontophoresis, others|
|Chromophore||Riboflavin (source name)||Rose Bengal, others|
|Chromophore carrier||Dextran||hydroxypropyl methylcellulose (HPMC), others|
|Chromophore osmolarity||Iso-osmolar||Hypo-osmolar, others|
|Chromophore concentration||0.1%||0.2%, others|
|Light source||Device name (company name)|
|Irradiation mode (interval)||Continuous||Pulsed (1 minute), others|
|Protocol modifications||Contact lens–assisted||Penetration enhancers (list details), others|
|Protocol abbreviation in manuscript||S-CXL(3*30) (Standard)||A-CXL(10*9) (Accelerated), others|