Accelerated corneal collagen cross-linking should be modified

Dear editor

We have read with interest the recently published comparative study regarding the accelerated versus conventional corneal collagen cross-linking (CXL) in the treatment of mild keratoconus. We would like to underline the importance of the CXL treatment time reduction in this time consuming operation.¹ Accelerated CXL became popular due to patient and doctor comfort in comparison to the previously widespread use of Dresden protocol which is successful in terms of safety and efficacy. Based on the Bunsen-Roscoe law of reciprocity many modifications to the time and irradiation settings have been proposed while the total energy dose delivered to the cornea should be maintained at 5.4 J/cm².²

We already proved, by measuring (with the use of anterior segment optical coherence tomography) the demarcation line depth at 1 month postoperatively after CXL, that the treatment depth was significantly different (significantly shallower in accelerated protocol) between the 10 minute accelerated protocol with ultraviolet-A (UV-A) irradiation intensity of 9 mW/cm² and the 30 minute standard Dresden protocol with UV-A of 3 mW/cm².² Our results suggested that Bunsen-Roscoe law of reciprocity may not directly apply to CXL in living cornea tissue, thus, an increased total energy dose should probably be applied to the keratoconic cornea in order to achieve a treatment effect comparable to the already proven effective standard Dresden CXL protocol.

Consequently, we have proceeded with relevant modifications for the UV-A time settings of the currently proposed accelerated CXL protocol (10 minutes) by increasing the UV-A irradiation time to 14 minutes (40% increase) and we achieved a treatment effect comparable with the Dresden protocol (as indicated by the demarcation line depth).³

In the recently published article by Sherif, it is presumed that the accelerated group of patients received CXL treatment according to Bunsen-Roscoe law which should have been 3 minutes of UV-A with irradiation intensity of 30 mW/cm² corresponding to 5.4 J/cm² total energy dose delivered to the cornea.¹ Interestingly, Sherif mentioned that the accelerated group received UV-A treatment with 30 mW/cm² for 4 minutes and 20 seconds; thus the accelerated group received about 40% more UV-A irradiation time, which is comparable to our time setting modifications (from 10 to 14 minutes). Moreover it should be clarified whether the author modified the time settings manually or if these modifications were made according to the UV-A device manufacturer’s instructions (Avedro, Inc., Waltham, MA, USA). In addition we would like to enquire whether the author performed measurements (eg, endothelial cell density) concerning the safety of the time and irradiation intensity settings used in this study.⁴

As we previously published, an indirect and non-contact method to measure the effectiveness of CXL treatment is the demarcation line depth provided with anterior segment optical coherence tomography; our results were the same with the reliable but more invasive (due to contact with the treated cornea) confocal microscopy.⁵ Thus, measurement of the demarcation line depth at 1 month postoperatively could provide useful information in suggesting modifications to any of the CXL treatment settings.⁶ It should be of great interest whether the author could provide such measurement results concerning the studied groups of this article. Moreover, we should bring to the attention that in cases of mild keratoconus it should probably need a longer follow-up period to establish reliable results concerning the effectiveness of treatment in arresting keratoconus progression.

In conclusion we believe that accelerated CXL treatment settings in agreement to Bunsen-Roscoe law of reciprocity should be revised thoroughly and new modifications have to be carefully made regarding time and irradiation intensity adjustments keeping the safety aspect of CXL treatment as the first priority.

Disclosure

The authors report no conflicts of interest in this communication.

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References

1.		Sherif AM. Accelerated versus conventional corneal collagen cross-linking in the treatment of mild keratoconus: a comparative study. Clin Ophthalmol. 2014;8:1435–1440.
2.		Kymionis GD, Tsoulnaras KI, Grentzelos MA, et al. Corneal stroma demarcation line after standard and high-intensity collagen crosslinking determined with anterior segment optical coherence tomography. J Cataract Refract Surg. 2014;40(5):736–740.
3.		Kymionis GD, Tsoulnaras KI, Grentzelos MA, et al. Evaluation of Corneal Stromal Demarcation Line Depth Following Standard and a Modified-Accelerated Collagen Cross-linking Protocol. Am J Ophthalmol. 2014;158(4):671–675.e1.
4.		Kymionis GD, Grentzelos MA, Kankariya VP, et al. Safety of high-intensity corneal collagen crosslinking. J Cataract Refract Surg. 2014;40(8):1337–1340.
5.		Kymionis GD, Grentzelos MA, Plaka AD, et al. Correlation of the corneal collagen cross-linking demarcation line using confocal microscopy and anterior segment optical coherence tomography in keratoconic patients. Am J Ophthalmol. 2014;157(1):110–115.e1.
6.		Kymionis GD, Grentzelos MA, Plaka AD, et al. Evaluation of the corneal collagen cross-linking demarcation line profile using anterior segment optical coherence tomography. Cornea. 2013;32(7):907–910.