Corneal collagen cross-linking is considered a favorable treatment option to slowdown the progression of keratoconus. This method is considered highly safe without significant damages to the endothelium or inner structures of the eye such as crystalline lens and retina in terms of adherence to standard protocols, indications, and contraindications. It has been shown that keratocyte loss within 300 μm of the stroma occurs immediately after the procedure, which takes about 6 months until repopulation [5].

The cytotoxic effect of riboflavin/UV-A combination on corneal endothelium has been revealed previously [6]. It seems human corneal endothelial cells are much more resistant to riboflavin-enhanced UV-A radiation than the animal corneal endothelial cells [7]. This finding may be related to the presence of collagen fibers which act as a protective factor. Moreover, thickness of 400 μm for saturation with riboflavin reduces the amount of radiation to the endothelial cells into level of 0.18 mW / cm2, which is half of the required level for cytotoxic effect (0.36 mW/cm2 (0.65 J/cm2) [5]. Hence, the corneal thickness of less than 400 μm has been identified as the most important risk factor for developing post CXL endothelial cell damage [6].

Several factors have been introduced that might play a role in endothelial damage including inadvertent delivery of excessive energy due to poor calibration and focusing, intraoperative corneal thinning secondary to dehydration caused by epithelium removal or application of dextran containing riboflavin drops, inaccurate pachymetry reading during surgery, acute hydrops, pre-existing Fuchs endothelial dystrophy, extreme intra-CXL treatment of corneal thinning occurring during CXL, and endothelial cell damage due to waterjet wave during intraoperative irrigation procedure [8]. Also, herpetic disciform edema and noninfectious endotheliitis caused by direct injury to the endothelial cells by UV-A are the other possibilities [9]. However, clinical and imaging findings of our case were not compatible with those of the two latter differential diagnoses. To the best of the author’s knowledge, only 4 reports (containing 13 cases) of post CXL corneal edema are available on the Pubmed/Medline database, as summarized in Table 2.

Table 2 Review on similar reported reports regarding post CXL corneal edema

Our case developed corneal edema immediately after the procedure which completely was resolved within further follow-up visits. Multimodal imaging such as confocal microscopy, specular microscopy, and ASOCT was performed to evaluate corneal edema. Confocal microscopy revealed the corneal endothelial cell density of about 1860 cells which was 60% of cell density of the untreated fellow eye (Table 1). Furthermore, specular microscopy after clearing the corneal edema showed decreased number of endothelial cells, polymorphism, and polymegatism considered as other witnesses of endothelial cell damage during this procedure. However, endothelial cells count before CXL was unknown, but based on medical records and the referring surgeon’s claim, preoperative clinical examination did not reveal any endothelial abnormalities.

The ASOCT showed an increase in the depth of cross-linking, in which the demarcation line was observed in the posterior part of the stroma and the center area on the endothelium. However, it normally should be detected between the anterior third and posterior two-third of the stroma. Other causes of corneal edema such as acute hydrops and rupture of the Descemet membrane were ruled out by this imaging.

In addition to decrease in the number of endothelial cells in the acute phase, confocal microscopy showed the effects of cross-linking in the form of hyper-reflective lines with a reticular pattern at posterior stroma and endothelium (depth of 456 μm), which was another confirmation of the increase in cross-linking depth. Also, it seems needle-like structures are representative for new synthesized collagen produced by activated keratocytes at the transition zone [12]. Although the referring surgeon insisted on following the standard protocols, an error in performing cross-linking can be considered as one of the possible causes for this complication. Furthermore, it seems one of the pitfalls in the management of this patient is lack of intraoperative pachymetry since it has been shown remarkable alteration in pachymetry is not an uncommon event during CXL.

Improper focus or calibration of the ultraviolet light source and closer position of the eye in machines using only one light-emitting diode (LED) as the UV-A source can cause delivery of higher energies and subsequent cytotoxic damages to the corneal endothelium. Moreover, the presence of intact film of riboflavin during the procedure is so important. On the one side, riboflavin acts as a photosensitizer increasing the absorption of UV, which results in collagen cross-linking. On the other side, riboflavin has a protective role blocking the delivery of high energy to inner structures like endothelium. Moreover, continuity in providing riboflavin prevents from dehydration and subsequent corneal thinning [10]. It has been reported dextran–riboflavin solution can lead to about 10% corneal thinning [13]. So, frequent instillation of this agent during the procedure should be considered.

Beside the corneal thickness, proper calibration and focusing, removal of the lid speculum during instillation of riboflavin drops to prevent excessive thinning secondary to evaporation, providing intact continuous film of riboflavin, transepithelial CXL, accelerated CXL, and frequent intratreatment checks of the corneal thickness with re-administration of hypotonic solution if the thickness drops to less than 350 μm are the considerable factors for preventing from collateral damages to other structures of the eye such as endothelium [14].

In conclusion, our case highlights that the corneal thickness of more than 400 μm cannot guarantee the absence of corneal edema after corneal collagen cross-linking, which can pertain to several factors such as inadvertently using higher energy due to improper calibration or focus as well as the incorrect observance of all guidelines, instructions, and other precautions, even by a trained surgeon.

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