CXL is a technique employed in managing keratoconus and in association with refractive surgery, thanks to its property of strengthening the covalent bonds of stromal collagen. It is considered mainly a safe procedure [10], even though epithelial debridement is a risk factor for stromal haze, persistent epithelial defects, microbial infection, sterile inflammation, stromal melting and, ultimately, corneal perforation [6, 11].

Up to date, only a few cases of corneal melting and perforation have been reported in the literature after CXL (Table 1).

We conducted literature research in PubMed using the keywords “corneal cross-linking, CXL, corneal melting, corneal infection”. We included all the case reports that described the development of corneal melting with perforation or impending perforation. For each paper, we extracted the sex and age of the patients, the protocol of CXL used, the aetiology of corneal melting, and its management.

Infective keratitis was responsible for disruption of the stroma in some cases, which eventually led to corneal perforation. Both bacterial [15, 20] and fungal [22] keratitis have been described. Rama et al. [12] reported an atypical case of corneal perforation after CXL caused by Acanthamoeba keratitis related to improper use of contact lenses.

Abuse of nonsteroidal anti-inflammatory drug (NSAID) drops has also been identified as a cause of corneal melting in patients who underwent CXL. Gokhale et al. [21] reported a case of corneal melting and perforation that occurred 1 week after CXL in a 19-year-old patient treated with diclofenac sodium and proparacaine eyedrops. Noriega et al. [16] described another case of inappropriate use of NSAID eye drops, resulting in corneal melting, in a 50-year-old diabetic patient. Topical NSAIDs have been reported to cause corneal melting and perforation postoperatively, especially in the presence of epithelial breakdown [23]. Impairment of wound healing, resulting from the analgesic property of these drugs, alongside activation of matrix metalloproteinases (MMPs) are the suggested mechanisms [23, 24]. High levels of MMP-2, MMP-3, MMP-8 and MMP-9 have been found in the epithelium and stroma of melted and perforated corneas after topical NSAID use and in patients with diabetes [25]. Our patient did not use NSAID eye drops after the treatment and did not present any known risk factor related to the occurrence of postoperative corneal melting such as diabetes, Down syndrome, vernal keratoconjunctivitis, lagophthalmos and blepharitis [26, 27]. We performed a microbiological investigation; the results were negative for the corneal scraping and the corneal stroma excised at the time of keratoplasty.

In some cases, it is not possible to identify the causative agent of corneal melting [18]. Labiris et al. [13] described a case of a 23-year-old male who developed corneal melting and descemetocele a few days after CXL. They performed a complete laboratory examination for autoimmune and infectious diseases; the patient was also evaluated for hypersensitivity to riboflavin and other components of the B vitamin complex as well as a series of common allergens. However, all of the investigations were negative. Similarly, Tillmann et al. [20] and Angunawela et al. [14] described cases of corneal melting after CXL without a well-defined aetiology. They proposed atopia and hypersensitivity to Streptococcus pneumoniae antigens as possible triggers for the inflammation. Finally, Zhang et al. [17] identified a mutation in the ZNF469 gene, which encodes a protein involved in corneal extracellular matrix development and maintenance, as a predisposing factor for corneal perforation after CXL.

In our case, all allergy tests to the eye drops used and allergenic substances tested (contact lens, chloramphenicol/betamethasone drops, dexamethasone drops, monofloxacin and levofloxacin drops and riboflavin) were negative. Thus, what triggered the patient’s inflammatory response remains unclear. Moreover, our patient did not present signs and symptoms of atopic dermatitis. This condition is known to be associated with an immune dysregulation characterised by increased expression of Th17 and interferon gamma, increased circulating regulatory T cell and increased CLA-Th2 subsets [28], which could lead to an abnormal immune and inflammatory response.

We achieved something remarkable in managing our patient: we avoided PK à chaud and instead performed DALK, which has numerous safety advantages, including larger diameter grafts with a reduced risk of rejection, particularly in children and young patients [29]. Performing a conjunctival flap allowed us to turn off the inflammation and to avoid perforation, promoting healing of the stroma. It has been used successfully in cases with deep ulcers, descemetocele or corneal perforation [30, 31]. We used the technique described by Gundersen [9] in 1958, which involves covering the whole cornea with a conjunctival flap dissected from the upper bulbar conjunctiva and approximating and suturing the cut edges. The flap is capable of restoring ocular surface integrity while providing metabolic and mechanical support for corneal healing, allowing the chance to perform DALK at a later time. Most of the cases of corneal perforation after CXL reported in the literature were treated with PK à chaud (Table 1) [12, 13, 15, 16, 18, 20,21,22]. This procedure is effective in restoring eye integrity and vision but exposes patients to prolonged steroid therapy and the risk of graft rejection, endothelial failure, secondary glaucoma and cataract formation [20]. Sasaki et al. [19] described a case of amniotic membrane transplant (AMT), which allowed them to control the inflammation, to prevent perforation and to avoid PK. AMT may be considered an alternative option to a conjunctival flap for the treatment of acute stromal melting. In our opinion, a conjunctival flap offers a more effective tectonic support in cases with a high risk of perforation and its longer duration allows delaying surgery until the acute inflammatory phase has resolved. In the case of infective aetiology, AMT may impair treatment penetration and visualisation of the response to therapy. Therefore, it should be performed after the initial response to antimicrobials, or once the infectious component has been adequately controlled [32].

In conclusion, CXL is a safe and effective technique in the treatment of keratoconus in children and adults; however, it can have serious complications that could eventually lead to corneal perforation. While identification of the causative agent is essential in guiding the therapy, it is not always possible to define a certain aetiology. To our knowledge, this is the first case of severe non-infectious corneal melting that was managed with a conjunctival flap and subsequent DALK. A conjunctival flap is an excellent option to save the integrity and to promote healing of the cornea, with the purpose of performing subsequent reconstructive surgery in an elective setting. When possible, DALK allows preserving the host corneal endothelium, reducing the risk of rejection and late endothelial failure that are particularly relevant in young patients.