Severe Complications after Corneal Collagen Cross-Linking (CXL)

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TL;DR

This case series reports four rare but severe complications after corneal collagen cross-linking (CXL) for keratoconus, including infectious keratitis, autoimmune keratolysis, and corneal edema from eye rubbing. All complications occurred within one month post-procedure and resulted in permanent corneal scarring or thinning in three cases. The findings highlight the importance of patient compliance, careful postoperative monitoring, and appropriate microbiological workup to manage these rare events.

Full summary

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**Background** Corneal collagen cross-linking (CXL) is a widely used procedure to halt the progression of keratoconus and other corneal ectatic disorders. Introduced in 2003 by Wollensak et al., CXL strengthens corneal collagen fibers through UV-A irradiation and riboflavin, mimicking premature ageing of the cornea. The standard epithelium-off (epi-off) Dresden protocol involves 30 minutes of riboflavin instillation followed by 30 minutes of UV-A at 3 mW/cm² (total fluence 5.4 J/cm²). Accelerated protocols use higher irradiance (e.g., 10 mW/cm² for 9 minutes). While CXL is generally safe with a low complication rate, severe complications can occur, particularly during the postoperative healing phase. This case series from the Department of Ophthalmology at the University Hospital Zurich, Switzerland, presents four eyes of four patients with severe complications within one month after CXL.

**Methods** This was a single-center descriptive case series covering the period from 2012 to 2022. All patient files were reviewed to identify cases with severe complications after CXL. Four eyes of four patients were included. Demographic data, CXL protocol, type of complication, treatment, and outcomes were recorded.

**Key Results** All four patients were male, with a mean age of 20.3 ± 10.0 years (range 11–34 years). Three patients had undergone standard Dresden epi-off CXL, and one had accelerated epi-off CXL. The median time from CXL to complication was 10.0 days (Q1 2.5, Q3 20.0; mean 12.5 ± 3.1 days). The median time to resolution was 45.5 days (Q1 15.5, Q3 85.3; mean 55.3 ± 52.9 days).

- **Case 1**: A 15-year-old male presented 3 days after accelerated epi-off CXL with pain, hand movements visual acuity (VA), conjunctival injection, large stromal infiltrate, and hypopyon. Corneal swabs identified *Streptococcus pneumoniae*. Treatment with ceftazidime 5% hourly, ofloxacin 0.3% hourly, cyclopentolate 1% BID, and oral doxycycline 100 mg BID stabilized the eye over 2 weeks, resulting in stromal scarring and VA of counting fingers. - **Case 2**: An 11-year-old male presented 3 days after standard Dresden CXL with pain, VA 0.05 decimal, missing bandage contact lens, and massive corneal edema (central pachymetry 1298 µm). No infectious cause was found. Repeated history revealed intensive eye rubbing. With topical ofloxacin 4×/day, dexamethasone 0.1% 4×/day, and strict contact lens wear, the edema resolved completely over 18 days, and VA recovered to 0.6 decimal. - **Case 3**: A 35-year-old male presented 29 days after standard Dresden CXL with VA 0.25 decimal and subepithelial/anterior stromal crystalline infiltrates. Cultures identified *Staphylococcus hominis*, *Micrococcus luteus*, and *Streptococcus epidermidis*. Despite treatment with ceftazidime 5%, ofloxacin 0.3%, vancomycin 5% hourly, and oral valaciclovir 500 mg TID, the condition worsened at 14 days with new infiltrates and anterior chamber reaction. Suspected mycotic superinfection prompted natamycin 5% hourly and oral voriconazole 600 mg/day, but repeated scrapings were negative for fungi. The infection stabilized over 3 months, with final VA 0.4 decimal. - **Case 4**: A 21-year-old male presented 12 days after standard Dresden CXL with pain, VA hand movements, and an ulcerative lesion with extensive conjunctival and anterior chamber involvement. Initial swabs were negative. Despite broad-spectrum antibiotics (ceftazidime 5%, ofloxacin 0.3%, tobramycin 0.3% hourly), the lesion progressed over 2 weeks with corneal lysis and descemetocele formation. An autoimmune keratolytic process was suspected, and treatment with dexamethasone 0.1% eight times/day and intravenous methylprednisolone 500 mg/day was added. An amniotic membrane patch and botulinum toxin-induced ptosis were used for stabilization. The defect stabilized over 4 months with autologous serum eye drops, resulting in final VA 0.05 decimal and a stable but thin cornea.

**Clinical Implications** Severe complications after CXL are rare but can lead to permanent corneal scarring and vision loss. The most common causes are indirect, occurring during the epithelial healing phase. Risk factors include bandage contact lenses, topical steroids, atopic disease, and patient noncompliance (e.g., eye rubbing). Correctly performed corneal scrapings with repeated microbiological analysis and detailed patient history are essential for diagnosis, especially in cases unresponsive to standard therapy. The authors suggest that more efficient epithelium-on techniques could further reduce complication rates.