Photorefractive Intrastromal Cross-Linking

From EyeWiki
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Assigned status Update Pending
 by Severin Pouly, M.D. on January 6, 2023.


Corneal collagen cross-linking (CXL) was FDA-approved for the treatment of keratoconus in April of 2016[1]and has since become routine for stabilizing corneal ectasia.[2] Post-CXL improvement in visual acuity as a result of corneal stiffening has been reported in the literature.[3] [4] [5] To achieve more pronounced refractive changes, higher fluence of UV light was used in the CXL procedure, thus creating photorefractive intrastromal cross-linking (PiXL).[1] PiXL is a refractive procedure. Achievability of predictable refractive changes and tolerability of this procedure have been confirmed.[6]

Objectives & Candidates

PiXL is appropriate for patients with low myopia or hyperopia as a second line to conventional refractive surgeries (i.e. LASIK, PRK, intraocular lens implant), and for patients who require correction of residual refractive error or refractive regression after conventional refractive surgeries.[7] PiXL is recommended for patients with corneal topography inappropriate for conventional refractive surgeries, i.e. forme fruste keratoconus, because corneal tissue ablation is unnecessary. PiXL has also been applied to presbyopia.[8]


PiXL is a high-fluence CXL administered in a customizable pattern and intensity in order to steepen or flatten the cornea through corneal strengthening.[6] The specific application of UV-A for each patient takes into account the refractive error and corneal topography.[7] The major components of the therapy are riboflavin injection and UV-A irradiation, and the procedure is followed by a course of topical antibiotics and corticosteroids. Details of the procedure and patient positioning are depicted in the figures below (Figures 1 and 2).

Figure 1: PiXL Procedure.[9]

Figure 2: PiXL Patient Positioning. [10]

Types of PiXL

Epithelium-On or Transepithelial: No debridement of corneal epithelium

  • Advantages:
    • Improved post-procedure comfort
    • Lower risk of corneal infection
  • Disadvantages:
    • Less stable result in hyperopic patients

Epithelium-Off: Debridement of corneal epithelium

  • Advantages:
    • More stable result in hyperopic patients
  • Disadvantages:
    • Higher risk of the following:
    • Corneal infection
    • Sub-epithelial haze
    • Sterile corneal infiltrates
    • Corneal scarring
    • Endothelial damage
    • Herpetic activation


None [11]


PiXL offers the potential for immediate improvement in visual acuity without pain or discomfort.[6] The adverse effect profile includes moderate to severe dry eyes.[7] No significant changes in endothelial cell counts or corneal clarity have been reported.[6] PiXL has shown sustained visual acuity results up to 12 months of follow-up.[7] In one study of myopic patients an average of 2.3D of visual acuity improvement occurred in the first post-procedural (epithelium-on) week, which regressed to 1.44D at 1 month and subsequently remained stable at the 6 month follow-up.[6] This is consistent with results from other studies, which cite a reduction of myopic refractive error with epithelium-on approach by -1.00 to -1.35D3 and 0.72+/-0.43D.[7] A study of PiXL in hyperopia has achieved a +0.85D hyperopic correction with an epithelium-on method.[2] While PiXL is a novel refractive surgical option for low myopia, recent studies have shown that the refractive results of Pixl may be inferior to those of alternative refractive surgical procedures such as photorefractive keratectomy (PRK).[12]


  1. 1.0 1.1 Editor, M. S. (2016, July 05). At Last, Cross-Linking Comes to U.S. Surgeons. Retrieved September 30, 2017, from
  2. 2.0 2.1 Kanellopoulous AJ, Asimellis G. Hyperopic correction: Clinical validation with epithelium-on and epithelium-off protocols, using variable fluence and topographically customized collagen Cross-linking. Clinical Ophthalmology. 2014;8:2425–2433.
  3. Ghanem RC, Santhiago MR, Berti T, Netto MV, Ghanem VC. Topographic, corneal wavefront, and refractive outcomes 2 years after collagen crosslinking for progressive keratoconus. Cornea. 2014;33(1):43–48.
  4. Arora R, Jain P, Goyal JL, Gupta D. Comparative Analysis of Refractive and Topographic Changes in Early and Advanced Keratoconic Eyes Undergoing Corneal Collagen Crosslinking. Cornea. 2013 Aug 22; Epub.
  5. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008;34(5):796–801.
  6. 6.0 6.1 6.2 6.3 6.4 Kanellopoulos, A. J. (2014). Novel myopic refractive correction with transepithelial very high-fluence collagen cross-linking applied in a customized pattern: early clinical results of a feasibility study. Clinical Ophthalmology (Auckland, N.Z.), 8, 697–702.
  7. 7.0 7.1 7.2 7.3 7.4 Lim, W. K., Soh, Z. D., Choi, H. K. Y., & Theng, J. T. S. (2017). Epithelium-on photorefractive intrastromal cross-linking (PiXL) for reduction of low myopia. Clinical Ophthalmology (Auckland, N.Z.), 11, 1205–1211.
  8. Kanellopoulos, A. J., & Asimellis, G. (2015). Presbyopic PiXL cross-linking. Current Ophthalmology Reports, 3(1), 1-8.
  9. Krader, C. G. (2016). Crosslinking showing potential for refractive correction.
  10. Say Hello To PiXL™ — The New Non-Invasive Vision Improvement Procedure. (n.d.). Retrieved September 30, 2017, from
  11. Healthegy Follow. (2016, May 13). OPHTHALMOLOGY INNOVATION SHOWCASE - Avedro. Retrieved September 30, 2017, from
  12. S El Hout, M Cassagne, T Sales de Gauzy, S Galiancy, F Malacaze, P Fournie. Transepithelial photorefractive intrastromal corneal crosslinking versus photorefractive keratectomy in low myopia. J Cataract Refract Surg. 2019 Apr;45(4):427-436.
  1. Nawaz S, Gupta S, Gogia V, Sasikala NK, Panda A. Trans-epithelial versus Conventional corneal collagen cross-linking: a randomized trial in keratoconus. Oman J Ophthalmol. 2015;8(1):9–13.
  2. Matthias Elling, PiXL for Myopia: Clinical results of a controlled prospective clinical trial. ESCRS; Athens: 2016.
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