Effect of Corneal Collagen Cross-Linking on Corneal Innervation, Corneal Sensitivity, and Tear Function of Patients with Keratoconus Georgios A. Kontadakis, MD, MSc, George D. Kymionis, MD, PhD, Vardhaman P. Kankariya, MD, Aristophanis I. Pallikaris, MSc Purpose: To evaluate the effect of corneal collagen cross-linking (CXL) on corneal innervation, corneal sensitivity, and tear function in patients with keratoconus. Design: Prospective, interventional case series. Participants: Twenty-four patients with bilateral keratoconus (30 eyes) who presented to the Institute of Vision and Optics, University of Crete, from May 2008 to October 2008. Methods: Patients underwent CXL. Confocal microscopic analysis of corneal sub-basal nerve plexus (total nerve length per image), corneal sensitivity (assessed with the Cochet–Bonnet esthesiometer), basic tear secretion (assessed with Schirmer’s I test with anesthesia), and tear film stability (evaluated by means of tear film break-up time [TFBUT]) were assessed preoperatively and at 1, 3, 6, 9, 12, 18, and 24 months postoperatively. Main Outcome Measures: Comparisons between preoperative and each postoperative value of total nerve length per image, corneal sensitivity, Schirmer’s I test results, and TFBUT. Results: Total nerve length per image and corneal sensitivity were significantly decreased until postopera- tive month 6 (for both parameters: P0.05 paired-samples t test at 1, 3, and 6 months postoperatively). Total nerve length per image tended to increase up to 2 years postoperatively, when it reached the preoperative level, but differences with the preoperative values after the sixth post-CXL month were insignificant. The results of Schirmer’s I test and TFBUT had no statistically significant difference at any time point. Conclusions: A transient decrease in corneal innervation and corneal sensitivity can be observed up to 6 months after CXL. No significant effect of CXL could be detected on basic tear secretion and tear film stability in our group of patients. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:917–922 © 2013 by the American Academy of Ophthalmology. Corneal surgical procedures have been associated with loss of corneal sensitivity and dry eye symptoms in several studies. 1–13 Ablation of corneal tissue in refractive surgery, flap creation in LASIK, and clear corneal incisions in cat- aract surgery are procedures that affect corneal innervation and reduce corneal sensation. 13–17 Loss of corneal sensation diminishes the reflex that stimulates blinking and tear pro- duction (lacrimal and mucus secretion). Because of these aspects, iatrogenic dry eye postsurgery is one of the main complications of corneal procedures. This affects patients’ quality of life and may become severe in those with preop- erative dry eye symptoms. 18 Corneal collagen cross-linking (CXL) with the combina- tion of riboflavin and ultraviolet A (UVA) radiation is a novel corneal surgical procedure to stabilize progressive keratoconus. 19 –21 The method is based on the absorption of UVA (370 nm) radiation by the cornea after the photosen- sitizer riboflavin is infused in the stroma. This procedure is considered to build up the bonds between the collagen molecules and therefore increase corneal rigidity and sta- bility. 21–25 Corneal confocal microscopic studies have dem- onstrated a reduction in subepithelial nerve plexus density after CXL, which seems to return to the preoperative status several months after the procedure. 26,27 Reduction of nerve density is expected to adversely affect corneal sensitivity and tear function. This could be more prominent because keratoconic patients may already have tear film disorders and reduced corneal sensitivity as a result of the abridged and misshapen corneal nerves and the abnormal corneal shape in keratoconus. 28 –31 The purpose of the current study is to evaluate the alterations of corneal innervation, corneal sensitivity, and tear function in patients undergoing CXL for the treatment of progressive keratoconus. Materials and Methods In this prospective interventional case series, we included subjects from a continuous cohort of patients with keratoconus who sought consultation at the Institute of Vision and Optics of the University of Crete. Patients with progressive keratoconus, with corneal 917 © 2013 by the American Academy of Ophthalmology ISSN 0161-6420/13/$–see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2012.10.012