title: Corneal Nerve Regeneration After Collagen Cross-Linking Treatment of Keratoconus: A 5-Year Longitudinal Study.
abstract: OBJECTIVE
  It is unknown whether a neurotrophic deficit or pathologic nerve morphology persists in keratoconus in the long term after corneal collagen cross-linking (CXL) treatment. Nerve pathology could impact long-term corneal status in patients with keratoconus.
  
  
  OBJECTIVE
  To determine whether CXL treatment of keratoconus results in normalization of subbasal nerve density and architecture up to 5 years after treatment.
  
  
  METHODS
  Observational study of 19 patients with early-stage keratoconus indicated for a first CXL treatment with longitudinal follow-up to 5 years postoperatively (examinations were performed from 2009 to 2015; analysis was performed from February to May 2015) and 19 age-matched healthy volunteers at a primary care center and a university hospital ophthalmology department.
  
  
  METHODS
  The patients with keratoconus underwent standard epithelial-off UV-A/riboflavin CXL treatment with 30-minute UV-A exposure at 3 mW/cm2 irradiance.
  
  
  METHODS
  Central corneal subbasal nerve density and subbasal nerve architecture by use of laser-scanning in vivo confocal microscopy; subbasal nerve analysis by 2 masked observers and by use of a fully automated method; wide-field mosaics of subbasal nerve architecture by use of an automated method; and ocular surface touch sensitivity by use of contact esthesiometry.
  
  
  RESULTS
  Mean (SD) age of the 19 patients with keratoconus was 27.5 (7.1) years (range, 19-44 years), and minimal corneal thickness was 428 (36) μm (range, 372-497 μm). Compared with the mean (SD) preoperative subbasal nerve density of 21.0 (4.2) mm/mm2 in healthy corneas, the mean (SD) preoperative subbasal nerve density of 10.3 (5.6) mm/mm2 in the corneas of patients with stage 1 or 2 keratoconus was reduced 51% (mean difference, 10.7 mm/mm2 [95% CI, 6.8-14.6 mm/mm2]; P < .001). After CXL, nerves continued to regenerate for up to 5 years, but nerve density remained reduced relative to healthy corneas at final follow-up (mean reduction, 8.5 mm/mm2 [95% CI, 4.7-12.4 mm/mm2]; P < .001) despite recovery of touch sensitivity to normal levels by 6 months. Preoperatively, more frequent nerve loops, crossings, and greater crossing angles were observed in the corneas of patients with keratoconus compared with healthy corneas. Postoperatively, the frequency of nerve looping increased, crossings were more frequent, and nerve tortuosity increased. Wide-field mosaics indicated persistent disrupted orientation of the regenerating subbasal nerves 5 years after CXL.
  
  
  CONCLUSIONS
  Keratoconus is characterized by a neurotrophic deficit and altered nerve morphology that CXL treatment does not address, despite providing a positive biomechanical effect in the stroma. Given the widespread use of CXL in the management of patients with keratoconus, the progression of abnormal innervation after CXL should be recognized.
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway2The Norwegian Dry Eye Clinic, Oslo, Norway.
authors.forename: Marlen
authors.initials: M
authors.lastname: Parissi
authors.affiliation: The Norwegian Dry Eye Clinic, Oslo, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Randjelovic
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Enea
authors.initials: E
authors.lastname: Poletti
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Pedro
authors.initials: P
authors.lastname: Guimarães
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ruggeri
authors.affiliation: Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Department of Ophthalmology, Linköping University, Linköping, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Fragkiskou
authors.affiliation: Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Department of Ophthalmology, Linköping University, Linköping, Sweden.
authors.forename: Thu Ba
authors.initials: TB
authors.lastname: Wihlmark
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway2The Norwegian Dry Eye Clinic, Oslo, Norway5Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway.
authors.forename: Tor Paaske
authors.initials: TP
authors.lastname: Utheim
authors.affiliation: Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Department of Ophthalmology, Linköping University, Linköping, Sweden.
authors.forename: Neil
authors.initials: N
authors.lastname: Lagali
mesh_terms: D000328:Adult; D003094:Collagen / Q000378:metabolism*; D003315:Cornea / Q000294:innervation*; D063171:Corneal Pachymetry; D003319:Corneal Stroma / Q000378:metabolism; D003432:Cross-Linking Reagents; D003941:Diagnostic Techniques, Ophthalmological; D005260:Female; D005500:Follow-Up Studies; D064368:Healthy Volunteers; D006801:Humans; D007640:Keratoconus / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D018613:Microscopy, Confocal; D009416:Nerve Regeneration / Q000502:physiology*; D017319:Photosensitizing Agents / Q000627:therapeutic use; D011446:Prospective Studies; D012256:Riboflavin / Q000627:therapeutic use; D014276:Trigeminal Nerve / Q000502:physiology*; D014466:Ultraviolet Rays; D055815:Young Adult
chemical_list: D003432:Cross-Linking Reagents; D017319:Photosensitizing Agents; D003094:Collagen; D012256:Riboflavin