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Original Investigation |

Corneal Nerve Regeneration After Collagen Cross-Linking Treatment of Keratoconus A 5-Year Longitudinal Study

Marlen Parissi, MSc1,2; Stefan Randjelovic, MSc2; Enea Poletti, PhD3; Pedro Guimarães, PhD3; Alfredo Ruggeri, PhD3; Sofia Fragkiskou, MD4; Thu Ba Wihlmark, MD4; Tor Paaske Utheim, MD, PhD1,2,5; Neil Lagali, PhD4
[+] Author Affiliations
1Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway
2The Norwegian Dry Eye Clinic, Oslo, Norway
3Department of Information Engineering, University of Padova, Padova, Italy
4Faculty of Health Sciences, Institute for Clinical and Experimental Medicine, Department of Ophthalmology, Linköping University, Linköping, Sweden
5Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
JAMA Ophthalmol. 2016;134(1):70-78. doi:10.1001/jamaophthalmol.2015.4518.
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Importance  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.

Design, Setting, and Participants  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.

Exposure  The patients with keratoconus underwent standard epithelial-off UV-A/riboflavin CXL treatment with 30-minute UV-A exposure at 3 mW/cm2 irradiance.

Main Outcomes and Measures  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 and Relevance  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.

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Figure 1.
Subbasal Nerve Density in the Central Cornea in 19 Patients With Early-Stage Keratoconus (Before CXL Treatment) vs 19 Healthy Age-Matched Volunteers

The horizontal line in the middle of each box indicates the median, while the top and bottom borders of the box indicate the 75th and 25th percentiles, respectively. The whiskers above and below the box indicate the 90th and 10th percentiles. The points beyond the whiskers are outliers. CXL indicates collagen cross-linking.

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Figure 2.
Subbasal Nerve Regeneration up to 5 Years After CXL Treatment of Progressive Keratoconus

A and B, The horizontal line in the middle of each box indicates the median, while the top and bottom borders of the box indicate the 75th and 25th percentiles, respectively. The whiskers above and below the box indicate the 90th and 10th percentiles. C, The error bar indicates 95% CI, and the points indicate mean values.

aManual analysis of subbasal nerve density indicated a significant reduction in the early postoperative period (A). Automated analysis yielded a similar pattern of nerve regeneration as did manual analysis (B).

bA significant but minor reduction in sensitivity is indicated 3 months after collagen cross-linking (CXL) treatment (P = .02) (C).

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Figure 3.
Nerve Architecture in Healthy and Keratoconic Corneas

A, Subbasal nerve plexus with roughly parallel nerve fiber bundles, low tortuosity, and rare crossings (black arrowheads). B, Looping nerves (white arrowheads) and increased number of crossings (black arrowheads). C, Persistent looping nerves (white arrowhead), crossings (black arrowheads), and tortuous nerve paths (yellow arrowheads). All images are 400 × 400 µm.

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Figure 4.
Quantitative Analysis of Subbasal Nerve Morphology

A, Number of subbasal nerve crossings per image frame. B, Minimum crossing angle of subbasal nerves in cases of crossings. C, Nerve tortuosity. CXL indicates collagen cross-linking.

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Figure 5.
Nerve Plexus Mosaics in 6 Different Patients 5 Years After Corneal Collagen Cross-Linking Treatment of Keratoconus

A, Circumferential nerve paths emerging from penetration points (black arrowheads), and tortuous paths (white arrowheads). B, Crossings (magenta arrowheads) at intersections of radial and circumferential nerves, and loops (yellow arrowheads). C, Loops (yellow arrowheads) varying between radial and circumferential orientations. D, Tortuous paths (white arrowheads). E, Nerves penetrate (black arrowheads) and orient radially. Crossings (magenta arrowheads), where radial and circumferential nerves intersect, tortuosity (white arrowhead), and loops (yellow arrowheads). F, After penetration (black arrowheads), abrupt orientation changes (yellow arrowheads) form loops. Scale bars represent 400 µm.

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