Outcome of Corneal Collagen Crosslinking (CXL) in the Pediatric Age Group Ömür Uçakhan-Gündüz, MD Betül N. Bayraktutar, MD Department of Ophthalmology , Ankara University Faculty of Medicine Ankara, TURKEY The authors have no financial interest in any device mentioned in this study

Background Pediatric keratoconus has some unique features in that it has a reportedly higher likelihood and speed of progression compared to adult keratoconus.1,2 Corneal collagen crosslinking is the only management technique that has the potential to halt the progression of keratoconus. If possible, halting the progression of the disease in pediatric keratoconus patients is critical. Purpose Our purpose in this study is to evaluate the long-term safety and efficacy of CXL performed with the atandard protocol in halting the progression of keratoconus in pediatric patients.

Methods Surgical technique 107 eyes of 59 keratoconus patients younger than 19 years included into this prospective study. The following parameters were evaluated at baseline and at 1, 3, 6, 12, 18 months and yearly thereafter UDVA (Uncorrected distance visual acuity) CDVA (Best corrected distance visual acuity) Manifest refraction Corneal topography and central/thinnest corneal thickness (Pentacam, Oculus GmBH, Germany) Confocal microscopy (HRT III, Rostock Cornea Module; Heidelberg, Germany) Slit lamp biomicroscopy Progression was defined as; a loss of 2 lines in CDVA, or an increase of 2 D in Kmax. Surgical technique All procedures were performed under topical anesthesia using the standard (Dresden) protocol.3 Following 8 mm keratectomy, 0.1% riboflavin solution (Mediocross, Germany) was applied every two minutes for 30 minutes, then the central corneal thickness (CCT) was measured. When the thickness was above 400 µm, riboflavin solution was continued to be applied every two minutes for another 30 minutes, and in the meanwhile the cornea was irradiated with UVA light (UV-X, Germany) (370 nm, 3mW/cm2, 30 minutes). In cases in whom the CCT was less than 400 µm after the first half hour of riboflavin application, hypotonic riboflavin (<0.1%, in sterile water, Mediocross, Germany) was used to increase the thickness to the desired level.

Results 107 eyes of 59 patients were evaluated The mean age was; 15.6 ± 2.0 years (11-18 years) The mean follow-up was; 20.0±10.7 months (3-54 months) Follow-up 3 Months 6 Months 12 Months 18 Months 24 Months 36 Months 48 months # Eyes (%) 107 (100%) 105 (98%) 95 (89%) 74 (69%) 56 (53%) 31 (30%) 6 (6%)

Results Change in UDVA & CDVA (n=31, Mo-36) Pre-CXL Post-CXL Mo-12 Post-CXL Mo-24 Post- CXL Mo-36 p (Mo-36 vs Preop) UDVA 0.85±0.43 (20/100) 0.59±0.37 (20/80) 0.62±0.47 (20/80) 0.60±0.47 (20/80) 0.003 CDVA 0.36±0.21 (20/50) 0.21±0.17 (20/32) 0.26±0.25 (20/32) 0.25±0.26 (20/32) 0.002 The mean UDVA and CDVA improved significantly at Month-1 and stayed stable thereafter until Month-36

Results Change in CDVA (preop vs mo-36, n=31) Change in UDVA (preop vs mo-36, n=31) Change in CDVA (preop vs mo-36, n=31) There was no loss of vision in any patient eye. At month-36, 61% of eyes gained at least 1 line of CDVA Snellen Line Change in UDVA & CDVA (Mo-36, n=31)

Results Change in MRSE Change in Keratometry N=31 Pre-CXL Post-CXL Mo-12 Post-CXL Mo-24 Post-CXL Mo-36 ∆ (0-36 mo) P MR Sph (D) -4.31±3.46 -4.04±3.34 -3,75±3.47 -4.01±4.41 0.30±2.21 0.054 MR Cyl (D) 5.22±2.10 5.04±2.23 4.81±2.58 4.00±2.77 1.22±3.12 0.051 MRSE (D) -6.95±3.79 -6.65±3.55 -5.98±3.90 -6.02±4.49 0.93±2.48 0.04 Change in Keratometry N=31 Pre-CXL Post-CXL Mo-12 Post-CXL Mo-24 Post-CXL Mo-36 ∆ (0-36 Mo) P Kmax (D) 60.1±6.2 60.1±6.0 59.3±6.6 58.0±4.1 -0.83±2.12 0.04 Kf (D) 48.4±4.0 48.3±4.4 47.9±4.5 48.0±4.3 -0.39±1.17 0.09 Ks (D) 54.2±3.8 54.1±3.7 53.7±3.9 53.6±3.4 -0.62±1.15 0.02 Km (D) 51.1±3.8 51.3±4.1 50.6±4.1 50.6±3.8 -0.48±0.54 <0.01

Results Change in Central Corneal Thickness (CCT) The central and thinnest corneal thicknesses were still statistically significantly lower at post-operative Month-36 compared to preop. Change in Central Corneal Thickness (CCT)   Pre-CXL Post-CXL Mo-36 ∆ (Mo-36 vs Preop) P CCT (μm) (Pentacam) 446±26 427±30 -18.8±18.9 <0.001 Change in Thinnest Corneal Thickness (TCT)   Pre-CXL Post-CXL Mo-36 ∆ (Mo-36 vs Preop) P TCT (μm) (Pentacam) 434±27 412±35 -21.7±17.2 <0.001

Results Keratoconus Indices Most of the topographic keratoconus indices were improved after CXL. The mean ISV, IVA, Rmin, and MAE values were significantly reduced at postoperative Month-36. Keratoconus Indices  n=31 Pre-CXL Post-CXL Mo-12 Mo-24 Mo-36 P (Mo-36 vs Preop) ISV 110.7±37.5 109.5±34.2 107.8±34.7 103.9±34.9 0.01 IVA 1.09±0.40 1.08±0.36 1.11±0.41 1.02±0.37 0.04 KI 1.26±0.09 1.25±0.09 1.26±0.08 1.25±0.10 >0.05 CKI 1.09±0.05 1.09±0.06 Rmin 5.66±0.55 5.68±0.54 5.75±0.57 5.74±0.60 IHA 43.3±23.5 43.5±24.1 33.8±20.7 47.2±36.1 IHD 0.106±0.048 0.111±0.049 0.102±0.045 0.159±0.147 MAE (μm) 41.9±16.5 41.2±13.9 40.5±14.7 36.2±13.7 0.003 MPE (μm) 79.9±33.6 77.2±38.7 78.5±30.5 78.2±29.4 ACD: Anterior chamber depth ACV: Anterior chamber volume CV: Corneal volume ISV: Index of surface variance IVA: Index of variance asymmetry IHA:Index of height asymmetry IHD: Index of height decentration Rmin: Minimum radius of curvature KI: Keratoconus index CKI: Central keratoconus index MAE: Maximum anterior elevation MPE: Maximum posterior elevation

Grade 0 : Clear cornea Grade 0.5 : Mild opacity Grade 1 : Moderate, no effect on refraction Grade 2 : Moderate, effects refraction Grade 3 : Opacity hindering refraction Grade 4 : Anterior chamber details not visible Results Post-CXL day-3 Post-CXL day-7 Post-CXL day-15 At postoperative month-2, more than grade 0.5 haze was not seen in any patient eye. Sterile infiltrates were noted in 2 patient eyes, but complete resolution was achieved with topical corticosteroids. The mean preoperative endothelial cell density was 3254 ± 232 cells/mm2 , and 3258 ± 219 cells/mm2 at postoperative month-36 (p>0.05). No sight threating complications were encountered in any patient eye.

Results At the end of Mo-36; There was no progression in any patient eye CDVA was stable or improved in; 100% Kmax was stable or improved in; 77.5% (24/31) 1D steepening in Kmax was noted in 3 eyes (9.5%) Flattening rate (flattening of Kmax>1.0 D) was; 64.5% (20 eyes)

Discussion & Conclusion Knowledge about the long-term efficacy of CXL in pediatric keratoconus patients is scarce. In our study, CXL was safe and effective in halting the progression of pediatric keratoconus in 3- year follow-up. Additionally, the procedure results in an improvement in visual acuity, refractive and keratometric readings, together with regularization of the corneal topography. Clinical outcomes of CXL are time dependent, and, vision, refraction and topographical changes seem to continue even in long-term follow-up. Further prospective controlled studies with longer follow-up are required to establish the safety and efficacy of CXL in pediatric keratoconus. References Chatzis N, Hafezi F. Progression of keratoconus and efficacy of pediatric corneal collagen cross-linking in children and adolescents. J Refract Surg 2012;28:753-8. Léoni-Mesplié S, Mortemousque B, Touboul D et al. Scalability and severity of keratoconus in children. Am J Ophthalmol 2012;154:56-62. Wollensak G, Spoerl E, Seiler T. Riboflavin/UVA-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-7. Soeters N, van der Valk R, Tahzib NG. Corneal cross-linking for treatment of progressive keratoconus in various age groups. J Refract Surg 2014 ;30:454-60. Arora R, Gupta D, Goyal JL, Jain P. Results of corneal collagen cross-linking in pediatric patients.J Refract Surg 2012;28:759-62.