Keratoconus progression is frequent and faster in children when the age at the time of diagnosis is younger than 18 years.1–3 Corneal transplant may be required at an early age for cases with advanced keratoconus with or without scarring. In children, graft failure rates are higher and visual prognosis is poor with penetrating keratoplasty.4,5
Corneal collagen cross-linking (CXL) is a promising treatment modality for keratoconus, as it is the only intervention that can potentially slow down the progression of the disease.6 In this procedure, riboflavin (vitamin B2) is administered in conjunction with ultraviolet A (UVA, 365 nm). The interaction of riboflavin and UVA causes the formation of reactive oxygen species, leading to the formation of additional covalent bonds between collagen molecules, with consequent biomechanical stiffening of the cornea.7
Recently, studies by Caporossi et al1,2 and Vinciguerra et al8 have reported good clinical results concerning safety and efficacy of epithelium-off CXL treatment in patients aged 18 years or younger. In this study, we analyzed primary visual acuity and refractive and topographic outcomes in 15 eyes from 15 children with keratoconus with advanced disease in the fellow eye.
Patients and Methods
Fifteen eyes from 15 children aged 15 years or younger (range: 10 to 15 years) were enrolled in the study from September 2009 to March 2011. Inclusion criteria were patients with stage I or II keratoconus (Amsler Krumeich classification)9 and advanced disease in the fellow eye at presentation, corneal thickness at the thinnest point ⩾400 μm, and maximum corneal curvature ⩽53.00 diopters (D). Only one eye of each patient underwent CXL. Six patients had been previously managed for corneal hydrops in fellow eyes, 3 patients underwent deep anterior lamellar keratoplasty, and 6 patients were awaiting corneal transplant for advanced keratoconus in the worse fellow eye. Progression of keratoconus was not an inclusion criterion for CXL.
Exclusion criteria were corneal thickness <400 μm at the thinnest point, severe vernal keratoconjunctivitis, severe dry eye, history of herpetic keratitis, concurrent autoimmune diseases, previous ocular surgeries, and central or paracentral opacities. All patients (n=9) with mild to moderate vernal keratoconjunctivitis were controlled prior to the procedure. All patients underwent uncorrected (UDVA) and corrected (CDVA) distance visual acuity assessment, slit-lamp microscopy, basal Schirmer testing, tonometry by Tonopen (Reichert, Depew, New York), dilated fundus examination, endothelial biomicroscopy (Topcon Specular Microscope SP-3000P; Topcon Corp, Tokyo, Japan), and pachymetry and optical tomography with the Orbscan II (Bausch & Lomb, Rochester, New York). Patients were followed in the immediate postoperative period at 1, 3, and 7 days and 1, 3, 6, and 12 months after surgery.
Corneal CXL was performed according to the standard protocol for CXL. It was performed under topical anesthesia in 7 patients. Eight patients underwent the procedure under general anesthesia, as they were uncooperative despite one of the parents being present in the operating theater. The central 8.0-mm epithelium was removed by mechanical debridement. Riboflavin (0.1% in 20% dextran T500 solution) was administered topically every 2 minutes for 30 minutes. Ultrasound pachymetry (PACSCAN 300A; Sonomed Escalon, Lake Success, New York) was performed and if the corneal stroma was thinner than 400 μm, hypotonic riboflavin (0.1% in sterile water) was administered, 1 drop every 10 seconds for 2-minute sessions, after which repeat ultrasound pachymetry was performed to ascertain that the stroma had swollen to >400 μm. This was repeated until adequate corneal thickness was obtained. The cornea was aligned and exposed to UVA 365-nm light for 30 minutes at an irradiance of 3.0 mW/cm2 (CSO-VEGA X-linker; Scandicci, Florence, Italy). During UVA exposure, isotonic riboflavin administration was continued every 5 minutes. After surgery, patients received 2% homatropine (Homatropine hydrobromide; Java Pharmaceuticals, Delhi, India) and gatifloxacin drops (Zymar; Allergan, Bangalore, India). A soft bandage contact lens was applied until reepithelialization was complete. Topical 0.3% gatifloxacin was given four times daily for 7 days, loteprednol acetate 0.5% drops (L-pred; Allergan Inc, Irvine, California) were administered three times daily for 20 days, and hypromellose 0.3% drops (Genteal; Novartis Pharmaceuticals, Basel, Switzerland) were applied six times daily for 45 days.
All patients were followed for 1 year. Table 1 summarizes the change in UDVA, CDVA, manifest refraction spherical equivalent (MRSE), and astigmatism over 12-month follow-up. Change in UDVA failed to reach statistical significance when compared with baseline at 1 and 3 months; however, at 6 and 12 months, a statistically significant change was noted. Mean CDVA remained unchanged at 1 and 3 months, whereas at 6 and 12 months, compared to baseline, it was statistically significant. In 8 (53%) patients, CDVA improved by 1 or more Snellen lines.
Table 1: Refractive and Visual Outcomes
At 3 months, MRSE improved by 1.14 D. At 12 months, mean change in MRSE was 0.99 D from baseline, which was also statistically significant. Change in mean astigmatism was not statistically significant at any follow-up as compared to baseline. Four patients who were contact lens–intolerant prior to CXL were fitted successfully with rigid gas permeable lenses in the postoperative period after 6 months.
Serial tomographic parameters on Orbscan II are outlined in Table 2. For the entire cohort, a decrease in average K was noted over the period of 12 months, which was not statistically significant. Apical K changed significantly over 3 months. When compared to baseline, the change in apical K at 6 months was also significant. Mean change in apical K over 12 months was statistically significant. The change in steep and flat K at 12 months was not significant.
Table 2: Topographic Measurements by Orbscan II
Pachymetry details are summarized in Table 3. Mean central corneal thickness and thinnest pachymetry decreased significantly at 1 month and then thickened over the next 12 months.
Table 3: Pachymetry by Orbscan II
The time for complete epithelium healing ranged from 7 to 10 days (mean: 8.5 days). Postoperative healing was unremarkable except in two patients in whom corneal haze developed, which resolved over 1 to 2 weeks.
Cross-linking has been shown in adults to not only stabilize the cone, but in many cases, improves visual, topographic, and refractive outcomes.10 Recent studies1,2,8,11 of CXL in pediatric patients aged 18 years or younger with progressive keratoconus have reported significant and rapid functional improvement after riboflavin-UVA–induced CXL. Keratoconus stability was also noted up to 24 to 36 months after CXL.1,2,8,11
We decided to conduct this study when several patients presented with hydrops in one eye and three patients had advanced cone at presentation for which deep anterior lamellar keratoplasty was performed. The patients’ fellow eyes had either mild to moderate keratoconus.
In our study, we found significant improvement in both UDVA and CDVA at 6 and 12 months after CXL compared to baseline. Similar results have also been reported by Vinciguerra et al8 and Caporossi et al1 at 12 months. Caporossi et al1 described faster functional recovery in patients with corneal thickness <450 μm and have attributed this to a greater percentage of cross-linked corneal tissue. However, the present study did not show any statistical improvement in UDVA or CDVA in the first 3 months over baseline; however, the cases in our study were more advanced than reported in the earlier study.
A significant change in MRSE of 0.99 D at the end of 12 months was observed in the present study. Other studies have reported the change in MRSE over 24 months to be 1.57 D in patients aged younger than 18 years.8 Different follow-up periods may explain the difference in the decrease of MRSE. The visual outcome in our study was in concordance with other studies in adults where mean change in MRSE ranged from 0.40 to 2.20 D.12–15 Although significant change in astigmatism has been reported in previous studies including adults,12,15 this was not the case in our study.
No significant changes were noted in flat K, steep K, or central power in the present study whereas other studies10,12–14 have reported significant changes in these parameters. Apical K, or maximum K, which is a topographic indicator of the success of CXL,15 improved significantly in our study. Other studies in children have not commented on the apical K. The difference in the observation could be due to the higher mean preoperative values of simulated K in the present study. Corneal thickness measurements obtained with the Orbscan system used in the present study after CXL may be underestimated artifacts due to physical limitations of white light source and light scattering related to changes in corneal reflectivity after treatment. Anterior segment OCT pachymetry, as demonstrated in the literature,16 provides reliable postoperative measurement of corneal thickness after CXL. Unfortunately, anterior segment OCT was not available in our setup, and is noted as a limitation of the study.
Results of CXL in children with keratoconus in the present study are encouraging, as no evidence of disease progression was seen at 12 months. No complications were observed, which may suggest that it can be performed safely in this age group.
We recommend CXL be performed early in children, especially in those patients with advanced disease in their fellow eyes, without waiting for keratoconus progression. This could potentially avoid loss of visual acuity at an amblyogenic age and reduce the need for an early corneal graft.
- Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Denaro R, Balestrazzi A. Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea. 2012;31(3):227–231. doi:10.1097/ICO.0b013e31822159f6 [CrossRef]
- Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Denaro R. Age-related long-term functional results after riboflavin UVA corneal cross-linking. J Ophthalmol. 2011;2011:608041.
- Reeves SW, Stinnett S, Adelman RA, Afshari NA. Risk factors for progression to penetrating keratoplasty in patients with keratoconus. Am J Ophthalmol. 2005;140(4):607–611. doi:10.1016/j.ajo.2005.05.029 [CrossRef]
- Limaiem R, Chebil A, Baba A, Ben Youssef N, Mghaieth F, El Matri L. Pediatric penetrating keratoplasty: indications and outcomes. Transplant Proc. 2011;43(2):649–651. doi:10.1016/j.transproceed.2011.01.055 [CrossRef]
- Aasuri MK, Garg P, Gokhle N, Gupta S. Penetrating keratoplasty in children. Cornea. 2000;19(2):140–144. doi:10.1097/00003226-200003000-00004 [CrossRef]
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620–627. doi:10.1016/S0002-9394(02)02220-1 [CrossRef]
- Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg. 2003;29(9):1780–1785. doi:10.1016/S0886-3350(03)00407-3 [CrossRef]
- Vinciguerra P, Albe E, Freuh BE, Trazza S, Epstein D. Two-year corneal cross-linking results in patients younger than 18 years with documented progressive keratoconus. Am J Ophthalmol. 2012;154(3):520–526. doi:10.1016/j.ajo.2012.03.020 [CrossRef]
- Alió JL, Shabayek MH. Corneal higher order aberrations: a method to grade keratoconus. J Refract Surg. 2006;22(6):539–545.
- Vinciguerra P, Albè E, Trazza S, et al. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology. 2009;116(3):369–378. doi:10.1016/j.ophtha.2008.09.048 [CrossRef]
- Soeters N, Van der Lelij A, van der Valk R, Tahzib NG. Corneal crosslinking for progressive keratoconus in four children. J Pediatr Ophthalmol Strabismus. 2011;48:e26–e29.
- Grewal DS, Brar GS, Jain R, Sood V, Singla M, Grewal SP. Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus: one-year analysis using Scheimpflug imaging. J Cataract Refract Surg. 2009;35(3):425–432. doi:10.1016/j.jcrs.2008.11.046 [CrossRef]
- Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen; preliminary refractive results in an Italian study. J Cataract Refract Surg. 2006;32(5):837–845. doi:10.1016/j.jcrs.2006.01.091 [CrossRef]
- Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37(1):149–160. doi:10.1016/j.jcrs.2010.07.030 [CrossRef]
- Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen cross-linking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008;34(5):796–801. doi:10.1016/j.jcrs.2007.12.039 [CrossRef]
- Mazzotta C, Caporossi T, Denaro R, et al. Morphological and functional correlations in riboflavin UV A corneal collagen cross-linking for keratoconus. Acta Ophthalmol. 2012;90(3):259–265. doi:10.1111/j.1755-3768.2010.01890.x [CrossRef]
Refractive and Visual Outcomes
|UDVA (logMAR) (Snellen)
|CDVA (logMAR) (Snellen)
Topographic Measurements by Orbscan II
||Mean±Standard Deviation (D)
Pachymetry by Orbscan II
||Mean±Standard Deviation (μm)
|Central corneal thickness