KEY CONCEPTS
Patients at risk of progression
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Younger age (less than 17 years old)
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Maximum keratometry greater than 55 D at time of diagnosis
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Family history
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Connective tissue disorders, Down syndrome, Leber congenital amaurosis
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Eye rubbing
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Inflammation.
Keratoconus in a child
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More aggressive and active
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Progresses rapidly
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Already at advanced stages when diagnosed.
Transepithelial CXL versus epi-off CXL
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TE-CXL is an option that minimizes the risks associated with epithelial debridement.
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Both can halt the progression of keratoconus
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Epi-off corneal cross-linking (CXL) shows higher flattening effect and slower progression rate after procedure.
Introduction
Keratoconus (KC) is an illness that affects corneas in the first three decades of life. , KC may progress aggressively and rapidly in the pediatric population. Unfortunately it is diagnosed at advanced stages in a significant percentage of cases. Almost 30% of cases are diagnosed when the disease is at stage IV, and advanced KC cases progress more rapidly and severely. When KC is diagnosed in a child, it is usually more severe and with greater risk of progression than when it is first diagnosed in an adult. Management in the child should, therefore, be more aggressive.
In a review of 2650 patients that required corneal transplantation over a 13-year follow-up period that, ectasia and thinning represented the most common indications for corneal transplantation. Collagen corneal cross-linking (CXL) should be considered early in children, to avoid a corneal transplantation as there is a higher incidence of complications, such as allograft rejection and glaucoma, in this population. , It is, therefore, important to halt the progression of KC in the child, given that more than 80% of the pediatric KC patients progress without treatment, compared with the 20% to 35% who progress after CXL. , ,
In a hypothetical model, an analysis of cost-effectiveness showed early CXL demonstrated superiority when compared with penetrating keratoplasty. The 10-year effect after early treatment with CXL would provide a net increase in quality-adjusted life years and an increase in cost-effectiveness ratios compared with standard management.
CXL in Children
Corneal collagen cross-linking was approved for progressive KC and post-LASIK ectasia in 2016. It is currently the only US Food and Drug Administration (FDA)-approved treatment available to halt the progression of KC, but it has not been approved in children. However, to date, there are at least 20 published articles documenting the use of CXL in children with more than 10 years follow-up. The application of CXL in the child should be preceded by a careful assessment of risks and benefits based on the principles of the Declaration of Helsinki.
Epi-Off CXL (Dresden Protocol)
The Dresden protocol, also called standard epi-off CXL, is used in adults and children. The corneal epithelium is removed manually or with a laser over the central 9 mm; riboflavin solution is then applied every 5 minutes for 30 minutes, and finally an ultraviolet A (UVA) irradiation is performed for 30 minutes (3 mW/cm 2 ) in conjunction with continued riboflavin application. The riboflavin used for this procedure is the so-called isotonic riboflavin that is composed of 0.1% riboflavin and 20% dextran. However, when corneal thickness is less than 350 to 400 μm, hypotonic riboflavin can be used in children as well. This procedure has provided excellent results, with the longest registered follow-up available in the literature.
In the vast majority of the studies, uncorrected and/or best-corrected visual acuity (UCVA and BCVA, respectively) demonstrated statistically significant improvement. KC stabilization was achieved in nearly 65% to 100% of the cases, and there was a mean reduction in keratometric readings of 1 to 2 diopters (D). Table 28.1 shows the results of studies using epi-off CXL in children.
| Author, Year | Age (Years) | No Eyes | Follow-Up (Months) | Significant Improvement | Significant Worsening K Readings | Irradiation Time/Energy | Adverse Effects | Comparative Study | Randomized Study | ||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Chatzis and Hafezi, 2012 | 9–19 | 46 | 26.3 | BCVA | No | 30’ (3 mW/cm 2 ) | No | No | No | ||
| Caporossi et al., 2012 | 10–18 | 77 | 36 | K, asymmetry index | No | 30’ (3 mW/cm 2 ) | No | Subgroup analysis | No | ||
| Vinciguerra et al., 2012 | 9–18 | 40 | 24 | UCVA, BCVA, coma and spherical aberrations | No | 30’ (3 mW/cm 2 ) | No | No | No | ||
| Zotta et al., 2012 | 11–16 | 8 | 36 | VA | No | 30’ (3 mW/cm 2 ) | No | No | No | ||
| Magli et al., 2013 | 12–18 | 19 | 12 | K, SAI, I-S, IHA, AE | No | 30’ (3 mW/cm 2 ) | Corneal edema | Epi-off vs. TE-CXL | No | ||
| Viswanathan et al., 2014 | 8–17 | 25 | 20 | K | No | 30’ (3 mW/cm 2 ) | No | No | No | ||
| McAnena and O’Keefe, 2015 | 13–18 | 25 | 12 | BCVA | No | 4’ (30 mw/cm 2 ) | No | No | No | ||
| Uçakhan et al., 2016 | 10–18 | 40 | 48 | BCVA, K max | No | 30’ (3 mW/cm 2 ) | No | No | |||
| Wise et al., 2016 | 11–18 | 39 | 12 | No | No | 30’ (3 mW/cm 2 ) | No | No | No | ||
| Godefrooij et al., 2016 | 11–17 | 54 | 12 | BCVA, K | No | 30’ (3 mW/cm 2 ) | No | No | No | ||
| Ulusoy et al., 2016 | <18 | 28 | 17 | BCVA, K | No | 10’ (9 mW/cm 2 ) | No | Subgroup analysis | No | ||
| Sarac et al., 2016 | 9–17 | 72 | 24 | UCVA | No | 30’ (3 mW/cm 2 ) | No | Subgroup analysis | No | ||
| Henriquez et al., 2017 | 12–15 | 25 | 12 | BCVA | No | 30’ (3 mW/cm 2 ) | No | TE accelerate vs. epi-off | No | ||
| Padmanabhan et al., 2017 | 8–18 | 194 | 42 | BCVA, topographic ast | No | 30’ (3 mW/cm 2 ) | No | No | No | ||
| Zotta et al., 2017 | 10–17 | 20 | 91 | K, topographic cylinder | No | 30’ (3 mW/cm 2 ) | No | No | No | ||
| Eraslan et al., 2017 | 12–18 | 18 | 24 | BCVA, K | No | 30’ (3 mW/cm 2 ) | Epi-on vs. epi-off | No | |||
| Henriquez et al., 2018 | 10–17 | 26 | 36 | BCVA | No | 30’ (3 mW/cm 2 ) | No | No | No | ||
| Mazzotta et al., 2018 | <18 | 62 | 120 | UCVA, BCVA | No | 30’ (3 mW/cm 2 ) | No | No | |||
| Sarac et al., 2018 | 10–17 | 87 | 24 | UCVA (accelerate CXL) | No | 30’ (3 mW/cm 2 ) and 10’ (9 mW/cm 2 ) | Corneal haze | Mechanical vs. PTK epithelial removal | No | ||
| Buzzonetti et al., 2019 | 9–18 | 20 | 36 | BCVA | No | 30’ (3 mW/cm 2 ) | 20% corneal haze, resolved without sequelae | I-CXL TE vs. epi-off CXL | No | ||
| Henriquez et al., 2020 | 10–17 | 46 | 60 | BCVA, cylinder, K, asphericity | No | 30’ (3 mW/cm 2 ) | No | TE accelerate vs. epi-off | No |
Henriquez et al, published results of the epi-off procedure with follow-up of up to 5 years, in 46 eyes of 46 patients under 18 years of age (range 10–17), and found that KC was stopped in 100% of cases, with an average reduction in mean keratometry of 3.18 +/− 5.17 D and significant improvement in the BCVA. In a prospective study of 47 keratoconic patients younger than 18 years old, with a follow-up of 10 years, Mazzotta et al. found KC stability in nearly 80% of the patients. There was significant improvement in the UCVA, BCVA, and maximum keratometry readings from the sixth month of treatment until the eighth year of follow-up. After the eighth postoperative year, they noted that the maximum keratometry improvement had lost its statistical significance. Only 4.35% of the patients needed a corneal graft due to KC progression.
Based on the current literature, we can say that CXL is effective in halting the progression of KC at least at 8 years of follow-up.
Transepithelial CXL
Transepithelial corneal collagen cross-linking (TE-CXL), usually termed epi-on CXL, has been used in children in the same way as it is used in adults. , , , It is based on the use of a specially formulated riboflavin solution that enhances passage through intact epithelium, thereby avoiding the need for epithelial debridement. The theoretical basis of TE-CXL lies in the use of a hydrophilic macromolecule such as riboflavin that penetrates intact corneal epithelium, avoiding the need for epithelial debridement.
In children, trometamol and sodium, ethylenediaminetetraacetic acid (EDTA), and benzalkonium chloride have been used in association with riboflavin as enhancing substances with no associated adverse effects. Table 28.2 shows the results of the studies using TE-CXL in children.
| Author, Year | Age | No Eyes | Follow-Up (Months) | Significant Improvement | Significant Worsening K Readings | Irradiation Time (Energy) | Adverse Effects | Riboflavin Used | Comparative Study | Randomized Study | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Buzzonetti and Petrocelli, 2012 | 8–18 | 13 | 18 | BCVA | Yes | 30’ (3 mW/cm 2 ) | No | Ricrolin TE a | No | No | ||
| Magli et al., 2013 | 12–18 | 14 | 12 | K, AE, corneal SI | No | 30’ (3 mW/cm 2 ) | No | Ricrolin TE; Sooft b | Epi-off vs. TE-CXL | No | ||
| Salman, 2013 | 13–18 | 22 | 12 | UDVA, K apex, AE, TP | No | 30’ (3 mW/cm 2 ) | Epithelial defect, transient hyperemia mild foreign-body sensation | TE riboflavin c | TE-CXL vs. conservative treatment | No | ||
| Buzzonetti et al., 2015 | 10–18 | 14 | 15 | BCVA | No | 9’(10 mW/cm 2 ) | No | Ricrolin+ b | No | No | ||
| Salman, 2016 | <18 | 22 | 12 | UCVA, K max , peak 1, peak 2 | No | 30’ (3 mW/cm 2 ) | No | Ricrolin TE Sooft b | No | No | ||
| Magli et al., 2016 | 11–18 | 13 | 18 | UCVA, BCVA, ISV, KI | No | 9’ (10 mW/cm 2 ) | No | Ricrolin+ Sooft | I-TE-CXL general vs. topic anesthesia | No | ||
| Henriquez et al., 2017 | 8–16 | 36 | 12 | None | No | 5’ (18 mW/cm 2 ) | TE riboflavin d | Epi-off vs. accelerate TE-CXL | No | |||
| Eraslan et al., 2017 | 12–18 | 18 | 24 | BCVA | Yes | 30’ (3 mW/cm 2 ) | No | TE riboflavin d | Epi-off vs. epi-on | No | ||
| Tian et al., 2018 | 14.44 ± 1.98 | 18 | 12 | None | No | 5’ 20’’ (365-nm UV-A light and 45 mW/cm 2 (pulsed mode) | No | ParaCel solution e / VibeX Xtra solution d | No | No | ||
| Buzzonetti et al., 2019 | 9–18 | 20 | 36 | No | Yes | 9’(10 mW/cm 2 ) | 45% superficial punctate | Ricrolin+ a | I-TE-CXL vs. epi-off CXL | No | ||
| Henriquez et al., 2020 | 8–16 | 32 | 60 | Asphericity, BCVA | No | 5’ (18 mW/cm 2 ) | No | TE riboflavin d | Epi-off vs. accelerate TE | No |
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