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Year : 2019  |  Volume : 26  |  Issue : 2  |  Page : 95-100  

Safety and efficacy of corneal cross-linking in pediatric patients with keratoconus and vernal keratoconjunctivitis

1 Cornea and Anterior Segment Division, King Khaled Eye Specialist Hospital; Division of Ophthalmology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
2 Jeddah Eye Hospital, Jeddah, Saudi Arabia
3 College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
4 Cornea and Anterior Segment Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
5 Cornea and Anterior Segment Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA

Date of Web Publication26-Aug-2019

Correspondence Address:
Dr. Donald U Stone
427 S. Bernard Street, Spokane, Washington 99204

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/meajo.MEAJO_240_18

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PURPOSE: The purpose of the study is to determine the safety and efficacy of corneal collagen cross-linking for keratoconus in pediatric patients with and without vernal keratoconjunctivitis (VKC).
METHODS: This is a retrospective analysis of 89 eyes of 58 patients <18 years of age that underwent corneal collagen cross-linking for progressive keratoconus; inclusion criteria included a minimum of 2-year follow-up after cross-linking. The main outcomes measures included keratometry, pachymetry, vision, and complications following epithelial-off cross-linking with the Dresden protocol.
RESULTS: VKC patients were more likely to be male; 81.6% of the non-VKC patients and 96.3% of VKC patients were male (P = 0.038). Comparing pretreatment to the 2-year follow-up, there was no statistically significant change in the mean steep or flat keratometry, corneal thickness, and uncorrected visual acuity or best spectacle-corrected visual acuity in either group. There were no statistically significant differences in the mean visual, keratometric, or adverse event outcomes between the two groups. The proportion exhibiting progression of ectasia at 2 years was 18.5% in the VKC group and 16.7% in the non-VKC group (P = 0.83).
CONCLUSIONS: Cross-linking appears to be as safe and effective in pediatric patients with vernal keratoconjunctivits as in those without, with similar outcomes, adverse events, and progression of keratoconus after treatment. The proportion of patients exhibiting progression appears to be higher in pediatric patients than adults, and there is an association between male sex and diagnosis of VKC.

Keywords: Cornea, crosslinking, keratoconus, pediatric, vernal keratoconjunctivitis

How to cite this article:
Alrobaian M, Elsayed M, Alotaibi AK, AlHarbi M, May W, Stone DU. Safety and efficacy of corneal cross-linking in pediatric patients with keratoconus and vernal keratoconjunctivitis. Middle East Afr J Ophthalmol 2019;26:95-100

How to cite this URL:
Alrobaian M, Elsayed M, Alotaibi AK, AlHarbi M, May W, Stone DU. Safety and efficacy of corneal cross-linking in pediatric patients with keratoconus and vernal keratoconjunctivitis. Middle East Afr J Ophthalmol [serial online] 2019 [cited 2022 Aug 19];26:95-100. Available from: http://www.meajo.org/text.asp?2019/26/2/95/265368

   Introduction Top

Keratoconus is an ectatic noninflammatory bilateral disorder of the cornea that is characterized by abnormalities in the structure and stability of corneal collagen fibers.[1],[2] It commonly presents in the second decade of life with the loss of visual acuity as the cornea develops the characteristic conical shape with thinning and irregular astigmatism.[2],[3] The incidence varies among populations but appears to be more common in the Middle East and Arabian peninsula.[4],[5],[6] Earlier onset is associated with more aggressive disease and faster progression.[7],[8]

Corneal collagen cross-linking (CXL) is the only intervention that targets the progressive nature of keratoconus. It appears to strengthen the cornea by the creation of covalent bonds between the collagen fibers and has been associated with a decreased risk of disease progression.[9],[10],[11] The safety and efficacy of CXL have been well validated in the adult population. However, studies recently reported in children and adolescents suggested that CXL is safe in the pediatric age group with a rate of complications similar to that found in adults.[12],[13],[14],[15],[16],[17]

Keratoconus that manifests in early childhood is commonly associated with vernal keratoconjunctivitis (VKC).[18],[19],[20],[21] It is possibly related to frequent eye rubbing and chronic corneal exposure to inflammatory mediators and cytokines. The safety and efficacy of CXL has not been validated in pediatric patients with VKC and keratoconus. This study aimed to determine the relative safety and efficacy of CXL in children and adolescents (<18 years) with keratoconus and VKC.

   Methods Top

The Institutional Review Board approved this study, and it adhered to the tenets of the Helsinki Declaration. This was a retrospective case–control analysis of 87 eyes of 58 children and adolescents (>18 years) that underwent CXL for progressive keratoconus between August 2008 and April 2014 with at least 2-year follow-up. Keratoconus was diagnosed by slit-lamp examination and corneal tomography utilizing the Orbscan II (Bausch and Lomb, Orbtek, Salt Lake City, UT); the diagnosis of progression and decision to treat was at the discretion of the treating physician. Exclusion criteria include advanced keratoconus at the presentation that mandated keratoplasty, history of ophthalmic disease other than keratoconus or VKC (e.g., previous infectious keratitis, ocular trauma or uveitis), previous ocular surgery, and preoperative corneal thickness of <400 μ.

The patients were divided into two groups: Group 1 with keratoconus and VKC and Group 2 with keratoconus but no VKC. VKC was diagnosed by the presence of either typical limbal follicles or tarsal cobblestone papillae at any time point; patients were not offered treatment until the VKC was deemed to be under control by the treating physician. The control (non-VKC) group included consecutive patients from the same time period as the VKC group. Data analysis of each group included gender, age at the procedure, and time to last follow-up. The main outcome measures included uncorrected distance visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), intraocular pressure (IOP), manifest refraction, steep and flat K reading, and thinnest corneal area on Orbscan tomography; each data point was extracted from the pretreatment, 6-month follow-up, and last follow-up examinations. The rate of adverse events including acute keratitis, corneal decompensation, delayed epithelial healing, corneal haze at 1 month, corneal haze at 6 months, corneal vascularization, increased IOP >21 mmHg, and worsening of VKC in 6 months following intervention were also recorded and compared between the VKC and non-VKC groups. The UCVA and BSCVA were expressed in logarithm of minimal angle of resolution (LogMAR) ± standard deviation (SD). Progression of ectasia was defined as a steepest keratometry (K max) value change of >2 diopters and/or decrease in thinnest corneal point of >30 μ, comparing 6-month posttreatment to last follow-up measurements.

Statistical analysis

Sample size was calculated for a 1:2 case–control study (with VKC patients as cases and non-VKC patients as controls) using a comparison of means test between two independent groups where α error is set to 0.05, confidence intervals to 95%, anticipated power to 80%, design effect to 0.5, and ß error to 0.20. The software used was G*Power version 3.0.10 (Franz Fauel, University Kiel, Germany, 2008). The actual power after implementation was 81.2%.

Data were collected from the health record using a specific data collection sheet; data were then cleaned, managed, and coded using Microsoft Excel 2013® (Microsoft Corporation, Redmond, Washington, USA). The analysis was performed using SPSS version 22 (IBM Inc., Chicago, Illinois, USA).

Demographic variables were analyzed per patient, and ocular data points were analyzed per individual eye. Descriptive analysis was performed, where categorical variables were presented in the form of frequencies and percentages and continuous variables in the form of mean (±SD). Inferential analysis was conducted to test the significance of potential associations across different study groups. Chi-square test (or Fisher exact test whenever indicated) was used to detect any association between different characteristics. Wilcoxon signed rank test was used to investigate whether there was any significant difference between pre- and postintervention measures. A confidence interval level was set to 95% where a corresponding P value threshold was identified as 0.05; any output P < 0.05 was interpreted as an indicator of statistical significance. A Bonferroni correction of 1.27 did not alter the statistical significance of any result.

Description of procedure

All patients underwent epithelium-off CXL utilizing the standard (Dresden) protocol. The treatment was performed under topical anesthesia (or general anesthesia in patients <12 years of age) with aseptic technique. The eyelashes and eyelid skin were cleaned with 5% povidone-iodine solution. A sterile wire speculum was used to open the lids, and alcohol 20% was applied to the central cornea within an 8-mm optical zone well for 20 s. The alcohol was removed with a sponge, and the ocular surface was irrigated with balanced saline solution; the corneal epithelium was then manually removed. Ultrasound pachymetry was used to confirm a central corneal thickness of at least 400 μ. The cornea was soaked with riboflavin 0.1% solution (10 mg of riboflavin-5-phosphate in 10-ml dextran solution) applied every 2 min for 30 min. After that, CXL was performed with an ultraviolet (UV) energy dose of 5.4 J/cm 2 for 30 min; the UV source was confirmed to be 10 cm from the cornea in every patient. During the CXL procedure, riboflavin was applied every 2 min. At the end of the procedure, topical moxifloxacin 0.5% (Vigamox, Alcon, Fort Worth, TX, USA), topical prednisolone acetate 1%, and a bandage contact lens were administered. After surgery, all patients received topical moxifloxacin 0.5% four times daily for 1 week, topical prednisolone acetate 1% beginning four times daily and tapered off over 4–6 weeks, and lubricants (Tears Naturale Free, Alcon) as needed. Patients who had been receiving topical therapy for VKC continued their pretreatment regimen, typically a mast-cell stabilizer and cyclosporine A 1%. Patients were seen postoperatively at day 2–3 and again at day 7. The bandage contact lens was removed once the epithelial defect was completely healed.

   Results Top

Eighty-seven eyes of 58 patients met inclusion criteria. Twenty-seven eyes of 19 patients had the diagnosis of keratoconus with VKC (Group 1) and 60 eyes of 39 keratoconus patients did not have a diagnosis of VKC (Group 2). Four eyes in the VKC and 1 in the non-VKC group had corneal vascularization prior to the intervention (P = 0.052); the groups were otherwise similar in preoperative characteristics [Table 1]. All patients in both groups were reported to have normal preoperative retina and optic nerve status. Seventy-one (81.6%) of the eyes were of male and 16 (18.4%) were of female patients. In the VKC group, 26 (96.3%) were eyes of male patients and 1 (3.7%) was of a female patient (P = 0.038). The mean age of the VKC group was 15.8 years (range 9.9–17.9) and 15.6 years (8.4–17.8) for non-VKC. The mean follow-up for Group 1 was 2.8 years (2–7) and 2.9 years (2–7) for Group 2. The proportion of patients with bilateral disease was similar between VKC and non-VKC patients (29.6% of VKC patients compared to 35.6% for non-VKC, P = 0.587).
Table 1: Baseline characteristics before cross-linking

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Vernal keratoconjunctivitis group

[Table 2] details the preoperative, 6-month post-CXL, and last follow-up parameters. There was no significant difference between the baseline and last follow-up of UCVA (P = 0.60) and BSCVA (P = 0.99). There was no significant difference between keratometry values at baseline and at last follow-up. The thinnest corneal area became thinner after CXL compared with the preoperative value; however, this difference was not statistically significant (P = 0.093 at 6 months and P = 0.17 at last follow-up).
Table 2: Vision and keratometric variables before and after cross-linking, vernal keratoconjunctivitis group

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No vernal keratoconjunctivitis group

As reported in [Table 3], the UCVA at baseline and last follow-up are similar with no significant difference. There was a statistically significant improvement in BSCVA at 6 months after CXL compared to the baseline (P = 0.026). However, the difference at the last follow-up was not (P = 0.15). The other variables were analyzed at baseline, 6 months after CXL, and at last follow-up with no statistically significant differences.
Table 3: Vision and keratometric variables before and after crosslinking, nonvernal keratoconjunctivitis group

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Comparison of efficacy in vernal keratoconjunctivitis and nonvernal keratoconjunctivitis groups

[Table 4] compares the differences between the clinical indices at presentation and at the last follow-up in the two groups. There were no statistically significant differences between the two groups. The proportion of eyes developing progression of ectasia was also compared between the two groups. Five of 27 eyes with VKC exhibited progression (18.5%) and 10 of 60 non-VKC eyes exhibited progression (16.7%); there was no significant difference in the proportions (P = 0.83).
Table 4: Comparison of change (pretreatment to posttreatment) in mean visual and keratometric variables, vernal keratoconjunctivitis , and nonvernal keratoconjunctivitis patients

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Adverse events

The adverse events following CXL were compared in each group [Table 5], with no significant difference for any variable. In all patients, the epithelium healed completely during the 1st week after CXL and no patient developed corneal vascularization. One patient developed acute keratitis (in the VKC group); it was diagnosed clinically as herpetic epithelial keratitis which was treated and responded well to topical ganciclovir gel. There was no corneal decompensation documented in either group, and no treated eyes underwent keratoplasty.
Table 5: Adverse events after cross-linking

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   Discussion Top

Management of keratoconus in children is difficult and presents unique challenges compared with adults. If keratoconus progresses to an advance stage and the best spectacle-corrected vision is unsatisfying, wearing gas permeable contact lenses carries additional challenges in these patients; this may be especially true when associated with ocular surface disease such as VKC. Furthermore, the rate of developing acute hydrops is inversely proportional to age, and young age is an independent risk factor for requiring keratoplasty in keratoconus.[21],[22] CXL is the only modality of treatment that has been demonstrated to decrease the risk of progression and the associated morbidities.[23] CXL appears to be a safe and effective intervention in children with and without VKC. No patients in our cohort developed acute hydrops or underwent keratoplasty in the cross-linked eye. Both groups had similar rates of corneal haze, which mostly resolved 6 months after CXL. There were no signs of limbal stem cell deficiency in either group. It seems that corneal vascularization that was present before CXL regressed; this may be attributed to topical steroids, a primary angiodestructive effect of CXL or secondary to inaccuracies in documentation. Only two patients with VKC exhibited exacerbations of VKC in the first 6 months after CXL, whereas no patient had any VKC symptoms or signs following CXL in the non-VKC group, alleviating concerns that the treatment may stimulate severe ocular surface inflammation.

In both groups, CXL was associated with a similar rate of posttreatment progression. Mean UCVA, BSCVA, manifest SE, manifest astigmatism, keratometry values, and thinnest corneal area were stable with no significant differences between the baseline and last follow-up. There was a nonsignificant increase in astigmatism; this could be attributed to the contribution of the subset of patients with progression. Without a placebo group, it is not possible to state with certainty that CXL reduced the risk of progression, but the natural history of progressive keratoconus is accepted to be continued progression without intervention, especially in the pediatric age group. The rate of progression after CXL in this cohort (16.9%) is somewhat higher than reported in some series of adults but similar to other studies of pediatric patients.[14],[17],[24] In this study population, there was a strong male association with VKC, which has been previously described but is not well understood.

Weaknesses of this study include the retrospective design and the inherent inaccuracies and imprecision of retrospective data collection. Potential sources of bias include differing indications for recommending cross-linking in each group or other difference in postoperative care that were not measured or controlled in this study. The objective corneal parameters that were derived from automated devices (such as keratometry and pachymetry) are unlikely to vary from what would be gathered in a masked prospective study, but the accuracy of other subjectively documented data points such as corneal haze and vascularization may suffer from the chart review method of data collection. For example, the wide range of corneal thickness measurements in the VKC group at 6 months (388.25 ± 146.73 μ) suggests that some of the measurements were not accurate (not surprising in a pediatric population), but we assume that these types of inaccuracies were evenly distributed between the groups, as well as between pre- and posttreatment measurements. Patients with <2 years of post-CXL data were excluded which could have introduced selection bias. Finally, the status of the hospital as a tertiary treatment center and the relative prevalence of VKC or other confounding factors in the study population may also result in skewed results compared to other populations.

Future areas of research may include identification of risk factors for progression after crosslinking in children, such as patient characteristics or variations in operative technique. Other modulations of cross-linking technology, such as transepithelial or accelerated treatments, and combining CXL with excimer keratectomy or intracorneal ring segments, should be specifically studied in children before widespread adoption of these techniques in the pediatric keratoconus population. Long-term studies are also required, as there may be a greater risk of treatment failure in children compared to adults.

   Conclusions Top

CXL is safe and effective in pediatric patients with and without VKC. At 2-year follow-up, the efficacy and rate of complications after CXL appear to be similar in patients with and without VKC.


The authors would like to thank Ahmed Mousa, MSc, PhD, for his contribution to the biostatistical design and analysis of this study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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