Keratoconus is the most common progressive ectatic corneal disease.1 Although keratoconus is the second most common indication for corneal transplantation worldwide,2 the introduction of corneal cross-linking (CXL) has led to a reduction in the number of patients requiring a corneal transplant.3,4 Developments in corneal topography and tomography have enabled the detection of keratoconus at an early stage.5 The rate and speed of the progression of keratoconus has been reported to be higher in children6,7 and, as a result, patients with an earlier onset may be more likely to require subsequent corneal transplant surgery. The aim of CXL is to reduce or halt progression and leave the patient with satisfactory visual acuity.8–10 Due to the increased popularity of CXL, the number of patients with keratoconus suitable for CXL treatment is likely to increase, with a potential increase in waiting time to treatment. As a consequence, it is important to address the risk of the progression of keratoconus while waiting for treatment to prevent any further deterioration. In this study, we investigated whether morphological worsening of keratoconus occurs while patients are waiting for CXL and whether there are identifiable risk factors that could help stratify patients to reduce the risk of progression.
Patients and Methods
In this prospective, doublecenter, uncontrolled clinical study, we included 104 eyes of 104 patients that were referred for CXL at either The Royal Liverpool University Hospital, United Kingdom (64 patients), or The Eye Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy (40 patients), between September 2016 and March 2017. The study received institutional review board approval from both centers and was conducted according to the tenets of the Declaration of Helsinki, as revised in 2000.
The inclusion criteria were patients with keratoconus who had been referred for CXL. The patients were referred for documented progression of keratoconus. Progression was defined as a change in the curvature within the cone area of at least 1.00 diopter (D) on tangential map and a thinning of 20 μm in minimum corneal thickness when measured at least 3 months apart. Exclusion criteria were a history of herpetic keratitis, dry eye, severe corneal infection, concomitant ocular or systemic autoimmune disease, diagnosed pregnancy or breastfeeding, and a minimum corneal thickness of less than 400 microns.
The following parameters were assessed at baseline (day of listing for CXL) and on the day of CXL treatment: slit-lamp biomicroscopy, keratometry (maximum [Kmax], minimum, and mean), and thinnest corneal thickness using one scan of corneal tomography (Pentacam; Oculus Optikgeräte GmbH, Wetzlar, Germany). The documentation of the progression and all preoperative and postoperative morphological tests were performed in an identical manner in the two centers.
Statistical analysis was performed using SPSS statistical software (version 20.0; IBM Corporation, Armonk, NY). Data are described as mean ± standard deviation. Data were analyzed and stratified by age according to a previous report.10 The Student's t, analysis of variance, and post hoc tests were applied to assess the significance of differences between data. A P value of less than .05 was considered significant. A multivariate model was used with progression (yes/no) as the dependent variable against known risk factors, including waiting time, age, atopy, non-white European ethnicity, and advanced disease.
One hundred four eyes of 104 patients were prospectively evaluated. Seventy-two (69%) patients were male. The mean age was 25.2 ± 6.9 years (range: 14 to 50 years). Fifty-six (53%) patients were classified as atopic because they had a history of allergic eye disease, asthma, eczema, or hay fever. The overall waiting time was 84.8 ± 62.9 days.
Twenty-five percent of patients showed evidence of progression (ie, a change in maximum corneal curvature [Kmax] within the cone area of at least 1.00 D on tangential map) while waiting for treatment (Table 1). Patients who progressed while waiting for treatment were younger (22.2 ± 6.79 years) compared to those who did not show evidence of progression (25.4 ± 5.62 years) (P = .01).
To further investigate the significant difference in age between patients who had and had not progressed while waiting for treatment, patients were separated into three groups: younger than 18 years (28 patients), 18 to 26 years (40 patients), and older than 26 years (44 patients) (Table 2). Although there was a trend toward longer waiting times between groups, there was no significant difference in waiting times (P = .06) or distribution of patients with atopy within the groups (percentages of atopic patients were 47%, 60%, and 51% in patients younger than 18 years, 18 to 26 years, and older than 26 years, respectively). However, there was a significant worsening of Kmax during the waiting time in patients younger than 18 years. That is, Kmax increased by 1.18 ± 1.37 D in patients younger than 18 years compared to 0.085 ± 0.88 D in patients 18 to 26 years (P = .002) and 0.41 ± 1.24 D in patients older than 26 years (P = .042) (Figure 1). In a multivariate model that considered the Kmax difference with waiting time, age, and atopy, there was a significant association between the change in Kmax and age (P = .028). Any correlation was highlighted by a multivariate model that used progression (yes/no) as the dependent variable against known risk factors, including waiting time, age, atopy, non-white European ethnicity, and advanced disease (P = .10).
Morphological Changes Between Groups
Scatterplot showing the changes in maximum keratometry (Kmax) versus the age of the patient.
CXL is becoming an established procedure to reduce the progression of keratoconus.10–12 Currently, although there are no clear international guidelines for the exact cut-off to indicate clear progression, an increase of curvature supported by another criterion is usually required. This has been defined as an increase of Kmax11 or astigmatism,13 a subjective loss of vision,14 or a corneal thinning of more than 20 μm in minimum corneal thickness.12,15
When a patient with keratoconus has shown evidence of progression, CXL is indicated,16 regardless of the age of the patient.17 We found that younger patients, particularly those younger than 18 years, had a significantly greater incidence of progression during the waiting period, with a change in Kmax that was greater than the standard cut-off to indicate CXL. This was despite a trend of older patients waiting for a longer period of time. This is important because the change in Kmax in younger patients was more than 1.00 D and may have affected vision with irreversible loss of sight because CXL is not always able to regress the progression of the disease.18
Although atopy was not found to be a significant factor for progression during the waiting period, this result should be taken with caution considering the relatively small number of patients. Additionally, the definition of atopy may need to be restricted to evidence of atopic conjunctivitis and whether the atopy is active or controlled.
However, even if the accepted cut-off for progression of keratoconus is 1.00 D, this could be mistaken for an error of the measurement in some cases. As a matter of fact, it is known that the 95% interobserver limit of agreement for Kmax is 1.01 D for Pentacam-derived Krumeich stage 1 or 2, but can go up to 3.86 D for stages higher than stage 2. Of concern, even if the mean waiting list time was just longer than 2 months, this was sufficient time for there to have been an increase in Kmax of more than 1.00 D. This value, even if it might be incorrect for keratoconus with a stage higher than 2, should cause suspicion of progression inside the waiting list.19
There are a few studies in the literature that have shown an increased rate of progression in patients with pediatric17,20,21 and atopic22,23 keratoconus, but none of them evaluated the waiting list time. However, Chatzis et al.17 proposed that waiting for documentation of progression should not be mandatory and CXL in children and adolescents should be performed as soon as the diagnosis has been made.
Our results confirm the previous literature findings indicating that pediatric patients tend to have a faster progression of the disease compared to the other age groups. Of concern, even if the mean waiting list time was just longer than 2 months, this was sufficient time for there to have been an increase in Kmax of more than 1.00 D. This outcome highlights the need to create different waiting list times according to age and possibly other identifiable risk factors. Although speculative, based on our results, if we consider a linear progression of the patients during the waiting period, patients younger than 18 years would worsen by 0.50 D in 4 to 6 weeks, which is half of the cut-off to consider that a patient has progressed. For this reason, we suggest a waiting time of no longer than 12 weeks for patients older than 18 years and less than 6 weeks for those younger than 18 years.
- Sabti S, Tappeiner C, Frueh BE. Corneal cross-linking in a 4-year-old child with keratoconus and down syndrome. Cornea. 2015;34:1157–1160. doi:10.1097/ICO.0000000000000491 [CrossRef]
- Gain P, Jullienne R, He Z, et al. Global survey of corneal transplantation and eye banking. JAMA Ophthalmol. 2016;134:167–173. doi:10.1001/jamaophthalmol.2015.4776 [CrossRef]
- Godefrooij DA, Gans R, Imhof SM, Wisse RP. Nationwide reduction in the number of corneal transplantations for keratoconus following the implementation of cross-linking. Acta Ophthalmol. 2016;94:675–678. doi:10.1111/aos.13095 [CrossRef]
- Sandvik GF, Thorsrud A, Råen M, Østern AE, Sæthre M, Drolsum L. Does corneal collagen cross-linking reduce the need for keratoplasties in patients with keratoconus?Cornea. 2015;34:991–995. doi:10.1097/ICO.0000000000000460 [CrossRef]
- Vinciguerra R, Ambrósio R Jr, Elsheikh A, et al. Detection of keratoconus with a new biomechanical index. J Refract Surg. 2016;32:803–810. doi:10.3928/1081597X-20160629-01 [CrossRef]
- Léoni-Mesplié S, Mortemousque B, Mesplié N, et al. Epidemiological aspects of keratoconus in children [article in French]. J Fr Ophtalmol. 2012;35:776–785. doi:10.1016/j.jfo.2011.12.012 [CrossRef]
- Léoni-Mesplié S, Mortemousque B, Touboul D, et al. Scalability and severity of keratoconus in children. Am J Ophthalmol. 2012;154:56–62. doi:10.1016/j.ajo.2012.01.025 [CrossRef]
- Vinciguerra P, Romano V, Rosetta P, et al. Transepithelial iontophoresis versus standard corneal collagen cross-linking: 1-year results of a prospective clinical study. J Refract Surg. 2016;32:672–678. doi:10.3928/1081597X-20160629-02 [CrossRef]
- Rossi S, Orrico A, Santamaria C, et al. Standard versus transepithelial collagen cross-linking in keratoconus patients suitable for standard collagen cross-linking. Clin Ophthalmol. 2015;9:503–509. doi:10.2147/OPTH.S73991 [CrossRef]
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|Waiting time (days)||67.73 ± 34.89||90.7 ± 69.60||.10|
|Age (y)||22.2 ± 6.79 (14 to 37)||25.4 ± 5.62 (14 to 39)||.01|
|Topographic indices at listing|
| Kmax (D)||50.50 ± 6.00||49.40 ±4.96||.33|
| Kmin (D)||45.80 ± 4.19||45.20 ±3.75||.49|
| Kmean (D)||46.60 ± 2.91||46.80 ± 3.89||.80|
| ThCT (μm)||447.6 ± 63.25||462.3 ± 53.79||.25|
Morphological Changes Between Groupsa
|Measurement||Patients < 18 Years (n = 21)||Patients 18 to 26 Years (n = 40)||Patients > 26 Years (n = 43)||P|
|Age (y)||16.09 ± 1.33||23.12 ± 1.98||31.58 ± 5.16||–|
|Waiting time (days)||65.85 ± 28.96||76.55 ± 50.77||101.95 ± 79.89||.06|
|Δ Kmax (D)||1.18 ± 1.37||0.085 ± 0.88||0.41 ± 1.24||.003|
|Δ Kmin (D)||0.55 ± 1.51||0.05 ± 0.84||−0.23 ± 1.66||.10|
|Δ Kmean (D)||0.35 ± 0.80||0.12 ± 0.78||−0.06 ± 1.04||.21|
|Δ ThCT (μm)||−3.62 ± 12.68||2.30 ± 25.42||−0.65 ± 21.11||.63|