Abstract
Purpose:
To assess the effect of corneal crosslinking on vision and keratometry in children and young adults with progressive keratoconus.
Methods:
A retrospective medical records review was conducted of patients ≤ 22 years of age with keratoconus who underwent corneal crosslinking between January 2013 and November 2019 at Byers Eye Institute at Stanford University. Outcome measures included logMAR corrected distance visual acuity (CDVA), keratometry, including maximum keratometry (Kmax), pachymetry, and total wavefront aberration. Measurements were taken at baseline and 12 and 24 months postoperatively.
Results:
Fifty-seven eyes of 49 patients aged 12–22 years were assessed. The mean preoperative CDVA was logMAR 0.38 ± 0.32 (20/48), with mean postoperative CDVA of 0.29 ± 0.31 (20/39) and 0.31 ± 0.31 (20/41) at 12 and 24 months postoperatively. Compared to preoperative mean Kmax, there was an improvement of −0.8 D to a mean postoperative Kmax of 59.1 ± 9.1 D at 12 months and −1.3 D to 59.7 ± 8.8 D at 24 months. Sub-analysis excluding the second eye of patients who underwent bilateral crosslinking showed similar results. Linear mixed modelling showed significant improvement in Kmax at both 12 and 24 months postoperatively. Minimum central corneal thickness initially decreased but stabilized at 24 months following crosslinking. Total wavefront aberration remained stable.
Conclusion:
Corneal crosslinking stabilizes, and in some cases improves, visual and corneal parameters in pediatric and young adult patients with keratoconus. The procedure is safe and well-tolerated and may prevent keratoconus progression in young patients.
Keywords: keratoconus, corneal crosslinking, pediatric
Introduction
Altering the biomechanical behavior of the cornea by artificial crosslinking was first reported in the late 1990s, when it was shown that riboflavin and ultraviolet-A (UVA) radiation applied to porcine corneas resulted in increased stiffness.1 In 2003, a study of patients with moderate to advanced keratoconus demonstrated the clinical usefulness of the procedure, halting progression of corneal ectasia in all treated eyes.2 In 2016, the United States Food and Drug Administration (US FDA) approved corneal crosslinking for progressive keratoconus in adults and children. Although crosslinking has been safely performed in adults for various indications, the procedure may be especially helpful in treating pediatric keratoconus, which is often more severe at diagnosis and progresses more rapidly.3–5
A recent US study assessing the effects of epithelium-off crosslinking in both keratoconus and post-refractive ectasia in 39 pediatric eyes demonstrated improvement in maximum keratometry and stability in visual acuity over 24 months.6 Long-term outcomes outside the United States following crosslinking for pediatric keratoconus have also been promising. Mazzotta et al. assessed 62 eyes of 47 patients less than 18 years of age with progressive keratoconus and showed that both uncorrected and corrected distance visual acuity were significantly improved in the majority of eyes after 10 years.7 Given the relatively recent FDA approval however, published experience with pediatric crosslinking in the United States remains sparse with insufficient long-term data in this population. This study aimed to analyze visual and corneal outcomes following epithelium-off corneal crosslinking for keratoconus in a young patient cohort.
Materials and Methods
Study population
A retrospective medical records review was conducted of patients 22 years of age or younger who had undergone corneal crosslinking for keratoconus at Byers Eye Institute at Stanford University from January 2013 to November 2019. Crosslinking, which was performed by one cornea surgeon (EEM), was recommended after considering risk factors and/or signs of progression of keratoconus, including changes in topography and mean keratometry. Progression was defined as ≥1 D of increase in Kmax over a period of 12 months. Eyes with severe corneal scarring or opacification, as well as those with advanced keratoconus requiring corneal transplantation were excluded. Any underlying disease, including allergic or atopic conjunctivitis, was treated prior to the procedure. Eye rubbing was discouraged. Informed consent was obtained from the patient or patient’s parents or legal guardian prior to the procedure. The study (protocol number 42080) adhered to the tenets of the Declaration of Helsinki and was approved by the Stanford Institutional Review Board (IRB).
Surgical procedure
The crosslinking procedure was performed by anesthetizing the ocular surface with proparacaine 0.5% (Akorn Inc, Lake Forest, IL) and using Betadine 5% (Alcon Inc, Fort Worth, TX) to scrub the eyelids and irrigate the eye. A speculum was placed and a 9-mm optical zone was marked in the central cornea where epithelium was removed using mechanical debridement with a PRK spatula. Alternating drops of riboflavin 5’-phosphate in 20% dextran ophthalmic solution (Photrexa® Viscous, Avedro, Inc. Waltham, MA), and riboflavin 5’-phosphate ophthalmic solution (Photrexa®, Avedro, Inc., Waltham, MA) were instilled in the eye every 1 minute for 30 minutes, after which ultrasound pachymetry (Corneo-Gage Plus, Sonogage, Inc, Cleveland, OH) was performed on the central cornea to ensure that the minimal corneal thickness was at least 400 microns. Alternating viscous and non-viscous riboflavin is standard practice for the operating surgeon. The UVA crosslinking light source (3 mw Avedro KXL light source, Avedro, Inc., Waltham, MA) was centered over the eye and applied for 30 minutes. Alternating drops of riboflavin were continued every minute during the 30-minute irradiation period. A bandage contact lens was placed at the conclusion of the treatment. Patients were instructed to use topical moxifloxacin four times daily until the bandage contact lens was removed and topical prednisolone acetate 1% four times daily for one week, then two times daily for one week. Patients received a prescription for postoperative oral analgesia.
Data collection
Patients were evaluated preoperatively and at 12 and 24 months postoperatively. The main outcomes measures were corrected distance visual acuity (CDVA), keratometry (K), including flat meridian K, steep meridian K, and maximum keratometry (Kmax), pachymetry and total root mean square (RMS) wavefront aberration error. Visual acuity was measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart and then converted to logarithm of the Minimum Angle of Resolution (logMAR).8 Aberrometry measurements were obtained using the iDesign® Refractive Studio (Johnson and Johnson Vision, Inc., Jacksonville, FL) and pre- and postoperative optical pachymetry were obtained using the Pentacam® (Oculus Optikgerate GmbH, Wetzlar, Germany).
Statistical Analysis
Statistical analyses were calculated using RStudio (Boston, MA). Small sample sizes were tested for normality using the Shapiro-Wilk test, and assessed using the non-parametric paired Wilcoxon signed-rank test if they violated normality. The threshold for statistical significance (alpha) for pairwise testing was Bonferroni corrected to account for multiple performed tests and set at p=0.00625. Of the analyzed variables, Kmax was the only variable that fulfilled the assumption of normality and was further assessed within a linear mixed model, which took into account the repeated postoperative measurements in each eye. A p value of less than 0.05 was considered significant in the linear mixed model.
Results
A total of 86 eyes of 71 consecutive patients aged 12–22 years underwent corneal crosslinking for keratoconus, of which 57 eyes of 49 patients had at least 12 months of postoperative data and were included in the final analysis. Of these patients, 8 underwent bilateral crosslinking. Our sample included 40 male and 9 female patients with an average age at intervention of 16.4 ± 2.5 years. Fifty-three eyes had complete follow-up data at 12 months and 24 eyes at 24 months following crosslinking. Table 1 outlines the preoperative and postoperative visual and keratometry measurements grouped by pairwise comparisons.
Table 1:
Preoperative and postoperative visual and keratometry measurements and results of pairwise Wilcoxon signed-rank tests for full cohort of 57 eyes of 49 patients
| Variable | Month | n | Mean | SD | Median | Min | Max | Paired Wilcoxon Signed-Rank | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Test Months | V-stat | p-value | ||||||||
| Corrected Distance Visual Acuity (logMAR) | 0 | 57 | 0.38 | 0.32 | 0.30 | 0 | 1.70 | |||
| 12 | 53 | 0.29 | 0.31 | 0.20 | 0 | 1.82 | 0–12 | 925 | 0.03194 | |
| 24 | 24 | 0.31 | 0.31 | 0.20 | −0.04 | 1.30 | 0–24 | 191 | 0.11020 | |
| Minimum Central Corneal Thickness (μm) | 0 | 57 | 461.33 | 37.76 | 464 | 379 | 540 | |||
| 12 | 51 | 453.82 | 39.56 | 451 | 373 | 541 | 0–12 | 1013 | 0.00029 | |
| 24 | 24 | 453.71 | 42.08 | 450 | 370 | 537 | 0–24 | 175.5 | 0.11490 | |
| Total Wavefront Aberration (RMS Error) | 0 | 45 | 4.59 | 4.36 | 3.52 | 0.69 | 27.1 | |||
| 12 | 32 | 3.58 | 2.30 | 3.23 | 0.63 | 8.87 | 0–12 | 334 | 0.19370 | |
| 24 | 17 | 4.42 | 2.43 | 5.15 | 0.81 | 7.93 | 0–24 | 74 | 0.92650 | |
| Maximum Keratometry (D) | 0 | 57 | 60.28 | 8.84 | 59 | 46.3 | 86.1 | |||
| 12 | 51 | 59.14 | 9.10 | 57.6 | 47.9 | 88.1 | 0–12 | 925.5 | 0.00551 | |
| 24 | 24 | 59.74 | 8.84 | 58.45 | 46.9 | 78.9 | 0–24 | 225 | 0.03326 | |
| Flat Keratometry (D) | 0 | 57 | 47.26 | 4.84 | 45.7 | 40.5 | 63.1 | |||
| 12 | 51 | 46.95 | 5.08 | 45.9 | 39.9 | 63.0 | ||||
| 24 | 24 | 47.15 | 5.14 | 46.05 | 40.3 | 63.0 | ||||
| Steep Keratometry (D) | 0 | 57 | 52.50 | 6.43 | 51.4 | 41.4 | 67.2 | |||
| 12 | 51 | 52.03 | 6.63 | 51 | 41.0 | 71.8 | ||||
| 24 | 24 | 52.28 | 6.02 | 51.4 | 41.8 | 65.4 | ||||
The mean preoperative CDVA was logMAR 0.38 ± 0.32 (20/48). The mean postoperative CDVAs were logMAR 0.29 ± 0.31 (20/39) and 0.31 ± 0.31 (20/41) at 12 and 24 months postoperatively. Paired Wilcoxon signed-rank test showed no significant difference in CDVA at each postoperative examination compared to the preoperative visual acuity, although there was a trend showing improvement at 12 months following crosslinking as shown in Figure 1.
Figure 1:
Corrected distance visual acuity (CDVA; logMAR) at each postoperative follow-up examination (A- 12 months, B- 24 months) compared to preoperative measurements. Mean indicated by black dot within box plot
The mean preoperative flat K was 47.3 ± 4.8 D (40.5–63.1 D). The mean preoperative steep K was 52.5 ± 6.4 D (41.4–67.2 D). There was no significant difference in either flat or steep Ks postoperatively compared to baseline values. When compared to the mean preoperative Kmax of 59.9 ± 9.0 D (46.3–86.1 D) in patients with 12 months of follow-up data, an improvement of −0.8 D was observed, with a mean postoperative Kmax of 59.1 ± 9.1 D (47.9–88.1 D). At 24 months, there was an improvement of −1.3 D to 59.7 ± 8.8 D (46.9–78.9 D). Wilcoxon signed-rank test showed a significant difference between the pre- and 12-month postoperative Kmax distributions (p=0.0055) (Figure 2). Linear modelling, when accounting for repeated postoperative measurements of the same eye, showed a significant improvement in Kmax at both 12 (p=0.013) and 24 months (p=0.001) postoperatively (Table 2).
Figure 2:
Maximum keratometry (Kmax) at each postoperative follow-up examination (A- 12 months, B- 24 months) compared to preoperative measurements. Mean indicated by black dot within box plot
Table 2:
Response of Kmax (D) as predicted by post-operative month
| Predictors | Estimates | ||
|---|---|---|---|
| (Intercept) | 60.95 | CI | p |
| Age Group [Young] | −1.36 | 57.76 – 64.14 | <0.001 |
| Month [12] | −0.83 | −5.88 – 3.17 | 0.556 |
| Month [24] | −1.44 | −1.48 – −0.18 | 0.013 |
| Random Effects | −2.33 – −0.55 | 0.001 | |
| σ | 2.85 | ||
| τ00 EYE_NEW | 74.61 | ||
| ICC | 0.96 | ||
| N EYE_NEW | 57 | ||
| Observations | 132 | ||
| Marginal R2 / Conditional R2 | 0.010 / 0.964 | ||
At 12 months postoperatively, a decrease in Kmax of >1 D was observed in 17 eyes. Nine eyes had a decrease of >2 D, and 6 eyes had a decrease of >3 D. The greatest decrease in Kmax was −6 D (n=2). Twelve eyes had no change in Kmax. At 12 months, 5 eyes had an increase in Kmax of up to 1 D, 7 eyes had an increase of >1 D, and 3 eyes had an increase of >2 D. The greatest increase in Kmax was 5 D (n=1) (Figure 3). Of the 12 eyes that had an increase in Kmax of ≥1 D at 12 months, 7 also had 24-month postoperative data, showing that over the following year there was a mean change in Kmax of −1.9 ± 4.1 D. These 7 eyes had a mean preoperative Kmax of 60.7 ± 14.0 D and mean 24-month postoperative Kmax of 60.9 ± 10.9 D.
Figure 3:
Distribution of the changes in Kmax (D) at 12 months following crosslinking
The mean flat K, steep K and Kmax in patients aged 12–17 years were compared to patients aged 18–22 years and were not found to be significantly different at any time point (Figure 4).
Figure 4:
Flat keratometry (K), steep K and Kmax in patients aged 12–17 years compared to patients aged 18–22 years preoperatively and at 12 and 24 months postoperatively
Minimum central corneal thickness (CCT) was significantly reduced at 12 months following crosslinking, however thickness was not significantly different from preoperative values in eyes with 24 months of follow-up data (p=0.11) (Figure 5).
Figure 5:
Minimum central corneal thickness at each postoperative follow-up examination (A- 12 months, B- 24 months) compared to preoperative measurements. Mean indicated by black dot within box plot
Overall wavefront aberration remained relatively stable when compared to preoperative values. Thirty-two patients with 12-month follow-up data had a mean preoperative RMS error of 3.66 ± 2.60 and a mean postoperative RMS error of 3.58 ± 2.30 (p=0.19) (Figure 6).
Figure 6:
Total wavefront aberration (RMS error) at each postoperative follow-up examination (A- 12 months, B- 24 months) compared to preoperative measurements. Mean indicated by black dot within box plot
A sub-analysis which excluded the second eye of patients who underwent bilateral crosslinking (n=8) was performed. The results were similar to the full cohort analysis (Table 3). The mean preoperative Kmax was 60.8 ± 8.9 D with an improvement of −0.80 D to a mean 12-month postoperative Kmax of 60.0 ± 9.2 D. At 24 months, there was an improvement of −1.4 D to 59.8 ± 9.0 D.
Table 3:
Preoperative and postoperative visual and keratometry measurements and results of pairwise Wilcoxon signed-rank tests for partial cohort of 49 eyes of 49 patients
| n | Mean | SD | Median | Min | Max | Paired Wilcoxon Signed-Rank | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Variable | Month | Test Months | V-stat | p-value | ||||||
| Corrected Distance Visual Acuity (logMAR) | 0 | 49 | 0.41 | 0.33 | 0.30 | 0.00 | 1.70 | |||
| 12 | 46 | 0.32 | 0.33 | 0.22 | 0.00 | 1.82 | 0–12 | 680 | 0.06741 | |
| 24 | 23 | 0.32 | 0.31 | 0.22 | −0.04 | 1.30 | 0–24 | 170 | 0.16250 | |
| Minimum Central Corneal Thickness (μm) | 0 | 49 | 460.55 | 36.95 | 461 | 379 | 540 | |||
| 12 | 44 | 454.23 | 36.60 | 453.5 | 373 | 527 | 0–12 | 732 | 0.00179 | |
| 24 | 23 | 452.61 | 42.67 | 450 | 370 | 537 | 0–24 | 163 | 0.10200 | |
| Total Wavefront Aberration (RMS Error) | 0 | 38 | 5.09 | 4.57 | 4.22 | 0.69 | 27.1 | |||
| 12 | 27 | 3.93 | 2.31 | 3.95 | 0.92 | 8.87 | 0–12 | 249 | 0.15510 | |
| 24 | 16 | 4.49 | 2.50 | 5.35 | 0.81 | 7.93 | 0–24 | 64 | 0.86030 | |
| Maximum Keratometry (D) | 0 | 49 | 61.15 | 8.76 | 60.00 | 46.3 | 86.1 | |||
| 12 | 44 | 60.01 | 9.19 | 58.00 | 48.3 | 88.1 | 0–12 | 679.5 | 0.01286 | |
| 24 | 23 | 59.80 | 9.04 | 58.40 | 46.9 | 78.9 | 0–24 | 209 | 0.03198 | |
| Flat Keratometry (D) | 0 | 49 | 47.48 | 4.68 | 46.30 | 40.5 | 63.1 | |||
| 12 | 44 | 47.16 | 4.96 | 46.10 | 40.5 | 63.0 | ||||
| 24 | 23 | 47.23 | 5.24 | 46.50 | 40.3 | 63.0 | ||||
| Steep Keratometry (D) | 0 | 49 | 53.01 | 6.21 | 51.50 | 41.5 | 67.2 | |||
| 12 | 44 | 52.56 | 6.57 | 51.25 | 41.0 | 71.8 | ||||
| 24 | 23 | 52.40 | 6.13 | 51.50 | 41.8 | 65.4 | ||||
Anterior stromal haze, measured by slit lamp biomicroscopic examination using the Fantes classification, was the most commonly documented postoperative corneal finding related to the crosslinking procedure in 54 eyes and had resolved by the last follow-up examination in 50 eyes. Two eyes continued to have mild stromal haze at the 24-month follow up examination, which was not visually significant in either eye. Persistent epithelial defects were reported in 2 eyes, one of which was present at the 1-month follow-up but had resolved by the 6-month follow-up examination. The other occurred for the first time 8 weeks post-operatively and may have been unrelated to crosslinking. It resolved 1 month later. No other adverse effects were documented.
Discussion
Keratoconus, a degenerative corneal disorder characterized by irregular astigmatism, corneal thinning and visual impairment, is more severe and progresses more rapidly in children.3,4,9,10 Although it usually starts at puberty, keratoconus has been reported in children as young as 4 years old.11 Younger age has been reported to be an independent risk factor for corneal transplantation, which carries its own challenges and potential complications in young patients, including a higher risk of graft rejection.5,12 Corneal crosslinking is a first-line treatment in halting the progression of keratoconus in adults.13 Although international studies have reported a similar efficacy of the procedure for pediatric keratoconus, North American data on long-term outcomes remains limited. There is presently no standardization of management for this condition in children. Given the serious risk of visual morbidity, it is important to assess outcomes in this age group and modify current practices accordingly.
The findings of our study support the previously reported stabilizing effect of crosslinking in children and young adults with keratoconus both in visual and corneal parameters with minimal adverse side effects. Perez-Straziota et al. reviewed 14 studies assessing epithelium-off corneal crosslinking for keratoconus in patients younger than 19 years of age with follow up ranging between 12 to 72 months.14 Change in CDVA ranged from zero to 3 Snellen acuity lines, with 4 studies reporting no change in CDVA,9,15–17 and 4 studies each reporting 1- and 2-line improvements.10,18–24 The smallest study, which assessed 15 eyes for a period of 12 months, reported an average of 3 lines of CDVA improvement.25 Soeters et al. found that the subset of patients younger than 18 years demonstrated the most improvement in CDVA (−0.23 ± 0.40 logMAR, p=0.044).22 Uçakhan et al. reported improvement in CDVA of 2 or more lines in 31 of 40 eyes up to 48 months following crosslinking.24 In our study, pairwise testing showed that CDVA at each follow up examination was comparable, with no worsening observed postoperatively.
Epithelium-off corneal crosslinking has demonstrated improvement in corneal steepness.15–18,22–24 A prospective cohort study by Knutsson et al. showed a significant decrease in Kmax from 59.30 ± 7.08 diopters (D) to 57.07 ± 6.46 D (p<0.001) after 2 years. This decrease in Kmax was also observed in eyes that had severe keratoconus with preoperative Kmax ≥ 60 D. Another study reported a similar improvement in keratometry which was also maintained at 48 months following crosslinking.24 The steepest preoperative Kmax in our study was 86.1 D. This eye had only trace scarring and never required corneal transplantation. At 24 months, the Kmax had decreased to 77.2 D. Nonetheless, in a study of patients under 18 years of age followed for 10 years, the trend for Kmax improvement compared to baseline was no longer statistically significant after 8 years.7 In our study, the mean change in Kmax at 12 and 24 months following crosslinking were −0.80 D and −1.3 D, respectively. When accounting for repeated measurements of each eye, Kmax had significantly improved at 12 and 24 months postoperatively in our cohort. At 1 year post-crosslinking, 53% of the treated eyes showed regression of corneal steepening.
In our study, 7 eyes (14%) had progression of >1 D in Kmax 12 months following crosslinking. These finding are in keeping with previously reported progression rates of 11–20% following the standard crosslinking protocol.9,10,14,18,20,23 Mazzotta et al. reported a progression rate of 24% at 10 years, with 13 eyes of 9 patients showing >1 D of Kmax steepening and 2 eyes of 2 patients requiring grafting.7 No eyes in our cohort required corneal transplantation.
The eyes that had Kmax progression of ≥1 D at 12 months (n=12) and that also had 24-month postoperative data (n=7) were assessed. The patients were 12–20 years old (mean 16 ± 2.7 years) with no predilection for younger age. The mean change in Kmax between postoperative 12 and 24 months was −1.9 ± 4.1 D. These eyes had similar preoperative and 24-month postoperative mean Kmax values, demonstrating overall stability up to 2 years following crosslinking in this small sub-sample. Except for high preoperative Kmax, no other common characteristics were observed. Of note, the patient who had an increase in Kmax of 5 D at 12 months was 13 years old at the time of corneal crosslinking and had a preoperative Kmax of 55.7 D. There was minimal progression between postoperative 12 and 24 months, with Kmax of 60.7 and 60.9 D, respectively.
Progressive corneal thinning is common in keratoconus, and a thinner central cornea may indicate greater severity of disease.26 In our study, preoperative central corneal thickness (CCT) ranged from 379–540 μm (mean 461.3 ± 37.8 μm). There was significant thinning at postoperative month 12, however CCT improved and stabilized at 24 months.
Uçakhan et al. reported significant improvements in anterior corneal horizontal and vertical coma and anterior spherical aberration from 6 to 48 months postoperatively.24 Greenstein et al. also reported a decrease in the mean total corneal aberrations 1 year following crosslinking for both keratoconus and corneal ectasia.27 In our study, the overall wavefront aberration was relatively stable at each follow-up examination.
Reported complications related to epithelium-off corneal crosslinking include transient stromal haze, corneal edema, delayed epithelial healing and rarely, persistent haze. In our study, the most common finding was transient corneal haze, which resolved in most eyes by 3 to 6 months postoperatively. Two eyes continued to have mild haze at the 24-month examination, but this was not visually significant. There were no cases of microbial keratitis or delayed epithelial healing beyond 1 month in our sample.
The feasibility of any procedure in the pediatric population is most often limited by the need for sedation. This limitation of crosslinking is significant for young children and potentially older children as well who may be unable to undergo the procedure without sedation due to anxiety. The youngest patient in our cohort, who was 12 years old, was able to tolerate the procedure without general anesthesia. If there is evidence of rapidly progressing disease, sedation may be warranted in order to proceed with crosslinking given the findings of this and other studies demonstrating corneal stabilization.
The strengths of this study include the relatively large number of eyes studied at 12 months, as well as assessment of wavefront aberration data, which has been infrequently reported in other studies assessing crosslinking in a pediatric population. The retrospective design and lack of a control group are limitations of this study. Not all patients who underwent crosslinking returned for all subsequent follow up examinations, reducing the number of data points at various follow up periods. A randomized control trial with randomization of each eye in a patient with symmetric disease to either crosslinking or observation would yield the most meaningful results, however no such study exists to our knowledge at this time.
Our study corroborates the efficacy of corneal crosslinking in children and young adults with keratoconus, demonstrating that vision and corneal parameters are stable up to 24 months following the procedure. Any initial changes following crosslinking, including a trend toward thinner corneal thickness and presence of corneal haze, had either resolved or were visually insignificant by the last follow up examination. Given no lasting adverse effects, our study also supports the safety of crosslinking in this young population. Corneal crosslinking appears to be an efficacious and well-tolerated management option in the treatment of children and young adults with keratoconus.
Acknowledgements
The authors thank Liam J Epp, M.Sc., for his invaluable assistance with the statistical analysis for this study.
Supported in part by NIH P30 EY026877 and Research to Prevent Blindness, Inc, New York, NY
Footnotes
Meeting presentation: Previously presented, in part as a poster, at AAPOS on March 20, 2018 Washington, D.C. USA.
Conflict of interest statements:
Solin Saleh, Euna B Koo and Scott R Lambert do not have financial or proprietary interest in any material or method mentioned in this study.
References
- 1.Sporl E, Huhle M, Kasper M, et al. [Increased rigidity of the cornea by intrastromal cross-linking]. Ophthalmologe 1997;94(12):902–906. [DOI] [PubMed] [Google Scholar]
- 2.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] [PubMed] [Google Scholar]
- 3.Leoni-Mesplie S, Mortemousque B, Touboul D, et al. Scalability and severity of keratoconus in children. Am J Ophthalmol 2012;154:56–62. [DOI] [PubMed] [Google Scholar]
- 4.Ertan A, Muftuoglu O. Keratoconus clinical findings according to different age and gender groups. Cornea 2008;27:1109–1113. [DOI] [PubMed] [Google Scholar]
- 5.Reeves SW, Stinnett S, Adelman RA, et al. Risk factors for progression to penetrating keratoplasty in patients with keratoconus. Am J Ophthalmol 2005;140:607–611. [DOI] [PubMed] [Google Scholar]
- 6.Ansah DO, Wang J, Lu K, et al. Post-FDA Approval Results of Epithelium-Off, Full-Fluence Dresden Protocol Corneal Collagen Crosslinking in the USA. Ophthalmol Ther 2020;online ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Mazzotta C, Traversi C, Baiocchi S, et al. Corneal Collagen Cross-Linking With Riboflavin and Ultraviolet A Light For Pediatric Keratoconus: Ten-Year Results. Cornea 2018;37(5):560–566. [DOI] [PubMed] [Google Scholar]
- 8.Holladay JT. Visual acuity measurements. J Cataract Refract Surg 2004;30(2):287–290. [DOI] [PubMed] [Google Scholar]
- 9.Viswanathan D, Kumar NL, Males JJ. Outcome of corneal collagen crosslinking for progressive keratoconus in pediatric patients. Biomed Red Int 2014;2014:140461–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Chatzis N, Hafezi F. Progression of keratoconus and efficacy of pediatric [corrected] corneal collagen cross-linking in Indian children with progressive keratoconus. J Refract Surg 2012;28(11):753–758 [DOI] [PubMed] [Google Scholar]
- 11.Imbornoni LM, Wise RE, Taravella MJ, et al. Keratoconus and corneal morphology in patients with Down syndrome at a pediatric hospital. JAAPOS 2020;24(3):140.e1–140.e5. [DOI] [PubMed] [Google Scholar]
- 12.Vanathi M, Panda A, Vengayil S, et al. Pediatric keratoplasty. Surv Ophthalmol 2009;54:245–271. [DOI] [PubMed] [Google Scholar]
- 13.Raiskup-Wolf F, Hoyer A, Spoerl F, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008;34:796–801. [DOI] [PubMed] [Google Scholar]
- 14.Perez-Straziota C, Gaster RN, Rabinowitz YS. Corneal cross-linking for pediatric keratoconus review. Cornea 2018;37(6);802–809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Magli A, Forte R, Tortori A, et al. Epithelium-off corneal collagen crosslinking versus transepithelial crosslinking for pediatric keratoconus. Cornea 2013;32(5):597–601. [DOI] [PubMed] [Google Scholar]
- 16.Peyman A, Kamali A, Khushabi M. Collagen crosslinking effect on progressive keratoconus in patients younger than 18 years of age: a clinical trial. Adv Biomed Res 2015;4:245. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Wise S, Diaz C, Termote K, et al. Corneal crosslinking in pediatric patients with progressive keratoconus. Cornea 2016;35(11):1441–1443. [DOI] [PubMed] [Google Scholar]
- 18.Kumar Kodavoor S, Arsiwala AZ, Ramamurthy D. One-year clinical study on efficacy of corneal cross-linking in Indian children with progressive keratoconus. Cornea 2014;33(9):919–922. [DOI] [PubMed] [Google Scholar]
- 19.Godefrooij DA, Soeters N, Imhof SM, Wisse RP. Corneal Cross-Linking for Pediatric Keratoconus: Long-Term Results. Cornea 2016;35(7):954–958. [DOI] [PubMed] [Google Scholar]
- 20.Padmanabhan P, Rachapalle Reddi S, Rajagopal R, et al. Corneal Collagen Cross-Linking for Keratoconus in Pediatric Patients-Long-Term Results. Cornea 2017;36(2):138–143. [DOI] [PubMed] [Google Scholar]
- 21.Vinciguerra P, Albé E, Frueh 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] [PubMed] [Google Scholar]
- 22.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(7):454–460. [DOI] [PubMed] [Google Scholar]
- 23.McAnena L, O’Keefe M. Corneal collagen crosslinking in children with keratoconus. J AAPOS 2015;19(3):228–232. [DOI] [PubMed] [Google Scholar]
- 24.Uçakhan Ö, Bayraktutar BN, Saglik A. Pediatric Corneal Collagen Cross-Linking: Long-Term Follow-Up of Visual, Refractive, and Topographic Outcomes. Cornea 2016;35(2):162–168. [DOI] [PubMed] [Google Scholar]
- 25.Arora R, Gupta D, Goyal JL, Jain P. Results of corneal collagen cross-linking in pediatric patients. J Refract Surg 2012;28(11):759–762. [DOI] [PubMed] [Google Scholar]
- 26.Krumeich JH, Daniel J. [Live epikeratophakia and deep lamellar keratoplasty for I-III stage-specific surgical treatment of keratoconus]. Klin Monbl Augenheilkd 1997;211(2):94–100 [DOI] [PubMed] [Google Scholar]
- 27.Greenstein SA, Fry KL, Hersh MJ. High-order aberrations after corneal collagen crosslinking for keratoconus and corneal ectasia. J Cataract Refract Surg 2012;38(2):292–302. [DOI] [PubMed] [Google Scholar]