The Comparison of Accelerated Corneal Crosslinking Treatment for Progressive Keratoconus in the Pediatric and Adult Age Groups: One-Year Results

Purpose: To investigate the short-term results of accelerated crosslinking (A-CXL) treatment for progressive keratoconus in the pediatric and adult age groups. Materials and methods: The records of the 62 eyes of 40 patients who had undergone the A-CXL procedure (9 mV/cm2, 10 min) for progressive keratoconus between January 2015 and January 2019 were evaluated retrospectively. The patients were divided into 2 groups as the pediatric group (aged 17 years or less) and the adult group (aged 18 years or more) for statistical analysis. Pre- and post- 12th month A-CXL best-corrected visual acuity (BCVA), maximum keratometry (Kmax), sim K1, sim K2, corneal thickness at the thinnest point (thCT), and corneal astigmatism (CA) values of the patient groups were recorded. Results: The 29 eyes of 16 patients were included in the pediatric group and the 33 eyes of 24 patients were included in the adult group. The mean age was 13.50±3.05 years in the pediatric group and 23.58±4.37 years in the adult group. A signicant improvement in BCVA and a signicant decrease in thCT values were present in both groups 12 months after the surgery compared to the preoperative period. A decrease was present in the Kmax, sim K1, sim K2 and CA values in the pediatric group, but was not statistically signicant. The decrease in Kmax, sim K1 and sim K2 values compared to the preoperative period was signicant in the adult group, but the decrease in CA values was not signicant. When the two groups were compared at the end of 12 months, only the sim K1 value was signicantly lower in the adult group, and there was no signicant difference between the other measurements. Conclusions: Better visual acuity improvement, a higher attening rate, and less progression occur after 12 months with A-CXL treatment for progressive keratoconus in the adult age group compared to the pediatric age group.


Introduction
Keratoconus is a bilateral, progressive, and non-in ammatory corneal degenerative disease that causes irregular astigmatism and visual impairment as a result of the steepening and thinning of the cornea. The disease is usually asymmetrical. It begins at puberty and can be progressive until the age of 35-40 years.
The incidence of the disease has been reported as 1 in 2000 in some studies and 1 in 7500 in some others [1,2]. The incidence has been reported to be higher in the Asian population compared to the Caucasian population [3,4]. Keratoconus has a more serious and progressive course in the pediatric age group than in the advanced age group [5,6]. It is one of the most common keratoplasty indications in the pediatric age group, with a rate of 15-20% [7]. Therefore, slowing or stopping the progression of the disease in the pediatric age group is of great importance. Although the etiology and pathophysiology of the disease are not fully understood, a genetic predisposition being triggered by environmental factors is most commonly considered. Keratoconus has a strong association with allergic eye diseases and eye rubbing [1,8]. It may be associated with ocular diseases such as vernal conjunctivitis, Leber's congenital amaurosis, and retinitis pigmentosa, as well as systemic diseases such as Down syndrome, Turner syndrome, Ehlers-Danlos syndrome, atopy, and osteogenesis imperfecta. High K values in the paracentral cornea and irregular astigmatism with Placido disk-based scheimp ug corneal topography, in addition to Vogt lines, Fletcher ring, and the Munson and Rizzoti signs in the cornea on biomicroscopic examination have an important place in the diagnosis. Progression has been de ned as an increase of 0.75 D after 6 months and 1 D after 12 months in Kmax values as measured by Placido disk-based Scheimp ug corneal topography and a decrease of 2 lines after 12 months in the best-corrected visual acuity (BCVA) [9].
Corneal Crosslinking (CXL) was rst de ned by Wollensak et al. in 2003 in order to slow or stop the progression or decrease the need for keratoplasty in keratoconus treatment [10]. The aim of CXL treatment is to slow or stop the progression of keratoconus by strengthening the covalent bonds between the collagen brils in the corneal stroma and increasing the resilience and rigidity of the cornea by using ribo avin (vitamin B2) and ultraviolet A [11]. When compared with 30-minute exposure to 3 mV/cm2 UVA in the standard CXL treatment (Dresden protocol), the shorter exposure to higher-intensity UVA in the accelerated CXL treatment protocol may be an advantage in the pediatric age group who may have treatment compliance problems. There are many studies showing that standard CXL and Accelerated CXL (ACXL) treatments are effective and safe in stopping the progression of keratoconus [12][13][14][15].
According to the Bunsen-Roscoe reciprocity law, it is theoretically possible to achieve the same energy dose by setting a higher UVA power at a shorter exposure time and provide a proportional biological effect with the accelerated CXL procedure [16][17][18]. It has been predicted that a shorter exposure duration could be ensured with higher irradiation intensity, and results similar to those obtained with the standard CXL treatment have been seen with different irradiation intensities and durations in the ACXL procedure, as de ned based on this assumption [19][20]. A shorter treatment period provides advantages in terms of preventing adverse conditions such as preventing peroperative corneal dehydration and thinning and postoperative infection [15].
We aimed to reveal the results of ACXL treatment used for the treatment of progressive keratoconus in the pediatric and young adult age groups in the current study by comparing the postoperative 12th month topographical characteristics and disease progression.

Material And Method
The 62 eyes of 40 patients treated with crosslinking (CXL) for progressive keratoconus between January 2015 and January 2019 at the Gaziantep Göznuru Hospital were included in this retrospective study.
Ethics committee approval was obtained from the Gaziantep Sani Konukoğlu University Ethics Committee. The study was conducted in accordance with the Helsinki Declaration principles. The patients were divided into two groups as the pediatric group (age 8-17 years) and the adult group (age 18-35 years). All patients underwent a comprehensive ophthalmological examination. Visual acuity was measured with a Snellen chart and converted into logmar.
The diagnosis of keratoconus was made with by observing the Munson and Rizotti signs, a Fletcher ring and Vogt striae with slit lamp biomicroscopy, and the typical topographic ndings obtained with the scheimp ug imaging system (Sirius, CSO, Italy). Keratoconus progression was con rmed by corneal topographic and pachymetric analyses and the best-corrected visual acuity. Progression was de ned as a 1 D increase in the maximum keratometry value in 1 year.
All patients were examined preoperatively and 12 months after the surgery. Examinations included bestcorrected visual acuity measurement with the Snellen chart, slit lamp biomicroscopy, maximum keratometry value as measured by corneal topography (Sirius, CSO, Italy), sim K1, sim K2, corneal thickness at the thinnest point, and corneal astigmatism values. The patients were divided into stages based on the Amsler-Krumeich keratoconus staging system [21]. The presence of 5D or lower induced myopia and/or astigmatism, 48 D or lower keratometric value, Vogt lines, and a typical topographic appearance was identi ed as stage 1. The presence of induced myopia or astigmatism above 5 D and below 8 D, 53 D or lower keratometric value, and 400 µm or lower corneal thickness at the thinnest point was identi ed as stage 2. The presence of induced myopia and/or astigmatism above 8 D and below 10 D, a keratometric value above 53 D, and a corneal thickness of 200-400 µm at the thinnest point was stage 3. Refractive values that could not be measured, keratometric value above 55 D, a corneal thickness of 200 µm or less at the thinnest point, and scarring on the cornea indicated stage 4. Patients at stage 1, 2 and 3 were included in the study.
Patients at the age of 8 to 35, who were diagnosed with progressive keratoconus based on the the progression criteria and received corneal crosslinking treatment, had a follow-up of at least 1 year, had a corneal thickness of 350 µm and above at the thinnest point, had not undergone previous corneal crosslinking surgery or another eye surgery, and had no other systemic disease were included in the study. Patients with stage 4 keratoconus, corneal thickness less than 350 µm at the thinnest point, herpetic keratitis scar on the cornea, any disease that causes scarring in the cornea, an additional systemic disease, a history of continuous drug use, and those who were pregnant or breastfeeding were not included in the study.

Surgical Procedure
The surgery was performed under sterile conditions. After instillation of topical anesthetic (0.5% proparacaine), the central 9 mm area of the epithelium was mechanically separated. Afterwards, 0.1% ribo avin (MedioCross, Kiel, Germany) was administered to the cornea every 2 minutes for 30 minutes. The cornea was exposed to an Ultraviolet A beam of 370 nm (9 mV/cm2) for 10 minutes by using the CCL-VARIO (Peschke Ltd, Borsigstrabe, Germany) device. After the procedure, the surgery was concluded by placing a therapeutic bandage contact lens on the eye. The patients were prescribed topical antibiotics (moxi oxacin, Vigamox, Alcon Laboratories, Inc., Fort Worth, Texas, USA) to be used four times a day.
Postoperative follow-up took place on the 1st and 4th days. The contact lens was removed on the 4th day if the corneal epithelium was completely healed and the drops were continued for one month.
The IBM SPSS Statistics 23 software program was used in the analysis of the data. Mean and standard deviation values are provided for the measurable continuous variables, and frequency and percentage values for the qualitative variables as descriptive statistics. The compliance of the continuous variables with a normal distribution was evaluated with the Kolmogorov-Smirnov test. When comparing two independent groups, the t-test for independent groups was used for continuous variables, and the Pearson chi-square or chi-square test with continuity correction was used based on the relevance of the data for the qualitative variables. The paired groups t-test was used for the comparison of two dependent measures. A p value < 0.05 was considered statistically signi cant in all evaluations.

Results
The 62 eyes of 40 patients treated with A-CXL for progressive keratoconus were included in the study. The mean age of the patients was 18.74 ± 6.27 (range 8-35) years. The patients were divided into two groups based on their age as pediatric and adult groups. The 29 eyes of 16 patients in the pediatric group (aged  An increase of more than 1 diopter in the Kmax value at the postoperative 12th month was de ned as progression. The progression rate was 24.1% in the pediatric group patients and 12.1% in the adult group patients, with no statistically signi cant difference (p:0.367). Postoperative attening was de ned as more than 1 diopter decrease in Kmax value 12 months after the CX surgery. The attening rates were 48.2% ( 1D) and 20.6% ( 2D) in the pediatric group and 51.5% ( 1D) and 24.2% ( 2D) in the adult group with higher rates observed in the adult group.
No postoperative complication was found in any of the patients.

Discussion
Keratoconus has different characteristics in the pediatric and adult age group in terms of the progression and severity of the disease. Keratoconus has a more progressive and severe course in pediatric patients [22]. Stabilization of the disorder as soon as possible is of great importance in this age group in terms of providing better visual function and decreasing the need for keratoplasty. The standard corneal crosslinking procedure (S-CXL, Dresden protocol) has been used for years to stop the progression of keratoconus, after being de ned by Wollensak et al [10]. There are many studies reporting that the procedure (30-minute exposure to 3 mW/cm2 UVA rays) is an effective and reliable treatment for the stabilization of pediatric and adult progressive keratoconus [23][24][25][26][27]. The accelerated cross linking (A-CXL) procedure is based on the Bunsen-Roscoe reciprocity law using the principle that shorter exposure to higher intensity UVA rays has similar photochemical effects on the cornea. A short procedure time has advantages such as higher compliance with treatment in the pediatric age group, less corneal dehydration, and less intraoperative corneal thinning. S-CXL and A-CXL procedures have been reported in many studies to have similar e ciency and reliability in the stabilization of progressive keratoconus in the pediatric and adult age groups [28][29][30][31][32][33]. The 1-year results of accelerated CXL (9 mV/cm2 UVA, 10 min) treatment for progressive keratoconus in the pediatric and adult age groups were compared in the current study.
Flattening after the CXL procedure was rst de ned as a decrease of 1D in the Kmax value by Koller et al. in their 2011 study [34]. The ratio of the eyes with a Kmax decrease of more than 1D was reported as 37.7% while the ratio of a Kmax decrease of more than 2D was 13% at the 12th month following the CXL  [25]. They have attributed the high attening rate in the pediatric patients to their high corneal collagen plasticity. Unlike the study of Soeters et al., the attening rates in the current study were 48.2% ( 1D) and 20.6% ( 2D) in the pediatric age group, and 51.5% ( 1D) and 24.2% ( 2D) in the adult age group, with the attening rates found to be higher in the adult group.
The progression rate after corneal CXL has been the subject of a multitude of studies. Keratoconus has been found to be more progressive and more aggressive in the pediatric age group in many of these [22,[36][37][38][39]. Barbisan  where they investigated the 10-year results on 62 pediatric age group eyes with a mean age of 14.1 years who had received standard CXL treatment [41]. Uçakhan et al. have found no progression at the postoperative 24th month in the standard CXL group with a mean age of 23.13 years while the progression rate in the group receiving accelerated CXL with a value of 9 mW/cm2 and with a mean age of 24.69 years was 11.1% in their study where they compared the standard CXL and 9 mW/cm2 accelerated CXL procedures [42]. The postoperative 12th month progression rate was 24.1% in the pediatric patient group and 12.1% in the adult group in the current study where the accelerated CXL procedure was performed with a value of 9 mW/cm2 for progressive keratoconus, and the difference between the two groups was not statistically signi cant (p:0.367). and adult (aged 26 years) age groups [25]. We also found a signi cant BCVA improvement in the postoperative 12th month compared to the preoperative period in both the pediatric and adult patient groups, but the improvement was more signi cant in the adult group, unlike the Soeters et al. study (p:0.033, p:0.001). This can be explained by the fact that keratoconus is more progressive and aggressive in the pediatric patients. The difference between the BCVAs of the groups after 12 months was not statistically signi cant in our study (p: 0.091). Similarly, the BCVA difference between the two groups at the postoperative 12th month was reported not to be signi cant in the Barbisan  year in their recent study where the 192 eyes of 122 patients treated with standard CXL were divided into two groups as pediatric (aged ≤ 18 years) and adult (aged 18 years) [27]. Comparison of the pediatric and adult groups revealed no signi cant difference between the postoperative 12th month mean CA values (p: 0.125). We did not nd any study investigating the pre and post CXL CA values in the pediatric and adult age groups.

Best-corrected visual acuity
Only a limited number of studies have compared the results of CXL treatment in pediatric and adult patients with progressive keratoconus [25][26][27]. The S-CXL protocol has been used in all these studies. In contrast, we have compared the 1st year results of A-CXL (9 mV/cm2 for 10 minutes) treatment between two groups in our study. As far as we know, our study is a rst in this eld.
The limitations of our study can be listed as its retrospective nature, the small number of patients, not including optic aberrations, and not providing spherical equivalent information.
In conclusion, the A-CXL (9 mV/cm2 for 10 minutes) procedure is an effective and reliable method for the treatment of pediatric and adult progressive keratoconus patients. Better visual acuity improvement, a higher attening rate, and less progression occur with A-CXL treatment after 12 months in adult progressive keratoconus patients compared to the pediatric age group. Besides, there was a greater decrease in Kmax, simK1 and simK2 values in the adult group. Further studies with larger participation and longer follow-up are required for results with greater impact.

Declarations
Funding No funding was received for conducting this study.
Con icts of interest/Competing interests All authors certify that they have no a liations with or involvement in any organization or entity with any nancial interest or non nancial interest in the subject matter or materials discussed in this manuscript Availability of data and material The data supporting the ndings of the study are available from the corresponding author upon request.
Ethical approval The study protocol was approved by the Institutional Review Board of Sani Konukoglu University School of Medicine Hospital.
Informed consent The study was performed in accordance with the Declaration of Helsinki principles, and written informed consent about having their medical information used in the study analysis was routinely provided from all of the patients at their rst presentation to our clinic.