Corneal Curvature Changes and Uncorrected Distance Visual Acuity after Corneal Collagen Cross-Linking for Progressive Keratoconus: A one year follow-up survey

Corneal collagen cross-linking (CXL) is a therapeutic intervention to decrease the progression of keratoconus and reduce the need for keratoplasty. The present study aimed to efficacy of CXL on corneal curvature changes and uncorrected distance visual acuity (UDVA) through a one-year follow-up survey. This was a descriptive and analytical study conducted on 38 eyes of 27 patients aged 15-25 years who underwent CXL on progressive keratoconus. The levels of uncorrected distance visual acuity and the front and back surface curvatures of the cornea (using a sagittal pentacam map) were determined before and one year after surgery. The data were analyzed with statistical package SPSS (version 19). The UDVA, steep, flat, and mean curvatures of the anterior surface significantly improved by 0.10 ± 0.25 LogMAR (P=0.012), 0.75 ± 1.09D, 0.79 ± 1.23D, and 0.79 ± 1.10 D (P< 0.05), respectively. The Kmax (0.21 ± 1.65 (P=0.421)), and anterior surface astigmatism -(0.04±0.84 (P=0.745)) of the cornea did not show significant changes, whereas back surface curvatures increased. CXL is an effective strategy to halt and reduce progression of keratoconus and can have an important role in limiting decrease of vision.


INTRODUCTION
Keratoconus is a non-inflammatory, bilateral, asymmetrical, progressive, and ecstatic disease of the cornea; causing thinning of the cornea and reducing its mechanical strength due to the weakness of stromal collagen fibers.Irregular astigmatism and impairment in visual function is secondary to changes in the structure and organization of stromal collagen 1,2 .In a long-term research, the incidence of keratoconus has been reported as 20/100000 and 22.3/100000 in America 3 and in an area of Iran 4 , respectively.Progressive keratoconus may eventually lead to keratoplasty (PK, DALK).Hence, in recent years, finding a solution to stop its progression has been taken into account and in this regard, corneal collagen cross-linking (CXL) has been introduced.Wollensak et al. (2003) used cross-linking for keratoconus for the first time 5 .Studies have shown that CXL can effectively improve and stop progressive keratoconus 6 , make better corneal rigidity 7,8 , enhance corneal resistance to enzymatic degeneration 9 and be raised as a strategy to limit vision loss and reduce the need for keratoplasty 10 .Radiation of uvA 365 nm and the use of riboflavin, as photo sensitizer, can create new covalent bonds between collagen molecules, fibers and microfibrils by photosensitized oxidation 11 .Studies on CXL safety have demonstrated that under appropriate UV irradiation endothelial damage will not occur and corneal thickness (excluding epithelium) is not less than 400 microns [12][13][14] .However, no serious side effects were reported 5,13,[15][16][17] .According to the new practice of CXL and that it has not still been fully approved by the FDA, confirmation of its effectiveness requires further research in this field, especially in Iranian population with progressive keratoconus.Therefore, this study aims to evaluate the efficacy of CXL on corneal curvature changes and uncorrected distance visual acuity.

MATERIALS AND METHODS
This was a descriptive and analytical study conducted on 38 eyes of 27 patients underwent CXL on progressive keratoconus.The CXL was carried out according to the following procedures: 1. Prep & drape; 2. Epithelial treatment with 20% alcohol for 20 sec; 3. Epithelium removal; 4. Riboflavin drop application 10 times in 30 min; 5. Ultraviolet exposure for 30 min + riboflavin; and 6.Use of bandage contact lens.Antibiotic and corticosteroid drops were prescribed, afterwards.
The inclusion criteria included that the patient suffers no ophthalmic and systemic disease except progressive keratoconus; no use of lens at least for 3 weeks before the operation; having corneal thickness > 400 microns of; Kmax d" 60 D; and lack of reaching corneal opacity or scarring phase of keratoconus.
The participants aged 15-25 years with progressive keratoconus underwent CXL follwoing clinical examinations and required test on eyes in the Farabi Eye Specialty Hospital (Tehran, Iran).
Patients who had undergone CXL according to the inclusion criteria of the study were reviewed through an observational method and the patients eligible for the required examinations (20% higher than the sample size) were selected one year after the operation/surgery.After calling back the patients, their postsurgery UDVAs were determined and their corneal front and back surface topographies, including steep curvature (Ks), flat curvature (Kf), mean curvature (Kmean), maximum curvature (Kmax) and astigmatism level in both anterior and posterior surfaces of the cornea were examined using pentacam.Their CXL pre-and post-operative data were then compared and statistically analyzed.
Finally, the collected data were analyzed with statistical package SPSS (version 19).The data were represented as mean ± standard deviation.To compare the normally distributed variables and those without normal distributions, paired t-test and Wilcoxon test were employed, respectively.
The posterior surface showed an increase in curvature (a significant change) (Fig. 4) and the astigmatism level showed no significant changes (0.03 ± 0.21; P =0.303).

DISCUSSION
The corrective methods for progressive keratoconus are conventionally pursued based on the two purposes: 1. Prevention and control of its progression and 2. Improvement of sight (including using lenses, specs, Intacs, Myoring, ICI, Toric Artisan, PK, and DAIK) The CXL process has been considered as an effective intervention that can be effective in controlling progressive keratoconus hence this study aimed to investigate its effectiveness by assessing corneal curvature changes and uncorrected distance visual acuity.
The use of UV length wavelength radiation and cross-linking to retrofit a material is not new as the former is used to toughen dental filling materials in dentistry and produce strong adhesives in the polymer industry, while the latter is used in orthopedics.Meanwhile, cross-linking as a natural phenomenon occurs in the cornea and eye lens with aging.Corneal fibril thickness of about 4.5% increases during a person's life due to glycosylation cross-linking caused with age.Also, lens crystalline changes due to molecular weight and stiffness are caused by age-related cross-linking.The idea of using CXL for corneal stiffening was conceived in Germany in the 1990s .Researchers at the University of Dresden, Germany, found that keratoconus does not occur to or develop in diabetic patients due to glycosylation-mediated cross-linking which results in stromal resistance.Therefore, investigators tried to create the same conditions for non-diabetic persons.The ultimate results necessitated the application of riboflavin drop and 370 nm UV radiation to create cross-links between stromal collagen fibers.Therefore, the positive application of CXL for progressive keratoconus can be promising.Furthermore, the results of this study showing significant changes in UDVA, steep, flat, and mean corneal front surface curvatures suggest that keratoconus did not only progress in the study population but also improved (Table 1).
These findings were consistent with several previous studies 16,[18][19][20][21][22][23] .In addition, Kmax represented stability in keratoconus level.However, the difference in the values may be due to sample size, patients' ages, follow-up periods, and keratoconus intensity.The assessment of posterior surfaces showed that although curvatures significantly increased, the increases are not clinically significant compared to the anterior surface changes.This means that the CXL does not have a positive effect on back surface curvatures, while the trivial impact of corneal posterior compared to the anterior surface on eye refraction can be the reason for not addressing the assessment of posterior surfaces in other studies.The findings of this study can be used in developing new therapeutic modalities as well as new high-tech approaches such as brain computer interface technique based on visual interface 25 .

CONCLUSION
Progressive keratoconus may ultimately necessitate keratoplasty (PK, DAIK).Thus, considering the problems of graft rejection, high astigmatism, and long-term complications, CXL presents an important strategy to halt the progress of keratoconus and improve it, while it can also play an effective role in limiting vision loss and reducing the need to have a corneal transplant.

Fig. 1 :Fig. 2 :
Fig.1: The mean uncorrected distance visual acuity before and after CXL surgery in terms of Log MAR (P=0.05)

Fig. 3 :Fig. 4 :
Fig. 3: The mean curvature of corneal anterior surface before and after CXL surgery (P=0.05) In a prospective case series study byHashemi et al. (2013) on 40 eyes of 32 patients to evaluate CXL long-term results of patients with progressive keratoconus, mean UDVA decreased from 0.67 ±0.52 Log MAR before surgery to 0.65 ±0.51 Log MAR 5 years after surgery.The averaged Kmax and Kmean were respectively reduced by 0.16 ±2.20 D and 0.1 ±1.69 D.. Additionally, astigmatism level changed from -3.14 ±2.22 D to -2.49 ±1.71 D. They concluded that Kmean, Kmax, UDVA, and astigmatism did not change during the 5 years after surgery, while CXL as a safe operation can stop keratoconus progression and limit the need for keratoplasty(24).Our findings support these findings where the mean UDVA varied from 0.56 ±0.51 Log MAR before surgery to 0.45 ±0.42 Log MAR after surgery, while the variations of averaged Kmax and Kmean values occurred within the ranges of 0.21 ±0.65 D and 0.79 ±0.10 D, respectively.Astigmatism change was also from -3.13 ±1.58 D to -3.18 ±1.68 D).This insignificant difference can be attributed to the study duration, keratoconus severity (bias caused by the inclusion Kmax value), and patients' ages.However, Hashemi et al. did not study the steep and flat curvatures of frontal surfaces alone, nor evaluated the curvatures and astigmatism level of corneal back surface.

Table 1 .Distributions of mean and standard deviation statistics of the research variables and their distributions of mean differences before and 1 year after CXL surgery Variable Number Pre op. 1-year post op. Pre op. and 1-year post op. differences
UDVA: Uncorrected distance visual acuity; F: front surface of cornea; B: back surface of cornea; K: Keratometry; s: steep; f: flat; max: maximum; min: minimum; ast: astigmatism