Evaluation of Corneal Tomographic, Densitometric, and Aberrometric Features Following Accelerated Corneal Cross-Linking in progressive keratoconus

Abstract

Purpose

To evaluate the 12 months' changes in tomographic, densitometric, and aberrometric parameters in keratoconic eyes after accelerated corneal cross-linking (CCL) and classify a densitometric course in different stages of the keratoconus separately (Mild, moderate, and severe).

Methods

In a prospective observational study, 67 keratoconic eyes of 67 patients that underwent accelerated epithelium-off corneal cross-linking (9 mW/cm2 and 10 minutes) for treatment of progressive keratoconus were included. Corneal tomographic, densitometric, and aberrometric values obtained using the Pentacam HR were recorded at the baseline and 3, 6, and 12 months post-operatively.

Result

One year after treatment, corrected distance visual acuity (CDVA) was improved, and maximum keratometry, thinnest pachymetry, higher order, and total Root Mean Square (RMS) were significantly decreased. (p < 0.001) Corneal densitometry values showed a significant elevation 3 months post-surgery compared to baseline and then decreases to baseline values at 1 year. Only the Anterior 0–2 mm zone densitometry at the third month was different between the three groups. RMS at 1 year correlated with Anterior 0–2 mm, Anterior 2–6 mm, total corneal 0–2 mm, and total corneal 2–6 mm densitometry values in the third month. Final CDVA at 12th-month follow-up correlated with the Anterior 0–2 mm corneal densitometry in the third month.

Conclusion

Anterior 0–2 mm zone densitometry at the third-month post accelerated CCL can be used to detect different staging of keratoconus. Due to the correlation between final aberrometric and peak densitometric values in keratoconic eyes, peak densitometric values can be used as a prognostic factor for the final visual outcomes after accelerated CCL.

1. Background

Keratoconus is a progressive non-inflammatory disease of the cornea that defines by conical protrusion, progressive thinning, and changes in biomechanical properties of the cornea (1). Although it has been reported in different ethnicities, published data shows more prevalence in Asian countries. (2) In Iran the prevalence has been estimated at around 2.5 to 3.3 percent. (3)

Histopathology of the disease involves progressive degeneration of the corneal basal epithelial layer followed by bowman layer collagen fragmentation. The cornea progressively thins in the course of the disease and it suffers from collagen lamellar disarrangement. (4)

Treatment of the disease consists of refractive correction and halting the disease progression. Corneal collagen cross-linking (CCL) now approved by FDA (Food and Drug Administration), prevent the disease progression by utilizing ultraviolet light and riboflavin to cross-link between corneal collagen fibers. (5) Previously it was thought that cross-linking was not that effective for advanced stages of the disease, although cross-linking was shown to be safe and effective for advanced progressive keratoconus. (6, 7) Wollensak et al. developed a standard CCL protocol in 2003 (8), while accelerated protocols have been introduced since 2010 to achieve some advantages such as shortened operation time and reduced rate of complications (9). Accelerated protocols are carried out in 3, 5, and 10 minutes using 30, 18, and 9 mW/cm² irradiance, respectively without changing the cumulative irradiation dose of 5.4 J/cm². Kobashi et al, in the meta-analysis of randomized controlled trials, showed accelerated CCL had comparable efficacy and safety profile to standard CCL, and both methods similarly stopped the Keratoconus (KCN) progression (10).

The Pentacam HR (Oculus Inc., Wetzlar, Germany) using a rotating Scheimpflug camera system can analyze high-resolution anterior segment images, and it is possible to perform a tomographic evaluation of the anterior and posterior surfaces of the cornea, change in elevation, anterior chamber angle width, anterior chamber depth and volume, corneal aberrations, and densitometric evaluation of the cornea (11).

There are a variety of studies evaluating changes in tomographic, densitometric, and aberrometric parameters in keratoconic eyes after accelerated CCL with the Pentacam HR imaging system (12, 13, 14, and 15). Few studies in the literature investigated the outcomes of accelerated CCL using Pentacam (14, 15). The parameters most evaluated are maximum keratometry, central corneal thickness, visual acuity, spherical equivalent, and corneal biomechanical properties. Few studies have evaluated posterior corneal parameters and densitometric properties, and they have mainly investigated the effects of standard CCL (16, 17). As far as the authors are aware, there are limited studies in the literature evaluating the effects of accelerated CCL on topographic, densitometric, aberrometric, and visual parameters in keratoconic eyes based on different stages of the disease.

In this prospective, observational study with 1 year follow-up period, we study the natural course of tomographic, densitometric, aberrometric, and visual parameters changes after accelerated CCL in keratoconic eyes, and we classify a densitometric course in different stages of the disease separately (Mild, moderate and severe).

2. Methods

In a prospective, observational study, 67 patients over 18 years of age with progressive keratoconus that underwent accelerated corneal cross-linking, between January, 2020 and April 2021 in the Farabi Eye Hospital were enrolled in this study. Approval for the study was obtained from the ethical committee of the Tehran University of Medical Sciences which complies with the Helsinki Declaration. All patients received a thorough explanation of the study design and aim and were provided with written informed consent.

All patients were selected according to the following inclusion and exclusion criteria

Inclusion criteria

Age between 18 and 40 years, phakic patients with clear lenses, confirmed bilateral KCN based on clinical and topography findings, and documented progressive keratoconus defined as increase in maximum keratometry (K) of 1.00 diopter (D) in 1 year and deteriorating best corrected visual acuity (BCVA), and the bilateral minimum corneal thickness of 380 µm as measured with the Pentacam.

Exclusion criteria

The following cases were excluded from the study: nonprogressive KC, pseudophakia, a corneal thinnest point less than 380 µm, corneal scarring in either eye, ocular surface or tear problems, and coexistence of ocular pathologies other than KCN, systemic autoimmune diseases, pregnancy, history of corneal persistent epithelial defect, previous eye surgery, the pterygium or other corneal surface irregularities.

Preoperative evaluation

It included the following clinical history (age, complaint, ocular trauma or disease, optical correction, any systemic medical diseases, etc.) and ophthalmic examination: (1) The BCVA: after dry refraction, BCVA with spectacles, and BCVA with rigid gas permeable contact lens was measured as well. Visual acuity was then converted to the logMAR scale for analysis. (2) Slit‑lamp biomicroscopy: the cornea was examined for evidence of corneal edema, and corneal scars; the anterior chamber was examined for depth, regularity, aqueous flare, and cells; and Goldmann applanation tonometry to record baseline intraocular pressure. (3) Fundus examination: auxiliary lenses (+ 90 D lenses) were used to examine the central and mid-peripheral retina to exclude possible pathology, for example, macular scars or retinal breaks.

Special investigations

Scheimpflug Tomography imaging was obtained with pentacam device (Oculus Pentacam®; Oculus Optikgerate GmbH, Wetzlar, Germany).

Tomographic, densitometric, and corneal wavefront aberrometric data was extracted from pentacam analysis printouts.

All examinations and measurements were repeated at 3, 6, and 12 months post-operative visits. The measurements were performed by an expert operator in a standard dim room that was equal for all patients. They were repeated three times for each patient.

Only examinations with an ''OK'' quality check were considered for analysis. The Scheimpflug densitometry is Shown quantitatively in gray scale units (GSUs), which defines Corneal light backscatter on a scale of 0 (minimum scatter) to 100 (maximum scatter). Scheimpflug tomography can analyze the corneal densitometry at different concentric zones (0.0 to 2.0, 2.0 to 6.0, 6.0 to 10.0, 10.0 to 12.0 mm) and depths of the cornea; anterior stromal layer (120 microns), posterior stromal layer (60 microns) and middle layer between these anterior and posterior layers.

(Fig. 1)

Surgical technique

Accelerated epithelium-off protocol was used for corneal cross-linking.

Under topical anesthesia using Tetracaine eye drops (Anestocine, SinaDaru pharmaceutical co, Tehran, Iran) standard preparation of eyelid skin with povidine iodine was performed. After opening the eyelids apart with a lid speculum, for corneal debridement, 20% of alcohol was applied for 20 seconds on the cornea. Riboflavin 0.1% isotonic solutions in 20% dextran T-500 (SinaDaru pharmaceutical co, Tehran, Iran) were instilled every minute on the corneal surface for 20 minutes. Then the cornea was irradiated with UV light of 365nm wavelength for 10 minutes. Corneal collagen cross-linking was performed with a LightLink CCL device (LightMed, San Clemente, CA, USA). The device irradiation power was adjusted to 9.0 mW/cm2. During the light-on period, the corneal surface was moistened with riboflavin eye drops every 2 minutes.

In conclusion of the surgery antibiotic eye drops were applied over the ocular surface and a Bandage contact lens (pure vision, Bausch and Lomb co.) was placed over the cornea.

The routine postoperative drug regimen was Ofloxacin eye drops (Ofloxacin ophthalmic eye drops 0.5%, SinaDaru pharmaceutical co, Tehran, Iran) every 6 hours and betamethasone eye drops (Bethasonate 0.1%, SinaDaru pharmaceutical co, Tehran, Iran) every 6 hours. Antibiotic was continued till the cornea was fully re-epithelialized and then the contact lens was removed. Steroid drops were continued for 20 days after surgery.

Statistical analysis

Statistical analysis was performed using SPSS software version 24 (SPSS Inc., IBM). Kolmogorov-Smirnov test was used to assess the normality of the parameters. Wilcoxon test was used to evaluate the changes in parameters before and after surgery in each follow-up visit. The potential correlation between parameters was assessed using the Spearman correlation coefficient. Kruskal Wallis H test and Mann-Whitney U test were used to evaluate the mean difference in parameters in different groups (mild, moderate, and severe disease groups). For all statistical analyses, P value of less than 0.05 was considered statistically significant.

3. Results

Of 92 patients who underwent accelerated corneal cross-linking for progressive keratoconus, 25 patients failed to complete their follow-up visits and were excluded from the study.

67 Keratoconus eyes (64% male, 36% female) that completed the follow-up were included for statistical analysis. The baseline characteristics of patients in the study are summarized in Table 1.

The patients were classified as Mild, Moderate, or severe keratoconus using the the new ABCD classification (Table 2) and stage 1 were categorized as mild, stage 2 as moderate, and stage 3 and 4 of new ABCD classification was categorized as severe in this study.

 37 patients were classified as mild, 19 patients as moderate, and 11 patients as severe keratoconus.

Tomographic parameters change after accelerated CCL

The pre-operative and post-operative corneal tomographic parameters include Kmean (Mean Keratometry), Kmax (maximum keratometry of the cornea), and thinnest pachymetry (Thinnest point pachymetric thickness) and corrected distance visual acuity (CDVA) and mean refraction spherical equivalent is summarized in Table 3.

There was an initial increase in mean CDVA (logMAR) in the 3-month postoperative visit from the baseline value from 0.285 to 0.287 (p = 0.03), then the value return to baseline on the sixth-month post-operative visit (p = 0.374) and after 1 year the value decreases to less than baseline values. (p = 0.001; table-3; figure − 1)

There was a statistically significant decrease in maximum keratometry after 1 year of treatment. (p < 0.001) the mean keratometry also decreased after 1 year and it was statistically significant. (p = 0.016; table-3; figure − 2)

The mean thinnest pachymetry after 1 year decreased by approximately 9 microns and it was statistically significant. (p < 0.001)

The absolute value of mean Spherical equivalent decreased from baseline through 3, 6, and 12 months post-operatively.

Corneal aberrometric values change after accelerated CCL

Table 3 shows changes in mean Root Mean Square (RMS) changes for both total and high order corneal aberrations at baseline, on the third month, on the sixth month, and 1 year post-operatively. The total RMS values increase in the third month from a baseline value. (p < 0.001) it decreases after month 3 through month 12 and at a 1-year follow-up visit, the total RMS value decreases significantly from baseline. (p = 0.009; Table 3)

High order RMS values increases from baseline at month 3. (p < 0.001) and decreases from month 3 to month 12 and at 1-year follow-up visit the high order RMS decreased from the pre-operative value that was statistically significant. (p = 0.008; Fig. 3)

Corneal densitometric value changes after accelerated CCL

Table 4 shows mean corneal densitometric values for different concentric zones and different depths.

Anterior corneal densitometry 0–2 mm increases from baseline to its peak in the third month (from 22.48 to 30.1) (p < 0.001), then it decreases from month 3 to 6 but it's still increased compared to the pre-operative value (p < 0.001). After 1 year the densitometry value returns to baseline and there is no statistically significant difference from the pre-operative value (p = 0.9; Table 4; Fig. 4).

Anterior corneal densitometry 2–6 mm zone increases from baseline to its peak at month 3 (from 18.82 to 27.58) (p < 0.001) then it decreases from month 3 to 6 but it's still increased compared to pre-operative value. (p = 0.039) after 1 year the densitometry value returns to baseline and there is no statistically significant difference from the pre-operative value (p = 0.075).

Middle corneal densitometry in 0–2 mm zone increases from baseline to its peak at month 3 (from 14.9 to 18.34) (p < 0.001) then it decreases from month 3 to 6 but it's still increased compared to the pre-operative value. (p < 0.001) after 1 year the densitometry value returns to baseline and there is no statistically significant difference from the pre-operative value. (p = 0.1; Table 4; Fig. 5)

Middle corneal densitometry in 2–6 mm zone increases from baseline to its peak at month 3 (from 12.07 to 16.3; p < 0.001), then it decreases from month 3 to 6 but it's still increased compared to the pre-operative value. (p < 0.001) after 1 year the densitometry value returns to baseline and there is no statistically significant difference from the pre-operative value (p = 0.21; Table 4)

Corneal densitometric changes in different stages of keratoconus (mild, moderate, and severe) are summarized in Table 5, and the difference between these stages in different follow-ups is summarized in Tables 6, 7, and 8. The results of the Kruskal Wallis H test show that among all the analyzes performed, in the follow-up on the third month, the Anterior 0–2 mm zone densitometry of all three groups was different, and in this follow-up, using Mann Whitney U test the densitometric results of the mild and severe group were shown to be statistically different. (Table 7)  

To assess the prognostic value of peak densitometric numbers on final visual outcomes, the Correlation between peak densitometric values at 3 months and final visual acuity, total RMS, and higher order RMS at 12th month were evaluated and the table 9 and table 10 shows this correlation. 

Best corrected visual acuity at month 12 correlated with month 3 middle 0–2 mm zone corneal densitometry (p = 0.013), but there was no correlation between final visual acuity and other densitometric parameters. (Table 9)

Higher order RMS at 1 year correlated with Anterior 0–2 mm, Anterior 2–6 mm, total corneal 0–2 mm, and total corneal 2–6 mm densitometry values at the 3rd-month visit. (Table 10)

The correlation between high order RMS and total RMS at 12th months and densitometric parameters at 3 months was analyzed separately for each disease stage (mild, moderate, and severe).

 In severe keratoconus, there was no correlation between densitometric values and RMS. In moderate KCN subgroup analysis (N=19) there was a correlation between high order RMS at 12th month and third-month densitometric values including anterior 0-2 mm (p=0.008), anterior 2-6 mm densitometry (p=0.002), and total middle layer densitometry (p=0.030). In mild keratoconus (N=37) there was a correlation between high order RMS and anterior 2-6 mm densitometry (p=0.28) and total corneal 0-2 mm (p=0.035). 

These results show that we should use different densitometric zones in the third month to predict the final high order RMS at 1 year in a different stage of the disease.

4. Discussion

Most studies in keratoconus have compared the results of different CCL methods such as standard corneal cross-linking or epithelium-off CCL (epi-off CCL) and trans-epithelial corneal cross-linking (TE-CCL) (19, 20, 21). In recent years, several clinical trials have compared the therapeutic effects of the two methods (19, 22, 23), but studies on accelerated CCL are very limited.

Our study aim was to evaluate tomographic, densitometric, and aberrometric parameters in patients with progressive keratoconus after accelerated CCL and, because the appearance and natural course of postoperative haze after corneal cross-linking will assist physicians in knowing what to anticipate postoperatively and in counseling patients regarding postoperative expectations, firstly, we classify densitometric outcomes of accelerated CCL in different stages of the KCN separately (Mild, moderate and severe), and we have answered the question whether the severity of keratoconus affects the corneal haze after CCL?

Accelerated CCL resulted in stabilization of the CDVA during the 12-month follow-up, which is similar to the results obtained in some other studies (24, 25), although most of the comparative studies have reported improvement in CDVA. Although our results demonstrated minimal changes in refractive and keratometric values, CDVA was significantly improved, respectively. This visual improvement after accelerated CCL could be explained by the improvement in the Root Mean Square (high order aberration).

The two most significant indicators of visual acuity improvement after corneal cross-linking were the low CDVA (≥ 0.3 LogMAR) preoperatively and high maximum keratometry values (≥ 55 D). In the current study, final CDVA at month 12 correlated with month 3 middle 0–2 mm zone corneal densitometry.

In our study, we found statistically significant flattening in maximum keratometry value after a one-year follow-up. In addition, the flattening effect on maximum and mean keratometry was in agreement with the results of previous well-known studies (13, 24, 25). Current study results are consistent with those of recent studies that have decreased the Thinnest pachymetry values after accelerated CCL (21, 27). The physiology of this corneal thinning after CCL is still not identified: however, structural changes occur in corneal collagen fibrils (28), such as changes in corneal hydration (29), compression of collagen fibrils (30), edema (31), and keratocyte apoptosis (31) are discussed in the literature. It should be borne in mind that previous studies have shown that due to the difference between the Pentacam and ultrasound pachymetry, pachymetric values obtained from Pentacam printout should be interpreted with extreme discretion (32).

As reported in our study, as in the epidemiological study (33), progressive KCN was more common in men than in women.

Root mean Square (high order aberration) is part of the refractive errors which are not correctable with sphere and cylinder corrections, and it is among errors in the optical system of the eye which can exacerbate the quality of the retinal image (34, 35). Since Higher order aberration (HOA) RMS can have a considerable effect on visual function and contrast sensitivity; It’s considered an important value in the context of vision quality (35, 36). In the present study, the High order RMS value was significantly increased at 3 months after CCL and then decreased at one year, relative to the baseline. Naderan et al (38), and Ahmed et al (39), reported the efficacy of corneal cross-linking in improving HOA parameters in eyes with progressive KCN, and their results showed that there is a statistically significant correlation between pre-operative values of HOAs parameters with corrected distance visual acuity.

To determine the prognostic strength of peak densitometric values on final visual outcomes, the Correlation between peak densitometric numbers at 3 months post-op and final visual acuity, total RMS, and higher order RMS at 12th months were evaluated, and the results showed that RMS at 1 year correlated with densitometric values of Anterior 0–2 mm area, Anterior 2–6 mm area and total corneal 0–2 mm and 2–6 mm areas at the third month. This relationship means that the aberrometric effect in final visual acuity is due to its effect on densitometric factors.

Mathews et al (40) showed for the first time a correlation between densitometric value changes at 6 months and higher order aberrations after CCL with the Dresden protocol. We found a similar correlation in eyes with keratoconus after accelerated CCL.

Also, for the first time, we studied densitometric factors in different stages of keratoconus patients, and our results showed that the relationship between Higher order RMS at 12th months and peak densitometric values have different natures in different stages of progressive KCN.

For example, densitometric values in the severe stage did not correlate with RMS at the 12th month. But we showed a correlation in multiple zones in mild and moderate stages. These results may bring to mind that in addition to the possible effect of a densitometric factor on aberrometric values, there must be other factors that affect aberrometric factors, and consequently, the patient's CDVA in more advanced stages of KCN and the prognostic value of peak densitometric parameters is a weekend in the more advanced stage of the disease, while this is maybe due to high aberration and distorted retinal images in advanced cases.

CCL often leads to a preliminary decrease in visual acuity postoperatively. This reduction of visual acuity can be attributed to the loss of transparency of the corneal stroma (41, 42). During the first months after CCL, increased corneal densitometry numbers; which are clinically detectable as haze, can often be observed. Pircher et al. showed that standard CCL causes various changes in the corneal stroma which leads to an increased densitometric value, particularly in the anterior (120 µm) and central corneal zone (from 0 to 2 mm) (26).

This study evaluates corneal densitometry values obtained from Pentacam and evaluates their effect on parameters, such as visual acuity and aberrometric features after accelerated CCL in keratoconic eyes at different stages. In the study, corneal densitometry was measured by the Pentacam imagining system which offers the possibility of analyzing densitometric values at different corneal depths and concentric zones.

Our results reveal a significant increase in corneal densitometry numbers in anterior and middle stromal layers 3 months after accelerated CCL. The highest change in densitometry was captured in the anterior layer of the stroma, especially in two central concentric zones (0–2 mm and 2–6 mm zone). This is in agreement with a previous report by Böhm et al who also reported a significant increase in densitometric values, especially 3 months after accelerated corneal cross-linking, mostly in the anterior layer of the two central zones in eyes with progressive keratoconus, and their results showed the greatest corneal densitometry changes in the anterior stromal layer within the central 0 to 2 mm zone of the cornea (43).

Our result consistent with the previous studies of corneal densitometry showed that the significant increase in densitometric values in the third month of postoperative visit after accelerated CCL is more pronounced in the anterior layer. It can be assumed that stray light in the anterior stromal layer of the cornea is more prominent because of the UV-A light intensity, oxygen concentration decline toward the middle and deeper stromal layers, and riboflavin concentration.

Our study first examined and classify densitometric course after accelerated CCL in a different stage of KCN. Our result showed no correlation between disease staging and densitometric parameters in different concentric corneal zones and different corneal depths in keratotonic eye before CCL, but after accelerated CCL, during 12 months follow-up, only the Anterior 0–2 mm zone densitometry of all three groups was different, and patients in the higher stage of keratoconus had higher densitometry values, therefore, it seems that Anterior 0–2 mm zone densitometry at third-month post accelerated CCL can be used to detect different staging of KCN. The most likely reason for this finding seems to be a complex corneal healing process after CCL comprising of a transformation of keratocytes into myofibroblasts, which are associated with stromal remodeling, that is followed by a haziness in the cornea. These factors are different from the Amsler-Krumeich variables that use for staging keratoconus patients.

Although recent studies did not demonstrate a correlation between corneal densitometry values and visual acuity outcomes (29, 33, 43), in our study, final CDVA at 12th-month follow-up correlated with the changes in corneal densitometry of the Anterior 0–2 mm zone densitometry on the third month (Correlation coefficient: 0.303; P: 0.013). However, due to the lack of a control group, the results of our study could not be confirmed nor rejected; thus, it is necessary to conduct future, further research with a larger sample size, a control group, and a longer follow-up period studies in the future.

5. Conclusion

In conclusion, corneal changes induced by accelerated CCL seemed to be greatest in the anterior stromal layer in the Anterior 0–2 mm zone, and given the Anterior 0–2 mm zone densitometry difference at third months post-CCL; In different stages of keratoconus patients, Anterior 0–2 mm zone densitometry at third-month post accelerated CCL can be used to detect different staging of KCN. The increase in Anterior 0–2 mm zone densitometry at the third-month post CCL and, thus, decrease in corneal transparency, however, influence final visual acuity, since the correlation between the changes of corneal densitometry of the anterior stromal layer (0–2 mm), and CDVA was found.

Declarations

Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript

 Competing Interests: The authors have no relevant financial or non-financial interests to disclose.

 Author Contributions: Masoumeh Mohebbi came with the idea of research and performed the surgeries. Bijan Samavat extracted data from patients’ files, analyzed and interpreted the patients’ data and was a major contributor in writing the manuscript. Abbas Mohammadi rechecked the analyzed data and statistical tests and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Ethics approval: Approval for the study was obtained from the ethical committee of the Tehran University of Medical Sciences which is in compliance with the Helsinki Declaration. All patients received a thorough explanation of the study design and aims, and were provided with written informed consent.

Consent to participate: Informed consent was obtained from all individual participants included in the study

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