Journal of Refractive Surgery

Original Article Supplemental Data

Evaluation of Corneal Changes After Conventional Versus Accelerated Corneal Cross-linking: A Randomized Controlled Trial

Hesam Hashemian, MD; Mahmoud Jabbarvand, MD; Mehdi Khodaparast, MD; Kambiz Ameli, MD

Abstract

This article has been amended to include factual corrections. To read the erratum, click here. The online article and its erratum are considered the version of record.

PURPOSE:

To evaluate the outcome of accelerated and conventional corneal cross-linking (CXL) procedures regarding their effect on morphological and optical properties of the cornea.

METHODS:

One hundred fifty-three eyes of 153 patients were evaluated before and during a 15-month follow-up period after CXL (76 eyes in the conventional group and 77 eyes in the accelerated group). Measured variables include corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), refraction, maximum keratometry, endothelial cell density, anterior and posterior stromal keratocyte density, and subbasal nerve density. All variables were compared between the two study groups.

RESULTS:

Cylindrical and spherical components of refraction improved significantly during 15 months of follow-up. No difference was observed between the two study groups. UDVA and CDVA improved in the same manner, with no intergroup differences. Endothelial cell density did not change significantly during the follow-up period in either group. K-max increased slightly in the first month of the follow-up, but started to decrease at postoperative visits without any significant difference in the two groups. Anterior stromal keratocyte density and subbasal nerve density decreased significantly in both groups 1 month postoperatively. Both variables had a more significant decrease in the conventional group at all visits before the 1-year visit. At the final 15-month visit, there were no significant differences in any value between the two groups.

CONCLUSIONS:

Accelerated and conventional CXL seem to have a comparable and acceptable effect on keratoconus in the short-term follow-up period.

[J Refract Surg. 2014;30(12):837–842.]

From the Ophthalmology Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.

The authors have no financial or proprietary interest in the materials presented herein.

AUTHOR CONTRIBUTIONS

Study concept and design (HH, MJ); data collection (HH, MK, KA); analysis and interpretation of data (HH, MJ); drafting of the manuscript (HH, MK, KA); critical revision of the manuscript (HH, MJ, MK, KA); statistical expertise (HH, MK, KA); administrative, technical, or material support (MJ); supervision (HH, MJ, MK)

Correspondence: Hesam Hashemian, Eye Research Center, Farabi Eye Hospital, South Kargar St., Tehran, Iran. E-mail: h-hashemian@tums.ac.ir

Received: August 01, 2014
Accepted: October 13, 2014

Abstract

This article has been amended to include factual corrections. To read the erratum, click here. The online article and its erratum are considered the version of record.

PURPOSE:

To evaluate the outcome of accelerated and conventional corneal cross-linking (CXL) procedures regarding their effect on morphological and optical properties of the cornea.

METHODS:

One hundred fifty-three eyes of 153 patients were evaluated before and during a 15-month follow-up period after CXL (76 eyes in the conventional group and 77 eyes in the accelerated group). Measured variables include corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), refraction, maximum keratometry, endothelial cell density, anterior and posterior stromal keratocyte density, and subbasal nerve density. All variables were compared between the two study groups.

RESULTS:

Cylindrical and spherical components of refraction improved significantly during 15 months of follow-up. No difference was observed between the two study groups. UDVA and CDVA improved in the same manner, with no intergroup differences. Endothelial cell density did not change significantly during the follow-up period in either group. K-max increased slightly in the first month of the follow-up, but started to decrease at postoperative visits without any significant difference in the two groups. Anterior stromal keratocyte density and subbasal nerve density decreased significantly in both groups 1 month postoperatively. Both variables had a more significant decrease in the conventional group at all visits before the 1-year visit. At the final 15-month visit, there were no significant differences in any value between the two groups.

CONCLUSIONS:

Accelerated and conventional CXL seem to have a comparable and acceptable effect on keratoconus in the short-term follow-up period.

[J Refract Surg. 2014;30(12):837–842.]

From the Ophthalmology Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.

The authors have no financial or proprietary interest in the materials presented herein.

AUTHOR CONTRIBUTIONS

Study concept and design (HH, MJ); data collection (HH, MK, KA); analysis and interpretation of data (HH, MJ); drafting of the manuscript (HH, MK, KA); critical revision of the manuscript (HH, MJ, MK, KA); statistical expertise (HH, MK, KA); administrative, technical, or material support (MJ); supervision (HH, MJ, MK)

Correspondence: Hesam Hashemian, Eye Research Center, Farabi Eye Hospital, South Kargar St., Tehran, Iran. E-mail: h-hashemian@tums.ac.ir

Received: August 01, 2014
Accepted: October 13, 2014

In recent years, corneal cross-linking (CXL) has proved to be an effective intervention to halt the progression of keratoconus.1–11 CXL increases corneal stiffness and bio-mechanical strength by initiating a photochemical reaction in the corneal tissue.1,5–9 CXL has been performed with different techniques, including conventional, transepithelial, and accelerated methods (with different durations of irradiation).2,12 Conventional CXL is time-consuming, particularly in combination with corneal laser surgery (takes up to 1 hour). Both the patient and the ophthalmologist wish to reduce the time required for treatment. Therefore, new accelerated CXL is becoming more popular, although its comparative efficacy is still controversial.

The current study was designed to compare the effects and results of conventional and accelerated corneal CXL.

Patients and Methods

One hundred fifty-three eyes of 153 patients (70 males and 83 females) diagnosed as having progressive keratoconus were enrolled in this prospective randomized clinical trial. All patients gave informed consent to participate in the research and to undergo the proposed treatment once other treatment options were explained to them. The tenets of the Declaration of Helsinki were followed and both procedures and research protocol were approved by the Institutional Review Board of Farabi Hospital of Tehran University of Medical Sciences.

The inclusion criteria were being older than 14 years, documented progressive keratoconus, and the thinnest corneal point being greater than 400 μm. Progressive keratoconus was detected by one of the following criteria in a 6-month period: a mean central keratometry reading change of 1.5 diopters (D) or greater and more than 5% decrease in the mean central corneal thickness through three consecutive examinations.1

The exclusion criteria included history of any ocular surgery, diabetes, history of contact lens use, history of chemical injury or delayed epithelial healing, pregnancy, or lactation.

Patients were randomly divided into two groups. The first group was treated with a conventional corneal CXL method and the second group with an accelerated method. Only 1 eye of each patient was entered in the study. If both eyes of a patient needed surgery, the eye with more severe disease was included in the study.

Treatment Protocols

All patients received 0.5% tetracaine hydrochloride eye drops (Anestocaine; Sinadaru, Tehran, Iran) and pilocarpine eye drops (Sinadaru) prior to the procedure. The procedure consisted of first removing the epithelium with a spatula in the central 9-mm diameter and then instilling drops of riboflavin 0.1% in 20% dextran for 30 minutes. A limbal-perforated shield was used prior to irradiation. Afterward, 365-μm ultraviolet-A (UVA) illumination was performed (CCL-VARIO; Peschke Meditrade GmbH, Huenenberg, Switzerland) for 30 minutes on the cornea at 3 mW/cm2 in the conventional group. In the accelerated group, irradiation was performed using 10 minutes of UVA 365-μm light with 9 mW/cm2 (5.4 J/cm2 dose in each group) irradiance. The exact settings of illumination were provided by the instrument itself. Finally, a therapeutic contact lens was placed on the cornea and the patient used betamethasone 0.1% drops (Betasonate; Sinadaru) in a tapering dosage for 2 months. Patients used chloramphenicol drop (Cholobiotic; Sinadaru) during the epithelial healing time prior to contact lens removal.

Examinations and Imaging

A full ophthalmological examination and refraction was performed preoperatively and 1, 3, 6, 12, and 15 months after the operation. Corneal Scheimpflug imaging (Pentacam; Oculus, Wetzlar, Germany), in vivo confocal microscopy (Cornea Module HRT II; Rostock, Heidelberg, Germany), and specular photomicroscopy (Konan; Hyogo, Japan) were performed during each visit.

The outcome measures of the study, evaluated during each visit, included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), subjective refraction, endothelial cell density, percentage of hexagonal endothelial cells, coefficient of variation of endothelial cells, maximum keratometry (Kmax), corneal haze, anterior stromal keratocyte density (50- to 150-μm corneal stroma), posterior stromal keratocyte density (300- to 400-μm corneal stroma), and subbasal nerve density. Endothelial cell density, hexagonal endothelial cells, and coefficient of variation were calculated using specular microscopy. Epithelial healing time was determined by slit-lamp examination based on the days required for epithelial defect healing.

Confocal microscopy was performed by the same operator during all visits using a Heidelberg II confocal microscopy with Rostock Corneal Module, as defined in the literature.13 Keratocyte density was calculated as the mean of the number of cells in five images in each stromal depth, counted manually within a 250- × 250-μm square. The results are provided as cells per square millimeter.

A minimum of five confocal images of the subbasal nerve plexus were used for the analysis of nerve density. One masked observer analyzed the images for total number of nerve trunks. Subbasal nerve density was defined as the total number of nerves in one image, including main nerve trunks and branches.

Three-dimensional Scheimpflug images were analyzed for corneal haze. Central corneal density measurements were transformed into a value between 0 and 100 as grayscale. The density of 13 images avoiding the eyelid and eyelash (from 45° to 135°) was averaged as central corneal density.14

Differences between preoperative and postoperative measurement for each factor were determined. Statistical analysis was conducted using SPSS software (SPSS, Inc., Chicago, IL). The normal distribution of data was analyzed by the Kolmogorov–Smirnov test. Student’s t test, Mann–Whitney U test, and general linear modeling were used for data analysis. We compared postoperative values to preoperative values in each group using the paired sample t test. P values less than .05 were considered significant.

Results

Seventy-six eyes in the conventional group and 77 eyes in the accelerated group were entered in the study. There was no significant difference in demographic data among the two study groups. Mean ages of patients in the conventional and accelerated groups were 22.3 ± 4 and 22.6 ± 4 years, respectively (P = .46). There was no significant difference in female:male ratio among the two groups (38:38 in the conventional group vs 45:32 in the accelerated group; P = .5).

Preoperative measurements are demonstrated in Table A (available in the online version of this article). There were no significant differences in any preoperative values. Differences between preoperative and postoperative measurements are summarized in Tables 1 and B (available in the online version of this article).

Change of Each Value Compared to Preoperative Values of Each Group

Table 1:

Change of Each Value Compared to Preoperative Values of Each Group

Cylinder and sphere in subjective refraction and CDVA improved significantly at the final visit compared to their preoperative values. Mean spherical value changed from −4.3 ± 1.6 to −2.9 ± 2.0 D and from −4.8 ± 1.9 to −3.5 ± 2 D in the conventional and accelerated groups, respectively. Mean cylindrical value decreased from −5.9 ± 1.8 to −4.6 ± 1.8 D in the conventional group and from −4.6 ± 1.5 to −3.2 ± 1.6 D in the accelerated group after 15 months. Differences in cylinder among the two groups were not significant during the follow-up period. Coefficient of variation, endothelial cell density, and hexagonal endothelial cells had not changed significantly at any visit compared to their preoperative values. Kmax increased slightly in the first month after the procedure, but then decreased significantly in both groups. There was no significant difference between the two procedures at any visit.

No significant difference in other parameter changes between the two groups was observed at any time, except for anterior stromal keratocyte density (Figure 1) and subbasal nerve density (Figure 2). These two parameters had a greater significant decrease in the conventional group at all visits prior to the 1-year visit. On the final 15-month visit, there were no significant differences in any value between the two groups.

Time course of corneal collagen cross-linking (CXL)-associated anterior stromal keratocyte density changes using confocal microscopy in the conventional and accelerated CXL groups. * indicates significance of difference between the two groups at each visit.

Figure 1.

Time course of corneal collagen cross-linking (CXL)-associated anterior stromal keratocyte density changes using confocal microscopy in the conventional and accelerated CXL groups. * indicates significance of difference between the two groups at each visit.

Time course of corneal collagen cross-linking (CXL)-associated subbasal nerve density changes using confocal microscopy in the conventional and accelerated CXL groups. * indicates significance of difference between the two groups at each visit.

Figure 2.

Time course of corneal collagen cross-linking (CXL)-associated subbasal nerve density changes using confocal microscopy in the conventional and accelerated CXL groups. * indicates significance of difference between the two groups at each visit.

Epithelial healing time was not significantly different, although it was shorter in the accelerated group (5.3 ± 2.0 vs 4.7 ± 1.9 days in the conventional and accelerated groups, respectively; P = .06).

Discussion

Standard CXL has been reported to improve refraction1 and to decrease cylinder up to 1 D during 6 months to 5 years of follow-up.4,15,16 Mean spherical and cylindrical values decreased in both groups with no significant differences between groups. In previous reports with 6 months to 3 years of follow-up, mean spherical value decreased approximately 0.5 D in both the accelerated and conventional groups.4,15

Both UDVA and CDVA improved significantly during the 15-month follow-up in both groups. Previous studies have reported comparable results with both conventional and accelerated CXL after 6 months to 5 years of follow-up.4,6,15,16 In the current study, there was no difference among the two groups.

Endothelial damage has been reported as a complication of CXL, caused by ultraviolet light effect.17 The endothelial damage threshold was shown to be at an irradiance of 0.35 μmW/cm2, which is approximately twice that of the 0.18 μmW/cm2 that reaches the corneal endothelium when using the current protocol. Consistent with previous studies of conventional CXL with a 1-year follow-up,18 endothelial cell density did not change significantly during 15 months of follow-up in either group in the current study. Hexagonality and coefficient of variation also did not change significantly in either of the groups during the follow-up period, which is in accord with previous reports 6 months after accelerated and conventional CXL.2,19 On the other hand, higher doses of irradiance are shown to cause apoptosis of endothelial cells.20

CXL is known to improve corneal topography in patients with keratoconus.1 In the current study, a non-significant increase in Kmax in both groups was observed in the first month of follow-up. But after 6 months, significant corneal flattening with a decrease in Kmax was observed at the visits in both groups, with no significant difference among them. Decrease in Kmax has been attributed to changes in epithelial thickness in the postoperative period.18,21 A decrease of 2 D is reported 1 year after conventional CXL.10

There are reports of changes in corneal collagen, keratocytes, swelling property of the cornea, and corneal haze in more than 90% of the patients during 12 to 25 months of follow-up after conventional CXL.3,22 In the current study, corneal haze was never significantly different in the two groups, although there was an increase in the total amount of haze in the early postoperative months.

Several studies have examined corneal microstructural alterations after conventional CXL using confocal microscopy.1,2,13 However, there is little information about alternate methods of CXL. Most of the effect of CXL is in the anterior 300 μm of the cornea.3 Previous studies have found significant keratocyte apoptosis and corneal epithelial, Bowman layer, and anterior stromal damage during 1 year of follow-up after conventional CXL.23–25 Keratocyte apoptosis is more severe in CXL compared to corneal epithelial removal and UVA or riboflavin used alone.23 After both conventional and accelerated CXL, the population of keratocytes in the anterior stroma decreased significantly, with signs of repopulation of keratocytes 3 months after the operation,2,23 which is comparable to our results in both groups. In a recent study, the keratocyte density was not significantly different from baseline density after 12 months.23 In the current study, consistent with previous reports on conventional CXL,1,23 a significant reduction in anterior stromal keratocyte density was observed immediately after CXL in both groups. The reduction was more prominent in the conventional method. The difference between the two groups as far as the rate of keratocyte density reduction was prominent at all visits before the 1-year follow-up visit. The difference between the two groups was not significant at the 12- and 15-month visits in which keratocytes had repopulated the anterior stroma in both groups.

CXL influences mostly the anterior stroma3,10 and no significant change has been reported in keratocyte density after CXL in posterior stroma.23,26–28 A recent study observed no change in deep stromal keratocyte density in both conventional and accelerated CXL methods.2 Similarly, in the current study, there was no significant reduction in posterior keratocyte density in either group.

Several studies have documented a severe decrease in subbasal nerve plexus density postoperatively after both standard and accelerated CXL, particularly in the first few months.2,23,28–30 Although nerve degeneration continued for 6 months, it was finally regenerated.1 In the current study, a significant reduction in nerve density was observed in the first 6 postoperative months, but after that, there were no significant differences in nerve population relative to preoperative values. In the current study, decrease in the nerve density during the first 6 months was more significant in the conventional group compared to the accelerated group. This may be due to longer time of ultraviolet light exposure on deepithelialized stroma and its effect on nerve plexus. After 12 months, the nerve plexus was fully regenerated in both groups, although regeneration was faster after accelerated CXL. In a recent study, full regeneration of nerve plexus was reported 12 months after conventional CXL, consistent with the current report.23

Epithelial healing duration is important because it is the time when the cornea is prone to bacterial and fungal keratitis.20 Touboul et al. reported no significant difference in healing time between conventional and accelerated CXL.2 Similarly, in the current study, no significant difference was observed between the two study groups.

The results of accelerated 4.5-minute ultraviolet light exposure were comparable to the conventional method in the study by Sherif.31 Wernli et al.32 concluded from their study on 100 porcine eyes that the effect of CXL will decrease with less than 2-minute illumination time and higher than 40- to 45-mW/cm2 intensities. Kymionis et al.33 reported similar demarcation line depths between 3 mW/cm2 for 30 minutes and 9 mW/cm2 for 14 minutes. In another study on porcine corneal strips, Schumacher et al.34 reported comparable stress–strain measurement results in the rapid (10 mW/cm2, 9 minutes) and standard (3 mW/cm2, 30 minutes) groups. Tomita et al.35 compared the accelerated (30 mW/cm2, 3 minutes) and conventional (3 mW/cm2, 30 minutes) CXL procedures and reported comparable visual acuity, keratometry readings, morphologic changes, existence of demarcation line, and corneal biomechanical profile after 1 year of follow-up. In the current study, similar results between accelerated and conventional CXL were reported after 15 months of follow-up.

Ocular hysteresis was not compared between the two groups in this report. Further studies are needed to compare the effect of CXL in the two groups using ocular hysteresis.36 The depth of the demarcation line was not evaluated in this study.

The novel technique of accelerated CXL seems to have the same effect on patients with keratoconus as in conventional CXL. Anterior stromal keratocyte density and subbasal nerve density decrease more severely in the conventional method compared to the accelerated method, although there is no significant difference after 15 months compared to preoperative values. Further studies with longer follow-ups and larger populations are needed to confirm this finding.

References

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Change of Each Value Compared to Preoperative Values of Each Group

Parameter 1 m Postop–Preop 3 m Postop–Preop 6 m Postop–Preop 12 m Postop–Preop 15 m Postop–Preop





Group 1 Group 2 Pa Group 1 Group 2 Pa Group 1 Group 2 Pa Group 1 Group 2 Pa Group 1 Group 2 Pa
Cylinder (D) −0.48 ± 0.7 −0.37 ± 0.31 .28 −0.49 ± 0.8 0.18 ± 0.43 .06 1.29 ± 0.46 1.21 ± 0.13 .33 1.15 ± 0.47 1.31 ± 0.12 .09 1.32 ± 0.47 1.40 ± 0.12 .19
Sphere (D) 0.20 ± 0.14 0.09 ± 0.12 .05 0.37 ± 0.13 0.27 ± 0.14 .08 1 ± 0.14 0.91 ± 0.13 .09 1.13 ± 0.14 1.20 ± 0.13 .07 1.29 ± 0.12 1.29 ± 0.14 .92
UDVA (logMAR) 0.11 ± 0.17 0.10 ± 0.19 .65 −0.007 ± 0.19 0.01 ± 0.20 .38 0.11 ± 0.2 0.18 ± 0.18 .01 0.22 ± 0.2 0.12 ± 0.2 .30 0.21 ± 0.19 0.19 ± 0.20 .64
CDVA (logMAR) 0.02 ± 0.1 0.05 ± 0.1 .14 0.01 ± 0.12 0.01 ± 0.11 .72 0.08 ± 0.11 0.01 ± 0.11 .21 0.14 ± 0.10 0.13 ± 0.09 .65 0.17 ± 0.10 0.16 ± 0.09 .58
ECD −29 ± 55 −18 ± 57 .22 −22 ± 58 −12 ± 58 .40 −10 ± 60 11 ± 56 .08 −7 ± 62 18 ± 53 .09 −11 ± 66 3 ± 58 .08
HEXA −3.7 ± 4.63 −4.16 ± 3.74 .67 −2.8 ± 3.92 −2.8 ± 4.09 .93 −2.09 ± 4.2 −2.37 ± 3.9 .65 −1.13 ± 4.18 −0.80 ± 3.5 .64 −1.22 ± 3.80 −0.70 ± 4.35 .64
CV 1.1 ± 2 1.38 ± 2 .20 −1.2 ± 2 − 0.9 ± 2.3 .47 2.15 ± 1.8 2.1 ± 1.9 .47 1 ± 1.9 0.77 ± 1.95 .36 1.6 ± 1.9 2.1 ± 1.9 .09
Kmax (D) 0.48 ± 0.9 0.48 ± 0.89 .09 −0.46 ± 1.04 0.53 ± 0.85 .73 −1.20 ± 0.93 −1.32 ± 0.92 .56 −1.69 ± 0.14 −1.94 ± 0.13 .19 −1.98 ± 0.93 −1.85 ± 0.99 .36
Haze 8 ± 1.8 8.1 ± 1.84 .59 4 ± 1.9 4.1 ± 1.8 .86 2 ± 1.9 1.9 ± 2 .79 1.06 ± 2.1 1.18 ± 1.8 .44 0.06 ± 2.1 −0.15 ± 2 .45
Ant str −702 ± 38.85 −425 ± 44.7 .00 −630 ± 44.9 −383 ± 45.3 .00 −420 ± 42 −303 ± 45 .00 −116 ± 37 −63 ± 42 .07 −141 ± 39 −40 ± 42 .08
Post str −19 ± 44 −19.2 ± 39 .79 −36 ± 39 −39 ± 36 .87 −15.5 ± 37 −13.2 ± 35 .88 11.9 ± 41 11.9 ± 41 .28 15 ± 37 12 ± 42 .20
Nerve −4.2 ± 0.87 −2.8 ± 1.1 .00 −3 ± 0.81 −1.95 ± 0.63 .00 −2.15 ± 0.7 −0.58 ± 0.9 .02 −1.25 ± 1.1 −0.36 ± 0.5 .06 −0.1 ± 0.3 +0.12 ± 0.2 .09

10.3928/1081597X-20141117-02

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