Journal of Refractive Surgery

Original Article Supplemental Data

Assessment of Corneal Haze After PRK and the Effect of Sutureless Amniotic Membrane Graft by Corneal Densitometry

Anthony R. Cox, MD; Rose K. Sia, MD; Boonkit Purt, MD; Denise S. Ryan, MS; Hind Beydoun, PhD; Marcus H. Colyer, MD; Bruce A. Rivers, MD; Kraig S. Bower, MD

Abstract

PURPOSE:

To assess whether densitometry analysis appropriately monitors the development of haze in myopic patients after photorefractive keratectomy (PRK) when compared to subjective slit-lamp haze grade examinations, and whether sutureless cryo-preserved amniotic membrane reduced postoperative haze development when compared to the standard bandage contact lens.

METHODS:

In this retrospective cohort at the Center for Refractive Surgery, Walter Reed National Military Medical Center, a secondary analysis of prospectively collected data was performed. In the prospective study, participants underwent PRK for myopia. Postoperatively, a standard bandage contact lens was applied to the dominant eye and a sutureless cryo-preserved amniotic membrane graft to the nondominant eye. Participants were evaluated at 1, 3, and 6 months postoperatively for haze formation and corneal densitometry using slit-lamp biomicroscopy and Scheimpflug imaging, respectively.

RESULTS:

Densitometry measurements at 6 months postoperatively were positively and significantly associated with the presence or absence of haze as assessed by slit-lamp examination in 39 patients (78 eyes; age range: 21 to 44 years). Eyes with increased densitometry measurements had 2.3 to 3.4 times the odds (P ⩽ .014) of having clinical haze on slit-lamp examination. Eyes with the amniotic membrane graft showed a positive correlation with increased corneal densitometry throughout most layers of the cornea.

CONCLUSIONS:

Densitometry analysis appears to be a useful tool to supplement slit-lamp examination in monitoring haze development after PRK. The amniotic membrane failed to show a reduction in corneal densitometry in myopic eyes after PRK.

[J Refract Surg. 2020;36(5):293–299.]

Abstract

PURPOSE:

To assess whether densitometry analysis appropriately monitors the development of haze in myopic patients after photorefractive keratectomy (PRK) when compared to subjective slit-lamp haze grade examinations, and whether sutureless cryo-preserved amniotic membrane reduced postoperative haze development when compared to the standard bandage contact lens.

METHODS:

In this retrospective cohort at the Center for Refractive Surgery, Walter Reed National Military Medical Center, a secondary analysis of prospectively collected data was performed. In the prospective study, participants underwent PRK for myopia. Postoperatively, a standard bandage contact lens was applied to the dominant eye and a sutureless cryo-preserved amniotic membrane graft to the nondominant eye. Participants were evaluated at 1, 3, and 6 months postoperatively for haze formation and corneal densitometry using slit-lamp biomicroscopy and Scheimpflug imaging, respectively.

RESULTS:

Densitometry measurements at 6 months postoperatively were positively and significantly associated with the presence or absence of haze as assessed by slit-lamp examination in 39 patients (78 eyes; age range: 21 to 44 years). Eyes with increased densitometry measurements had 2.3 to 3.4 times the odds (P ⩽ .014) of having clinical haze on slit-lamp examination. Eyes with the amniotic membrane graft showed a positive correlation with increased corneal densitometry throughout most layers of the cornea.

CONCLUSIONS:

Densitometry analysis appears to be a useful tool to supplement slit-lamp examination in monitoring haze development after PRK. The amniotic membrane failed to show a reduction in corneal densitometry in myopic eyes after PRK.

[J Refract Surg. 2020;36(5):293–299.]

Photorefractive keratectomy (PRK) is a commonly performed surgical procedure that involves photoablating the surface of the cornea for the correction of refractive errors. In PRK, an epithelial defect is created with the use of alcohol or a brush. The laser then ablates the anterior corneal stroma, effectively re-shaping the stroma and producing a change in corneal refraction. Despite the recent advances in refractive technology, PRK still has its inherent risks. Photoablation incites a complex inflammatory response that is integral to the healing of the corneal epithelium and stroma. If this complex interplay of inflammatory mediators and growth factors goes awry, it can lead to the development of stromal scarring and subepithelial corneal haze.1 Corneal haze typically starts 1 month after PRK and peaks in intensity between 3 and 6 months postoperatively.2 The presence of haze is inversely related to corneal transparency and primarily manifests clinically as a reduction in low contrast visual acuity and difficulty with night vision.3,4

To minimize haze formation after PRK, various techniques and treatment regimens have been used, such as the application of prophylactic mitomycin C or topical steroid postoperatively, but these are not without associated risks.5 Allografts derived from amniotic membrane have been successfully used in a wide array of ocular settings6–9; however, the therapeutic benefits for reducing haze and scar formation after refractive surgery have not been clearly established.10–13

Corneal haze is typically monitored by slit-lamp examination postoperatively. Haze has been graded subjectively according to a standardized scale introduced by Hanna et al14 based on microscopic findings and used by the U.S. Food and Drug Administration.15 This grading system, although widely used in clinical practice, may have some degree of intraobserver or interobserver variations. Alternatively, it has been proposed that the densitometry analysis add-on to the latest software of the Pentacam (Oculus Optikgeräte GmbH) using Scheimpflug imaging may be able to objectively detect and quantify corneal haze.16 The software is able to generate a corneal densitometry map that depicts the amount of backscattered light in different regions of the cornea and other anterior eye structures.17

Corneal densitometry has been used to assess the development of corneal haze in patients following refractive surgery and a variety of other procedures, inflammatory conditions, and pathologies15,18–23 To the best of our knowledge, the use of corneal densitometry to evaluate patients treated with amniotic membrane graft has not yet been reported. Corneal densitometry analysis may be able to supplement slit-lamp examination findings to monitor corneal haze after PRK. This study had two aims: (1) to determine whether corneal haze graded subjectively by slit-lamp examination was appropriately characterized by objective densitometry analysis and (2) to evaluate whether amniotic membrane reduced haze development after PRK when compared to the standard bandage contact lens (Acuvue Oasys; Johnson & Johnson Vision).

Patients and Methods

This was a retrospective, secondary analysis of prospectively collected data from a nonrandomized controlled trial consisting of 78 eyes of 39 patients. Each patient had one experimental eye to which a sutureless amniotic membrane graft was applied (ProKera; BioTissue) and one control eye to which a standard bandage contact lens was applied after myopic PRK. The prospective study was granted Institutional Review Board approval by the Walter Reed National Military Medical Center prior to initiation. Active-duty U.S. Soldiers eligible to undergo refractive surgery through the Army Warfighter Refractive Eye Surgery Program were recruited to participate. For inclusion into the study, patients were required to be 21 years of age with at least 12 months of stable visual acuity, able to be corrected to 20/20 or better, and planned to stay in the greater Washington, DC, area for 12 months postoperatively. Patients with active ophthalmic disease or systemic or ocular conditions that might affect epithelial healing were excluded.

A comprehensive preoperative evaluation was performed on each patient, including, but not limited to, slit-lamp biomicroscopy, manifest refraction, uncorrected distance visual acuity, corrected distance visual acuity, and corneal topography. Mitomycin C was not used during the surgery. Immediately after surgery, a sutureless amniotic membrane graft was inserted in the nondominant eye and a bandage contact lens in the fellow dominant eye. Operative procedure and postoperative medication regimen were otherwise the same for all eyes as described by Vlasov et al.13 Postoperative slit-lamp examinations were conducted daily until complete epithelial healing was achieved in both eyes. Follow-up examinations were conducted at 2 weeks and 1, 3, and 6 months postoperatively.

Corneal Clarity

Corneal clarity was subjectively assessed during slit-lamp biomicroscopy both preoperatively and postoperatively. Corneal clarity was graded by the following: 0 = clear cornea; 1+ = faint haze detectable only with broad tangential illumination; 2+ = discrete haze visible with difficulty by focal illumination; 3+ = moderately dense opacity partially obscuring iris detail; and 4+ = dense opacity completely obscuring intraocular detail. This is the same standardized scale adopted by the U.S. Food and Drug Administration for the evaluation of corneal haze.15

Corneal Densitometry Analysis

Densitometry values were provided in different annuli around the apex (Figure AA, available in the online version of this article) in three different layers of the cornea (Figure AB). The “anterior” and the “posterior” layer refer to the first 120 µm and the last 60 µm of the complete corneal thickness in the apex. The “central” layer represents the volume between these boundaries. “Total” layer gives the average density over the complete corneal thickness. In clear corneas, the maximum is located anterior and represents the back scattering at the Bowman's layer. Densitometry values were given in grayscale units (GSUs). The GSU scale is defined by a minimum light scatter of 0 and a maximum light scatter of 100. For data analysis, variables include: pachymetry at the pupil apex; anterior layer corneal density from apex to 2-mm radius (0 to 2 mm Anterior); central layer corneal density from apex to 2-mm radius (0 to 2 mm Central); total corneal density from apex to 2-mm radius (0 to 2 mm Total); anterior layer corneal density from 2-mm radius to 6-mm radius around the apex (2 to 6 mm Anterior); central layer corneal density from 2-mm radius to 6-mm radius around the apex (2 to 6 mm Central); and total corneal density from 2-mm radius to 6-mm radius around the apex (2 to 6 mm Total).

Schematic diagram of (A) corneal annuli analyzed by densitometry. (B) Corneal layers analyzed by densitometry.

Figure A.

Schematic diagram of (A) corneal annuli analyzed by densitometry. (B) Corneal layers analyzed by densitometry.

Statistical Analysis

Data were analyzed using STATA version 15 software (StataCorp). First, we described baseline and follow-up demographic and clinical data overall and by type of treatment (amniotic membrane vs contact lens). Summary statistics included frequencies and percentages for categorical variables and means and standard deviations for continuous variables. Second, we performed logistic regression models using corneal densitometry values as predictor variables and the subjective haze grade as the dependent variable at 1, 3, and 6 months postoperatively to address the first research question. For these models, haze grades 1 and 2 were combined to compare with grade 0 due to sample size limitation. For the second inquiry, we transposed the original database from wide to long and included both patient variable and follow-up (1, 3, and 6 months) as random effects in the process of evaluating type of treatment (amniotic membrane vs contact lens) as a predictor of repeated measures at 1, 3, and 6 months of postoperative follow-up, controlling for follow-up time, and interaction between type of treatment and several baseline and follow-up confounders. Baseline confounders were age, sex, amniotic membrane graft removal (time), average keratometry, manifest refractive spherical equivalent, and ablation depth. Follow-up (time-varying) confounders were pachymetry at 1, 3, and 6 months of postoperative follow-up. Two-sided statistical significance was assessed at an alpha level of 0.05.

Sample Size and Power Calculations

Assuming a two-sided independent samples t test whereby the total sample size was 78 eyes and there was an equal number of eyes with and without haze (39 eyes/group) that are compared on densitometry measures, when the estimated mean in the control group is 20, the standard deviation is 5, alpha = 0.05, Power = 0.8, we would be able to detect a difference of 3.21 or approximately 0.64 standard deviations. Furthermore, assuming a two-sided independent samples t test whereby the total sample size was 30 eyes and there was an equal number of eyes with amniotic membrane (experimental group) and with bandage contact lens (control group) (15 eyes/group) that are compared on postoperative haze development at 6 months of follow-up, when the estimated mean in the control group is 15, the estimated standard deviation in the control group is 2, and the estimated standard deviation in the experimental group is 5, alpha = 0.05, Power = 0.8, we are able to detect a difference of 2.46 or approximately 0.70 standard deviations. Accordingly, a clinically meaningful effect size can be detected despite sample size limitations.

Results

Forty (40) patients underwent PRK. The corneal densitometry data were unavailable for 1 patient (2 eyes), who was therefore removed from statistical analysis. Table 1 shows the demographics and clinical characteristics by type of treatment. The mean ablation depth between each group was similar between the bandage contact lens and the amniotic membrane groups. The bandage contact lens group had a combined total of 31 subjective haze measurements grade of 1 or above for all designated follow-up periods. The amniotic membrane group had a total of 70 subjective haze measurements grade of 1 or above for all designated follow-up periods. Table 2 shows the average preoperative densitometry values characterized by annulus and corneal layer. The corneal density by annulus, corneal layer, and examination date are displayed in Figure 1. The Standard Graphs for Refractive Surgery for this cohort were previously presented by Vlasov et al.13

Demographic and Clinical Characteristics by Type of Treatment for Each Individual Eye

Table 1:

Demographic and Clinical Characteristics by Type of Treatment for Each Individual Eye

Corneal Densitometry (Annulus and Layer Averages ± SEM) at Preoperative Baseline

Table 2:

Corneal Densitometry (Annulus and Layer Averages ± SEM) at Preoperative Baseline

Corneal densitometry values per haze grade at (A) 1, (B) 3, and (C) 6 months postoperatively.

Figure 1.

Corneal densitometry values per haze grade at (A) 1, (B) 3, and (C) 6 months postoperatively.

A logistic regression model analysis showed that all densitometry measurements (by annulus and layer) at 6 months postoperatively were positively and significantly associated with the presence or absence of haze as assessed by slit-lamp examination. Based on the odds ratios as presented in Figure 2, a 1-unit increase in corneal densitometry values at 6 months postoperatively was associated with 2.3 to 3.4 times the odds of haze on slit-lamp examination (P ≤ .014). No similar pattern was seen at 1 and 3 months postoperatively. Additionally, simple logistic regression models demonstrated that corneal densitometry values obtained at preoperative baseline did not appear to be a significant predictor of postoperative haze (Figure 3).

Logistic regression models (presented as odds ratios [ORs]) for corneal densitometry values from each of the follow-up visits as predictors for presence or absence of haze as evaluated by slit-lamp examination.

Figure 2.

Logistic regression models (presented as odds ratios [ORs]) for corneal densitometry values from each of the follow-up visits as predictors for presence or absence of haze as evaluated by slit-lamp examination.

Logistic regression models (presented as odds ratios [ORs]) for preoperative corneal densitometry values as predictors for presence or absence of postoperative haze.

Figure 3.

Logistic regression models (presented as odds ratios [ORs]) for preoperative corneal densitometry values as predictors for presence or absence of postoperative haze.

A mixed-effects linear model was used to evaluate corneal densitometry following treatment with a bandage contact lens versus the amniotic membrane. The results are presented in Table 3. All linear regression models showed a positive relationship demonstrating increased corneal density in the eye when the amniotic membrane was applied versus the control group. Five of the six models were statistically significant at an alpha level of 0.05.

Mixed-Effects Linear Model Comparing Densitometry in the AM Eye Versus the BCL Eye (Control Eye)

Table 3:

Mixed-Effects Linear Model Comparing Densitometry in the AM Eye Versus the BCL Eye (Control Eye)

Discussion

Densitometry analysis appears to add information that could supplement a slit-lamp examination in monitoring corneal healing after PRK. In this retrospective cohort study, objective densitometry measurements were positively associated with slit-lamp examinations (Figure 2). At the 6-month postoperative mark, densitometry was statistically significant and positively associated with corneal haze. Our results show that higher densitometry values within all different annuli and layers have as much as two to three times the odds of having clinical haze on slit-lamp examination.

Koc et al24 showed preoperative corneal densitometry to be a useful objective measure before undergoing accelerated corneal cross-linking. They found preoperative densitometry to be predictive for both increasing corneal density and corneal scar formation, which is useful in the risk stratification of patients. In our study, there was no observed association between preoperative densitometry and the subsequent development of haze after PRK as noted by slit-lamp examination. This suggests preoperative corneal density is not a significant predictor of postoperative haze development (Figure 3).

An increase in postoperative densitometry values occurred primarily within the 0- to 2-mm annuli (Figure 2). These findings agree with those of Takacs et al,15 who observed all statistically significant changes within corneal densitometry took place within the 0-to 2-mm corneal annuli following a myopic laser treatment. Such laser treatments are aimed at flattening the central area of the cornea, which subsequently receives most of the laser energy and increases the incidence of developing stromal scarring and subsequent opacities. Additionally, intraoperative destruction of the epithelial basement membrane further contributes to the development of stromal opacities because the epithelial basement membrane limits the release of cytokines, growth factors, and inflammatory mediators into the stroma, modulating keratocyte activation.25,26

Corneal opacities resulting from stromal scarring secondary to photoablation occur within the subepithelial stromal layer. The average ablation depth in our study was 59.83 µm. An increase in densitometry occurred primarily within the anterior layer, which incorporates the uppermost 120 µm of cornea and is likely responsible for producing clinically significant visual opacities (Figure 2). Patel et al27 showed that corneal density was highest in the anterior 10% of the central stroma, adjacent to Bowman's layer, and decreased with depth. Poyales et al28 showed a similar finding with the highest corneal density values for patients after PRK reflected in the anterior layer. Takacs et al15 reported their postoperative PRK Pentacam findings by maximum corneal density. Their findings do not specify within which layer (anterior, central, or posterior) these values were obtained, making it difficult to confirm that the opacity was indeed subepithelial.

Amniotic membrane transplantation has been shown to reduce the inflammatory response observed in the postoperative PRK period by stimulating corneal epithelialization and preventing polymorphonuclear cell infiltration into the corneal stroma with a reduction in keratocyte apoptosis.29 Polymorphonuclear cells adhere to the amniotic membrane and eventually undergo apoptosis, which effectively suppresses corneal inflammation.30 The amniotic membrane also contains intrinsic growth factors that stimulate corneal epithelization and effectively prevent stromal scarring due to the down-regulation of several inflammatory regulators and cytokines.31,32

In comparing the amniotic membrane to the standard bandage contact lens, we hypothesized that the amniotic membrane would reduce densitometry values as a result of the amniotic membrane's intrinsic anti-inflammatory properties. Our results did not support our hypothesis, but rather showed an increase in densitometry values within the amniotic membrane eyes when compared to the bandage contact lens eyes (Figure B, available in the online version of this article). These results are in line with previous studies involving the amniotic membrane after refractive surgery that have not clearly demonstrated a clinical benefit in reducing haze formation postoperatively.10–12

Corneal densitometry (corneal annulus and layer average) by treatment over time. AM = amniotic membrane; BCL = bandage contact lens

Figure B.

Corneal densitometry (corneal annulus and layer average) by treatment over time. AM = amniotic membrane; BCL = bandage contact lens

In our study, the amniotic membrane was outfitted on a large conformer ring, which is suspected to have caused some mechanical trauma during implantation and removal due to its size. The amniotic membrane was originally worn until reepithelization was complete. Mechanical trauma of the amniotic membrane's conformer ring may have delayed healing and, as a result, the amniotic membrane was removed on postoperative day 1. Overall, 16 patients wore the amniotic membrane until epithelization was complete, 30 patients wore the amniotic membrane until postoperative day 3, and 32 patients wore the amniotic membrane until postoperative day 1. These changes in protocol were accounted for statistically in our mixed-effects linear models. The increase in corneal density with use of the amniotic membrane may be due in part to the inability to remove the amniotic membrane without taking some layers of the newly formed epithelium with it. A similar observation was described by Lee et al12 because the newly formed epithelium was completely detached during removal of the amniotic membrane. They noted a positive correlation between the duration of the epithelial defect and subsequent stromal opacity. In their study, they altered their protocol from covering the entire surface with the amniotic membrane to applying a small strip of amniotic membrane at the inferior corneal limbus, which was secured with two interrupted sutures.

Our study is not without limitations. The number of patients within our sample size was small. Further, some patients were lost to follow-up at the 1-, 3-, and 6-month postoperative appointment, further reducing our sample size. Despite the limited sample size, a clinically meaningful effect can be detected because our experimental and control groups contained statistically significant power. Our population consisted solely of active-duty U.S. Army soldiers, which may limit the generalizability of our results to larger populations. Finally, Shalaby et al33 showed that intraoperative mitomycin C was effective in preventing significant haze formation. Mitomycin C was not used in this study because the aim was to objectively evaluate how the amniotic membrane affected corneal healing and haze development.

The findings of our study contribute to the discussion on the merits of the amniotic membrane after refractive surgery. These results differ from studies in the past that have shown clinical efficacy in the use of amniotic membranes to augment corneal healing in other inflammatory conditions,6–9 but are in line with the demonstrated variable effect observed following refractive surgery.10–12 Our results do not necessarily discount the benefits of amniotic membrane graft on regulating corneal wound healing, but are likely a consequence of the sutureless amniotic membrane graft's mechanical properties, such as being outfitted on a thick conformer, making its value after refractive surgery rather limited. In the future, the use of an amniotic membrane graft with a slimmer conformer design or an amniotic membrane extract that can be applied topically may yield results that differ from those obtained within our study. As a result, use of the amniotic membrane after refractive surgery remains speculative.

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Demographic and Clinical Characteristics by Type of Treatment for Each Individual Eye

CharacteristicTotal (N = 78)BCL (n = 39)AM Graft (n = 39)
Age (years)30.0 ± 6.830.0 ± 6.829.97 ± 6.79
Sex (male/female)32/732/732/7
AM removal (eyes, n)
  Until complete reepithelialization1688
  Postoperative day 3301515
  Postoperative day 1321616
Average keratometry (diopters)43.52 ± 1.2143.46 ± 1.2343.57 ± 1.21
Manifest spherical equivalent (diopters)−3.72 ± 1.85−3.76 ± 1.92−3.68 ± 1.79
Ablation depth (µm)59.83 ± 23.5360.50 ± 24.6859.15 ± 22.62
Pachymetry at apex (µm)551.5 ± 34.98551.07 ± 35.25551.93 ± 35.33

Corneal Densitometry (Annulus and Layer Averages ± SEM) at Preoperative Baseline

Parameter0 to 2 mm2 to 6 mm


All EyesBCLAM GraftAll EyesBCLAM Graft
Anterior layer (GSUs)23.36 ± 2.6722.86 ± 2.5123.86 ± 2.7721.53 ± 2.7521.05 ± 2.4322.03 ± 2.99
Central layer (GSUs)16.10 ± 2.1715.62 ± 1.7916.69 ± 2.4214.79 ± 2.2814.29 ± 1.7015.29 ± 2.67
Total (anterior to posterior) (GSUs)18.01 ± 2.2117.51 ± 1.8618.5 ± 2.4516.59 ± 2.3316.09 ± 1.8117.08 ± 2.69

Mixed-Effects Linear Model Comparing Densitometry in the AM Eye Versus the BCL Eye (Control Eye)

Annulus by LayerBeta CoefficientSE (n = 133)P
0 to 2 mm Anterior3.691.1.001
0 to 2 mm Central0.670.3.034
0 to 2 mm Total1.650.5.000
2 to 6 mm Anterior1.340.6.022
2 to 6 mm Central0.510.3.131
2 to 6 mm Total0.780.4.032
Authors

From the Uniformed Services University of the Health Sciences, Bethesda, Maryland (ARC); Warfighter Refractive Eye Surgery Program and Research Center, Fort Belvoir, Virginia (RKS, DSR, BAR); Walter Reed National Military Medical Center, Washington, DC (BP, MHC); the Department of Research Programs at Fort Belvoir Community Hospital, Fort Belvoir, Virginia (HB); and Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland (KSB).

Supported by grants from the Cooperative Research and Development Agreement from Carl Zeiss Meditec and TearSolutions, Inc. (RKS, DSR, BAR).

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

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Uniformed Services University, Defense Health Agency, Department of Defense, or U.S. Government. Discussion or mention of any commercial products or vendor names within this publication does not create or imply any Federal/DoD endorsement.

AUTHOR CONTRIBUTIONS

Study concept and design (ARC, RKS, BP, DSR, BAR, KSB); data collection (ARC, RKS, DSR, KSB); analysis and interpretation of data (ARC, RKS, DSR, HB, MHC, BAR); writing the manuscript (ARC, BP); critical revision of the manuscript (RKS, BP, DSR, HB, MHC, BAR, KSB); statistical expertise (HB); supervision (MHC, BAR, KSB)

Correspondence: Anthony R. Cox, MD, Uniformed Services University of the Health Sciences, Bethesda, MD 20814. Email: Arcoxjr@gmail.com

Received: January 03, 2020
Accepted: April 02, 2020

10.3928/1081597X-20200406-01

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