Directional Posterior Corneal Profile Changes in Fuchs' Endothelial Corneal Dystrophy

Abstract

Purpose: To determine directional changes in peripheral corneal thickness and corneal astigmatism over a range of severity of Fuchs' endothelial corneal dystrophy (FECD).

Methods: Eyes with FECD were categorized as mild, moderate, or advanced according to the area and confluence of guttae and the presence of clinical edema. Normal corneas were devoid of guttae. Peripheral thickness centered on the corneal apex, and radii of posterior curvature were measured with Scheimpflug imaging. Variables were compared between groups by using generalized estimating equation models.

Results: Scheimpflug images were acquired in 101 normal corneas and 112 corneas with FECD. Normal corneas were 8.6 ± 4.8 μm thicker vertically than horizontally (P = 0.001); the steep posterior meridian was vertical in 91% of corneas. The difference between vertical and horizontal thicknesses decreased to 4.7 ± 7.3 μm in advanced FECD (P = 0.008); 46% had a steep vertical posterior meridian (P = 0.001). Vertical radius of curvature was flatter than normal in moderate (by 0.2 mm, P = 0.011) and advanced (by 0.4 mm, P < 0.001) FECD. Mean posterior corneal power was less negative in moderate (by 0.2 diopters [D], P = 0.009) and advanced (by 0.4 D, P < 0.001) FECD compared to normal.

Conclusions: Posterior toricity is abnormal in advanced FECD because of relatively greater horizontal than vertical corneal thickening. Posterior corneal power decreases (i.e., is less negative) in moderate and advanced FECD, which can affect the choice of intraocular lens power during cataract surgery, and might explain the hyperopic shift after Descemet membrane endothelial keratoplasty.

The posterior corneal surface produces negative corneal power because of its shape and the decrease in refractive index between the cornea and aqueous. The role of the posterior corneal surface in corneal power has been poorly understood until recently, mainly because of limited ability to determine its shape accurately. Since early reports of the posterior corneal profile examined with a custom Scheimpflug camera,¹ commercially available Scheimpflug and anterior segment optical coherence tomography (AS-OCT) instruments have enhanced our understanding of the effect of posterior corneal shape on visual outcomes after endothelial keratoplasty² and toric intraocular lens implantation.³ Normal posterior corneas are steeper in the vertical meridian, which induces against-the-rule astigmatism, in 87% of subjects with minimal variation with age,⁴ and this might be explained by normal peripheral corneas being thicker vertically than horizontally.⁵ In contrast, the steep meridian of the anterior corneal surface tends to be vertical (with-the-rule astigmatism) in young subjects and becomes more horizontal (against-the-rule astigmatism) with increasing age.^1,4,6,7 The relationship between the anterior and posterior corneal surface is important with the posterior cornea compensating for approximately 13% of anterior corneal astigmatism.⁸ 

Fuchs' endothelial corneal dystrophy (FECD) is characterized by progressive central corneal edema because of endothelial dysfunction,^9,10 with bulging of the posterior corneal plane toward the anterior chamber when edema is clinically detectable.^11,12 This change in the relationship between anterior and posterior corneal surfaces might have implications on corneal power, and has been suggested to cause the hyperopic shift after Descemet membrane endothelial keratoplasty.¹³ Because corneal changes are known to start earlier in the course of FECD than when keratoplasty is clinically indicated,^14,15 changes in posterior corneal power and toricity might also be important when considering refractive cataract surgery in these eyes. 

In this study, we assessed changes in the profiles of the anterior and posterior corneal surfaces over a range of severity of FECD and normal corneas by using Scheimpflug imaging. We examined the relationships between corneal surface profiles, corneal power, and corneal thickness. We hypothesized that the radius of curvature of the posterior corneal surface increases according to severity of FECD with loss of normal posterior surface toricity. 

Methods

Participants and Clinical Grading

All participants were recruited from the cornea service at Mayo Clinic, Rochester, Minnesota, or were healthy volunteers. Corneas were categorized as normal (no guttae, grade 0) or assigned a severity of FECD by using slit-lamp biomicroscopy. Fuchs' endothelial corneal dystrophy was graded clinically based on the area and confluence of guttae and the presence of edema.^10,16 Corneas with 1 to 12 or >12 nonconfluent central guttae (grades 1 and 2) were considered to have mild FECD; corneas with confluent guttae of 1- to 2-mm and 2- to 5-mm diameter (grades 3 and 4) were considered to have moderate FECD; and corneas with >5-mm diameter of confluent guttae or any visible stromal or epithelial edema (grades 5 and 6) were considered to have advanced FECD.^10,14 Participants were excluded if they had eyelid or orbital pathology that might affect corneal shape, corneal pathology (other than FECD in the FECD groups), previous ocular surgery except uncomplicated phacoemulsification with posterior chamber intraocular lens implantation, or if they were using systemic or topical medications known to affect the cornea. This study was reviewed and approved by the Institutional Review Board at Mayo Clinic; the research followed the tenets of the Declaration of Helsinki. Informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. 

Imaging and Data Acquisition

Participants were positioned at the chin rest in front of a noncontact rotating Scheimpflug camera (Pentacam HR; Oculus, Lynnwood, WA, USA). After aligning the camera manually according to software instructions, the standard automatic recording system completed the fine alignment and captured 25 cross-sectional images within 1 second. All Scheimpflug images were checked for data acquisition errors. The manufacturer software (Pentacam software version 1.20r29) fitted three-dimensional surface models to the anterior and posterior images of the corneal surfaces. Axial resolution of our instrument, estimated by measuring a titanium-embedded contact lens with known central thickness (515 μm),¹⁷ was 11.8 μm per pixel (range, 11.5–12.4 μm per pixel); however, because the software uses a surface-fitting algorithm, axial resolution should be better than the resolution of one pixel. Others have reported the precision of central corneal thickness to be within 3 to 7 μm (Schwiegerling J, et al. IOVS 2007;48:ARVO E-Abstract 3539).¹⁸ 

Corneal Thickness Profile

Peripheral corneal thickness data at a 4-mm diameter centered on the corneal apex and the pupil center were exported. Peripheral corneal thickness at a 6-mm diameter was available only centered on the pupil center. Central corneal thickness (CCT) was determined at the corneal apex and over the pupil center, and peripheral corneal thickness was determined at four points defined by the intersection of the ring and the vertical and horizontal meridians. Differences between vertical (mean of superior and inferior) and horizontal (mean of temporal and nasal) peripheral corneal thickness were calculated for each diameter. 

Corneal Radius of Curvature and Astigmatism

The Scheimpflug imaging software reported horizontal and vertical radii of curvature of the anterior and posterior surfaces centered on the corneal apex. Refractive indices of 1.3375 (n_km, keratometric index), 1.0 (n_air , air), 1.332 (n_aq, aqueous humor), and 1.376 (n_co, cornea) were assumed for calculations of corneal power. Mean anterior (P_a) and posterior corneal power (P_p) were calculated as Display Formula and Display Formula , where r̄_a and r̄_p were the mean of the steep and flat radii of curvature of the anterior and posterior surfaces, respectively.⁴ Posterior astigmatism was the difference in power between steep and flat meridians; when determining the correlation between posterior astigmatism and the difference between vertical and horizontal corneal thicknesses, we determined the difference in power between the posterior vertical and horizontal meridians. Total corneal power was calculated as P_total = P_a + P_p − d * P_a * P_p, where d was the reduced distance to air between the two surfaces, or Display Formula .¹⁹ Mean keratometric corneal power (P_km) was calculated as Display Formula . Astigmatism was considered to be horizontal if the steep corneal meridian was at 0° to 29° or 150° to 180°, vertical if the steep corneal meridian was at 60° to 119°, and oblique for the remaining meridians^4,5; for analyses of the direction of anterior and posterior astigmatism, normal subjects were included only if age 40 years or older because anterior axis is known to change with age.^4,6,7  

Statistical Analysis

We reported unadjusted summary statistics with mean ± standard deviation by severity of FECD. For hypothesis testing, variables were compared by using generalized estimating equation (GEE) models to account for possible correlation between fellow eyes of the same subject.²⁰ Generalized estimating equation models were used to calculate population-averaged mean differences between FECD groups with respective 95% confidence intervals (95% CI). All analyses were adjusted for age; peripheral corneal thickness decreases with age,^10,21 and other posterior corneal surface parameters could also vary with age.^4,6,7 Contingency tables were analyzed with Fisher's exact test. Multinomial logistic regression was used to analyze the angle of astigmatism. Association of variables was assessed by using age-adjusted partial correlations. Differences were considered statistically significant if P < 0.05. All statistics were calculated by using Stata version 13.1 (StataCorp, College Station, TX, USA). 

Results

Participants

One hundred and twelve corneas from 64 participants with FECD and 101 corneas from 54 participants with normal eyes were examined (Table 1). Median age was 68 years in the FECD group (range, 42–89 years) and 51 years in the control group (range, 18–80 years; P < 0.001). Eighty-five eyes (76%) were phakic in the FECD group, whereas 93 eyes (94%) were phakic in the control group (P = 0.001). 

Table 1

 

Participants' Characteristics

 

Central and Peripheral Corneal Thickness Profile

Central corneal thicknesses at the apex and over the pupil center were increased in moderate (P < 0.001) and advanced (P < 0.001) FECD compared to controls (Table 2). After adjusting for age and correlation between fellow eyes, central corneas were thicker by 27 μm (95% CI, 12–42 μm) in moderate FECD and by 40 μm (95% CI, 25–55 μm) in advanced FECD compared to controls. There was no significant difference between peripheral measurements along meridians passing through the corneal apex or the pupil center except for temporal thickness (P = 0.02, Table 2). In normal eyes, CCT was not significantly correlated with age (P = 0.09), whereas horizontal corneal thickness decreased by 4.5 μm per decade (95% CI, 0.8–8.2 μm, r = −0.24; P = 0.02) and vertical thickness decreased by 5.1 μm per decade (95% CI, 1.3–8.9 μm, r = −0.23; P = 0.008) at a 6-mm diameter. 

Table 2

 

Central and Peripheral Corneal Thickness Among Fuchs' Endothelial Corneal Dystrophy (FECD) and Normal

 

The peripheral cornea at a 4-mm diameter was thicker superiorly compared to inferiorly in 95% of normal eyes and in 63% of FECD eyes (P < 0.001; Table 2; Fig. 1). This difference was 23 μm (95% CI, 19–27 μm) in normal corneas and 11 μm (95% CI, 5–16 μm) in FECD. Corneas were thicker on the vertical meridian than on the horizontal meridian in 95% of normal eyes and in 82% of FECD eyes (P = 0.008). This difference was 9 μm (95% CI, 8–10 μm; P < 0.001) in normal corneas and 7 μm (95% CI, 5–8 μm; P < 0.001) in FECD. The difference between thickness on vertical and horizontal meridians at a 4-mm diameter in advanced FECD was 4 μm (2–7 μm), and this was less than normal (P = 0.003). 

Figure 1

 

Peripheral corneal thickness and the difference between vertical and horizontal thicknesses. Peripheral corneal thickness was measured at 4-mm diameter centered on the apex and at 6-mm diameter centered on the pupil center by Scheimpflug imaging among Fuchs' endothelial corneal dystrophy (FECD, n = 112) and normal corneas (n = 101). (A) Vertical corneal thickness was increased in moderate FECD by 23 μm (95% CI, 7–40 μm; P = 0.005) and advanced FECD by 29 μm (95% CI, 13–45 μm; P < 0.001) compared to normal. (B) Similarly, horizontal thickness was increased in moderate FECD by 24 μm (95% CI, 8–40 μm; P = 0.003) and in advanced FECD by 34 μm (95% CI, 19–49 μm; P < 0.001) compared to normal (C, D). Peripheral corneas were thicker vertically than horizontally. The difference between vertical and horizontal thicknesses was decreased in advanced FECD compared to normal by 4 μm (95% CI, 2–7 μm; P = 0.008) at 4-mm diameter and by 9.0 μm (95% CI, 4–14 μm; P = 0.001) at 6-mm diameter. Each point represents one observation; black lines indicate the median.

At a 6-mm diameter, the peripheral cornea was thicker superiorly compared to inferiorly in 95% of normal eyes and in 91% of FECD eyes (P = 0.003). This difference was 31 μm (95% CI, 26–37 μm) in normal corneas and 25 μm (95% CI, 18–32 μm) in FECD. Corneas were thicker on the vertical meridian than the horizontal meridian in 94% of normal eyes and in 71% of FECD eyes (P < 0.001), with a difference of 13 μm (95% CI, 10–16 μm) in normal corneas and 7 μm (95% CI, 4–10 μm) in FECD. The difference between thickness on vertical and horizontal meridians at a 6-mm diameter in advanced FECD was 9 μm (95% CI, 4–14 μm), and this was less than normal (P = 0.001). In advanced FECD, thicknesses on vertical and horizontal meridians were not significantly different (P = 0.12). The difference between thickness on vertical and horizontal meridians decreased by 0.3 μm (95% CI, 0.2–0.6 μm; P = 0.036) for every 10 μm that CCT increased in FECD. 

Corneal Radius of Curvature and Power

There was no significant difference between FECD and normal with respect to anterior corneal radii of curvature in the horizontal (P = 0.7) and vertical (P = 0.2) meridians and calculated anterior corneal power (P = 0.4; Table 3). Mean anterior corneal power (P_a) was 48.5 ± 1.6 diopters (D) among all groups. 

Table 3

 

Corneal Radius of Curvature (r) and Power (P) Among Fuchs' Endothelial Corneal Dystrophy (FECD) and Normal

 

Along the horizontal posterior meridian, radius of curvature was increased in advanced FECD by 0.4 mm (95% CI, 0.2–0.5 mm; P < 0.001) compared to normal. Along the vertical posterior meridian, radius of curvature was increased in moderate FECD by 0.2 mm (95% CI, 0.1–0.4 mm; P = 0.011) and in advanced FECD by 0.4 mm (95% CI, 0.3–0.6 mm; P < 0.001) compared to normal (Table 3; Fig. 2). The posterior corneal radius of curvature was steeper vertically than horizontally in 99% of normal eyes and 70% of eyes with advanced FECD (P < 0.001). 

Figure 2

 

Corneal astigmatism. Corneal power was calculated in Fuchs' endothelial corneal dystrophy (FECD, n = 112) and normal (n = 101) eyes according to radii of curvature determined with Scheimpflug imaging. (A) Anterior corneal power (P_a) was not significantly different in FECD compared to normal (P = 0.4). (B) Mean posterior corneal power (P_p) was decreased (corresponding to less minus power) in moderate FECD by 0.2 D (95% CI, 0.04–0.3; P = 0.009) and advanced FECD by 0.4 D (95% CI, 0.2–0.5 D; P <0.001) compared to normal. (C) Total corneal power (P_total) was not significantly different in FECD compared to control. (D) However, the difference between keratometric power and total corneal power (P_km − P_total) was decreased in moderate FECD by 0.1 D (95% CI, 0.03–0.2 D; P = 0.007) and in advanced FECD by 0.3 D (95% CI, 0.2–0.4 D; P < 0.001) compared to normal. (E, F) In normal corneas 40 years or older (n = 70), anterior and posterior steep meridians were predominantly vertical; in FECD, fewer eyes were steep vertically on anterior and posterior surfaces, indicating a change in axis. Significances were determined with GEE models adjusted for age. Each point represents one observation; black lines indicate the median (A–D).

Mean posterior corneal power (P_p) was decreased (i.e., less minus power) in moderate FECD by 0.2 D (95% CI, 0.04–0.3; P = 0.009) and in advanced FECD by 0.4 D (95% CI, 0.2–0.5 D; P < 0.001) compared to normal. In all eyes, the difference between posterior powers in the vertical and horizontal meridians was correlated with the difference between vertical and horizontal corneal thicknesses at 4-mm diameter (r = −0.46, −0.17 D per 10-μm difference; P < 0.001) and 6-mm diameter (r = −0.44, −0.08 D per 10-μm difference; P < 0.001). This correlation was strongest in normal eyes (4-mm diameter, r = −0.62, P < 0.001; 6-mm diameter, r = −0.66, P < 0.001; Fig. 3). 

Figure 3

 

Relationship of difference between vertical and horizontal posterior corneal powers and differences between corneal thicknesses along vertical and horizontal meridians. Difference between vertical and horizontal posterior corneal power as a function of the difference between vertical and horizontal corneal thicknesses (CT) in Fuchs' endothelial corneal dystrophy (FECD, n = 112; circles) and normal (n = 101; black diamonds) eyes. Differences were correlated in all eyes and normal eyes at a 4-mm diameter (A) and at a 6-mm diameter (B).

The difference between keratometric corneal power (P_km) and total corneal power (P_total) decreased in moderate FECD by 0.1 D (95% CI, 0.03–0.2 D; P = 0.007) and in advanced FECD by 0.3 D (95% CI, 0.2–0.4 D; P < 0.001) compared to normal (Table 3). 

Corneal Astigmatism

Posterior astigmatism was vertical (i.e., induced against-the-rule astigmatism) in 91% of normal eyes (n = 70, subjects under 40 years were excluded) and in 64% of FECD eyes (P < 0.001). It was horizontal in 0% of normal eyes and in 13% of FECD eyes (P < 0.001), and was oblique in 9% of normal eyes and in 22% of FECD eyes (P = 0.013; Fig. 2). Independent of participants' age, the proportion of subjects with posterior horizontal astigmatism increased with FECD severity (P < 0.001); subjects with advanced FECD were 13 times more likely to have oblique astigmatism than vertical astigmatism (95% CI, 2.4–73.4; P = 0.003). 

Anterior astigmatism was vertical (i.e., induced with-the-rule astigmatism) in 67% of normal eyes (subjects under 40 years were excluded) and in 48% of FECD eyes (P = 0.009). It was horizontal in 9% of normal eyes and in 35% of FECD eyes (P < 0.001), and oblique in 24% of normal eyes and in 17% of FECD eyes (P = 0.2). Independent of participants' ages, subjects with moderate FECD were five times more likely to have horizontal than vertical anterior astigmatism (95% CI, 1.5–15.1; P = 0.009), and subjects with advanced FECD were six times more likely to have horizontal than vertical astigmatism (95% CI, 1.7–21.6; P = 0.005). Oblique astigmatism was not significantly associated with participants' age (P = 0.08) or with FECD (P = 0.5). 

Discussion

In moderate and advanced FECD, the shape of the posterior corneal surface is more spherical compared to the ellipsoid shape of normal corneas. In normal eyes, corneas are thicker vertically than horizontally, contributing against-the-rule astigmatism from the posterior surface. In contrast, the difference between vertical and horizontal peripheral thickness decreases with increasing CCT and severity in FECD, resulting in decreased posterior corneal power (i.e., less minus power) and loss of normal posterior corneal toricity. These changes in FECD might be important when considering the refractive outcomes of cataract surgery. 

In 95% of normal eyes, corneas were thicker vertically than horizontally across a broad range of age (Fig. 1; Table 2). Our results from Scheimpflug imaging were similar to those of Ueno et al.,⁵ who used AS-OCT and found a 3.4 ± 1.8 μm (mean ± standard deviation) difference between vertical and horizontal thickness at a 3-mm diameter centered on the corneal apex. We examined corneal thickness more peripherally to assess the entire functional optical zone of the cornea, and knowing that FECD often involves the central cornea beyond a 5-mm diameter. We found that the difference between thickness along vertical and horizontal meridians increased with distance from the pupil center: 5.6 ± 3.8 μm at 3-mm diameter (data not shown), 8.6 ± 5.2 μm at 4-mm diameter, and 13.4 ± 9.4 μm at 6-mm diameter. Our results confirm that the posterior corneal surface in normal corneas has a steeper vertical than horizontal radius of curvature (6.3 ± 0.3 vs. 6.5 ± 0.3 mm), and helps confirm the direction of posterior corneal astigmatism.^3,6,7 This study found that peripheral corneal thickness decreased by 5 μm per decade at a 6-mm diameter in normal eyes, similar to previous studies.^4–7,10,21 

In FECD, CCT increased with disease severity as expected,^10,15 and also more than the peripheral thickness increased.¹⁰ Similar to normal corneas,⁵ the superior cornea in FECD was thicker than other peripheral regions, but the difference in peripheral thickness between vertical and horizontal meridians in FECD was less than that in normal corneas. Peripheral corneal thickness in advanced FECD increased along the horizontal meridian more than along the vertical meridian, so thicknesses in these regions were not different (Fig. 1; Table 2). Although the increase in posterior corneal radius in FECD, which renders a flatter posterior surface, has been described previously,²² our study found that this change began earlier in the course of disease (in moderate FECD) before the onset of clinically detectable edema, and that there was a directional change in corneal thickness.²³ 

The flatter posterior radius of curvature in FECD reduces the negative power of the posterior surface by 0.4 D (95% CI, 0.2–0.5 D), thereby increasing total power of the cornea by the same amount (because anterior corneal power is unchanged). This is important because it might explain the hyperopic shift of 0.3 to 0.5 D noted after Descemet membrane endothelial keratoplasty (DMEK), after which the posterior cornea presumably assumes its normal nonedematous contour.^13,22,24,25 The mean ± SD posterior corneal powers reported before and 6 months after DMEK (−5.6 ± 0.8 and −6.3 ± 0.4 D)²² were similar to those in the present study in advanced FECD and normal eyes (−5.3 ± 0.3 and −6.3 ± 0.3 D, respectively). This change in posterior corneal power in FECD might therefore be important when planning the refractive outcomes of cataract surgery, especially if endothelial keratoplasty might be required in the future. Keratometric power normally overestimates total corneal power, by 1.8 D in this study and by 1.2 in previous studies.⁸ We found that this overestimate was reduced in FECD, specifically in moderate and advanced FECD by 0.1 D and 0.3 D, respectively (Table 3). Our data suggest that eyes with moderate and advanced FECD should be rendered slightly myopic if Descemet membrane endothelial keratoplasty might be required in the future; this hypothesis warrants further investigation in a prospective analysis of posterior corneal profile changes after DMEK. 

That the posterior corneal surface flattens in FECD by a magnitude similar to that to which it steepens after DMEK is best explained by the development and resolution of corneal edema, respectively. The cornea swells posteriorly more than it does anteriorly,^26,27 which might explain why the anterior radius of curvature was unchanged in FECD. Changes in posterior curvature in moderate FECD suggest that corneal edema is present, but not clinically detectable, at this stage of the disease.^10,15 

The posterior corneal surface normally contributes a small amount of against-the-rule astigmatism (0.3–0.5 D),^3,4 which can influence the refractive outcome of toric intraocular lens placement in normal eyes. In FECD, we found that the directional change in peripheral corneal thickness can result in loss of normal posterior corneal toricity, and the axes of anterior and posterior corneal astigmatism can change significantly as FECD progresses, presumably because of subtle corneal edema. Therefore toric intraocular lenses and use of limbal relaxing incisions in FECD should be selected cautiously, if at all, considering that both corneal surfaces could change after DMEK. Surgeons should also recognize that corneal high-order aberrations can increase early in the course of FECD,¹⁴ and these can degrade optical quality after cataract surgery or endothelial keratoplasty.²⁸ 

In this study, we assumed that the entire cornea had a uniform refractive index of 1.376 and that parallel light rays were incident at the posterior corneal surface. In addition, we assumed that normal corneas and corneas with FECD had the same refractive indices. In animal models, the effect of corneal swelling on refractive index was minimal,²⁹ but chronic structural changes in the anterior cornea, the stroma, and the endothelium in FECD³⁰ might alter the refractive index. Nevertheless, Scheimpflug imaging of the posterior cornea with the same instrument used in this study has been validated using an innovative hybrid corneal model and in eyes with anterior corneal distortion after refractive surgery.³¹ Another limitation of our study, intrinsic to observational cross-sectional studies, was the lack of longitudinal data and the within-subject association of changes and disease progression. 

In summary, the normal posterior cornea has an ellipsoid shape that is manifest as against-the-rule astigmatism, whereas in FECD the posterior cornea is flatter and more spherical than normal, resulting in less negative power and loss of normal posterior surface toricity. These changes might explain the hyperopic shift after DMEK and have implications for planning refractive outcomes after cataract surgery in FECD. 

Acknowledgments

Supported by Research to Prevent Blindness, New York, New York, United States (unrestricted grant to the Department of Ophthalmology and SVP as Olga Keith Wiess Special Scholar); The Dr Jackstädt-Stiftung Foundation, Wuppertal, Germany (Research Fellowship to KW); and Mayo Foundation, Rochester, Minnesota, United States. The funding organizations had no role in the design or conduct of this research. The authors alone are responsible for the content and writing of the paper. 

Disclosure: K. Wacker, None; J.W. McLaren, None; S.V. Patel, None