Relationship of Fuchs Endothelial Corneal Dystrophy Severity to Central Corneal Thickness

CLINICAL SCIENCES Relationship of Fuchs Endothelial Corneal Dystrophy Severity to Central Corneal Thickness

Laura J. Kopplin, MD, PhD; Katie Przepyszny, MA; Brian Schmotzer, MS; Karen Rudo, MD; Denise C. Babineau, PhD; Sanjay V. Patel, MD; David D. Verdier, MD; Ula Jurkunas, MD; Sudha K. Iyengar, PhD; Jonathan H. Lass, MD; for the Fuchs’ Endothelial Corneal Dystrophy Genetics Multi-Center Study Group

Objective: To define the relationship between Fuchs Results: Average CCT was thicker in index cases for all endothelial corneal dystrophy (FECD) severity and cen- FECD grades compared with unaffected controls tral corneal thickness (CCT). (PՅ.003) and in affected family members with an FECD grade of 4 or greater compared with unaffected family Methods: We examined 1610 eyes from a subset of in- members (PՅ .04). Similar results were observed for sub- dex cases, family members, and unrelated control subjects without edema. Average CCT of index cases was jects with normal corneas from the FECD Genetics Multi- greater than that of affected family members with grades Center Study. To estimate the association between FECD 4, 5, and 6 FECD (PՅ.02). Intraocular pressure was also severity grade (7-point severity scale based on guttae con- associated with CCT (P=.01). fluence) and CCT measured by ultrasonographic pachymetry, a multivariable model was used that adjusted for eye, Conclusions: An increase in CCT occurs with increas- age, race, sex, history of glaucoma or ocular hyperten- ing severity of FECD, including at lower FECD grades sion, diabetes mellitus, contact lens wear, intraocular pres- in which clinically observable edema is not present. Moni- sure, and familial relationship to the index case. An interaction between FECD severity grade and edema toring CCT changes serially could be a more sensitive (stromal or epithelial) on slitlamp examination findings measure of disease progression with surgical therapeu- was used to investigate whether the effect of FECD se- tic implications. verity grade on CCT differed between those with and without edema. Arch Ophthalmol. 2012;130(4):433-439

ORNEAL ENDOTHELIAL DIS- tion that results in corneal edema. Thick- eases, notably the com- ening is believed to occur mainly in the monly occurring Fuchs later stages of FECD, manifesting as clini- endothelial corneal dys- cally apparent stromal and/or epithelial trophy (FECD), influ- edema.11,12 The relationship between ear- ence central corneal thickness (CCT),1,2 as lier stages of FECD and CCT is less clear. C 3,4 do genetic determinants and potentially Prior studies have been limited by small intraocular pressure (IOP).5-8 In healthy cor- samples sizes, a lack of consistent defini- neas, endothelial function is essential in tions of FECD severity, and heteroge- maintaining normal thickness. The endo- neous FECD study populations.1,2,13,14 To thelium acts as a leaky fluid barrier be- further elucidate understanding of the tween the aqueous humor and corneal pathogenesis of corneal thickening in stroma, enabling necessary nutrients to sup- FECD, we examined the relationship be- ply the cornea.9,10 The endothelium also acts tween FECD severity and CCT in sub- as an active transporter of ions across this jects from the FECD Genetics Multi- cell layer, creating an osmotic force that re- Center Study. moves fluid from the corneal stroma. The balance between these 2 functions is a prime METHODS determinant of corneal thickness. Factors Author Affiliations are listed at that impair the ability of the endothelium the end of this article. STUDY POPULATION Group Information: A list of to perform these functions disrupt this bal- members of the FECD Genetics ance with resultant corneal edema and an Subjects were selected from the FECD Genet- Multi-Center Study Group was increase in thickness. ics Multi-Center Study cohort, a study popu- published in Cornea. Fuchs endothelial corneal dystrophy is lation recruited to identify genetic risk factors 2012;31(1):26-35. characterized by endothelial cell dysfunc- for FECD that has been previously de-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 scribed.15 In brief, families enriched for FECD were ascer- STATISTICAL ANALYSES tained through severely affected probands, with an emphasis on identifying severely affected sibling pairs, although other The eyes from subjects were divided into the following 4 cat- family members, affected and unaffected, were also recruited. egories for analysis: (1) proband and unrelated cases (herein- In addition, unrelated FECD cases and control subjects after referred to as index cases), (2) affected family members matched to be 5 years older than index cases were also col- Ͼ 15 (FECD grade of 0), (3) unaffected family members (FECD lected. The controls have also been previously described and grade of 0), and (4) unrelated controls with normal corneas. included those with pseudophakic eyes at least 1 year from Enrollment under the genetic study design emphasized se- their surgery. Written informed consent was obtained from all verely affected probands and affected siblings with FECD grades subjects after institutional review board approval of the study. of greater than 4 in at least 1 eye, resulting in small sample sizes Demographic information and ocular and systemic medical in groups with FECD grades of 1 to 3. As such, these eyes were histories were obtained via a standardized questionnaire ad- combined into a single group for the index cases and affected ministered to the patient via interview, and each eye was family member categories. Using a generalized estimating equa- evaluated separately for inclusion in the present study. Eyes tions approach that accounted for correlation between eyes with were excluded from this study if they had undergone pen- an exchangeable working correlation structure, 2 multivari- etrating or endothelial keratoplasty; had cataract surgery able models were fitted to estimate the effect of FECD grade within 1 year of the study examination; had a history of blunt, on CCT. The first model adjusted for eye (right vs left), age, penetrating, or perforating trauma; or had evidence of other race (white vs nonwhite), presence of glaucoma/ocular hyper- corneal endothelial dystrophy. These exclusion criteria were tension, diabetes, contact lens wear (ever vs never), and IOP. chosen for their possible effect on corneal thickness and thus The FECD grade and relationship to the index case were also their potential to confound any relationship between FECD included as categorical variables with an interaction between grade and CCT. Subject age, the time of examination, sex, them. The second model adjusted for covariates from the first self-reported diabetes mellitus, contact lens wear of any type, model and spherical equivalent for each eye, the time of the use of ocular and systemic medications, and self-reported his- evaluation (morning vs afternoon), and whether the subject re- tory of ocular hypertension or glaucoma (open-angle or nar- ported symptoms of blurred vision in the morning for the eye. row-angle) were recorded. A slitlamp biomicroscopic exami- The second model was used to estimate the effects of these 3 nation by a cornea fellowship–trained ophthalmologist was variables on CCT because they had limited data compared with performed to determine the extent of corneal guttae and the the other variables included in the first model. presence of any stromal or epithelial edema, along with a Because clinically evident edema was observed in several sub- manifest refraction and measurement of IOP by means of ap- jects at FECD grades for which edema was not a defining grad- planation tonometry. Each ophthalmologist was trained on a ing criterion, an interaction between FECD grade and the pres- standardized protocol for assessing the FECD grading scale, ence or the absence of clinically apparent stromal or epithelial provided with photographic examples of each grade, and edema was also included to investigate whether the effect of tested by grading live patient examples at the outset of the FECD grade on CCT differed between those subjects with and study to ensure consistency in grading across enrollment 15 without edema. Unless otherwise indicated, data are ex- sites. The spherical equivalent was calculated from the pressed as mean (SD). manifest refraction for each eye.

RESULTS FECD GRADE AND CCT DETERMINATION In total, 3118 eyes from 1559 subjects were considered The FECD grade was determined on a semiquantitative scale for this study, with 1610 eyes from 969 subjects meet- from 0 to 6, modified from a previous severity scale.15 We used ing inclusion criteria. Of the excluded eyes, 945 had un- the following grade scale: 0 indicates no guttae; 1, 1 to 12 central/ dergone prior keratoplasty, 273 had undergone cataract paracentral nonconfluent guttae; 2, more than 12 central/ surgery within 1 year of study enrollment, 77 had a his- paracentral nonconfluent guttae; 3, 1 to 2 mm of confluent cen- tory of trauma, and 11 had findings consistent with an tral/paracentral guttae; 4, more than 2 to 5 mm of confluent additional corneal dystrophy. Eyes were also excluded central/paracentral guttae; 5, more than 5 mm of confluent cen- if data for CCT, FECD grade, or variables included in the tral/paracentral guttae; and 6, more than 5 mm of confluent cen- analysis models were missing. We included 18.1% of eyes tral/paracentral guttae with stromal and/or epithelial edema. from index cases, 40.1% from affected family members, Cases in which stromal or epithelial edema was observed over- lying regions of focally dense guttae were graded according to 34.2% from controls, and 7.5% from unaffected family the diameter of the area of guttae with edema independently members. The cohort was predominantly white (97.6% recorded. Central corneal thickness was measured by a tech- of subjects) and female (65.3% of subjects), similar to nician masked to the FECD grade of the subject; the techni- our larger cohort.15 Index cases were slightly older than cian was instructed to obtain measurements at the center of the affected family members (mean age, 68.9 [11.4] vs 63.2 cornea and centered over the pupil. Pachymeters were used from [12.8] years) (Table 1). Given the matching practice several manufacturers (Accutome, Bausch & Lomb Surgical, of the primary study of selecting controls 5 years older DGH Technology, KMI Surgical, Eye Technology, Inc, Haag- than corresponding cases,15 controls were older than the Streit, Sonogage, Sonomed, and Tomey). Each instrument in- index cases (mean age, 71.2 [7.6] years). Unaffected fam- ternally calibrates and takes repeated measurements to deter- ily members were the youngest group, with a mean age mine the thickness ultrasonographically. Given the difficulty in defining the exact center of the cornea, 3 separate readings of 52.2 (13.6) years. The proportion of female subjects were obtained immediately after each other, and the mean of was greatest in the affected family member group (72.6%) these measurements was used as the CCT. Eyes with any CCT compared with the index case, control, and unaffected measurement of less than 100 µm were excluded from further family member groups (61.5%, 59.7%, and 65.6%, re- analysis (n=4). spectively). A greater proportion of eyes from index cases

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Study Analysis Groupa

Affected Family Unaffected Family Index Cases Members Control Subjects Members Characteristic (n = 247) (n = 358) (n = 300) (n = 64) P Value Right eye 97 (39.3) 21 (5.9) 29 (9.7) 1 (1.6) Ͻ.001 Left eye 105 (42.5) 48 (13.4)b 20 (6.7) 7 (10.9) Ͻ.001 Both eyes 45 (18.2) 289 (80.7) 251 (83.7) 56 (87.5) Ͻ.001 Age, mean (SD), y 68.9 (11.4) 63.2 (12.8) 71.2 (7.6) 52.2 (13.6) Ͻ.001 White race 239 (96.8) 352 (98.3) 291 (97.0) 64 (100.0) .31 Male sex 95 (38.5) 98 (27.4) 121 (40.3) 22 (34.4) .003 Diabetes mellitus, ever 31 (12.6) 41 (11.5) 31 (10.3) 2 (3.1) .18 Afternoon FECD examination time, 140 (57.1) 188 (53.7) 100 (40.0) 29 (47.5) Ͻ.001 mean (SD), No. of casesc

Abbreviation: FECD, Fuchs endothelial corneal dystrophy. a Unless otherwise indicated, data are expressed as number (percentage) of subjects. Percentages have been rounded and might not total 100. b One family member who contributed 2 eyes to the study had 1 affected eye and 1 unaffected eye. c Data were available for 906 subjects, including 245 index cases, 350 affected family members, 250 controls, and 61 unaffected family members.

Table 2. Baseline Characteristics by Eye for the 4 Study Analysis Groups

Study Analysis Groupa

Affected Family Unaffected Family Index Cases Members Control Subjects Members Characteristic (n = 292) (n = 646) (n = 551) (n = 121) P Value Glaucomab 25 (8.6) 31 (4.8) 15 (2.7) 0 Ͻ.001 Ocular hypertensionb 6 (2.1) 12 (1.9) 18 (3.3) 0 .13 Contact lens wearb 40 (13.7) 152 (23.5) 111 (20.1) 57 (47.1) Ͻ.001 Spherical equivalence, mean (SD)c −0.28 (2.31) −0.20 (2.37) −0.02 (2.55) −1.77 (2.88) Ͻ.001 IOP, mean (SD), mm Hg 14.9 (3.1) 15.4 (3.1) 15.8 (3.2) 15.5 (3.5) Ͻ.001 Epithelial edemab 27 (9.2) 23 (3.6) 0 0 Ͻ.001 Stromal edemab 113 (38.7) 122 (18.9) 0 0 Ͻ.001 Epithelial or stromal edemab 134 (45.9) 138 (21.4) 0 0 Ͻ.001

Abbreviation: IOP, intraocular pressure. a Unless otherwise indicated, data are expressed as number (percentage) of eyes. One family member who contributed 2 eyes to the study had 1 affected eye and 1 unaffected eye. b P values are based on logistic regression models using the Firth method16 to account for the presence of zero cell frequencies (eyes are assumed independent). c Measurements were available for 1506 eyes, including 276 index cases, 613 affected family members, 504 controls, and 113 unaffected family members.

had epithelial or stromal edema than did eyes from af- borderline statistically significant association with CCT. fected family members (45.9% vs 21.4%) (Table 2). Eyes No significant relationship was found between CCT and from index cases had a higher prevalence of a history of eye, race, reported glaucoma or ocular hypertension, a glaucoma or ocular hypertension than did eyes from af- history of diabetes mellitus, contact lens wear, spherical fected family members or controls (10.6%, 6.6%, and equivalence, or time of the examination (PϾ.05). 6.0%, respectively). No unaffected family member re- We also found that mean CCT increased as the FECD ported a history of glaucoma or ocular hypertension. Mean severity grade worsened from 1 through 3 to 6 in the in- IOP was greatest in the controls (15.8 [3.2] mm Hg) and dex cases and affected family member groups (Figure). lowest in the index cases (14.9 [3.1] mm Hg) (Table 2). The mean CCT of eyes from index cases was signifi- Among patients who contributed both eyes to our sample cantly thicker at all grade levels than the CCT of eyes from of 1610 eyes, the Pearson correlation for CCT between controls, including the group containing eyes with FECD eyes was 0.92. grades 1 through 3 (PՅ.003) (Table 4). Similarly, the An estimate of the effect of several covariates on CCT mean CCT of eyes from affected family members was was also examined (Table 3). We found that for each thicker than the mean CCT of eyes from unaffected fam- 1–mm Hg increase in IOP, the cornea was on average 1.0 ily members for all grades (PՅ.04). Index case corneas µm thicker (95% CI, 0.2-1.8 µm [P=.01]). Blurred vi- were on average thicker than the corresponding cor- sion in the morning was also significantly associated with neas of affected family members for grade categories 4, CCT (P=.04). Symptomatic eyes had corneas 8.1 µm 5, and 6 (PՅ.02); there was no difference in thickness thicker (95% CI, 0.3-16.0 µm) on average than eyes within the affected family members with grades 1 through 3 out this symptom. Age and sex also appeared to have a (P=.12). Mean CCT in corneas from controls and unaf-

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Model 1 Model 2 (n = 1610) (n = 1395)

Covariate Effect Size (95% CI), µm P Value Effect Size (95% CI), µm P Value Right eye 0.9 (−0.5 to 2.3) .21 1.1 (−0.5 to 2.7) .20 Age, per 1-y increase −0.3 (−0.6 to 0.0) .03 −0.3 (−0.6 to 0.0) .06 White race 11.8 (−6.9 to 30.5) .22 13.9 (−4.7 to 32.6) .14 Male sex 6.1 (−0.1 to 12.2) .06 7.0 (0.3 to 13.6) .04 Glaucoma or ocular hypertension, 0.2 (−10.1 to 10.5) .96 −3.5 (−14.0 to 6.9) .51 ever Diabetes mellitus, ever 4.2 (−4.9 to 13.4) .36 4.6 (−5.0 to 14.2) .35 Contact lens wear, ever −6.4 (−13.8 to 1.1) .09 −6.0 (−14.0 to 1.9) .13 IOP, per 1–mm Hg increase 1.0 (0.2 to 1.8) .001 1.0 (0.2 to 1.8) .01 Spherical equivalent, per 1-D 0.1 (−1.0 to 1.3) .80 increase Afternoon FECD examination time 1.1 (−4.9 to 7.2) .71 Blurred morning vision 8.1 (0.3 to 16.0) .04

Abbreviations: D, diopter; FECD, Fuchs endothelial corneal dystrophy; IOP, intraocular pressure.

cluded in these results. Comparisons between index cases Controls Index cases and affected family members without edema demon- Unaffected family members Affected family members strated significantly thicker corneas in the index group for 900 subjects with FECD grades of 4 and 5 (P=.02). Alterna- tively, in the subjects with edema, the mean CCT in index 800 cases was thicker than the mean CCT in affected family

700 members only for grade 6 (P=.01). Subjects with a grade 5 guttae diameter and also observed to have edema were, m µ 600 by definition, classified as having FECD grade 6 and were

CCT, CCT, not included in these results. After adjustment for an in- 500 teraction between edema and FECD grade, there was evidence of an association among IOP, age, and contact lens 400 wear on CCT (PՅ.045, results not shown).

300 0 1-3 4 5 6 COMMENT FECD Grade

No. of eyes Controls 551 General understanding based on compensatory mecha- Unaffected 121 nisms in the deteriorating endothelium in FECD is that CCT Index 16 64 91 121 Affected 187 178 160 121 remains normal until the late stages of the disease, when there are extensive confluent guttae.11 Another possibil- Figure. Boxplots of central corneal thickness (CCT) among the study groups. ity, however, is that a gradual increase in CCT arises as Index cases and affected family members had Fuchs endothelial corneal FECD progresses. Studies have been limited in their abil- dystrophy (FECD) grades 1 through 3, 4, 5, or 6; unaffected family members ity to distinguish between these mechanisms because of a had an FECD grade of 0; and controls had normal corneas. The horizontal line in the middle of each box indicates the median and the ϩ indicates the lack of standardization of grading criteria, small sample sizes, mean, while the top and bottom borders of the box mark the 75th and 25th and a lack of prospective studies. The present study sug- percentiles, respectively. The whiskers above and below the box extend to gests that there is a gradual increase in CCT as FECD pro- the data point furthest from the box that is still within 1.5ϫ(75th gresses clinically. Significant differences in CCT were even percentile−25th percentile) of the box. Points beyond are marked individually. detectable at early grades of FECD compared with normal controls. Our results indicate that subjects with as few as 1 to 2 mm of confluent guttae may begin to develop cen- fected family members was not significantly different tral corneal thickening, pointing to a gradual process of en- (P=.97). dothelial dysfunction rather than an acute “tipping point” As anticipated, corneas with slitlamp-observed edema of endothelial decompensation as a likely mechanism of were thicker than corneas without edema (Table 5). Mean corneal edema in FECD. Our findings were not limited to CCT in index cases without edema was thicker than in con- 1 subset of our cohort but rather were observed in the af- trols for FECD grades 4 and 5 (PϽ.001), whereas mean fected family members and index cases, indicating this is CCT in affected family members without edema was thicker not an isolated phenomenon. than mean CCT in unaffected family members in the FECD Corneal hydration is mainly regulated by endothelial grade 5 group (PϽ.001). By definition, cases with FECD barrier function and ionic gradients set up by the Na/K- grade 6 had edema on examination and could not be in- ATPases (sodium-potassium–adenosine triphosphatase

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FECD Gradea Mean CCT (95% CI), µm P Valueb Mean CCT (95% CI), µm P Valuec Mean CCT (95% CI), µm P Valued Controls Unaffected Family Members Difference 0 558 (554 to 562) 558 (547 to 569) 0 (−12 to 12) .97

Index Cases Affected Family Members Difference 1-3 586 (567 to 605) .003 571 (564 to 577) .04 −16 (−36 to 4) .12 4 596 (584 to 607) Ͻ.001 574 (564 to 584) .03 −21 (−37 to −6) .005 5 612 (604 to 620) Ͻ.001 595 (584 to 607) Ͻ.001 −17 (−31 to −3) .02 6 648 (639 to 658) Ͻ.001 630 (618 to 642) Ͻ.001 −19 (−34 to −4) .01

Table 5. Estimates and Comparisons of CCT for Subjects Without and With Edemaa

Without Edema With Edema FECD Mean CCT P Mean CCT P Mean CCT P Mean CCT Mean CCT Mean CCT P Grade No. (95% CI), µm Valueb No. (95% CI), µm Valuec (95% CI), µm Valued No. (95% CI), µm No. (95% CI), µm (95% CI), µm Valuee Controls Unaffected Family Members Difference Controls Unaffected Family Difference Members 0 551 558 (554 to 562) 121 558 (548 to 569) 0 (−11 to 12) .96 0 0

Index Cases Affected Family Members Difference Index Casesf Affected Family Membersf Difference 1-3 12 576 (557 to 595) .06 182 570 (563 to 576) .06 −7 (−27 to 14) .52 4 629 (586 to 672) 5 592 (575 to 608) −37 (−83 to 9) .11 4 55 589 (577 to 600) Ͻ.001 166 571 (560 to 581) .09 −18 (−33 to −3) .02 9 628 (595 to 660) 12 626 (593 to 659) −1 (−48 to 45) .95 5 91 612 (603 to 620) Ͻ.001 160 595 (583 to 607) Ͻ.001 −17 (−31 to −2) .02 0 0 6 0 0 121 649 (640 to 658) 121 630 (619 to 641) −19 (−33 to −4) .01

Abbreviations: CCT, central corneal thickness; FECD, Fuchs endothelial corneal dystrophy. a Grades and study analysis groups are explained in the Figure and the “FECD Grade and CCT Determination” subsection of the “Methods” section. b Calculated as the comparison of the mean CCT between each index case FECD grade group and controls for subjects without clinically apparent edema. c Calculated as the comparison of the mean CCT between each affected family member FECD grade group and unaffected family members for subjects without clinically apparent edema. d Calculated as the comparison of the mean CCT between affected family members and index cases or between unaffected family members and controls for subjects without clinically apparent edema. e Calculated as the comparison of the mean CCT between affected family members and index cases for subjects with clinically apparent edema. f Subjects with edema at FECD grades 1 through 4 represent individuals with focally dense guttae observed to also have clinically evident edema on slitlamp examination findings. Subjects with FECD grade 5 and also noted to have clinically observed edema had findings equivalent to an FECD grade 6 and were classified accordingly.

pump). The physiological basis for corneal edema in The average CCT in our 2 groups of unaffected sub- FECD has been attributed to alterations in Na/K ATPase jects was consistent with the current understanding of nor- pump site density and/or breakdown in barrier func- mal corneal thickness measured by ultrasonographic tion. There is a possible increase in the pump site den- pachymetry.21 The lack of a significant difference in mean sity in early FECD stages,17 with a gradual decline as the CCT between explicitly recruited controls with normal cor- disease progresses.18,19 Conversely, one of the earliest de- neas on slitlamp biomicroscopy findings and unaffected fam- fects in FECD is a breakdown in barrier function that re- ily members collected during familial recruitment is reas- sults in the increased permeability of corneal endothe- suring. Affected family members had on average thinner lium to solutes and increased corneal thickening.1 corneas at a given FECD grade than those of the index cases Although our study did not specifically study the mecha- despite identical grading criteria for both groups. We hy- nisms of corneal edema, it corroborates these studies by pothesized that index cases, as the subjects who brought showing that corneal hydration could be affected in early the family to the attention of the study, were more likely stages of the disease process. Unfortunately, ultrasono- to be symptomatic and thus more likely to have greater cor- graphic pachymetry only measures total corneal thick- neal thickening, regardless of the extent of guttae. Our re- ness and cannot distinguish changes in thickness by in- sults show that index cases did indeed have a higher rate dividual corneal layer as can be accomplished by other of blurred vision in the morning than did affected family methods, such as confocal microscopy20; however, it seems members (50.3% vs 36.4%), but adjusting for this symp- feasible that subclinical thickening of the stroma may oc- tom in the model had no effect on the observed difference cur at lower FECD grades as endothelial function and between the 2 groups. This symptom as measured in our compensatory mechanisms become impaired. study might not be a sensitive enough symptomatic marker

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 to adequately account for the effect, or other hypotheses Numerous previous studies have examined the cor- for the phenomenon should be considered. Recent work relation between age and CCT without any obvious trends has examined the progressive loss of endothelial cell den- emerging.21,28 Our models show some evidence of lower sity in corneas with guttae without clinical edema and found CCT being associated with increased age (P=.06 in our that these eyes could be classified as likely asymptomatic main model and P=.02 in the model that includes an in- guttae, borderline guttae that may progress to develop- teraction between group and edema), consistent with the ment of corneal edema, and guttae likely to be a prelimi- ambiguity in the literature. Also, because our popula- nary form of FECD (as defined by the development of stro- tion was predominantly older (average age, 66 years), it mal or epithelial edema or other late-stage complications) is difficult to draw conclusions about age and CCT that based on changes in cell density.22 Our observed differ- could be generalized to a broader population. ence in CCT between index cases and affected family mem- The cross-sectional nature, the method chosen for as- bers may represent a greater proportion of index case eyes sessing CCT, and the measurement of thickness only in the falling into the latter 2 categories with resultant endothe- central cornea are limitations to this study. Within the gen- lial dysfunction. Because the other eye of each index case eral population, there is a normal variation of corneal thick- must have been severely affected for the subject to have ini- ness,21 and it is on this variability that the effects of FECD tially qualified for the study, it would not be surprising that are superimposed. Our study did not follow up subjects the companion eye would likely progress to late-stage FECD. longitudinally because the primary objective of the study Also of interest was the identification of a small subgroup was to assess the genetic factors associated with advanced of subjects with focally dense guttae that resulted in clini- late-onset FECD; thus, the change in CCT over time with cally evident edema, with a greater proportion of index cases advancing FECD and genetic factors associated with this thanaffectedfamilymembersencompassedinthissubgroup. phenotype by individual, as studied in several families with These subjects do not entirely account for the differences late-onset FECD,29,30 was not examined. Some subjects may in CCT between the index cases and affected family mem- have corneas thinner than 500 µm before development of bers because analyses excluding subjects with edema still advanced FECD31; therefore, they may never develop CCT identify differences in CCT. These subjects may partially values of greater than 700 µm, usually considered abnor- contribute to the findings of increased CCT at lower FECD mally thick, even with advanced disease. The spread in nor- grades because we observed the loss of a significant differ- mal CCT before disease onset was most likely reflected in ence in CCT between index cases and controls for FECD the CCT spread of our own index and affected family mem- grades 1 through 3 and affected and unaffected family member cases with FECD grade 6, in which some subjects had bers for FECD grades 1 through 3 and grade 4 when these a CCT of less than the average CCT for controls and un- subjects were excluded, although a trend toward an effect affected family members (Figure). As such, an individu- remained. The same factors that underlie the difference in al’s overall change in CCT will likely be most useful in clini- CCT between index cases and their affected familial coun- cal management rather than a comparison with the CCT terparts may also underlie the development of edema in the from other individuals with FECD. This observation par- presence of only focally dense guttae. ticularly affects decision making regarding cataract sur- Several factors, including IOP and contact lens wear, gery in the setting of FECD. The decision to perform cata- have been previously implicated in affecting corneal thick- ract surgery alone, cataract surgery with keratoplasty, or ness and were examined as potential confounders in the keratoplasty alone should be based on a number of fac- current study. There is a known association between in- tors, including the type and degree of cataract and the den- creased IOP and greater CCT.5-8 Multiple studies have also sity and location of the guttae, which may cause light scat- shown that subjects with ocular hypertension have in- tering and a decrease in visual acuity directly,32,33 as well creased CCT,7,23 and some evidence suggests that chronic as, based on our findings, the change in CCT between vis- elevation of IOP contributes to this increase.24 Within our its and the clinical presence of stromal and/or epithelial cohort, increases in IOP were significantly associated with edema rather than the absolute CCT value.34 With the ad- increased CCT, although the causal relationship re- vent of earlier surgical intervention in FECD with endo- mains unclear. Whether this represents the known as- thelial keratoplasty, the application of these proposed prin- sociation between IOP and CCT or whether FECD itself ciples and their role in the management of earlier stages of may have a relationship with IOP requires further study. FECD becomes even more important. Prior research has demonstrated an association be- Ultrasonographic pachymetry, our method for assessing tween corneal thinning and long-term extended wear of CCT, was chosen because it is commonly used clinically and contact lenses,25,26 although there appears to be signifi- was thus available across the many sites enrolling subjects cant individual variability in the corneal response to use for the genetic study. In using ultrasonographic pachym- of extended-wear contact lenses.27 Our models show some etry, we were unable to examine the individual layers of the evidence of lower CCT among those who have worn con- cornea for changes contributing to increased thickness. In tact lenses (P=.09 in our main model and P=.045 in the addition, thickness was solely measured in the center of the model that includes a groupϫedema interaction). Be- cornea for consistency; thus, our conclusions can apply only cause our study is limited by the lack of complete data to this measurement. The measurement of CCT may be an on the type, duration, and time interval of contact lens underestimate of the thickest area of the cornea when more wear, it is feasible that the contact lens effect in our study severe disease is located in the paracentral region. However, would be diluted compared with what has been shown paracentral measurement is confounded by the increasing previously in the literature and could explain why the thickness of the cornea from the center to the periphery and association is inconclusive despite the large sample size. by variability from subject to subject for a defined paracen-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 tral location. Despite these limitations, our study provides ness include COL5A1, AKAP13 and AVGR8. Hum Mol Genet. 2010;19(21): 4304-4311. evidence from a large cohort of subjects that changes in CCT 5. Ehlers N, Bramsen T, Sperling S. Applanation tonometry and central corneal occurinpatientswithFECDbeforeclinicallyapparentedema. thickness. Acta Ophthalmol (Copenh). 1975;53(1):34-43. Our findings provide evidence supporting the use of CCT 6. Eysteinsson T, Jonasson F, Sasaki H, et al; Reykjavik Eye Study Group. Central corneal thickness, radius of the corneal curvature and intraocular pressure in as a quantitative factor in following FECD progression in normal subjects using non-contact techniques: Reykjavik Eye Study. Acta Oph- addition to more subjective modalities, such as slitlamp ex- thalmol Scand. 2002;80(1):11-15. amination. A clear connection between CCT values and 7. Stodtmeister R. Applanation tonometry and correction according to corneal thickness. Acta Ophthalmol Scand. 1998;76(3):319-324. FECD severity grade points to the potential use of CCT to 8. Wolfs RC, Klaver CC, Vingerling JR, Grobbee DE, Hofman A, de Jong PT. Dis- guide treatment decisions and prognosticate for surgical tribution of central corneal thickness and its association with intraocular pres- intervention. The cross-sectional design of our study lim- sure: the Rotterdam Study. Am J Ophthalmol. 1997;123(6):767-772. 9. Kaufman PL, Alm A, Adler FH. Adler’s Physiology of the Eye: Clinical Application. its our ability to examine this question in the current co- 10th ed. St Louis, MO: Mosby–Year Book; 2003. hort; however, future prospective, longitudinal studies could 10. Waring GO III, Bourne WM, Edelhauser HF, Kenyon KR. The corneal endothe- do so. Our findings also highlight the benefit of collecting lium: normal and pathologic structure and function. Ophthalmology. 1982; 89(6):531-590. additional clinical data in a cohort initially assembled to 11. Eghrari AO, Gottsch JD. Fuchs’ corneal dystrophy. Expert Rev Ophthalmol. 2010; investigate genetic risk factors for FECD. Our insights into 5(2):147-159. the pathologic features of earlier stages of FECD enhance 12. Oh KT, Weil LJ, Oh DM, Mathers WD. Corneal thickness in Fuchs’ dystrophy with and without epithelial oedema. Eye (Lond). 1998;12(pt 2):282-284. the current clinical paradigm and add to the disease model 13. Polse KA, Brand RJ, Vastine DW, Demartini DR, Sanders TL. Clinical assess- through which the results of any future studies—genetic ment of corneal hydration control in Fuchs’ dystrophy. Optom Vis Sci. 1991; analyses or otherwise—will be interpreted. 68(11):831-841. 14. Wilson SE, Bourne WM, O’Brien PC, Brubaker RF. Endothelial function and aqueous humor flow rate in patients with Fuchs’ dystrophy. Am J Ophthalmol. 1988; Submitted for Publication: June 11, 2011; final revision 106(3):270-278. received September 30, 2011; accepted October 10, 2011. 15. Louttit MD, Kopplin LJ, Igo RP Jr, et al; for the FECD Genetics Multi-Center Study Group. A multicenter study to map genes for Fuchs endothelial corneal dystro- Author Affiliations: School of Medicine (Dr Kopplin), Cen- phy: baseline characteristics and heritability. Cornea. 2012;31(1):26-35. ter for Clinical Investigation (Ms Przepyszny, Mr 16. Heinze G, Schemper M. A solution to the problem of separation in logistic regression. Stat Med. 2002;21(16):2409-2419. Schmotzer, and Drs Babineau and Iyengar), and Depart- 17. Geroski DH, Matsuda M, Yee RW, Edelhauser HF. Pump function of the human ment of Epidemiology and Biostatistics (Drs Iyengar and corneal endothelium: effects of age and cornea guttata. Ophthalmology. 1985; Lass), Case Western Reserve University, and Department 92(6):759-763. 18. McCartney MD, Robertson DP, Wood TO, McLaughlin BJ. ATPase pump site den- of Ophthalmology and Visual Sciences, Case Western Re- sity in human dysfunctional corneal endothelium. Invest Ophthalmol Vis Sci. 1987; serve University and University Hospitals Eye Institute, Uni- 28(12):1955-1962. versity Hospitals Case Medical Center (Drs Rudo, Iyen- 19. McCartney MD, Wood TO, McLaughlin BJ. Moderate Fuchs’ endothelial dystrophy ATPase pump site density. Invest Ophthalmol Vis Sci. 1989;30(7):1560-1564. gar, and Lass), Cleveland, Ohio; Department of 20. Hecker LA, McLaren JW, Bachman LA, Patel SV. Anterior keratocyte depletion Ophthalmology, Mayo Clinic, Rochester, Minnesota (Dr in Fuchs endothelial dystrophy. Arch Ophthalmol. 2011;129(5):555-561. Patel); Verdier Eye Center, Grand Rapids, Michigan (Dr 21. Doughty MJ, Zaman ML. Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv Ophthalmol. 2000; Verdier); and Department of Ophthalmology, Harvard 44(5):367-408. Medical School, Boston, Massachusetts (Dr Jurkunas). 22. Hatou S, Shimmura S, Shimazaki J, et al. Mathematical projection model of vi- Correspondence: Jonathan H. Lass, MD, Department of sual loss due to Fuchs corneal dystrophy. Invest Ophthalmol Vis Sci. 2011; 52(11):7888-7893. Ophthalmology and Visual Sciences, University Hospi- 23. Brandt JD, Beiser JA, Kass MA, Gordon MO. Central corneal thickness in the Ocu- tals Case Medical Center, 11100 Euclid Ave, Cleveland, lar Hypertension Treatment Study (OHTS). Ophthalmology. 2001;108(10): OH 44106 ([email protected]). 1779-1788. 24. Herman DC, Hodge DO, Bourne WM. Changes in corneal thickness in patients Author Contributions: Drs Iyengar and Lass contrib- with treated and untreated ocular hypertension. Cornea. 2006;25(6):639-643. uted equally to this study. Drs Kopplin, Iyengar, and Lass 25. Holden BA, Sweeney DF, Vannas A, Nilsson KT, Efron N. Effects of long-term had full access to all the data in the study and take re- extended contact lens wear on the human cornea. Invest Ophthalmol Vis Sci. 1985;26(11):1489-1501. sponsibility for the integrity of the data and the accu- 26. Liu Z, Pflugfelder SC. The effects of long-term contact lens wear on corneal thick- racy of the data analysis. ness, curvature, and surface regularity. Ophthalmology. 2000;107(1):105-111. Financial Disclosure: None reported. 27. Schoessler JP, Barr JT. Corneal thickness changes with extended contact lens wear. Am J Optom Physiol Opt. 1980;57(10):729-733. Funding/Support: This study was supported by grants 28. Prasad A, Fry K, Hersh PS. Relationship of age and refraction to central corneal R01EY16482, R21 EY015145, and P30 EY11373 from Re- thickness. 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