Optic Disc Planimetry, Corneal Hysteresis, CentralCorneal Thickness, and Intraocular Pressure as Risk Factors

for Glaucoma

FRANCIS CARBONARO, PIRRO G. HYSI, SAMANTHA J. FAHY, ABHISHEK NAG, ANDCHRISTOPHER J. HAMMOND

� PURPOSE: To determine whether corneal hysteresisand central corneal thickness are independent risk factorsfor glaucoma.� DESIGN: Across-sectional population-based cohort study.� METHODS: Associationswere tested between corneal hys-teresis,measured in 1754 population-based subjects from theTwinsUK cohort, and glaucoma-related endophenotypes,including intraocular pressure (IOP), vertical cup-to-discratio, optic disc area, and optic disc cup area. Corneal hyster-esis, IOP, and central corneal thickness (CCT) weremeasured; optic disc photographs were analyzed; and multi-variable linear regression analysis was performed.� RESULTS: Data were available on 1645 individuals.Multiple regression analysis showed corneal hysteresisto be significantly negatively associated with age (betacoefficient [ L0.03, P < .00005) and IOP (betacoefficient [ L0.06, P < .00005). Corneal hysteresiswas also found to be associated with CCT (beta coeffi-cient [ 0.02, P < .0005). There was no significantassociation between corneal hysteresis and optic discarea (P[ .6), cup area (P[ .77), vertical cup-to-disc ra-tio (P [ .51), or spherical equivalent (P [ .08). CCTwas also found to be significantly associated with IOP(beta coefficient [ 3.3, P < .0005) and corneal hyster-esis (beta coefficient[ 9.4,P< .0005), but not with age(P [ .59) or spherical equivalent (P [ .16).� CONCLUSION: In this large cohort of healthy Britishtwins, we found no relationship between corneal hysteresisor CCT and quantitative measures of optic disc cupping,suggesting that corneal hysteresis andCCTare not indepen-dent risk factors for glaucoma. (Am J Ophthalmol2014;157:441–446. � 2014 by Elsevier Inc. All rightsreserved.)

GLAUCOMA IS THE LEADING CAUSE OF IRREVERS-

ible blindness worldwide.1 Characteristic cuppingof the optic disc is pivotal to the diagnosis of

Accepted for publication Oct 25, 2013.From the Department of Twin Research and Genetic Epidemiology,

King’s College, London, United Kingdom (F.C., P.G.H., A.N., C.J.H.);and Faculty of Medicine & Health Sciences, University of Nottingham,Nottingham, United Kingdom (S.J.F.).

Inquiries to Francis Carbonaro, Department of Twin Research andGenetic Epidemiology, King’s College London, St Thomas’ Hospitalcampus, Westminster Bridge Road, London SE1 7EH, UK; e-mail:francis.carbonaro@btopenworld.com

0002-9394/$36.00http://dx.doi.org/10.1016/j.ajo.2013.10.017

� 2014 BY ELSEVIER INC.

glaucoma and reflects the underlying loss of retinal ganglioncells, crucial in the pathogenesis of glaucoma. The change inoptic disc appearance is one of the important factors used inmonitoring glaucoma progression in individuals. There isconsiderable value in studying endophenotypes (such as ver-tical cup-to-disc ratio and intraocular pressure [IOP] forglaucoma), as they may provide more information thandichotomous disease affectation status and can be studiedquantitatively in population-based studies rather thanclinic-based case-control samples with potential for bias.Hysteresis is the term that describes the ability of an

elastic material to return to its natural shape after beingdeformed by an external force. Corneal hysteresis is theterm given to a measure of viscoelasticity of the cornea,and may be associated with glaucoma.2 Several studieshave shown corneal hysteresis to be reduced in glaucomapatients compared to normal controls.3–5 Other studiesfound that eyes with lower corneal hysteresis have visualfields that are more likely to worsen.2,6,7 It has also beenshown that with increasing age, lamina cribrosa surfacecompliance decreases and the cornea becomes morerigid.8 We have previously shown that corneal hysteresisis strongly heritable.9 The biomechanical characteristicsof the cornea and lamina cribrosa may be similar; an eyewith a more deformable cornea, or one with less viscousdamping, might also have an optic disc that is more vulner-able to glaucoma damage from raised IOP.10,11 There isconsiderable evidence to support that central cornealthickness (CCT) is a risk factor for glaucoma.12,13

If corneal hysteresis and/or CCT are independent riskfactors for glaucoma, we would expect them to be associ-ated with other glaucoma-related quantitative endopheno-types such as vertical cup-to-disc ratio, optic disc area, andoptic disc cup area.14–16 We therefore set out to examinethe relationship between both corneal hysteresis andCCT and optic disc parameters in a large Britishpopulation-based twin cohort.

METHODS

ATOTALOF 1754 PARTICIPANTSWERERECRUITED FROMTHE

TwinsUK Adult Twin Registry, based at St Thomas’ Hos-pital, London. They were unaware of any hypotheses or

441ALL RIGHTS RESERVED.

proposals for specific studies; only later were they invited tohave an eye examination. The St Thomas’ Hospital LocalResearch Ethics Committee approved the study, and all thetwin participants volunteered to join the TwinsUK Regis-try and gave informed consent to attend the hospital forphenotyping and for their data to be used for scientificresearch. All subjects with recorded IOP, optic disc planim-etry, and CCT were included, without exclusion for otherpathologies (such as early age-related macular degenera-tion). The study planned to exclude subjects who hadcorneal refractive surgery, but no participants reported hav-ing had this done. Twins were recruited for a wide range ofgenetic epidemiology studies; in this report the twin modelis not used, but the cohort is being used to study epidemi-ologic factors.17 Both subjects within each pair of twinswere used for analysis as the familial relatedness was takeninto account using cluster analysis.18 Individuals had 2readings done on both eyes with the Ocular ResponseAnalyzer (ORA; Reichert, Buffalo, New York, USA).The Ocular Response Analyzer was used to measurecorneal hysteresis, IOP, and CCT. All measurementswere done by 1 of 3 operators. A drop of proxymethacaine0.5% was instilled in both eyes prior to measuring CCT.For IOP, the Ocular Response Analyzer’s Goldmann-equivalent IOP was used, as this has been shown to mostclosely reflect Goldmann tonometry. Two measurementswere performed on each eye; first and second tests weretaken on 1 eye, then on the next; and if the accuracy waspoor a third reading was taken. Pearson correlation coeffi-cients between right and left eyes were calculated and asright and left eyes demonstrated significant correlation,right eye measures were arbitrarily used for further analyses.Autorefraction data were gathered using the ARM-10Autorefractor (Nakagi, Japan) and spherical equivalentwas incorporated in the regression analysis.

Simultaneous stereoscopic 15-degree optic disc photo-graphs were taken with a Nidek 3-Dx fundus camera(Nidek, Gamagori, Japan) (early TwinsUK subjects wereimaged with nonsimultaneous 30-degree stereophoto-graphs with a Kowa camera [Kowa-Europe, Dusseldorf,Germany]). Images from both cameras were analyzed ste-reoscopically with custom planimetric software (StereoDx,using a Z-screen; StereoGraphics Corp, Beverly Hills,California, USA).19 The inner margin of the optic discand the neuroretinal rim were delineated at the depth ofthe scleral plane, and images were modified for magnifica-tion using refraction and keratometry data.19,20 Datahandling and preliminary analyses were undertaken usingSTATA (Intercooled Stata for Windows 95, Version 5.0;StataCorp, College Station, Texas, USA; 1997).Corresponding to IOP and corneal hysteresis measures,right optic disc images were used, unless poor quality (eg,cataract or other media opacities) or exclusion criteriameant left eye data were included. Optic disc data wereexcluded if the film photograph quality was deemed toopoor. Of the 1754 twin volunteers, 102 individuals

442 AMERICAN JOURNAL OF

(5.8%) were excluded from the full analysis. Of the 1754volunteers, 32 (1.8%) had poor photographs, which werenot of sufficient quality for stereographic analysis, and70 (4%) were not analyzed because of missing digitizedimages. In 32 of 1754 cases (1.8%) the optic disc imagefrom the left eye was used owing to poor quality of the right.Given that many of the optic disc endophenotypes (ver-

tical cup-to-disc ratio, optic disc size, and optic cup areas)are correlated, multivariable linear regression wasperformed to analyze corneal hysteresis and CCT withrespect to other glaucoma-related endophenotypes. Thedata points for each subject included in regression withcorneal hysteresis as the dependent variable were opticdisc area, optic disc cup area, vertical cup-to-disc ratio,age, IOP, and spherical equivalent, as these are known tobe risk factors for glaucoma. Similarly, for CCT as depen-dent variable, the same measures were included in theregression analysis (with corneal hysteresis instead ofCCT).

RESULTS

DATA WERE AVAILABLE ON 1645 POPULATION-BASED

subjects from the TwinsUK cohort. Average age was 57years (range 16-83 years, standard deviation [SD]: 11.8).Of the 1645 participants available for analysis; 98% werefemale; 46.6% were monozygotic and 53.4% were dizygotictwins. 1.7% of the cohort had a diagnosis of glaucoma atthe time of testing. These participants with glaucomawere included in the final analysis to encompass the fullrange of vertical cup-to-disc ratio in the study population.The mean IOP was 15.6 mm Hg (range 5.4-39.1 mm Hg,SD: 3.2), mean CCT was 544 mm (range 311-662 mm,SD: 35.1), and mean vertical cup-to-disc ratio was 0.33(range 0.03-0.7, SD: 0.1). The means, ranges, and standarddeviations for all the parameters measured are shown inTable 1. As this is a national research cohort, subjectswith elevated IOPs were referred to their local family doc-tor, suggesting onward referral or review, so we do not havefinal glaucoma specialist opinion on the etiology ofelevated IOP; however, of the 2 cases that had IOPs above30 mm Hg, neither had a known cause of secondary glau-coma and they were therefore included. Ten subjects hadCCT below 450 mm; none of these reported previousrefractive surgery, keratoconus, or any other corneal pa-thology and their removal did not alter the results, sothey were included in the final analyses.Right/left eye correlations were as follows: IOP, 0.81

(P < .001); corneal hysteresis, 0.88 (P < .001); CCT, 0.83(P < .001). Corneal hysteresis was correlated with CCT(r ¼ 0.41, P < .0001), IOP (r ¼ �0.12, P < .0001), andage (r¼�0.25, P< .0001) and was at borderline significancewith optic disc area (r ¼ �0.04, P ¼ .08) but not withother optic disc endophenotypes. CCT was, as expected,

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TABLE 1. Optic Disc Planimetry, Corneal Hysteresis, andCentral Corneal Thickness as Risk Factors for Glaucoma:

Means and Ranges for All Parameters Measured and

Analyzed From This Sample

Measure Mean Minimum Maximum

Standard

Deviation

Age (y) 57 16 83 11.8

CH (mm Hg) 10.2 4.6 25.3 1.6

IOP (mm Hg) 15.6 5.4 39.1 3.2

CCT (mm) 544 311 662 35.1

Optic disc area (mm2) 2.6 0.6 5.3 0.65

Cup area (mm2) 1.4 0.1 4.4 1.4

VCDR 0.33 0.03 0.7 0.1

SE (diopters) �0.45 �14.5 8.1 2.87

CCT ¼ central corneal thickness; CH ¼ corneal hysteresis;

IOP ¼ intraocular pressure (Goldmann equivalent IOP); SE ¼spherical equivalent; VCDR ¼ vertical cup-to-disc ratio.

TABLE 2. Optic Disc Planimetry, Corneal Hysteresis, andCentral Corneal Thickness as Risk Factors for Glaucoma:

Multivariable Regression Analysis for Corneal Hysteresis

Parameter Coefficient P Value 95% Confidence Interval

Age (y) �0.03 <.0005 �0.03 to �0.02

IOP (mm Hg) �0.06 .001 �0.09 to �0.03

CCT (mm) 0.02 <.0005 0.021 to 0.025

Optic disc area (mm2) �0.04 .62 �0.19 to 0.11

Cup area (mm2) 0.04 .77 �0.25 to 0.35

VCDR �0.66 .51 �2.62 to 1.29

SE (diopters) 0.02 .07 �0.002 to 0.05

CCT ¼ central corneal thickness; CH ¼ corneal hysteresis;

IOP ¼ intraocular pressure (Goldmann equivalent IOP); SE ¼spherical equivalent; VCDR ¼ vertical cup-to-disc ratio.

TABLE 3. Optic Disc Planimetry, Corneal Hysteresis, andCentral Corneal Thickness as Risk Factors for Glaucoma:

Multivariable Regression Analysis for Central Corneal

Thickness

Parameter Beta Coefficient P Value

95% Confidence

Interval

Age (y) �0.4 .59 �0.18 to 0.10

IOP (mm Hg) 3.34 <.0005 2.94 to 3.77

CH (mm Hg) 9.42 <.0005 8.58 to 10.27

Optic disc area (mm2) �1.44 .43 �5.01 to 2.14

Cup area (mm2) �5.12 .16 �12.62 to 2.01

VCDR 37.38 .10 �7.31 to 82.08

SE (diopters) 0.34 .16 �0.13 to 0.83

CCT ¼ central corneal thickness; CH ¼ corneal hysteresis;

IOP ¼ intraocular pressure (Goldmann equivalent IOP); SE ¼spherical equivalent; VCDR ¼ vertical cup-to-disc ratio.

significantly correlated with IOP (r ¼ 0.30, P < .0001), age(r ¼ �0.09, P < .0001), and corneal hysteresis (r ¼ 0.41,as above), and with optic disc area (r ¼ �0.07, P ¼ .002),but not with vertical cup-to-disc ratio or cup area. Usingmultivariable regression analysis, corneal hysteresis wasfound to be significantly negatively associated with age(beta coefficient ¼ �0.03, P < .00005) and IOP (betacoefficient ¼ �0.06, P < .00005). Corneal hysteresis wasalso found to be associated with CCT (beta coefficient ¼0.02, P < .0005). There was no significant associationbetween corneal hysteresis and optic disc area (P ¼ .62),cup area (P ¼ .77), or vertical cup-to-disc ratio (P ¼ .51).There was also no association between corneal hysteresisand spherical equivalent (P ¼ .07). The R2 value for thesewas 0.28. These results are shown in more detail inTable 2. CCT was also found to be significantly associatedwith IOP (beta coefficient¼ 3.3,P< .0005) and corneal hys-teresis (beta coefficient ¼ 9.4, P < .0005), but not with age(P ¼ .59) or spherical equivalent (P ¼ .16) (Table 3). TheR2 value for these was 0.33. There was no significant associ-ation with the glaucoma-related optic disc parameters whenmultivariable analysis was used. Regression analyses using op-tic disc parameters as the dependent variables did not showany difference in relative results; the measures of verticalcup-to-disc ratio, disc area, and cup area were not associatedwith corneal hysteresis or CCT in the models.

DISCUSSION

IN THIS COHORTOF BRITISHTWINS,WEHAVE SHOWNTHAT

corneal hysteresis does not appear to be associated withglaucoma-related optic disc endophenotypes, although itis associated with IOP, CCT, and age; and in particular isnot associated with the degree of optic disc cupping, which

VOL. 157, NO. 2 CORNEAL HYSTERESIS AND OTHER

defines glaucoma and is related to the severity of glaucom-atous visual field loss when other factors such as optic discsize and IOP are taken into account. There was no associ-ation between CCT and optic disc parameters in the multi-variable regression analysis. CCT, therefore, also did notappear to be associated with cup area or vertical cup-to-disc ratio, although (as expected) it is strongly related toIOP. By contrast, as one might expect, IOP was associatedwith optic disc area, vertical cup-to-disc ratio, and cup areain multivariable regression (data not shown) and is there-fore, in our opinion, truly independently associated withdisease.There has been very little work examining the relation-

ship between healthy variation of corneal hysteresis andoptic disc parameters in unselected adult populations. Pre-vious studies have been small and were generally clinic-based series of glaucomatous or myopic subjects. Insulland associates analyzed 100 individuals, over a third ofwhom had glaucoma, and found no significant correlationbetween corneal hysteresis and optic disc parameters,

443RISK FACTORS FOR GLAUCOMA

which were measured using the Heidelberg Retinal Tomo-graph II.21 Lim and associates also found no correlationbetween corneal hysteresis and optic disc area in a groupof Singaporean children.22 Conversely, Chang and associ-ates found that corneal hysteresis inversely related to discarea and cup area in a cohort of 50 myopic individuals,suggesting that an increased elasticity in myopic eyes maybe a contributing factor for the increased risk of developingglaucoma in this group. A separate group also found aninverse association between corneal hysteresis and verticalcup-to-disc ratio, using confocal scanning laser ophthal-moscopy, in 42 untreated newly diagnosed open-angleglaucoma patients.23We found a borderline significant cor-relation between corneal hysteresis and optic disc area, butthis was no longer apparent after regression analysis; thesmall sample sizes and inclusion criteria may have contrib-uted to the difference between their findings and ours.

In terms of CCT, we found an inverse correlation withoptic disc area, which was no longer significant in multivar-iable regression analysis. This is similar to a recent study byCankaya and associates, who examined normal individuals;however, it does not appear that they used regression anal-ysis.12 There does not appear to be any clear evidence inthe literature of a relationship between CCT and opticnerve head topography in eyes without glaucoma,24 whichis in agreement with our findings. Congdon and associatesshowed a negative relationship between CCT and verticalcup-to-disc ratio in eyes with glaucoma.2 Several otherstudies also found this inverse relationship, but these allanalyzed data from glaucomatous or myopic eyes.23,25,26

Similar to our findings, Lim and associates showed thatcorneal thickness and the biomechanical properties ofthe cornea did not correlate with optic disc parameters ina cohort of Singaporean children; however, when thedata were stratified by disc tilt, CCT did correlate withglobal disc area in children with tilted discs.22Most of thesestudies used Heidelberg retinal tomography or confocalscanning laser ophthalmoscopy for their disc data andseveral of them go on to comment that outlining the opticnerve head in the Heidelberg retinal topography software issubjective and is therefore a possible weakness of theirstudy. To our knowledge, we are the only such study tohave used optic disc planimetry from stereoscopic photo-graphs, which also involves subjective marking of thedisc and cup borders. This subjective marking does give

444 AMERICAN JOURNAL OF

possible measurement error, which may have affected ourresults.There are significant advantages of using quantitative

endophenotypes for the study of glaucoma, where distinctclassification can be difficult and somewhat arbitrary andresults in exclusion from analysis of useful data. Genome-wide association studies have recently shown the strengthof this approach: for example, genome-wide associationstudies of variation in optic disc size and cupping in Rotter-dam and TwinsUK unselected cohorts identified theCDKN2A gene as associated, which was subsequentlyconfirmed in glaucoma case-control genome-wide associa-tion studies27,28 (and, similarly, the TMCO1 gene in agenome-wide association study of IOP in population-based cohorts16 was also found in an advanced glaucomacase-control genome-wide association study27).This study was based on a largely female volunteer twin

population; however, the previously diagnosed prevalenceof glaucoma of 1.7% in this cohort is similar topopulation-based studies.29–31 The values and normaldistribution of corneal hysteresis, CCT, and IOP aresimilar to other population studies,32,33 suggesting nosignificant biases. Results will need to be confirmed incohorts with more men, given the female predominancein this cohort. Generally, ophthalmic twin data aregeneralizable to the singleton population,34 and twinshave similar morbidity to the rest of the population.35

Although we did not use the twin model in this study,the twin data can be used in epidemiologic research, asthe large TwinsUK cohort is deeply phenotyped and geno-typed and has been used in many studies of healthy aging,17

providing that appropriate statistical measures are used totake the familial relatedness into account, such as the clus-tering used in our regression analyses.In conclusion, we found no association between corneal

hysteresis and optic disc endophenotypes such as disc areaand vertical cup-to-disc ratio in this large study of healthyvariation. This suggests that in this largest study, to ourknowledge, in an unselected population of predominantlyhealthy individuals, corneal hysteresis is not an indepen-dent risk factor for glaucoma as defined by endophenotypicvariation. We also found no association with CCT and op-tic disc parameters, although it was, as expected, associ-ated with IOP and hysteresis, suggesting that CCT mayalso not be an independent glaucoma risk factor.

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTERESTand none were reported. This study was funded by the Guide Dogs for The Blind, Reading, UK. The TwinsUKRegistry is supported by theWellcome Trustand the European Community’s Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for HealthResearch (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust andKing’s College London. C.J.H. is an NIHR Senior Research Fellow. Contributions of authors: design and conduct of the study (F.C., S.J.F., C.J.H.); collec-tion, management, analysis, and interpretation of the data (F.C., S.J.F., A.N., P.G.H., C.J.H.); and preparation, review, or approval of themanuscript (F.C.,P.G.H., C.J.H.).

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Spinoza as an

Baruch Spinoza (1632-1677), famous as a philoso-pher and pillar of the rational Enlightenment,for many years actually earned his living as a

maker of telescopic lenses. He was knowledgeable aboutall the contemporary ideas about the physics of lightand optics, especially the mathematics of refraction.Although he did not make significant contributions tooptical theory, he was an enthusiastic observer of thenew world revealed by telescopes and microscopes. Such

Submitted by Ronald Fishman MD from the Cogan Ophtha

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Optician

luminaries as Huygens and Leibnitz recognized Spinoza’ssterling reputation as a maker of lenses and optical in-struments. Unfortunately, Spinoza had respiratory symp-toms since childhood and his unavoidable exposure toglass dust probably contributed to his premature deathat 44.

REFERENCE: Nadler, S: Baruch Spinoza. Heretic, LensGrinder. Arch Ophthalmol. 2000. Vol. 118:1426.

lmic History Society.

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