QUT Digital Repository: http://eprints.qut.edu.au/

Read, Scott A. and Collins, Michael J. (2009) Diurnal variation of corneal shape and thickness. Optometry and Vision Science, 86(3). pp. 170-180.

© Copyright 2009 American Academy of Optometry

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The diurnal variation of corneal shape and thickness.

Scott A Read (PhD)*

Michael J Collins (PhD)

*Corresponding Author

Contact Lens and Visual Optics Laboratory

School of Optometry

Queensland University of Technology

Room B556, O Block, Victoria Park Road, Kelvin Grove 4059

Brisbane, Queensland, Australia

Phone: 617 3864 5739, Fax: 617 3864 5665

Email: sa.read@qut.edu.au

Number of figures: 4

Number of Tables: 2

Word count: 4822

Date: 11th September 2008

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Abstract:

Purpose: To investigate associations between the diurnal variation in a range of

corneal parameters, including anterior and posterior corneal topography, and

regional corneal thickness.

Methods: Fifteen subjects had their corneas measured using a rotating

Scheimpflug camera (Pentacam) every 3-7 hours over a 24-hour period. Anterior

and posterior corneal axial curvature, pachymetry and anterior chamber depth

were analysed. The best fitting corneal sphero-cylinder from the axial curvature,

and the average corneal thickness for a series of different corneal regions were

calculated. Intraocular pressure and axial length were also measured at each

measurement session. Repeated measures ANOVA were used to investigate

diurnal change in these parameters. Analysis of covariance was used to

examine associations between the measured ocular parameters.

Results: Significant diurnal variation was found to occur in both the anterior and

posterior corneal curvature and in the regional corneal thickness. Flattening of

the anterior corneal best sphere was observed at the early morning

measurement (p < 0.0001). The posterior cornea also underwent a significant

steepening (p < 0.0001) and change in astigmatism 90/180° at this time. A

significant swelling of the cornea (p < 0.0001) was also found to occur

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immediately after waking. Highly significant associations were found between

the diurnal variation in corneal thickness and the changes in corneal curvature.

Conclusions: Significant diurnal variation occurs in the regional thickness and

the shape of the anterior and posterior cornea. The largest changes in the

cornea were typically evident upon waking. The observed non-uniform regional

corneal thickness changes resulted in a steepening of the posterior cornea, and a

flattening of the anterior cornea to occur at this time.

Key words: Diurnal variation, corneal topography, posterior cornea, corneal

thickness.

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Introduction

The cornea (in conjunction with the pre-corneal tear film) is the eye’s most

anterior optical surface, and is responsible for approximately two-thirds of the

eye’s refractive power. In recent years, advances in ophthalmic instrumentation,

has enhanced our ability to accurately, precisely and comprehensively define a

range of different corneal parameters such as anterior and posterior corneal

topography and corneal thickness. Detailed assessment of these corneal

parameters can be important for a number of different clinical and research

applications including: the diagnosis and monitoring of corneal ectatic disorders

such as keratoconus1-7 and pellucid marginal degeneration,8,9 the monitoring of

corneal dystrophies,10,11 the evaluation of corneal grafts,12-16 rigid and soft

contact lens fitting and design,17-20 the detection and monitoring of contact lens

induced corneal changes,21-26 the pre and post-operative screening of refractive

surgery candidates,27-33 and for customized refractive corrections.34-37

Knowledge of the natural diurnal variation occurring in corneal parameters is of

particular relevance to any clinical or research application requiring accurate and

precise measurements of the cornea. The cornea is typically found to be at it’s

thickest upon waking and then returns quickly to baseline within the first 2 hours

of waking.21,38-42 Measurements of the curvature,43,44 topography39,45,46 and

aberrations46 of the anterior corneal surface have also been found to undergo

significant diurnal variation. Less however, is known about the natural diurnal

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variation that occurs in other corneal parameters such as the cornea’s regional

thickness and the shape of the posterior cornea.

The difference in refractive index between the posterior corneal surface and

aqueous humor means that the posterior cornea makes a lesser contribution to

the refractive power of the whole eye, compared to that of the anterior cornea.

However, recent research investigating the shape of the posterior cornea has

highlighted the importance of this surface, showing that the posterior cornea

contributes significantly to the astigmatism47 and spherical aberration48 of the

eye. It has also been suggested that measurement of the posterior cornea may

be important for the early detection of keratoconus,5,7,29 particularly in the

detection of early ectasia in pre- and post-operative corneal refractive surgery

patient screening.29,49

We investigated the normal variation that occurs in the cornea of young adult

subjects over a 24 hour period using an instrument capable of measuring the

anterior and posterior cornea and the regional thickness of the cornea. To

investigate the influence of variations of other ocular parameters on the observed

corneal changes, we also simultaneously measured intraocular pressure (IOP)

and ocular pulse amplitude (OPA) using dynamic contour tonometry (a

tonometric technique thought to provide IOP measures largely independent of

corneal thickness),50-53 as well as measuring the axial length of the eye.

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Methods

Subjects and procedures

Fifteen young healthy, emmetropic adult subjects aged between 20 and 27 years

(mean age 22 years) were recruited for this study. Subjects were primarily

recruited from the students and staff of our university. Eight of the subjects were

male. All subjects were free of significant ocular or systemic disease and had no

history of ocular surgery or significant trauma. None of the subjects were contact

lens wearers. Prior to the study, each subject underwent an initial ophthalmic

examination to ensure good ocular health and to determine their refractive status.

All subjects had normal visual acuity of logMAR 0.00 or better. The subjects’

mean ± SD best sphere refraction was found to be -0.3 ± 0.4 DS (range +0.25 to

-1.13 DS), with a mean ± SD cylinder refraction of -0.2 ± 0.3 DC (range 0.00 to -

1.00 DC). No subject exhibited anisometropia of greater than 0.75 DS. Approval

from the university human research ethics committee was obtained prior to

commencement of the study and subjects gave written informed consent to

participate. All subjects were treated in accordance with the tenets of the

declaration of Helsinki.

This study took place over 5 separate days, with 2-4 subjects participating on

each day. On each day, 6 separate measurement sessions took place every 3-7

hours over a 24 hour period. At each measurement session the corneal

parameters (i.e. measures of the anterior and posterior cornea and corneal

thickness), axial length, and IOP of each subject’s right eye were measured in

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the sitting position. The initial measurement session for all subjects took place in

the morning, at least two hours after their reported time of awaking on that day.

Following the initial measurement, subjects undertook their regular daily

activities, and returned to the research laboratory for each subsequent

measurement session. Over the course of the study, measurement sessions

occurred at the following mean times: session 1 at 09:40 (range: 08:35-11:00),

session 2 at 13:00 (12:00-14:10), session 3 at 17:30 (17:00-18:30), session 4 at

22:30 (22:00-23:20), session 5 at 06:00 (05:00-06:40) and session 6 at 09:20

(08:00-10:20). One subject was unable to attend for one of their scheduled

measurement sessions. Following session 4 (mean time 22:30), subjects went to

sleep in individual darkened rooms within the research laboratory. The next

morning, subjects were awakened and instructed to sit for 5 minutes with their

eyes closed prior to the beginning of measurement session 5, to ensure that

postural variations in IOP54,55 did not influence the results. Following session 5,

subjects remained awake until the final measurement session. At each

measurement session, the time taken to perform the entire series of

measurements on each subject was approximately 20 minutes.

Corneal parameters were measured using the Pentacam HR system (Oculus Inc,

Wetzlar Germany). The Pentacam is a non-contact instrument that utilizes a

rotating Scheimpflug camera to measure the anterior segment. Previous studies

have shown the Pentacam to have excellent repeatability for measurements of

central corneal thickness,56-59 peripheral corneal thickness,59 anterior59 and

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posterior59,60 corneal curvature and anterior chamber depth.59,61-63 The

instrument has also been found to provide measurements of corneal thickness

from normal subjects that are in reasonable agreement with previously validated

clinical instruments.56-58 The Pentacam’s “50 picture 3D Scan” measurement

mode was used for all measures. For each measurement, the Pentacam’s

internal fixation target was adjusted so that subjects were viewing the target with

relaxed accommodation. At each measurement session a total of 5 corneal

scans were performed on each subject. The instrument also outputs a ‘quality

specification’ for each measurement which provides information about the

reliability of each 3D scan (this checks for poor alignment, excessive eye

movements, or any missing or invalid data). Any measurements flagged as

unreliable were repeated until 5 valid measures were obtained. Following image

capture, the instrument analyses these 50 cross sectional images of the anterior

eye and provides axial corneal curvature (front and back surface), elevation (front

and back corneal surface) and pachymetry maps. Anterior chamber depth (ACD)

(defined as the axial distance from the corneal endothelium to the anterior lens

surface) and central corneal thickness (CCT) at the corneal apex was also

recorded.

Axial length (defined in this case as the distance from the anterior corneal

surface to the retinal pigment epithelium along the visual axis) was measured

with the IOLMaster (Zeiss Meditec, Jena, Germany). The IOLMaster is a non-

contact instrument based upon the principles of partial coherence laser

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interferometry (PCI)64 and has been found to provide highly precise

measurements of axial length.64-67 Prior to the study, the calibration of the

IOLMaster was checked using the instrument’s test eye. For each subject a total

of 5 measurements of axial length were taken at each measurement session and

the mean of these readings calculated. Any measurements of axial length from

the IOLMaster with a reported signal-to-noise ratio of less than 2.0 were repeated

until 5 valid readings were attained.

All IOP measures were carried out using the Pascal Dynamic contour tonometer

(DCT) (Ziemer Ophthalmic Systems, Port, Switzerland). The DCT is a contact

tonometer that works on the principle of contour matching. The instrument

outputs measures of mean IOP and ocular pulse amplitude (OPA) (defined as the

difference between the diastolic and systolic IOP) as well as a quality score

(where a score of 4 or 5 indicates an unreliable result) for each measurement.

The DCT has been found to exhibit good inter- and intra-observer repeatability,

comparable to Goldmann applanation tonometry.50 The tonometer’s calibration

was checked using the Pascal tonometer performance test kit prior to

commencement of the study. Measurements with the DCT were taken according

to manufacturer instructions, following the instillation of a drop of local anesthetic

(0.4 % oxybuprocaine hydrochloride). A total of 3 DCT measurements were

taken for each subject at each measurement session and the mean IOP and

OPA from the three measurements calculated. Any measurement displaying a

quality score of 4 or 5 was repeated until 3 valid measures were obtained. All

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DCT measurements were taken by one clinician, experienced in the use of the

instrument.

Following the IOP measurements, a careful slit lamp examination was carried out

to ensure that no substantial epithelial disruption occurred as a result of the

contact tonometry procedure or anesthetic drops. There have been some

previous reports of transient changes in corneal thickness (lasting up to 10

minutes) following the instillation of topical anesthetic eye drops.68-70 However,

other investigators have reported that anesthetic eyedrops and contact

tonometry71 or anesthetic eye drops alone72 do not cause a significant change in

corneal thickness measures. To ensure that the corneal measurements were not

influenced by any epithelial disruption brought about by contact tonometry or

local anesthetic instillation, the tonometry was always the final measurement

performed at each session. Each measurement session was also spaced apart

by 3-7 hours. It is therefore unlikely that the contact tonometry procedure would

have substantially influenced our corneal thickness and topography results.

Data analysis

Following data collection, a range of corneal data was exported from the

Pentacam. Pachymetry, and corneal axial curvature (anterior and posterior

corneal surface), maps were all exported from the instrument for further analysis.

These maps are output from the Pentacam in a square grid format with a data

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point spacing of 0.1 mm. These corneal data were analyzed using customized

software.

To investigate the average diurnal change in corneal thickness for our population

of subjects, data from each of the 5 pachymetry maps for each subject from each

session were analysed. The mean corneal thickness for the central 3.5 mm

diameter (i.e. Region ‘1’ in Figure 1a), and for the peripheral 3.5 mm annulus

outside of this central zone were calculated (i.e. Region ‘2’ in Figure 1a) for each

map. The average thickness of the central corneal region (region 1) and average

thickness of the peripheral corneal region (region 2) for each subject at each

measurement session was calculated. To investigate the diurnal variation in the

data from these two regions of the cornea, a repeated measures analysis of

variance (ANOVA) was carried out with two within-subject parameters: time of

measurement and corneal region (the one subject who did not have complete

sets of data from all 6 measurement sessions was not included in the ANOVAs,

since it required all subjects to have 6 complete data sets).

The corneal thickness within each of these measured regions was further

analysed to calculate the average thickness of the cornea within a 90° nasal

segment (i.e. segment ‘N’ in Figure 1b), a 90° supe rior segment (i.e. segment ‘S’

in Figure 1b), a 90° temporal segment (i.e. segment ‘T’ in Figure 1b) and a 90°

inferior segment (i.e. segment ‘I’ in Figure 1b) within both the central and

peripheral corneal regions at each session for each subject. The amplitude of

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corneal thickness change (i.e. the difference between the maximum and

minimum corneal thickness values over the 6 measurement sessions) within

each segment for each of the corneal regions was calculated for each subject.

To investigate for significant differences between the mean amplitude of corneal

change occurring in each of the measured areas, a repeated measures ANOVA

was carried out with two within-subject factors: corneal region (i.e. central and

peripheral) and corneal segment (i.e. nasal, superior, temporal and inferior).

To investigate the average diurnal change in the anterior and posterior corneal

surfaces, each of the curvature maps were converted into axial power, assuming

a corneal refractive index of 1.376 and a refractive index of 1.336 for the

aqueous. The best fit corneal sphero-cylinder was then calculated for each of the

axial power maps for each subject at each session using the methods of Maloney

et al73 for a 3.5 mm and a 7 mm diameter for both the anterior and posterior

cornea. The best fit corneal sphero-cylinder was converted into the power

vectors M (best sphere) J0 (astigmatism 90/180°) an d J45 (astigmatism

45/135°) 74 and the average corneal power vectors calculated for each subject at

each session. The mean amplitude of change for each power vector describing

the anterior and the posterior cornea for each subject was calculated.

Each subject’s mean axial length, IOP, OPA, CCT and ACD were also calculated

for each measurement session, and group mean values calculated for each

parameter. To investigate the associations between the variations in corneal

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curvature and the variation occurring in the other measured variables, an

analysis of covariance was carried out as described by Bland and Altman75 for

the analysis of repeated observations. The significance of the association is

determined based upon the F statistic from the analysis of covariance.

Results

A number of the measured corneal variables were found to undergo significant

diurnal variation for our population of young adult emmetropic subjects. The

largest magnitude of change in all of the measured corneal variables was

typically found to occur at measurement session 5 immediately after waking.

Corneal thickness

All subjects were found to exhibit a similar pattern of change in their corneal

thickness. A very slight decrease (thinning) from the mean corneal thickness

was observed throughout the day (between measurement sessions 1 and 4), with

a swelling of the cornea evident upon waking (measurement session 5). By

measurement session 6 (mean time 09:20) the corneal thickness had typically

returned close to its mean level. The mean ± SD corneal thickness for the

central 3.5 mm region and peripheral 3.5 to 7.0 mm annulus region was found to

be 0.540 ± 0.029 mm and 0.598 ± 0.034 mm respectively. The mean amplitude

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of change over the 24-hour measurement period was 0.019 ± 0.008 mm and

0.022 ± 0.008 mm for the central and peripheral regions respectively. Repeated

measures ANOVA revealed a significant diurnal variation in corneal thickness

with time (p <0.0001), a significant difference between the two corneal regions (p

<0.0001) and a significant time*corneal region interaction (p<0.0001). Figure 1a

illustrates the mean change in corneal thickness in the two corneal regions over

time.

The mean amplitude of change in the nasal, superior, temporal and inferior

segments for the central and peripheral corneal regions is illustrated in Figure 1b.

Repeated measures ANOVA revealed the mean amplitude of change to be

significantly different between the central and peripheral corneal regions (p

<0.0001), while the amplitude of change in the different segments approached

significance (p=0.062). A significant interaction was found between corneal

region and corneal segment (p = 0.01). This interaction was primarily brought

about by the peripheral temporal region exhibiting significantly smaller amplitude

of thickness change compared with the superior (pair-wise comparison with

Bonferroni adjustment p = 0.003) and nasal peripheral regions (p = 0.002). We

re-analysed this pachymetry data by expressing the change in corneal thickness

as the percentage of the mean thickness in each region, and similar statistical

trends were observed.

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In Figure 2, pachymetry maps illustrating the difference in corneal thickness

observed between the first measurement session (session 1, mean time 09:40)

and the early morning measurement session immediately after awaking (session

5, mean time 06:20), for a typical subject (subject 5) are shown.

Corneal curvature

Significant change was also found in the corneal axial curvature data. The

largest change was again typically found to be evident upon waking. Axial

curvature maps illustrating the difference between session 1 and session 5 for

both the anterior and posterior cornea surfaces from a typical subject are shown

in Figure 2. The anterior cornea was found to flatten at the early morning

measurement (with greater flattening typically observed in the central cornea)

and the posterior cornea was typically found to steepen, with some increases

also found in astigmatism (a steepening in the vertical meridian) at this time.

The best fitting corneal sphero-cylinder was found to undergo some significant

change (Table 1). The diurnal variation in the anterior corneal best sphere (M)

was highly significant (repeated measures ANOVA p <0.0001 for ‘time of

measurement’), with a mean amplitude of change of 0.36 ± 0.11 D and 0.27 ±

0.09 D for the 3.5 mm and 7.0 mm diameters. The largest changes (a flattening

of the cornea) were observed immediately after subjects awoke. The magnitude

of change for the 3.5 mm analysis diameter was significantly greater than the

magnitude of change for the 7.0 mm analysis diameter (two-tailed paired t-test p

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<0.0001). The posterior corneal best sphere (M) was also found to undergo a

significant diurnal change (repeated measures ANOVA p <0.00001) with a

steepening of the posterior corneal curvature found upon waking. The mean

amplitude of change in the posterior corneal best sphere was 0.05 ± 0.03 D and

0.04 ± 0.02 D for the 3.5 and 7.0 mm diameters. The mean amplitude of change

in the central (3.5 mm diameter) posterior cornea was significantly greater than

the amplitude of change in the peripheral (7.0 mm diameter) posterior cornea (p

= 0.02).

The mean change in the anterior and posterior corneal best sphere (M) is

illustrated in Figure 3. It should be noted that a steepening of the anterior cornea

will lead to an increase in positive dioptric power, whereas a steepening of the

posterior cornea will lead to a decrease in positive dioptric power (due to the

refractive index difference between the cornea and the aqueous). To illustrate

this, the mean axial power best fitting sphero-cylinder was converted into axial

curvature (expressed in mm) and is also presented in Figure 3. The changes in

axial curvature (mm) give an indication of the shape changes occurring in the two

corneal surfaces, whereas the changes in axial power (D) give an indication of

the effective change in dioptric power. It is clear from Figure 3 that there is a

change in anterior and posterior axial curvature of a similar magnitude in

opposite directions (i.e. a flattening of the anterior and a steepening of the

posterior cornea). The resulting change in axial power for the anterior and

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posterior cornea is in the same direction but is substantially smaller in the

posterior cornea due to the refractive index difference at the aqueous interface.

Anterior corneal J0 (astigmatism 90/180°) and the a nterior and posterior corneal

J45 (astigmatism 45/135°) were not found to undergo significant diurnal change

(p>0.05) (Table 1, Figure 3). The posterior corneal J0 (astigmatism 90/180°)

however, did undergo significant diurnal change (p < 0.0001). The mean

posterior corneal J0 was found to be -0.16 ± 0.05 D and -0.14 ± 0.03 D for the

3.5 mm and 7.0 mm diameters respectively with a mean amplitude of change of

0.05 ± 0.02 D and 0.03 ± 0.01 D. The amplitude of change in J0 was significantly

greater for the 3.5 mm diameter analysis (p = 0.0008). The largest change in

posterior corneal J0 was again evident upon waking, with a decrease in axial

power J0 observed. This change in axial power for posterior J0 is brought about

by a steepening of the curvature of the posterior cornea in the vertical meridian.

Associations between variables

The diurnal variation observed in IOP, OPA, CCT and ACD for our population

has been reported in detail elsewhere.76 A number of significant associations

were found between the variation in corneal power vectors and the change in

other measured variables (i.e. IOP, OPA, CCT and ACD). The results from the

analysis of covariance, the correlation coefficient (r) and it’s associated

significance (p) for each of the corneal power vectors (7 mm diameter) is

presented in Table 2.

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The anterior corneal best sphere (M) was found to have a significant association

with the CCT (r= -0.62, p=<0.0001), indicating that a flattening of the anterior

cornea is associated with an increase in the thickness of the central cornea. The

variation in anterior corneal M was also found to be associated with the change in

ACD (r= 0.39, p= 0.003), indicative that a shallower anterior chamber was

associated with a flattening of the anterior cornea. A significant association was

also found between the changes in anterior corneal J45 (astigmatism 45/135°)

and CCT (r = 0.42, p = 0.001).

The power vectors from the posterior cornea also exhibited some significant

associations. The variation in the posterior corneal best sphere (M) was

significantly associated with the change in CCT (r = 0.73, p <0.0001), (i.e. a

steepening of the posterior cornea is associated with a thickening of the cornea).

The change in posterior corneal J0 was found to be significantly associated with

the change OPA (r = 0.40, p = 0.002), the change in CCT (r = -0.43, p = 0.006)

and with the change in ACD (r = 0.35, p = 0.01).

Discussion

We have found that small but significant diurnal changes occur in a number of

parameters describing the anterior and posterior shape and thickness of the

cornea in our population of young adult subjects. The largest magnitude

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changes in most corneal parameters were observed to occur upon subjects’

waking, which is consistent with a number of previous studies of diurnal variation

of the cornea.38-42,45 The general pattern and magnitude of diurnal change that

we have observed in anterior corneal curvature39,45,46 and central corneal

thickness38-42 are also consistent with those of previous investigations.

Furthermore, the posterior corneal curvature was also found to undergo

significant diurnal variation. To our knowledge, this is the first study to report

upon the physiological diurnal variation that occurs in the posterior cornea. A

gradual flattening of small magnitude was observed over the course of the day

(between 9:40 and 10:30 pm), and a significant steepening and alteration in

astigmatism of the posterior cornea were evident upon waking. The strong and

highly significant correlations found between the diurnal variations in the posterior

corneal shape (both posterior corneal best sphere and astigmatism 90/180°) and

CCT are indicative that these posterior corneal changes are related to changes in

corneal hydration occurring over the diurnal period.

It is evident from Figure 3 (top right) that the magnitude of spherical shape

change found in the posterior corneal curvature (mean amplitude of change 0.05

± 0.02 mm for a 7 mm corneal diameter with a steepening upon first waking) was

approximately equal and opposite to the change found in the anterior cornea

(mean amplitude of change 0.05 ± 0.01 mm for a 7 mm corneal diameter with a

flattening upon first waking). The optical effects of these posterior corneal

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changes though, are small (mean amplitude of change in axial power of 0.05 D),

and will not substantially impact upon the refractive power of the cornea.

In recent years, there has been interest in the shape of the posterior cornea

following laser refractive surgery27-33,77 with some evidence of a steepening of

the posterior cornea in some patients after this procedure.27,28,77 It is conceivable

that different patterns of diurnal change in the posterior cornea may be observed

in patients who have undergone laser refractive surgery (due to alterations in

corneal biomechanical properties and stromal collagen architecture as a result of

refractive surgery), and this may be a worthwhile area for future investigation.

Upon first waking, we found a flattening of the anterior corneal surface, a

steepening of the posterior corneal surface, a thickening of the cornea (of slightly

greater magnitude in the peripheral cornea) and a concomitant reduction in the

ACD.76 The pattern of corneal and anterior chamber change observed upon first

waking, are therefore indicative of corneal swelling with a backward movement of

the posterior corneal surface and a slight forward movement of the anterior

corneal surface (more so in the peripheral corneal regions). A schematic

diagram summarising the average changes that we observed in the cornea and

anterior chamber is presented in Figure 4. A backward movement of the

posterior corneal surface into the anterior chamber upon waking is consistent

with previous research into the swelling properties of the cornea.78-80

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Our experimental findings indicate that some differences exist between the

diurnal variation occurring in the curvature of the anterior and posterior corneal

surfaces. Both spherical shape and the astigmatism of the posterior cornea were

found to vary significantly, whereas significant change was only found in the

spherical shape of the anterior cornea. Previous anatomical studies have noted

differences in the stromal collagen fibril architecture,81 the density of stromal

collagen lamellae82 and the distribution of stromal proteoglycans83 between

anterior and posterior corneal regions. The swelling properties of the anterior

and posterior stroma have also been found to differ.78,80 Differential swelling

between the anterior and posterior corneal stroma may therefore account for

some of the differences we have observed in the diurnal variation in the curvature

of the anterior and posterior corneal surfaces.

By utilizing the Pentacam instrument, we were able to observe that diurnal

variation also occurs in the regional thickness of the cornea, with greater

amplitude of diurnal change found in the peripheral cornea (on average 3.46 %

change was found in the central region compared to 3.74% change in the

peripheral corneal region). A uniform change in thickness would not alter the

axial radius of curvature of the corneal surfaces. Therefore the peripheral

thickening we observed explains the flattening of the anterior corneal radius and

steepening of the posterior corneal radius. The majority of previous studies

investigating the diurnal variation of corneal thickness have been limited to

central corneal thickness measurements,38,40-42 or central and peripheral

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thickness with peripheral estimates based upon single points in the corneal

periphery.39 Lattimore et al84 measured the diurnal variation of the cornea’s

regional thickness using a scanning-slit device in one subject and also found that

a greater amplitude of diurnal change was evident in the peripheral cornea. The

non-uniform diurnal variation that we have observed in corneal thickness from

centre to periphery may relate to differences in the arrangement of stromal

collagen fibrils in these different corneal regions. Boote et al85 using x-ray

diffraction techniques found that whilst the diameter of stromal collagen fibrils

remained constant from centre to the periphery, the fibril spacing was greater in

the peripheral cornea. The denser packing of fibrils within the central cornea is a

possible reason for the slightly smaller amplitude of swelling noted in this region

compared to the more peripheral cornea. Previous studies of the physiological

diurnal variation of anterior corneal curvature have also found that a significant

flattening of the cornea occurs in the early morning.39,43-45 This pattern of change

in the anterior corneal curvature is consistent with the pattern of topographical

swelling that we have observed (i.e. a greater swelling in the peripheral cornea

upon first waking).

Some previous studies investigating ‘closed eye’ corneal swelling with contact

lens wear25,86-91 and open eye corneal swelling (induced by exposing the eye to

an “hypoxic” nitrogen gas atmosphere)92,93 have noted a different pattern of

regional corneal swelling, with greater swelling reported in the central cornea

compared to the periphery. The different pattern of swelling noted between our

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current study and previous studies of closed eye swelling with contact lenses

may be indicative of the different causative mechanisms or magnitudes of

swelling involved (approximately 2-6% central corneal swelling in our current

study and 10-12% in previous contact lens studies25,86-91).

We found a number of significant associations exist between the diurnal variation

in corneal curvature and the variations in the other measured ocular variables.

The change in CCT was found to be significantly correlated with the change in

the corneal best sphere of both the anterior and posterior surface. The strong

associations found between corneal curvature of both the anterior and posterior

cornea and CCT indicate that a reasonable proportion of the diurnal variation in

the curvature of the cornea can be accounted for by changes in corneal

thickness. Interestingly, we found no significant associations between the change

in IOP and the diurnal variation of any of the measured corneal parameters.

Dynamic contour tonometry has previously been found to be able to measure

IOP independently of corneal thickness.50-53 The use of this instrument therefore

should allow any independent effects of fluctuations in the eye’s internal pressure

on the shape of the cornea to be evaluated. It therefore appears that the

changes of IOP within the physiological range found in our study (mean

amplitude of IOP change of 3.12 mmHg) were not enough to significantly

influence the measured corneal parameters.

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In conclusion, we have found that small but significant changes occur in the

thickness of the cornea, and the shape of the anterior and posterior cornea over

a 24-hour period. This is the first study to quantify the normal physiological

diurnal variation that occurs in the posterior cornea. The posterior cornea was

found to undergo significant steepening and changes in astigmatism upon first

waking. However these changes had largely returned to normal by two to three

hours after waking. Small changes were also observed in the posterior cornea

throughout the day (a slight flattening). A significant swelling of the cornea was

evident upon waking, with the peripheral cornea exhibiting a greater magnitude of

change. Significant associations were also found between the diurnal change in

corneal thickness and the change in both the anterior and posterior corneal

curvature.

Acknowledgements:

The authors thank Inez Hsing and Andrew Tran for their assistance with data

collection and analysis procedures. We also thank Brett Davis for his assistance

with software analysis.

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Figures:

Figure 1: a. The mean change in corneal thickness over the 24-hour

measurement period expressed as the average difference from the mean corneal

thickness (repeated measures ANOVA, p<0.0001 for ‘measurement time’).

b. Mean amplitude of change over the 24-hour measurement period for the

different measured regions (1, 2) and segments (N-I) (repeated measures

ANOVA p <0.0001 for corneal region, and p = 0.062 for corneal segment).

Vertical error bars represent the standard error of the mean, horizontal error bars

represent the standard error in the mean time that the measurements were

taken.

41

Figure 2: Pachymetry and anterior and posterior curvature maps illustrating the

difference in corneal parameters between measurement session 1 and

measurement session 5 (immediately after waking) for a subject representative of

42

the group (Subject 5).

43

Figure 3: Change in corneal best fitting sphero-cylinder. Change in best sphere

(M) top, Astigmatism 90/180 (middle) and astigmatism 45/135 (bottom) shown for

both anterior and posterior corneal surfaces. Change in axial power (D) (left) and

change in axial curvature (mm) (right) are both presented to give an indication of

the optical and shape changes occurring in the two corneal surfaces. Vertical

error bars represent the standard error of the mean, horizontal error bars

represent the standard error in the mean time that the measurements were

taken.

44

45

Figure 4: Schematic illustration of the changes found in the cornea and anterior

chamber upon waking. The solid line represents the baseline cornea and

anterior lens surfaces (measurement session 1) and the dashed line represents

these surfaces upon first waking (measurement session 5). This shows a

backward movement of the posterior cornea, and a slight forward movement of

the anterior cornea accompanying the increase in CCT observed upon waking.

Note the diagram is not to scale and is an interpretation of the likely movement of

the relative surfaces based on our experimental data.

46

Tables:

Table 1: Mean and amplitude of diurnal variation of corneal axial power M, J0

and J45 for both the anterior and posterior cornea. Results from repeated

measures ANOVA for the change in each parameter over time also displayed.

47

Corneal

surface

Power

vector

Analysis

diameter

Mean ±

SD (D)

Mean

amplitude

of change

± SD (D)

P-Values repeated measures ANOVA

Time Region Time*

Region

Anterior

M

3.5 mm 48.35

± 1.65

0.36

± 0.11 <0.0001 <0.0001 0.19

7.0 mm 48.17

± 1.66

0.27

± 0.09

J0

3.5 mm 0.25

± 0.19

0.16

± 0.08 0.10 0.18 0.27

7.0 mm 0.28

± 0.19

0.08

± 0.04

J45

3.5 mm -0.015

±0.16

0.12

± 0.05 0.32 0.054 0.23

7.0 mm 0.018

± 0.15

0.07

± 0.03

Posterior

M

3.5 mm -6.19

± 0.26

0.05

± 0.03 <0.0001 0.003 0.75

7.0 mm -6.22

± 0.26

0.04

± 0.02

J0

3.5 mm -0.16

± 0.05

0.05

± 0.02 0.004 0.002 0.3

7.0 mm -0.14

± 0.03

0.03

± 0.01

48

J45

3.5 mm 0.017

± 0.05

0.04

± 0.01 0.75 0.06 0.75

7.0 mm 0.006

± 0.03

0.03

± 0.01

Table 2: Results from analysis of co-variance investigating association between

the change in each of the corneal power vectors for the anterior and posterior

cornea (for a 7 mm analysis diameter) and the other measured ocular

parameters. Note p-values adjusted for multiple comparisons.

Surface Power

Vector

ANCOVA

result

Ocular variable

∆ IOP ∆ OPA ∆ Axial ∆ CCT ∆ ACD

49

length

Anterior

∆ M r

(p)

-0.16

(0.86)

0.19

(0.49)

-0.08

(1.00)

-0.62

(<0.0001)

0.39

(0.003)

∆ J0 r

(p)

-0.08

(1.0)

-0.11

(1.0)

-0.22

(0.32)

0.21

(0.34)

0.08

(1.0)

∆ J45 r

(p)

0.08

(1.0)

-0.01

(1.0)

-0.12

(1.0)

0.42

(0.001)

-0.03

(1.0)

Posterior

∆ M r

(p)

-0.26

(0.12)

0.05

(1.0)

-0.03

(1.0)

0.73

(<0.0001)

0.24

(0.17)

∆ J0 r

(p)

0.23

(0.27)

0.40

(0.002)

-0.13

(1.0)

-0.43

(0.0006)

0.35

(0.01)

∆ J45 r

(p)

-0.11

(1.0)

-0.11

(1.0)

0.21

(0.34)

-0.11

(1.0)

-0.01

(1.0)