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Ocular characteristics of anisometropia

Stephen J Vincent

BAppSc (Optom) (Hons)

Institute of Health and Biomedical Innovation

School of Optometry

Queensland University of Technology

Brisbane

Australia

Submitted as part of the requirements for the award of the degree

Doctor of Philosophy, 2011

Keywords

ii

Keywords

Anisometropia

Myopia

Asymmetry

Amblyopia

Aberrations

Dominance

Abstract

iii

Abstract

Animal models of refractive error development have demonstrated that visual

experience influences ocular growth. In a variety of species, axial anisometropia

(i.e. a difference in the length of the two eyes) can be induced through unilateral

occlusion, image degradation or optical manipulation. In humans, anisometropia

may occur in isolation or in association with amblyopia, strabismus or unilateral

pathology. Non-amblyopic myopic anisometropia represents an interesting

anomaly of ocular growth, since the two eyes within one visual system have grown

to different endpoints. These experiments have investigated a range of biometric,

optical and mechanical properties of anisometropic eyes (with and without

amblyopia) with the aim of improving our current understanding of asymmetric

refractive error development.

In the first experiment, the interocular symmetry in 34 non-amblyopic myopic

anisometropes (31 Asian, 3 Caucasian) was examined during relaxed

accommodation. A high degree of symmetry was observed between the fellow

eyes for a range of optical, biometric and biomechanical measurements. When the

magnitude of anisometropia exceeded 1.75 D, the more myopic eye was almost

always the sighting dominant eye. Further analysis of the optical and biometric

properties of the dominant and non-dominant eyes was conducted to determine

any related factors but no significant interocular differences were observed with

Abstract

iv

respect to best-corrected visual acuity, corneal or total ocular aberrations during

relaxed accommodation.

Given the high degree of symmetry observed between the fellow eyes during

distance viewing in the first experiment and the strong association previously

reported between near work and myopia development, the aim of the second

experiment was to investigate the symmetry between the fellow eyes of the same

34 myopic anisometropes following a period of near work. Symmetrical changes in

corneal and total ocular aberrations were observed following a short reading task

(10 minutes, 2.5 D accommodation demand) which was attributed to the high

degree of interocular symmetry for measures of anterior eye morphology, and

corneal biomechanics. These changes were related to eyelid shape and position

during downward gaze, but gave no clear indication of factors associated with near

work that might cause asymmetric eye growth within an individual.

Since the influence of near work on eye growth is likely to be most obvious during,

rather than following near tasks, in the third experiment the interocular symmetry

of the optical and biometric changes was examined during accommodation for 11

myopic anisometropes. The changes in anterior eye biometrics associated with

accommodation were again similar between the eyes, resulting in symmetrical

changes in the optical characteristics. However, the more myopic eyes exhibited

slightly greater amounts of axial elongation during accommodation which may be

Abstract

v

related to the force exerted by the ciliary muscle. This small asymmetry in axial

elongation we observed between the eyes may be due to interocular differences in

posterior eye structure, given that the accommodative response was equal

between eyes. Using ocular coherence tomography a reduced average choroidal

thickness was observed in the more myopic eyes compared to the less myopic eyes

of these subjects. The interocular difference in choroidal thickness was correlated

with the magnitude of spherical equivalent and axial anisometropia.

The symmetry in optics and biometrics between fellow eyes which have undergone

significantly different visual development (i.e. anisometropic subjects with

amblyopia) is also of interest with respect to refractive error development. In the

final experiment the influence of altered visual experience upon corneal and ocular

higher-order aberrations was investigated in 21 amblyopic subjects (8 refractive, 11

strabismic and 2 form deprivation). Significant differences in aberrations were

observed between the fellow eyes, which varied according to the type of

amblyopia. Refractive amblyopes displayed significantly higher levels of 4th order

corneal aberrations (spherical aberration and secondary astigmatism) in the

amblyopic eye compared to the fellow non-amblyopic eye. Strabismic amblyopes

exhibited significantly higher levels of trefoil, a third order aberration, in the

amblyopic eye for both corneal and total ocular aberrations. The results of this

experiment suggest that asymmetric visual experience during development is

associated with asymmetries in higher-order aberrations, proportional to the

magnitude of anisometropia and dependent upon the amblyogenic factor. This

Abstract

vi

suggests a direct link between the development of higher-order optical

characteristics of the human eye and visual feedback.

The results from these experiments have shown that a high degree of symmetry

exists between the fellow eyes of non-amblyopic myopic anisometropes for a range

of biomechanical, biometric and optical parameters for different levels of

accommodation and following near work. While a single specific optical or

biomechanical factor that is consistently associated with asymmetric refractive

error development has not been identified, the findings from these studies suggest

that further research into the association between ocular dominance, choroidal

thickness and higher-order aberrations with anisometropia may improve our

understanding of refractive error development.

Contents

vii

Table of Contents

Chapter 1: Literature Review ............................................................................... 1

1.1 Refractive error development ....................................................................... 1

1.1.1 Emmetropisation .................................................................................... 1

1.1.2 Biometric changes during emmetropisation ............................................ 2

1.1.3 Biometric basis of refractive errors .......................................................... 3

1.1.4 Altered visual experience during emmetropisation .................................. 4

1.1.4.1 Ocular pathology .............................................................................. 5

1.1.4.2 Refractive amblyopia ........................................................................ 6

1.1.4.3 Strabismic amblyopia........................................................................ 7

1.1.4.4 Form deprivation amblyopia ............................................................. 8

1.1.4.5 Treatment of amblyopia ................................................................... 8

1.1.5 Animal studies of refractive error development ...................................... 8

1.1.6 Retinal image manipulation in humans ................................................. 11

1.1.6.1 Orthokeratology ............................................................................. 11

1.1.6.2 Bifocal contact lenses ..................................................................... 12

1.1.6.3 Monovision .................................................................................... 14

1.1.7 Summary .............................................................................................. 16

1.2 Myopia development - aetiological factors .................................................. 18

1.2.1 Myopia development - optical factors ................................................... 20

1.2.1.1 Accommodation ............................................................................. 20

Contents

viii

1.2.1.2 Higher-order aberrations ................................................................... 22

1.2.1.3 Variables that influence higher-order aberrations ........................... 23

1.2.1.4 Interocular symmetry of higher-order aberrations .......................... 25

1.2.1.5 Compensatory mechanisms ............................................................ 31

1.2.1.6 Higher-order aberrations and refractive error development ............ 31

1.2.2 Summary .............................................................................................. 38

1.3 Myopia development - mechanical factors .................................................. 39

1.3.1 Mechanical changes during near work .................................................. 39

1.3.1.1 Convergence .................................................................................. 39

1.3.1.2 Ciliary body forces .......................................................................... 40

1.3.2 Intraocular pressure ............................................................................. 42

1.3.2.1 Animal models ............................................................................... 42

1.3.2.2 Intraocular pressure and myopia in children ................................... 44

1.3.2.3 Intraocular pressure and myopia in adults ...................................... 47

1.3.3 Summary .............................................................................................. 49

1.4 Non-amblyopic anisometropia .................................................................... 50

1.4.1 Genetic influence .................................................................................. 51

1.4.2 Longitudinal studies .............................................................................. 52

1.4.3 Biometric studies .................................................................................. 54

1.4.4 Theories of asymmetric refractive error development ........................... 56

Contents

ix

1.4.4.1 Optical factors ................................................................................ 56

1.4.4.2 Mechanical factors ......................................................................... 63

1.4.4.3 Other factors .................................................................................. 68

1.4.5 Summary .............................................................................................. 72

1.5 Amblyopia associated anisometropia .......................................................... 74

1.5.1 Emmetropisation in amblyopic eyes ...................................................... 74

1.5.1.1 Refractive amblyopia ...................................................................... 75

1.5.1.2 Strabismic amblyopia...................................................................... 76

1.5.2 Biometric studies of amblyopia ............................................................. 79

1.5.2.1 Cornea ............................................................................................ 79

1.5.2.2 Axial length .................................................................................... 80

1.5.3 Optical factors ...................................................................................... 83

1.5.3.1 Higher-order aberrations in amblyopia ........................................... 83

1.5.3.2 Accommodation in amblyopia ........................................................ 87

1.5.4 Summary .............................................................................................. 91

1.6 Rationale .................................................................................................... 92

Chapter 2: Interocular symmetry in myopic anisometropia ................................ 94

2.1 Introduction ................................................................................................ 94

2.2 Methods ..................................................................................................... 97

2.2.1 Subjects and screening .......................................................................... 97

Contents

x

2.2.2 Data collection procedures ................................................................... 98

2.2.2.1 Axial length .................................................................................... 99

2.2.2.2 Corneal topography ........................................................................ 99

2.2.2.3 Ocular biomechanics/biometrics .................................................. 103

2.2.2.4 Ocular aberrations ........................................................................ 103

2.2.2.5 Morphology of the palpebral fissure ............................................. 105

2.2.3 Statistical analysis ............................................................................... 108

2.3 Results ...................................................................................................... 109

2.3.1 Overview ............................................................................................ 109

2.3.2 Sighting ocular dominance .................................................................. 109

2.3.3 Morphometry of the palpebral fissure ................................................ 115

2.3.4 Ocular biomechanics ........................................................................... 120

2.3.5 Anterior eye biometrics ...................................................................... 122

2.3.6 Corneal optics ..................................................................................... 122

2.3.7 Corneal higher-order aberrations ........................................................ 125

2.3.8 Total ocular monochromatic aberrations ............................................ 129

2.4 Discussion ................................................................................................. 133

2.5 Conclusions ............................................................................................... 147

Chapter 3: Ocular changes following near work in myopic anisometropia........ 148

3.1 Introduction .............................................................................................. 148

Contents

xi

3.2 Methods ................................................................................................... 152

3.2.1 Subjects and screening ........................................................................ 152

3.2.2 Data collection procedures .................................................................. 152


3.3 Results ...................................................................................................... 156

3.3.1 Axial length ......................................................................................... 156

3.3.2 Corneal optics ..................................................................................... 159

3.3.2.1 Corneal changes following near work ............................................ 159

3.3.2.2 Corneal refractive changes and palpebral aperture morphology .... 166

3.3.2.3 Corneal refractive changes and corneal biomechanics ................... 168

3.3.2.4 Corneal aberrations ...................................................................... 170

3.3.3 Total ocular monochromatic aberrations ............................................. 172

3.4 Discussion ................................................................................................. 176

3.5 Conclusions ............................................................................................... 182

Chapter 4: Ocular changes during accommodation in myopic anisometropia ... 183

4.1 Introduction .............................................................................................. 183

4.2 Methods ................................................................................................... 187


4.2.2 Data collection procedures .................................................................. 188

4.2.3 Data analysis ....................................................................................... 192

Contents

xii


4.3 Results ...................................................................................................... 195

4.3.1 Interocular symmetry ......................................................................... 196

4.3.1.1 Biometrics .................................................................................... 196

4.3.1.2 Ocular coherence tomography ...................................................... 201

4.3.1.3 Optics ........................................................................................... 203

4.3.2 Ocular dominance ............................................................................... 206

4.4 Discussion ................................................................................................. 211

4.5 Conclusions ............................................................................................... 220

Chapter 5: Ocular characteristics in asymmetric visual experience ................... 221

5.1 Introduction .............................................................................................. 221

5.2 Methods ................................................................................................... 224


5.2.2 Data collection procedures ................................................................. 225


5.3. Results ..................................................................................................... 226

5.3.1 Overview ............................................................................................ 226

5.3.2 Morphology of the palpebral fissure ................................................... 229

5.3.3 Ocular biomechanics ........................................................................... 229

5.3.4 Corneal optics ..................................................................................... 232

Contents

xiii

5.3.5 Corneal astigmatism and palpebral aperture morphology ................... 236

5.3.6 Corneal aberrations ............................................................................ 239

5.3.7 Total ocular monochromatic aberrations ............................................. 246

5.4 Discussion ................................................................................................. 252

5.5 Conclusions ............................................................................................... 265

Chapter 6: Conclusions .................................................................................... 266

6.1 Summary and main findings ...................................................................... 266

6.1.1 Myopic anisometropia - ocular dominance .......................................... 266

6.1.2 Myopic anisometropia - near work and accommodation ..................... 270

6.1.3 Asymmetric visual experience - amblyopic anisometropia ................... 275

6.2 Future research directions ......................................................................... 278

References ...................................................................................................... 281

Appendices ...................................................................................................... 328

Appendix 1: Ethics ....................................................................................... 328

Appendix 2: Publications arising from the thesis .......................................... 335

Contents

xiv

List of Figures

Figure 1.1 Interocular mirror symmetry of refractive power maps in

isometropia. 26

Figure 2.1 Eyelid margin contour fit with polynomial function (Y = AX2 + BX +

C) 107

Figure 2.2 Correlation between spherical equivalent anisometropia (D) and

interocular difference in axial length (mm) in non-amblyopic

myopic anisometropia. 112

Figure 2.3 Scatter plot of sighting dominant eyes with respect to level of


Figure 2.4 Graphical representation of the morphology of the palpebral

aperture of the more and less myopic eyes during primary and

downward gaze. 118

Figure 2.5 Interocular symmetry of intraocular pressure in myopic

anisometropia. 121

Figure 2.6 Interocular symmetry of corneal biomechanics in myopic

anisometropia. 121

Figure 3.1 Example of experimental procedure. Measurements taken before

and after a short near work task with washout periods following

reading. 153

Figure 3.2 Change in axial length following reading for more and less myopic

eyes. 158

Contents

xv

Figure 3.3 Change in axial length following reading for dominant and non-

dominant eyes. 158

Figure 3.4 Refractive power maps for subject 22. The refractive power maps

and digital image of the left (less myopic) eye have been

transposed to right eyes using customised software to account for

mirror symmetry. 162

Figure 3.5 Mean refractive change (post – pre-reading) for more and less

myopic eyes (top) and dominant and non-dominant eyes (bottom)

after ten minutes of reading. Inner circle 4 mm diameter, outer

circle 6 mm diameter (n = 34 subjects). 164

Figure 3.6 Change in corneal vector M (D) following reading vs vertical

palpebral aperture in downward gaze (mm). 167

Figure 3.7 Change in corneal vector M (D) following reading vs vertical

distance from pupil centre to eyelid margin (mm). 167

Figure 3.8 Change in corneal astigmatism following reading vs corneal

resistance factor. Left panels: Change in vector J0 vs corneal

resistance factor. Right panels: Change in vector J45 vs corneal

resistance factor. 169

Figure 3.9 Group mean change in corneal RMS following reading for more

and less myopic eyes over 4 mm and 6 mm corneal diameters. 171

Figure 3.10 Correlation between change in corneal Zernike coefficients C(3,-3)

and C(3,-1) following reading over a 4 mm corneal diameter. 171

Contents

xvi

Figure 4.1 Diagram of the experimental setup to allow measurement of

ocular biometrics or ocular aberrations during accommodation. 191

Figure 4.2 Flow chart of the procedure used to improve the signal to noise

ratio of OCT images and measure the retinal and choroidal

thickness at the fovea. 194

Figure 4.3 Mean change in measured axial length during accommodation for

the more and less myopic eyes. 200

Figure 4.4 Mean change in corrected axial length during accommodation for

the more and less myopic eyes. 200

Figure 4.5 Correlation between the interocular difference in axial length

(mm) and the interocular difference in choroidal thickness

(microns). 202


the interocular difference in choroidal thickness (microns). 202

Figure 4.7 Correlation between the interocular differences accommodation

(more myopic minus less myopic eye) at 2.5 and 5.0 D stimuli. 209

Figure 4.8 Higher-order RMS and spherical aberration C(4,0) (microns) at 0,

2.5 and 5.0 D accommodation demands (natural pupil diameter). 210


interocular difference in axial length (mm) for all amblyopic

subjects (n = 21). 228

Contents

xvii

Figure 5.2 Graphical representation of the morphology of the palpebral

aperture of the amblyopic and non-amblyopic eyes during primary

gaze. 230

Figure 5.3 Correlation between corneal vectors M (D) and J0 (D) and

parameters describing anterior eye morphology (mm). 238

Figure 5.4 Third and fourth order mean Zernike corneal wavefront

coefficients (microns) for the amblyopic and non-amblyopic eyes

(6 mm analysis). 242


interocular difference in corneal wavefront Zernike coefficient of

primary horizontal coma C(3, 1) (microns) (6 mm analysis). 245

Figure 5.6 Correlation between the interocular difference in accommodative

response (D) and spherical equivalent anisometropia (D) (top

panel) and magnitude of amblyopia (logMAR) (bottom panel). 251

Figure 6.1 Diagram of ocular characteristics examined in non-amblyopic and

amblyopic anisometropia which may be associated with

asymmetric growth. 267

Contents

xviii

List of Tables

Table 1.1 Summary of studies examining interocular symmetry of

wavefront aberrations. 28

Table 1.2 Summary of studies examining intraocular pressure in

anisometropia. 67

Table 2.1 Overview of instruments used and parameters measured in

experiment 1. 100

Table 2.2 Overview of the more and less myopic eyes of the non-

amblyopic myopic anisometropes. 110

Table 2.3 Distribution of sighting dominant eyes in more and less myopic

eyes of anisometropes. 113

Table 2.4 Characteristics of the low and high anisometropia groups. 113

Table 2.5 Distribution of right and left eye dominance in low and high

anisometropia groups. 113

Table 2.6 Characteristics of right and left eyes in the low and high

anisometropia groups. 114

Table 2.7 Characteristics of dominant and non-dominant eyes in the low

and high anisometropia groups. 114

Table 2.8 Mean anterior eye morphology measurements in primary and

downward gaze for the more and less myopic eyes. 117

Table 2.9 Explanation of the anterior eye measurements and

abbreviations used in Table 2.8. 117

Contents

xix

Table 2.10 Correlation analysis for the interocular difference in anterior eye

morphology and spherical equivalent anisometropia (D). 119

Table 2.11 Mean and standard deviation of intraocular pressure and

corneal biomechanics in myopic anisometropia. 121

Table 2.12 Mean values for corneal and anterior chamber parameters in


Table 2.13 Mean corneal refractive power vectors M, J0 and J45 (D) for the

more and less myopic eyes (4 and 6 mm corneal diameters). 127

Table 2.14 Corneal RMS values for more and less myopic eyes (4 and 6 mm

corneal diameters). 127

Table 2.15 Interocular symmetry of corneal aberrations (Zernike

coefficients) in myopic anisometropia (4 and 6 mm corneal

diameters). 128

Table 2.16 Interocular symmetry of total monochromatic aberrations

(Zernike coefficients) in myopic anisometropia (4, 5 and 6 mm

pupil diameters). 130

Table 2.17 Total monochromatic aberrations (Zernike coefficients and RMS

values for the more and less myopic eyes (4, 5 and 6 mm pupil

diameters). 131

Table 2.18 Correlation analysis for the interocular difference of total

monochromatic aberrations (Zernike coefficients and RMS

values) and spherical equivalent anisometropia (D) (4, 5 and 6

mm pupil diameters). 132

Contents

xx

Table 3.1 Mean axial length (mm) pre and post reading task for the more

and less myopic eyes in myopic anisometropia. 157

Table 3.2 Mean axial length (mm) pre and post reading task for the

dominant and non-dominant eyes in myopic anisometropia. 157

Table 3.3 Mean corneal vectors M, J0 and J45 (D) before and after reading

for the more and less myopic eyes (4 and 6 mm corneal

diameters). 163

Table 3.4 Mean corneal vectors M, J0 and J45 (D) before and after reading

for the dominant and non-dominant eyes (4 and 6 mm corneal

diameters). 163

Table 3.5 Pre and post-reading corneal RMSE values (D) for the more and

less myopic eyes (4 and 6 mm corneal diameters). 165

Table 3.6 Total monochromatic aberrations (RMS values) before and after

reading for the more and less myopic eyes (various pupil

diameters). 174

Table 3.7 Total monochromatic aberrations (RMS values) before and after

reading for the dominant and non-dominant eyes (various pupil

diameters). 174

Table 3.8 Mean change in total monochromatic aberrations (individual

Zernike term coefficients) following reading for the more and

less myopic eyes (4, 5 and 6 mm pupil diameters). 175

Table 4.1 Mean biometric parameters from the Lenstar for the more and

less myopic eyes during three levels of accommodation. 197

Contents

xxi

Table 4.2 Mean ocular parameters from COAS analysis for the more and

less myopic eyes during three levels of accommodation (natural

pupil diameter). 207

Table 4.3 Mean ocular parameters from COAS analysis for the more and

less myopic eyes during three levels of accommodation (3 mm

pupil diameter). 208

Table 4.4 Distribution of subjects according to the dominant or non-

dominant eye displaying a greater accommodative response for

the 5 D stimuli. 209

Table 5.1 Overview of the amblyopic and non-amblyopic eyes in all

subjects (n = 21). 227

Table 5.2 Overview of the amblyopic and non-amblyopic eyes in the

strabismic (n = 11) and refractive (n = 8) amblyopes. 227

Table 5.3 Mean anterior eye morphology measurements in primary gaze

for the amblyopic and non-amblyopic eyes. 231

Table 5.4 Explanation of anterior eye measurements and abbreviations

used in Table 5.4. 231

Table 5.5 Mean and standard deviation of intraocular pressure and

corneal biomechanics in the amblyopic and non-amblyopic eyes. 233

Table 5.6 Mean values for corneal and anterior chamber parameters in

the amblyopic and non-amblyopic eyes. 235

Table 5.7 Mean corneal vectors M, J0 and J45 (D) in the amblyopic and

non-amblyopic eyes (4 and 6 mm corneal diameters). 235

Contents

xxii

Table 5.8 Correlation analysis of corneal vectors M, J0 and J45 (D) with

various palpebral aperture biometrics (mm) (6 mm corneal

diameter). 237

Table 5.9 Correlation analysis of interocular difference in corneal vectors

M, J0 and J45 (D) with interocular difference in palpebral

aperture biometrics (6 mm corneal diameter). 237

Table 5.10 Corneal aberrations (Zernike coefficients) for the amblyopic and

non-amblyopic eyes (4 mm analysis). 243

Table 5.11 Corneal aberrations (Zernike coefficients) for the amblyopic and

non-amblyopic eyes (6 mm analysis). 244

Table 5.12 Correlation analysis of interocular difference in corneal

aberrations (Zernike coefficients) (microns) and the magnitude

of spherical equivalent anisometropia (D). 245

Table 5.13 Total monochromatic aberrations for the amblyopic and non-

amblyopic eyes (distance fixation) (4 mm pupil diameter). 248

Table 5.14 Correlations analysis for the interocular difference in total

monochromatic aberrations (Zernike coefficients) (microns) and

spherical equivalent anisometropia (D) (4 mm pupil diameter). 249

Table 5.15 Lower (D) and higher-order monochromatic aberrations

(microns) during distance and near fixation for the amblyopic

and non-amblyopic eyes (n = 11) (4 mm pupil diameter). 250

Table 6.1 Hypotheses explaining the association between ocular

dominance and non-amblyopic myopic anisometropia. 271

Contents

xxiii

Table 6.2 Hypotheses investigated of asymmetric refractive error

development in non-amblyopic myopic anisometropia. 273

Table 6.3 Summary of findings for amblyopic anisometropia as a result of

asymmetric visual experience. 276

Abbreviations

xxiv

Abbreviations

ACC Accommodation

ACD Anterior chamber depth

ASL Anterior segment length

AXL Axial length

CCT Central corneal thickness

CH Corneal hysteresis

CRF Corneal resistance factor

GAT Goldmann applanation tonometry

HOA Higher order aberration

ILM Inner limiting membrane

IOD Interocular difference

IOP Intraocular pressure

IOPcc Corneal compensated intraocular pressure

IOPg Goldmann correlated intraocular pressure

K Corneal power

LT Lens thickness

NCT Non-contact tonometry

NITM Near work induced transient myopia

OPA Ocular pulse amplitude

POBF Pulsatile ocular blood flow

Q Corneal asphericity

RMS Root mean square

RPE Retinal pigment epithelium

SEq Spherical equivalent

TA Tonic accommodation

VCD Vitreous chamber depth

Statement of Authorship

xxv

Statement of original authorship

The work contained in this thesis has not been previously submitted for a degree or

diploma at this or any other higher education institution. To the best of my

knowledge and belief, the thesis contains no material previously published or

written by another person except where due reference is made.

Signature:

Date:

Acknowledgements

xxvi

Acknowledgements

I would like to thank my principal supervisor Professor Michael Collins for

welcoming me into the Contact Lens and Visual Optics Laboratory and for his

guidance, patience and expert advice over the last three years.

Thank you also to my associate supervisors Dr Scott Read and Professor Leo Carney,

for their assistance and attention to detail throughout all stages of my candidature.

Many thanks to Professor Maurice Yap, Mr Percy Ng and the staff at the Hong Kong

Polytechnic University who assisted with various aspects of the data collection.

I would also like to acknowledge Mrs Payel Chatterjee, Mr Ranjay Chakraborty and

Dr David Alonso Caneiro for their assistance with the data analysis in Chapter 4 and

Mr Stephen Witt and Dr Fan Yi for their help in translating foreign texts.

Furthermore, I would like to express my appreciation towards Dr Carol Lakkis who

encouraged me to pursue a research degree and Dr Geoff Sampson who has been a

reliable and helpful listener.

Finally, I am truly grateful for my wife Roslyn and her unwavering encouragement

and support throughout my studies.

Chapter 1

1

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11..11..11 EEmmmmeettrrooppiissaattiioonn

Emmetropia, the refractive condition in which distant objects are focused on to the

retina without accommodative effort, requires a precise correlation between the

optical components and axial length of the eye. During ocular growth, to maintain

emmetropia, the eye must coordinate corneal and lenticular flattening in order to

compensate for axial elongation (Brown et al 1999). Any disruption to the

coordinated growth of the ocular components will result in a refractive error.

There is a distinct difference in the distribution of refractive errors between

newborns and young children age 6-8. In newborns the range of refractive errors

approximates a normal distribution with a peak or mean of 2-3 D of hyperopia

(Ingram and Barr 1979, Wood et al 1995). By age 6 there is a significant reduction

in hyperopia and the distribution of refractive error becomes leptokurtic with a

peak at emmetropia or low hyperopia and a reduction in the magnitude and

variation in refractive errors (Saunders 1995). Emmetropisation is the term used to

describe the reduction in refractive errors during early life towards emmetropia.

Emmetropisation may be a genetically pre-determined process which occurs

naturally with normal eye growth; the optical components of the eye decrease in

proportion with eye growth to minimise refractive error. However, there is

Chapter 1

2

evidence from both human and animal studies of refractive error development that

visual experience regulates eye growth (Wildsoet 1997).

11..11..22 BBiioommeettrriicc cchhaannggeess dduurriinngg eemmmmeettrrooppiissaattiioonn

The most rapid period of ocular growth occurs within the first two years of life with

an increase in axial length of 3-4 mm. The rate of growth then reduces significantly

with an increase of approximately 1.2 mm from ages 2-5 and an additional 1.4 mm

increase during a slow juvenile growth phase from age 5 to teenage years (Larsen

1971a). The increase in anterior and vitreous chamber depth follows a similar

pattern to the changes observed in the total axial length (Larsen 1971b). A rapid

growth period during the first two years of life and then slower growth phases up

to puberty. While the axial dimensions of the anterior and vitreous chamber

increase during development lens thickness decreases from infancy throughout

childhood (Larsen 1971c).

These changes in axial length are accompanied by a flattening of the cornea and

crystalline lens. Mutti et al (2005) examined infants at 3 and 9 months of age and

observed a reduction in corneal and lenticular power of 1.07 D and 3.62 D

respectively. Zadnik et al (1993) observed a smaller reduction in lens power (1.35

D) between the ages of 6-14 years. Mutti et al (2005) also found that the reduction

in hyperopia during the first year of life was significantly correlated with the

increase in axial length, but not with the changes in corneal or lens power. This

Chapter 1

3

study suggests that axial growth is the most important factor in emmetropisation,

with changes in refractive power of the cornea or lens playing a smaller role.

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Several studies which have examined the correlations between the magnitude of

refractive error and the various ocular components suggest that axial length, in

particular vitreous chamber depth, is the primary determinant of refractive error.

Despite variations in subject age, ethnicity and experimental technique several

studies have reported correlation coefficients ranging from -0.74 to -0.77 for the

association between refractive error and axial length (van Alphen 1961, Garner et al

1990, Goss et al 1990, Goss et al 1997). As axial length increases, there is a

decrease in hyperopic refractive error or an increase in the amount of myopia. A

weaker correlation between corneal power and refractive error has also been

reported (r = -0.07 to -0.30) (van Alphen 1961, Garner et al 1990, Goss et al 1990,

Goss et al 1997, Carney et al 1997), suggesting that an increase in corneal power is

associated with higher levels of myopia. Crystalline lens power typically has a low

positive correlation with refractive error, suggesting it may play a less significant

role in the determination of refractive error (Garner et al 1990, Goss et al 1997).

Numerous studies, comparing different refractive error groups, have reported that

axial length and vitreous chamber depths are greater in myopic eyes compared to

emmetropes and hyperopes. Anterior chamber depth is also significantly larger in

Chapter 1

4

myopes compared to other refractive error groups; however the anterior chamber

depth does not make as significant a contribution to the magnitude of refractive

error. Although a large range of corneal powers have been observed in

emmetropic eyes, some studies have reported mean corneal powers from 1.12 D to

1.15 D greater in myopic eyes compared to emmetropes (Sorsby et al 1962a,

Grosvenor and Scott 1991) while others have found no statistically significant

differences between cohorts (McBrien and Millodot 1987a, McBrien and Adams

1997).

The axial length of the eye is the major determinant of the magnitude of refractive

error in both myopic and hyperopic eyes. This is also true in the condition of

anisometropia (an interocular difference in refractive error). In cases of myopic or

hyperopic anisometropia, antimetropia (one eye myopic and one eye hyperopic) or

anisometropia associated with amblyopia or strabismus, the interocular difference

in refractive errors is typically due to an interocular difference in axial length

(Sorsby et al 1962b).

11..11..44 AAlltteerreedd vviissuuaall eexxppeerriieennccee dduurriinngg eemmmmeettrrooppiissaattiioonn

During the emmetropisation period the neural connection between the retina and

primary visual cortex is also established. A degraded retinal image during this

period results in abnormal development of the neural pathway and may result in

amblyopia. Amblyopia is defined as a reduction in best-corrected visual acuity in

Chapter 1

5

the absence of ocular disease and is typically a result of altered visual experience

during development such as; form deprivation, uncorrected ametropia or

strabismus (Beauchamp 1990).

11..11..44..11 OOccuullaarr ppaatthhoollooggyy

In an early study, Nathan et al (1985) retrospectively examined the association

between refractive error and ocular disease in a large cohort of visually impaired

children. The distribution of refractive errors in children with ocular disease and

low vision was significantly wider and shifted towards myopia compared to a

control group of children with normal vision. When vision loss occurred at birth or

shortly thereafter, the resulting refractive error tended towards myopia, whereas

vision loss that began slightly later in life (ages 1-3) resulted on average in

hyperopic refractive errors. More recently Du et al (2005) examined the refractive

anomalies in vision impaired children. The magnitude and type of refractive error

was significantly influenced by age and the type of ocular condition. Although there

was a trend towards less hyperopia with increasing age (as in normal

emmetropisation), on average, the magnitude and prevalence of anisometropia

significantly increased with age, suggesting a defect in emmetropisation. However,

the magnitude of anisometropia did not vary according to the type of ocular

condition. Although biometric data was not included in either of these studies, the

results highlight that a degraded retinal image during infancy disrupts

emmetropisation and the age of onset of vision loss influences the final refractive

state.

Chapter 1

6

The above studies report the changes in refractive error and eye growth in

response to altered retinal image quality in young children. However, there is also

some evidence to suggest that the visual system of normal older children and adults

(beyond the plastic period of ocular development) may undergo changes in

refraction or axial length during periods of imposed retinal defocus.

11..11..44..22 RReeffrraaccttiivvee aammbbllyyooppiiaa

In refractive amblyopia, the retinal image is degraded by uncorrected refractive

error. This may be due to moderate but symmetric refractive errors in each eye or

anisometropia.

Isometropic amblyopia refers to the bilateral reduction in visual acuity which results

from moderate to high refractive errors in both eyes. This is typically due to high

hyperopia rather than myopia, as a clear retinal image cannot be obtained during

distance or near fixation. The magnitude of amblyopia is proportional to the

magnitude of the refractive error.

Anisometropic amblyopia refers to the unilateral reduction in visual acuity

associated with a greater refractive error in one eye. This form of amblyopia is

typically due to asymmetric hyperopia. An interocular difference of 1 D in

hyperopic anisometropia can lead to suppression of the more hyperopic eye as the

affected eye has reduced acuity during both distance and near fixation (Weakley

Chapter 1

7

1999, Weakley 2001). In these cases, the magnitude of amblyopia correlates with

the magnitude of anisometropia (Tanlamai and Goss 1979, Hardman Lea et al 1989,

Townshend et al 1993). In myopic anisometropia, amblyopia is less frequent as

both eyes will obtain some clear vision during near fixation.

Meridional amblyopia refers to amblyopia along one meridian typically caused by

uncorrected high astigmatic refractive errors. The magnitude of amblyopia varies

depending on the magnitude and orientation of the astigmatism (Abrahamsson and

Sjostrand 2003, Dobson et al 2003).

11..11..44..33 SSttrraabbiissmmiicc aammbbllyyooppiiaa

In strabismus, in which the line of sight of one eye is not coincident with the object

of regard, amblyopia may develop due to suppression or other sensory adaptations

to eliminate diplopia since the visual cortex receive different retinal images from

the two eyes (Griffin and Grisham, 1995a). Strabismic amblyopia may also be

associated with isometropic or anisometropic refractive errors.

The magnitude of amblyopia varies according to the age of onset, magnitude,

direction and frequency of the strabismus. Earlier onset, constant, larger angle

esotropias are associated with more severe reduction in visual acuity compared

with later onset, intermittent small angle exotropias (Griffin and Grisham, 1995b).

Chapter 1

8

11..11..44..44 FFoorrmm ddeepprriivvaattiioonn aammbbllyyooppiiaa

Deprivation of form vision during infancy results in the most severe form of

amblyopia. Retinal image degradation due to ptosis (O’Leary and Millodot 1979),

corneal scarring (Gee and Tabbara 1988), congenital cataract (von Noorden and

Lewis 1987) or vitreous haemorrhage (Miller-Meeks et al 1990) typically leads to

excessive axial elongation (form deprivation myopia) and dense amblyopia. The

magnitude of amblyopia is related to the degree and age of onset of the image

degradation.

11..11..44..55 TTrreeaattmmeenntt ooff aammbbllyyooppiiaa

The treatment of amblyopia involves correction of the underlying cause (e.g.

removal of cataract in form deprivation amblyopia, correction of refractive error in

refractive amblyopia or realignment of the eyes in strabismic amblyopia), followed

by a period of deprivation of the non-amblyopic eye (e.g. occlusion or penalisation)

to promote visual experience in the amblyopic eye (Kiorpes and McKee 1999). The

earlier therapy is commenced the greater the chance the child will have an

improvement in visual acuity and retain binocular vision (Stewart et al 2005).

11..11..55 AAnniimmaall ssttuuddiieess ooff rreeffrraaccttiivvee eerrrroorr ddeevveellooppmmeenntt

Animal models of refractive error development suggest that young eyes can modify

their refractive state in response to imposed defocus or deprivation of vision. A

wide range of different animal models have been used including; guinea pigs

Chapter 1

9

(Howlett amd McFadden 2009), tree shrews (Metlapally and McBrien, 2008),

kittens (Van Sluyters 1978) and fish (Shen et al 2005), however, animal studies most

frequently employ avian (typically chickens) and primate (typically monkeys)

models. Chickens have been used due to their rapid visual development

(emmetropisation approximately 6 weeks post hatching) however, monkeys may

provide a closer approximation to the human visual system due to their slower

development and binocular visual system (Boothe 1985).

Experiments using animals often employ a monocular treatment paradigm in which

the visual input for one eye is altered and the non-treated eye acts as a control.

Disruption of form vision is achieved through lid suture (von Noorden and Crawford

1978) or diffusers (Smith and Hung 2000) and results in axial elongation and

myopia. Retinal defocus has also been imposed using positive or negative spectacle

(Hung et al 1995) or contact lenses (Smith et al 1994) or modification of the

surrounding visual environment (Young 1961) and leads to alterations in eye

growth to compensate for the imposed defocus.

Young eyes (both avian and primate) appear to be able to distinguish both the

magnitude and the sign of imposed defocus and adjust the position of the retina to

achieve emmetropia. Such alterations in axial length are due to both alterations in

choroidal and scleral structure. The choroid is a vascular tunic of the eye which

supplies the outer retina. Myopic defocus results in expansion of the choroid

reducing the vitreous chamber depth, whereas hyperopic defocus promotes

choroidal thinning and an increase in vitreous chamber depth. These choroidal

Chapter 1

10

changes to modify the position of the retina occur rapidly and are transient in

nature, recovering after the imposed defocus is removed and normal vision returns

(Wallman et al 1995). However, slower and more permanent changes to the sclera

have also been observed suggesting that visual manipulation results in both short

term choroidal changes and long term alterations in eye length due to scleral

remodelling (Nickla et al 1997). Alterations in eye growth vary according to the

magnitude of the visual deprivation (Smith and Hung 2000) and the age of the

animal at the time of image disruption (Troilo and Nickla, 2005).

Numerous animal studies have attempted to determine the components of the

visual system that are essential for the regulation of refractive errors or

emmetropisation. The elimination of accommodation by cycloplegia (Schwahn and

Schaeffel 1994), ciliary nerve section (Schmid and Wildsoet 1996) or damage to the

Edinger-Westphal nucleus (Schaeffel et al 1990) does not prevent emmetropisation

to imposed defocus suggesting that accommodation is not an integral factor. In

addition, when the optic nerve has been severed, recovery from form deprivation

myopia can still occur (although less accurately) suggesting that higher order

processing within the visual system (connecting the retina to the brain) may not

play a significant role (Troilo and Wallman 1991). Further evidence for a local

mechanism within the eye regulating ocular growth is that when alteration of the

visual input is restricted to a certain aspect of the visual field, compensatory eye

growth is observed only in the affected region (Wallman et al 1987). Recent studies

of monkeys have shown that peripheral vision plays a significant role in the

regulation of refractive errors along the visual axis. Compensatory changes in axial

Chapter 1

11

length to imposed defocus (Smith et al 2009) and recovery from induced form

deprivation myopia (Smith et al 2005) following ablation of the macula with an

argon laser suggests that central vision is not essential for emmetropisation.

11..11..66 RReettiinnaall iimmaaggee mmaanniippuullaattiioonn iinn hhuummaannss

While animal studies have improved our understanding of the factors that regulate

emmetropisation, it has been suggested that these models may not be applicable to

the development of human refractive errors (in particular myopia) excluding those

associated with form deprivation during youth (Zadnik and Mutti 1995). In this

section we discuss studies in which visual input has altered biometric or optical

parameters in humans.

11..11..66..11 OOrrtthhookkeerraattoollooggyy

Orthokeratology is the process of deliberate corneal reshaping (flattening) using

custom designed rigid gas permeable contact lenses to temporarily correct myopia.

As well as optically correcting myopia, recent studies indicate that orthokeratology

may slow the progression of myopia. Following overnight lens wear, the cornea is

temporarily reshaped to focus light centrally at the fovea, while the peripheral

retina receives myopic defocus. This peripheral myopic defocus is thought to act as

a signal to slow axial elongation.

Chapter 1

12

Cohort studies examining myopia progression in children undergoing bilateral

orthokeratology treatment compared to single vision spectacles (Cho et al 2005)

and soft contact lenses (Walline et al 2009) have shown that annual axial elongation

is reduced by approximately 50% in orthokeratology subjects compared to control

groups.

Cheung et al (2004) observed asymmetric eye growth in a myopic anisometrope

undergoing unilateral orthokeratology treatment in the more myopic eye. Over a

two year treatment period, the less myopic eye grew 0.34 mm (an increase in

myopia of approximately 1 D) compared to the treated more myopic eye which

grew only 0.13 mm. It could be argued that the less myopic eye was growing at an

accelerated rate compared to the more myopic eye; however, Tong et al (2006)

reported that the rate of growth in Asian myopic anisometropes is comparable

between fellow eyes during youth. A more likely explanation is that the corneal

reshaping has slowed myopia progression in the treated eye.

11..11..66..22 BBiiffooccaall ccoonnttaacctt lleennsseess

Soft contact lenses may also slow myopia progression. Aller and Wildsoet (2008)

measured refraction and axial length over a two year period in a pair of young

myopic identical twins (age 12) with esophoria and a lag of accommodation to near

targets. In one year, the child fitted with bifocal soft contact lenses showed

minimal change in refractive error, while the sibling fitted with single vision contact

Chapter 1

13

lenses progressed more than 1 D. Given that the genetic and environmental factors

which may influence eye growth would have been very similar between the two

children during the study period, it appears that the bifocal contact lenses had an

inhibitory effect on axial elongation. The authors suggested this may be due to a

reduction in the esophoria and lag of accommodation during near work.

In a larger study, Anstice and Phillips (2011) examined the change in refraction and

axial length in 40 young non-anisometropic myopes (11-14 years old) over a period

of twenty months while wearing a different type of soft contact lens in each eye. A

single vision lens was worn in one eye and a multifocal lens (simultaneous vision -

distance centre) was worn in the fellow eye. The mean increase in myopia

progression (spherical equivalent and axial length) over ten months was

significantly reduced in the eyes wearing the multifocal lens (-0.44 ± 0.33 D and

0.11 ± 0.09 mm) compared to the single vision lens (-0.69 ± 0.38 D and 0.22 ± 0.10

mm). The decrease in myopia progression associated with multifocal lens wear was

attributed to the constant peripheral myopic defocus induced at all levels of

accommodation.

These contact lens studies demonstrate that manipulation of the retinal image in

young subjects may alter the refractive state of the eye, presumably through small

changes in axial length over time. Although the mechanism is unclear, it seems as

though myopic defocus (in particular, peripheral myopic defocus) retards axial

Chapter 1

14

elongation. However, manipulation of the retinal image in older presbyopic

subjects does not show a consistent pattern of refractive change.

11..11..66..33 MMoonnoovviissiioonn

Monovision is a common presbyopic refractive correction using either spectacles or

contact lenses in which one eye (typically the dominant sighting eye) is corrected

for distance vision and the fellow eye is corrected for near vision. Imposed myopic

defocus in the reading eye allows the presbyopic patient a range of clear vision

using a single vision contact lens or spectacle prescription rather than multifocals or

contact lenses in conjunction with reading spectacles. The alteration of axial length

in response to imposed retinal defocus has been well documented in a variety of

animal species; however, few studies have examined the effect of monovision

correction on the refractive state of the human eye.

In a retrospective clinical study, Wick and Westin (1999) observed that 29% of

monovision contact lens wearers developed anisometropia of 0.5D or more. The

near eye (experiencing distance blur) was the affected eye in 89% of patients who

developed anisometropia. The direction of refractive change appeared to be

dependent upon the initial refractive status. In monovision patients who developed

anisometropia, the near eye became more hyperopic in 75% of hyperopes and

100% of emmetropes. In 82% of myopes however, the near eye became more

myopic. The anisometropia induced lasted up to one year in some cases following

the cessation of monovision contact lens wear. As no significant corneal changes

Chapter 1

15

were observed in this study, this refractive error shift was assumed to be either

lenticular in nature or a change in the axial length of the eye. This study shows no

obvious trends in refractive change following long term monovision contact lens

wear. Image manipulation in older humans whose eyes have grown to adult

dimensions and stabilized may not result in predictable ocular changes observed in

animal models.

Monovision has also been used as a refractive correction in children in an attempt

to slow myopia progression. Phillips (2005) followed 13 eleven year old myopes

fitted with monovision spectacles over a period of thirty months. Using dynamic

retinoscopy, the author observed that all children accommodated to read using the

distance corrected dominant eye rather than the near corrected eye with additional

myopic defocus as is the case in presbyopic monovision. As a result, the near

corrected eye received myopic defocus at all levels of accommodation. Myopia

progression was significantly slower in the near corrected eye compared to the

fellow distance corrected eye. All subjects developed anisometropia due to the

interocular symmetry in vitreous chamber growth (interocular difference of 0.13

mm/year). When these subjects returned to conventional distance spectacle wear,

the anisometropia reduced to baseline levels within 18 months. These monovision

results are of particular interest as studies examining the effect of bilateral

undercorrection in young myopes have found higher progression rates in

undercorrected cohorts (+0.50 (Alder and Millodot 2006) and +0.75 D (Chung et al

2002) undercorrection) in comparison to fully corrected myopes. This suggests that

Chapter 1

16

either a higher level of myopic blur is necessary to reduce axial elongation or

perhaps some clear vision (the distance corrected eye in monovision) is required by

the visual system to act as a reference when regulating the eye growth of the

blurred eye.

Recently, Read et al (2010) examined the change in axial length and choroidal

thickness in young adults following one hour of monocular defocus. Using a highly

precise optical biometer, significant changes in axial length were observed which

corresponded to the direction of the induced defocus. Lens induced hyperopic

defocus (-3 D) and form deprivation (diffuser) both resulted in choroidal thinning

and axial elongation while lens induced myopic defocus (+3 D) resulted in a

thickening of the choroid and a decrease in axial length (only in the eye with the

imposed defocus). Like previous studies of young animals, this study suggests that

the adult human visual system is capable of detecting the direction of defocus and

adjusting the position of the retina to minimise the imposed blur by altering the

thickness of the choroid.

11..11..77 SSuummmmaarryy

In summary, during childhood there is a reduction in neo-natal refractive errors

towards emmetropia. This process, emmetropisation, is guided by visual

experience and correlates with an increase in axial length. Disruption of clear vision

during ocular development may result in abnormal eye growth, refractive error

Chapter 1

17

development and potentially amblyopia. Axial length and vitreous chamber depth

are strongly correlated with refractive error, whereas the power of the cornea and

crystalline lens display weaker associations. Myopic eyes, in comparison to

emmetropic and hyperopic eyes, have greater axial lengths (typically due to deeper

vitreous chambers) and in some instances greater corneal power (steeper corneal

curvature). Anisometropia, an interocular difference in refractive error, is primarily

due to a difference in axial length between fellow eyes. Animal models of refractive

error development highlight that emmetropisation is a vision dependent process.

Young eyes can distinguish the sign and magnitude of imposed retinal defocus and

can compensate for this blur by altering the position of the retina through choroidal

accommodation. The signal driving emmetropisation is from within the eye and

accommodation and higher-order processing in the visual pathway may not be

integral components. Recently, studies of imposed defocus suggest that a similar

mechanism for the regulation of axial length may exist in humans.

Chapter 1

18

11..22 MMyyooppiiaa ddeevveellooppmmeenntt -- aaeettiioollooggiiccaall ffaaccttoorrss

While hyperopic refractive errors are often associated with amblyopia and

strabismus and may result in reduced visual acuity and impaired binocular vision,

the majority of refractive error research has focussed on the development of

myopia. This may be due to the socio-economic cost of myopia (e.g. eye

examinations or refractive correction such as spectacles or contact lenses), the

ocular complications that may arise in severe cases of myopia (e.g. retinal

detachment or glaucoma). In recent decades there has also been a significant

increase in the prevalence of myopia, particularly in urbanised regions.

Myopia may be classified according to the age of onset (Grosvenor 1987).

Congenital myopia is defined as myopia present at birth which persists throughout

childhood. Early-onset or youth-onset myopia refers to myopia which presents from

approximately 6 to 15 years of age. Late-onset or adult onset myopia refers to

myopia which presents after the age of 15. It has been suggested that congenital

and early-onset myopia is primarily due to genetic factors, whereas environmental

factors such as near work may be the cause of late-onset myopia.

There is a strong genetic component in myopia development (Wu and Edwards

1999, Dirani et al 2006). Studies of families have shown that the likelihood of a

child becoming myopic increases as the number of myopic parents increase (Yap et

al 1993, Zadnik et al 1994, Pacella et al 1999, Wu and Edwards 1999, Mutti et al

Chapter 1

19

2002). Pacella et al (1999) observed that children with two myopic parents were

more than six times more likely to become myopic compared to children with one

or no myopic parents. The higher degree of concordance of refractive errors in

monozygotic compared to dizygotic twins also suggests a genetic contribution to

refractive error development (Sorsby et al 1962c, Angi et al 1993, Hammond et al

2001). The Genes in Myopia twin study (Dirani et al 2006) recently reported that

genetic factors accounted for up to 88% of the variability in refraction and 94% of

the variability in axial length.

However, due to an increase in the prevalence of myopia in recent decades, it

appears that environmental factors may also play an important role in refractive

error development (Morgan and Rose 2005). There is a greater prevalence of

myopia (Ip et al 2008, Zhang et al 2010) and a greater rate (Shih et al 2010) of

myopia progression in urban or more densely populated areas compared to rural

regions, suggesting urban development may be an important environmental factor.

Near work has also been suggested as a key issue. A high prevalence of myopia has

been found in occupations requiring intense near work such as microscopists

(Adams and McBrien 1992), and a lower prevalence observed in populations

without compulsory schooling (Garner et al 1985). In addition, a greater amount of

time spent reading has been associated with higher rates of myopia progression in

children (Parssinen and Lyyra 1993). Recent evidence also suggests that outdoor

and physical activities may protect against the development of myopia (Dirani et al

2009, Rose et al 2008).

Chapter 1

20

Whilst a range of different theories have been proposed to explain the

development of myopia, two commonly proposed hypotheses include those where

mechanical or optical factors promote excess axial eye growth/elongation.

11..22..11 MMyyooppiiaa ddeevveellooppmmeenntt -- ooppttiiccaall ffaaccttoorrss

11..22..11..11 AAccccoommmmooddaattiioonn

In both animals and humans, eye growth regulation is known to be vision

dependent. Therefore it is possible that altered retinal image quality in humans

during or following near work could play a role in axial elongation and the

development of myopia. When near work is performed the eyes typically converge

and accommodate in order to maintain clear, single binocular vision of near targets.

This results in a number of predictable biometric and optical changes which leads to

an increase in the refractive power of the eye. During accommodation there is a

steepening in curvature of the anterior and posterior crystalline lens surfaces, an

increase in lens thickness and a concomitant decrease in anterior chamber depth

(Drexler et al 1997, Bolz et al 2007). The magnitudes of these anterior biometric

changes are directly proportional to the accommodative demand. Recently, with

the advent of new technologies temporary alterations in the posterior shape of the

eye have also been reported.

Given the association between near work and myopia development, numerous

studies have compared the ocular changes during or following accommodation in

different refractive error groups to determine a link between accommodation and

Chapter 1

21

axial elongation. Insufficient accommodation during near work or an inability to

relax accommodation following near work are two theories that link

accommodation and myopia development.

Typically, greater lags of accommodation (under accommodation during near work)

have been reported in myopes compared to emmetropes (McBrien and Millodot

1986, Rosenfield and Gilmartin 1987, Rosenfield and Gilmartin 1988, Gwiazda et al

1993, Gwiazda et al 1995a) and in progressing myopes compared to stable myopes

(Abbott et al 1998). The hyperopic defocus associated with a lag of accommodation

may provide a cue to eye growth and myopic development and there is some

evidence to suggest that a lag of accommodation precedes the onset of myopia

development in children (Goss 1991).

It has also been suggested that near work induced transient myopia (NITM), a

transient shift in the distance refractive error following a period of near work, may

play a role in the development or progression of myopia (Ong and Ciuffreda 1995).

Previous studies have found that myopes demonstrate a larger amount of NITM

following near tasks compared to emmetropes or hyperopes (Ciuffreda and Wallis

1998, Ciuffreda and Lee 2002). In addition, late-onset myopes appear to be more

susceptible to this change in distance refraction compared to early-onset myopes

(Ciuffreda and Wallis 1998). NITM studies suggest that myopes display a degree of

adaptation during accommodation and fail to relax their accommodation following

Chapter 1

22

near work, resulting in transient increases in distance myopic refractive errors

following sustained near work.

11..22..11..22 HHiigghheerr--oorrddeerr aabbeerrrraattiioonnss

The term aberration describes any imperfection in, or departure from an ideal

optical wavefront. This may take the form of chromatic or monochromatic

aberrations. Chromatic aberration refers to the inability to refract all wavelengths

of light to a single focal point in an optical system due to dispersion.

Monochromatic aberrations occur due to the nature or geometry of an optical

system. This section will examine monochromatic aberrations of the eye and the

potential relationship with refractive error development.

The refractive elements which may contribute to the formation of ocular

aberrations include the cornea (primarily the anterior surface) and the crystalline

lens. Qualitatively, aberrations may be described as total ocular aberrations

(aberrations resulting from all the refractive elements of the eye), corneal

aberrations (arising from the anterior corneal surface) or internal aberrations

(attributed to the refractive elements within the eye).

Zernike polynomials are the most common method of quantifying or describing

wavefront aberrations. Zernike polynomials are a set of functions used to describe

the shape of an aberrated wavefront in the pupil of an optical system. The root

Chapter 1

23

mean square deviation (RMS) is another term used to describe the global error or

difference between an aberrated and an ideal wavefront (measured in

micrometers).

11..22..11..33 VVaarriiaabblleess tthhaatt iinnfflluueennccee hhiigghheerr--oorrddeerr aabbeerrrraattiioonnss

ii)) AAggee

Spherical aberration increases with age. This change is attributed to changes within

the refractive index gradient and surface curvatures of the crystalline lens (Amano

et al 2004, Fujikado et al 2004, Radhakrishnan and Charman 2007). Coma also

increases with age, however this is primarily due to corneal changes (Amano et al

2004, Fujikado et al 2004). Kuroda et al (2002) also reported a weak but significant

positive correlation between age and total ocular higher-order aberrations.

Brunette et al (2003) examined monochromatic higher-order aberrations in a

cohort of 114 subjects from ages 5-82. The change in aberrations with age was

approximated a second order polynomial. Higher-order aberrations decreased

throughout childhood and adolescence reaching a minimum level during the fourth

decade of life and then increased progressively from the fifth to eighth decade.

Chapter 1

24

iiii)) PPuuppiill ssiizzee

The influence of pupil size on optical systems and aberrations has been well

documented. As pupil size increases RMS values increase in an approximate

quadratic function (Castejon-Mochon et al 2002, Thibos et al 2002). This is an

important consideration that must be controlled for in comparative experiments by

employing a fixed artificial pupil size for all subjects either physically (i.e. fixed

aperture) or through appropriate analysis methods.

iiiiii)) RReettiinnaall eecccceennttrriicciittyy

In general, total aberrations or RMS values gradually increase in a linear fashion

with increase in retinal eccentricity; however there is significant intersubject

variation (Navarro et al 1998, Gustafsson et al 2001, Atchison and Scott 2002).

Gustafsson et al (2001) found that aberrations (oblique astigmatism) in the nasal

periphery were larger than in the temporal field and Atchison and Scott (2002)

reported similar findings.

iivv)) AAccccoommmmooddaattiioonn

Optical changes associated with accommodation not only include an increase in the

refractive power of the eye, but typically a negative shift in spherical aberration

which is proportional to the accommodative demand (Atchison et al 1995, Chen et

al 2004). Higher-order comatic terms also change with accommodation but the

Chapter 1

25

magnitude and direction of change is less predictable than that of spherical

aberration (Cheng et al 2004b).

vv)) OOccuullaarr ddiisseeaassee

Keratoconic eyes display higher amounts ocular aberrations in comparison to

normal eyes. This is due to the abnormal shape of the cornea (thinning and bulging

forward) which significantly increases the magnitude of coma-like aberrations

(Maeda et al 2002).

Dry eye patients exhibit increased levels of total higher-order aberrations compared

to normals after controlling for pupil size. This is due to the irregularity of the tear

film surface in dry eye (Montes-Mico et al 2004a). Insertion of lubricating drops can

significantly reduce the magnitude of ocular aberrations in dry eye patients

(Montes-Mico et al 2004b). This highlights the role of the tear film in providing a

smooth optical surface and that any attempt to measure aberrations in humans

should be conducted 2-3 seconds following a blink to eliminate any tear film

artefacts or abnormalities (Zhu et al 2007).

11..22..11..44 IInntteerrooccuullaarr ssyymmmmeettrryy ooff hhiigghheerr--oorrddeerr aabbeerrrraattiioonnss

Non-superimposable mirror-image symmetry (enantiomorphism) exists within the

body and is reflected in corneal topography and wavefront aberrations (Smolek et

al 2002) (Figure 1.1). Subsequently, when examining symmetry between right and

Chapter 1

26

Right eye Left eye

Figure 1.1: Interocular mirror symmetry of refractive power maps in isometropia.

Chapter 1

27

left eyes, care must be taken to account for this phenomenon. Studies examining

the interocular symmetry of ocular aberrations are summarised in Table 1.1 and

show that Zernike terms 4 (defocus), 5 (astigmatism), 6 (trefoil along 30 degrees)

and 12 (spherical aberration) are often highly correlated between right and left

eyes.

ii)) CCoorrnneeaall aabbeerrrraattiioonnss

It is generally accepted that in an individual with no eyelid abnormalities, the two

eyes display some degree of corneal symmetry (direct or mirror symmetry) with

respect to the axes of astigmatism (Dingeldein and Klyce 1989, Dunne et al 1994).

Keratoconics also tend to exhibit interocular mirror symmetry with respect to

topographic changes as a result of corneal thinning (Wilson et al 1991). Lid forces

upon the cornea from abnormalities such as ptosis or entropion may result in

distinct interocular asymmetry in both magnitude and orientation of astigmatism

(Ugurbas and Zilelioglu 1993).

Wang et al (2003) reported a moderate degree of mirror symmetry between right

and left eyes for all corneal higher-order aberrations (r = 0.57, p < 0.001). Third and

fourth order Zernike terms displayed the highest interocular correlations, in

particular spherical aberration, horizontal coma and vertical coma.

Chapter 1

28

Table 1.1: Summary of studies examining interocular symmetry of wavefront aberrations.

Wavefront examined Study N Total

Total cohort demographic Age (years)

Sphere or SEq (D) Cylinder (D)

N

Symmetry Pupil size (mm) Interocular correlation examined Significant Correlations

Significance level

Corneal Wang (2003) 134

20-79

94 6.0

Each Zernike term coefficient (all subjects averaged)

Total HOA (all subjects averaged)

Terms 6-10, 12-14, 17

r = 0.565

p < 0.002 < ± 3.25 SEq

< 2.00

Corneal Lombardo (2006) 30

24-52

30 4.0 & 7.0 Total HOA (individual subjects averaged)

53% of px’s correlated

97% of px’s correlated

p < 0.001 -1.75 to -8.75 SEq

NA

Internal Wang (2005) 114

20-69

30 6.0 Each Zernike term coefficient (all subjects averaged) Terms 12 and 24 p < 0.002 -10.68 to +3.47D SEq

NA

Total Liang & Williams (1997) 9

21-38

4 7.3 All Zernike term coefficients (all subjects averaged) “Slope close to 1” NA < ± 3.00 Sphere

< ± 3.00

Total Marcos & Burns (2000) 12

22-58

12 Unspecified (dilated) All Zernike term coefficients (all subjects averaged) r = 0.45 p < 0.0001 -6.50 to 0 Sphere

< 0.80

Total Porter (2001) 109

21-65

109 5.7 Each Zernike term coefficient (all subjects averaged) Terms 3-9, 12-17 p < 0.01 -12.00 to +6.00 Sphere

<3.00

Total Castejon-Mochon (2002) 59

20-30

35 7.0 Each Zernike term coefficient (all subjects averaged) Terms 4-8, 12-15 p < 0.05 Emmetropic

NA

Total Carkeet (2003) 34

5-7

33 5.0 Each Zernike term coefficient (all subjects) Terms 4-6, 12 p < 0.001 NA

NA

Horizontal peripheral total HOA’s up to ±40˚

(distance and near fixation) Lundstrom et al (2011) 22

22-32

22 4.0

Each Zernike term coefficient (all subjects and nasal/temporal averaged)

0 - 40˚ distance fixation

0 - 35˚ near fixation (4 D stimuli)

Terms 3-5, 7-9, 11-13

Terms 3-9,11-13

p < 0.01

p < 0.01

Emmetropes and myopes (-2.00 to -7.25 Sphere)

≤ 0.75

N Total (number of total study subjects), N Symmetry (number of study subjects examined for interocular symmetry), HOA (higher-order aberrations), SEq (spherical equivalent). Zernike term number defined as per Optical Society of America (Thibos et al 2002).

Chapter 1

29

Lombardo et al (2006) also examined the interocular symmetry of corneal higher-

order aberrations in a cohort of PRK patients prior to undergoing surgery. For a 4

mm pupil size they found 53% of patients had significant interocular correlations

and 97% for a 7 mm pupil size.

iiii)) TToottaall ooccuullaarr aabbeerrrraattiioonnss

Various studies have shown a degree of interocular symmetry exists for total

higher-order aberrations and individual Zernike terms after correcting for

enantiomorphism (Table 1.1). Liang and Williams (1997) compared total ocular

aberrations between right and left eyes of four subjects and observed a direct

positive correlation.

Marcos and Burns (2000) examined 12 subjects of varying age and refractive error

and found a highly significant correlation and trend for mirror symmetry of all

Zernike terms in five subjects and direct symmetry in one subject. The six

remaining subjects displayed no significant interocular symmetry. The authors also

report a substantial amount of intersubject variation in interocular symmetry of

aberrations. Some of the noise in this data may be explained by the protocol in

which the right and left eye measurements for each subject were conducted 120

days apart.

Chapter 1

30

Porter et al (2001) reported that 75% of Zernike terms were significantly correlated

between right and left eyes in 109 normal subjects over a large range of refractive

errors. Primary defocus, primary spherical aberration and primary astigmatism had

the highest interocular correlations. Castejon-Mochon et al (2002) also found a

trend towards interocular correlation for several of the same higher-order

aberrations in 35 young emmetropes. These findings suggest a degree of

interocular symmetry may exist independently of refractive error. Interocular

symmetry of total aberrations has also be reported in a population of young

Chinese children aged 5-7.

Wang et al (2005) reported a wide spread of intersubject internal aberrations and a

small but significant correlation between right and left eyes for total internal

aberrations (r = 0.53, p < 0.002). Examining Zernike terms individually, they found

significant interocular symmetry for fourth (r = 0.75, p < 0.002) and sixth order (r =

0.73, p < 0.002) spherical aberration.

Recently, Lundstrom et al (2011) observed a high degree of interocular symmetry

for total ocular aberrations measured up to 40 degrees nasal and temporal to the

fovea along the horizontal meridian. The between eye symmetry of peripheral

aberrations (2nd to 4th order) was similar during both distance and near fixation (4 D

stimuli).

Chapter 1

31

11..22..11..55 CCoommppeennssaattoorryy mmeecchhaanniissmmss

The eye exhibits some in-built active mechanisms which may reduce the degrading

effects of aberrations on image quality. For example, pupil miosis and fluctuations

in the level of accommodation during reading may vary in an attempt to minimise

image blur (Plainis et al 2005). Kelly et al (2004) suggested that a fine-tuning

mechanism exists within the eye that negates the effects of corneal aberrations to

some degree. In a cohort of 30 young subjects, they observed that the magnitude

of corneal astigmatism and lateral coma was significantly reduced by internal optics

during relaxed accommodation. The authors proposed that a balance between the

optics of the cornea and the gradient index of the crystalline lens might be

determined during emmetropisation to maximize retinal image quality. Similarly,

Artal et al (2001) suggested that modification of the lens position (tilting or

decentring) during emmetropisation may be a developmental process to counteract

corneal aberrations.

11..22..11..66 HHiigghheerr--oorrddeerr aabbeerrrraattiioonnss aanndd rreeffrraaccttiivvee eerrrroorr ddeevveellooppmmeenntt

Aberrations reduce the image quality of an optical system by blurring or distorting

the resultant image. Applegate et al (2002) showed that some aberrations

(defocus, spherical aberration, secondary astigmatism) have a greater detrimental

effect upon quality of vision (high and low contrast visual acuity) than others.

Similarly, Oshika et al (2006) reported a significant correlation between the

magnitude of coma and low-contrast visual acuity suggesting that higher order

aberrations may influence contrast sensitivity in normal subjects.

Chapter 1

32

Various studies have reported correlations between the degree of refractive error

and the magnitude of ocular aberrations (corneal and total) whereas others have

not found significant differences between refractive error groups. Studies that

report significant associations between corneal aberrations and refractive error

typically report similar findings for total ocular aberrations. This is due to the large

contribution of the cornea to the total refractive power of the eye.

There is inconsistency in the literature regarding the relationship between

refractive error and ocular aberrations. In particular, a lack of longitudinal studies

examining the progression of refractive error and aberrations during childhood

means the influence of higher order aberrations on refractive development remains

unknown.


Llorente et al (2004) compared corneal aberrations in age-matched groups of

myopes and hyperopes and found the magnitude of corneal spherical aberration to

be significantly higher in hyperopic eyes. Other studies have reported significantly

higher amounts of corneal aberrations in myopes in comparison to emmetropes

(Buehren et al 2005, Vasudevan et al 2007).

Significant horizontal band like corneal distortions corresponding with eyelid

position have been observed following reading tasks in a variety of refractive error

Chapter 1

33

groups. Such changes in corneal topography and subsequently corneal aberrations

are thought to arise due to eyelid pressure. The nature of the reading task (e.g.

computer work, or reading) directly influences the position and optical impact of

these corneal changes due to variation of eyelid position during with each task

(Collins et al 2006a). These lid-induced corneal aberrations may provide a minus

defocus cue for axial elongation resulting in myopia development.

Several corneal wavefront coefficients change significantly following reading.

Buehren et al (2005) observed significantly larger changes in corneal aberrations in

myopes compared to emmetropes following two hours of reading. The authors

attributed this to the difference in palpebral aperture size between the refractive

groups with myopes having smaller apertures and therefore, upper eyelid position

closer to the position of the pupil. Vasudevan et al (2007) reported similar findings;

greater corneal aberrations in myopes than emmetropes both before and after a

one hour reading task. These studies suggest that people who read for extended

periods of time may experience significant increases in corneal aberrations which

increase in magnitude with the duration of the reading task.


He et al (2002) reported significant differences in the amount of higher-order

aberrations in myopic and emmetropic children and young adults and suggested

that higher-order aberrations may cause sufficient retinal image blur to influence

myopia development or progression. Paquin et al (2002) also reported an increase

Chapter 1

34

in aberrations and a decrease in optical quality with increasing levels of myopia.

However, Cheng et al (2003) examined spherical aberration and higher-order

aberrations in a range of ametropes (+5.00 to -10.00 D, n=200) and found no

difference in comparison to emmetropes. Porter et al (2001) reported similar

findings.

The effect of accommodation on ocular aberrations has also been examined in

different refractive error groups. Collins et al (1995) observed significantly lower

fourth order aberrations in myopes compared to emmetropes for a variety of

accommodation levels. He et al (2000) reported that changes aberrations observed

during accommodation were not proportional to the magnitude of total ocular

aberrations and that changes were more noticeable in eyes with good optical

quality.

iiiiii)) PPeerriipphheerraall aabbeerrrraattiioonnss

Since animal studies have shown that the peripheral retina influences

emmetropisation (Smith et al 2007, Smith et al 2009) and in humans peripheral

relative refractive error varies with refractive error type (Mutti et al 2000), it is

possible that peripheral higher order aberrations may also play a role in the

development of refractive errors. Recently a small number of studies have

compared the peripheral total ocular aberration profile in myopes and emmetropes

during distance viewing and accommodation.

Chapter 1

35

Mathur et al (2009a) compared peripheral aberrations (42 x 32 degrees of the

central visual field) in a small group of myopes (n = 10) and emmetropes (n = 9)

during relaxed accommodation. Spherical aberration was similar at all peripheral

locations measured, but differed according to refractive error type (mean C(4,0)

0.023 ± 0.043 μm for emmetropes and -0.007 ± 0.045 μm for myopes). However,

overall only small differences were observed in the level of peripheral aberrations

(RMS values) between the two groups. In a second study, Mathur et al (2009b) also

measured the change in peripheral aberrations (over the same area of the visual

field) during accommodation in the cohort of emmetropes (n = 9). Although only

small changes in Zernike coefficients were observed during accommodation (4 D)

there was a moderate change in spherical aberration, which became more negative

at all peripheral locations. Lundstrom et al (2009) also examined the change in

peripheral aberrations (out to 40 degrees horizontally and 20 degrees vertically)

during accommodation but compared myopes and emmetropes. They observed

that while emmetropes became relatively more myopic in the periphery during

accommodation, myopes did not show a consistent change during accommodation

(i.e. peripheral aberrations remained relatively hyperopic).

These studies have shown that while peripheral aberrations are relatively similar

between myopic and emmetropic eyes during distance fixation (excluding spherical

aberration), during accommodation myopes display greater peripheral relative

hyperopia compared to emmetropes and less consistent changes in peripheral

Chapter 1

36

aberrations suggesting that the development of myopia may be related to

peripheral retinal defocus during near work.

iivv)) LLoonnggiittuuddiinnaall ssttuuddiieess ooff aabbeerrrraattiioonnss

Animal studies have also shown that aberrations decrease rapidly during infancy

suggesting a similar emmetropisation process for higher and lower order

aberrations. Ramamirtham et al (2006) examined the longitudinal changes of

higher-order aberrations in infant monkeys. Young monkeys displayed relatively

large amounts of third and fourth order aberrations (coma, trefoil and spherical

aberration) which diminished to typical adult levels after 200 days. Garcia de la

Cera et al (2006) reared new born chickens using a diffuser monocularly and

investigated the changes in higher-order aberrations in the normal and form

deprived eyes over a two week period. The control eyes developed normally with a

decrease in hyperopia and an increase in axial length, whilst the test eyes

developed axial myopia. Higher-order aberrations decreased in both eyes over

time, however after approximately one week, the myopic (form deprived) eyes

displayed significantly higher levels of aberrations. This study suggests that during

development, higher-order aberrations may decrease independent of visual

experience (passive higher-order emmetropisation). Tian and Wildsoet (2006) also

examined the longitudinal changes in the eyes of young normal chicks and eyes

which had undergone ciliary nerve section. Lower and higher-order aberrations

decreased during development in both the normal and sectioned eyes. Although

the eyes with a severed ciliary nerve had a larger pupil size and displayed greater

Chapter 1

37

levels of higher-order aberrations, the refractive development was similar between

the eyes.

Coletta et al (2010) longitudinally examined the development of wavefront

aberrations in both eyes of young marmosets over a period of 18 months using a

range of methods to alter the visual experience of the animals. From approximately

2-4 months of age three animals underwent form deprivation (monocular diffuser),

six were reared with binocular lens induced hyperopia or myopia and two control

animals were not treated. In the control group, there was a gradual shift from

hyperopia to myopia and a decrease in higher-order aberrations over time. In the

treated eyes, aberrations decreased with age, even during treatment period of lens

induced ametropia. However, the form deprived eyes of the monocularly deprived

animals had significantly greater levels of higher-order aberrations during and after

the treatment period. Compared to their fellow untreated eyes, form deprived

eyes had statistically significant higher levels of trefoil C(3,-3) and 5th and 7th order

RMS (i.e. orders containing asymmetric aberrations). In addition, 3rd order

aberrations were not correlated between the fellow eyes following monocular

deprivation, whereas the 4th to 7th order terms displayed a high degree of

interocular symmetry. The interocular difference in the magnitude of

anisometropia induced after treatment was significantly correlated with the

interocular difference in RMS values for 5th and 6th order aberrations. While several

animal studies using a monocular deprivation paradigm have demonstrated an

increase in aberrations following monocular altered visual experience (Garcia de la

Chapter 1

38

Cera et al 2006, Kisilak et al 2006, Tian and Wildsoet 2006), this is the first to report

the correlation between the interocular difference in refraction and higher-order

aberrations. The authors suggest that the higher levels of asymmetric aberrations

observed in form deprived eyes are a consequence rather than a cause of myopia

development.


While there is evidence to suggest a strong genetic component in the development

of myopia, environmental factors such as near work may also play a role. The

optical changes that occur within the eye during or following near work have been

investigated in various refractive error groups in order to identify a mechanism

underlying axial elongation and myopia development. Myopes typically exhibit a

greater lag of accommodation in comparison to emmetropes and hyperopes. The

hyperopic defocus associated with a lag of accommodation is thought to be a

potential trigger for axial elongation. Recently, the role of higher-order aberrations

in myopia development has been investigated due to their potential to degrade

retinal image quality. Studies comparing higher-order aberrations in myopic and

emmetropic subjects typically report similar levels of aberrations during distance

fixation, but higher levels of aberrations in myopic eyes during or following reading

tasks.

Chapter 1

39

11..33 MMyyooppiiaa ddeevveellooppmmeenntt -- mmeecchhaanniiccaall ffaaccttoorrss

Mechanical forces associated with near work such as those produced during

convergence, or ciliary muscle contraction could also potentially promote axial

elongation (Greene 1980, Bayramlar 1999). Recently, with the advent of new

technologies, small changes in axial length during or following accommodation have

been reported in both emmetropes and myopes (Drexler et al 1998, Mallen et al

2006). Transient axial length elongation due to contraction of the ciliary muscle

during near work may be a mechanical factor that influences myopia development.

Mechanical forces associated with IOP have also been suggested as a potential

factor associated with axial elongation and the development of myopia (Greene

1980, Pruett 1988).

11..33..11 MMeecchhaanniiccaall cchhaannggeess dduurriinngg nneeaarr wwoorrkk

11..33..11..11 CCoonnvveerrggeennccee

Forces exerted by the extraocular muscles during convergence are thought to have

the potential to lead to changes in axial length. Bayramlar et al (1999) concluded

that transient axial elongation associated with near work was a result of

convergence rather than accommodation after observing significant vitreous

chamber elongation measured with ultrasound biometry in young subjects

following near fixation with and without cycloplegia. Recently however, Read et al

(2009) reported that axial length as measured with partial coherence

interferometry appears largely unchanged in adults both during and following a

period of sustained convergence.

Chapter 1

40

11..33..11..22 CCiilliiaarryy bbooddyy ffoorrcceess

Ciliary muscle contraction (without convergence) has also been found to be

associated with small but significant increases in the eye’s axial length (Drexler et al

1998, Mallen et al 2006). Drexler et al (1998) observed small increases in axial

length (up to 19.2 microns), slightly larger in magnitude in emmetropes compared

to myopes during a short period of maximum accommodation. However, the

accommodation demand was not controlled between the myopic and emmetropic

cohorts. In a group of seven subjects, the authors also investigated the interocular

symmetry in axial elongation during accommodation and found no significant

difference between the fellow eyes.

Mallen et al (2006) also examined axial length changes during accommodation but

controlled for the accommodative demand between emmetropic and myopic

cohorts. Axial elongation was greater in myopic eyes compared to emmetropes,

and correlated positively with the level of accommodation. Read et al (2010) also

observed an increase in axial elongation during accommodation, which increased

with higher levels of accommodation, but found no significant difference in the

magnitude of axial elongation between myopes and emmetropes.

These studies suggest that accommodation can cause transient increases in axial

length proportional to the magnitude of accommodation, which dissipate quickly

when accommodation is relaxed. These changes in axial length are thought to be a

result of the mechanical effects of the contraction of the ciliary muscle and

Chapter 1

41

choroidal tension during accommodation. There is conflicting evidence regarding

the magnitude of axial length changes between different refractive error groups.

Transient axial length changes associated with near work may be linked to

refractive error development. If ciliary body forces or choroidal tension during

accommodation is the cause of such axial length changes, we might expect ciliary

body thickness to be larger in myopes compared to emmetropes or larger in the

more myopic eye of anisometropes relative to the fellow eye. This finding has been

reported previously in a cohort study of children (Bailey et al 2008), however,

factors other than ciliary body size may also influence the amount of force

transmitted to the choroid and sclera during accommodation such as structural and

biomechanical properties of the sclera.

Using a Badal system in conjunction with an autorefractor Walker and Mutti (2002)

approximated the change in the posterior ocular shape due to accommodation by

measuring the relative peripheral refractive error (RPRE) before, during and after

two hours of sustained near work (for a 3 D stimulus). Accommodation resulted in

a small hyperopic shift in the RPRE (mean change +0.37 D) suggesting that the

ocular shape had become more prolate. There was no relationship between

refractive error and the magnitude of change in RPRE. This change returned to

baseline levels 45 minutes after the cessation of the near task. The authors

Chapter 1

42

attributed the transient shift in refraction to changes in choroidal tension during

accommodation.

Woodman et al (2011) measured the change in axial length using a partial

coherence interferometer following a 30 minute reading task and observed greater

axial elongation in myopes compared to emmetropes. Ten minutes after the

reading task, axial length measures were not significantly different from baseline

measurements suggesting that the axial length changes associated with

accommodation are transient in nature.

11..33..22 IInnttrraaooccuullaarr pprreessssuurree

Another potential mechanical factor in myopia development is the eye’s intraocular

pressure (IOP). The role of intraocular pressure in myopia development has been

studied by a number of investigators in both animals and humans however the

findings have been equivocal.

11..33..22..11 AAnniimmaall mmooddeellss

Since myopia is primarily axial in nature, early theories proposed that raised IOP

was responsible for inflation or elongation of the globe. In a theoretical paper,

Greene (1980) suggested that the oblique muscles with posterior insertions may

significantly raise vitreous pressure during reading, enough to temporarily increase

axial length. Numerous studies with animals have explored the mechanical

relationship between IOP and axial length.

Chapter 1

43

Van Alphen (1986) demonstrated that increasing IOP in both enucleated cat and

human eyes resulted in significant axial elongation of the globe without radial

expansion. The author concluded that the tone of the ciliary muscle mediates the

tension within the choroid and subsequently the sclera, which in turn influences

expansion of the globe and increase in axial length.

Using a rabbit model and similar experimental techniques, Tokoro et al (1990) and

Akazawa et al (1994) examined the extensibility of the sclera following periods of

elevated IOP. Akazawa et al (1994) reported a positive linear relationship between

scleral strain and IOP (up to approximately 40 mmHg). Tokoro et al (1990)

observed scleral stretch in all eyes at the equator, but in only 50% of eyes at the

posterior pole (with the other 50% of eyes exhibiting scleral constriction). These

studies demonstrate that significant increases in IOP can modify the mechanical

properties of scleral tissue. However, such levels of IOP (> 40 mmHg) in humans are

rare and are associated with ocular disease.

Other animal models suggest axial elongation associated with myopia is more

complicated than a simple pressure and expansion relationship. Schmid et al (2000)

highlighted that factors apart from IOP must regulate eye growth by significantly

reducing IOP in developing chicks through therapeutic treatment (Timolol). The

reduction of IOP in test chicks did not reduce the degree of experimental myopia

induced, compared to controls. Using the chick model it has also been shown that

Chapter 1

44

a gradual increase in IOP is associated with normally developing eyes. However,

experimentally induced myopic eyes have higher IOP and are faster growing than

experimentally induced hyperopic eyes (Schmid et al 2003a).

11..33..22..22 IInnttrraaooccuullaarr pprreessssuurree aanndd mmyyooppiiaa iinn cchhiillddrreenn

Although animal studies have highlighted that increasing IOP can alter scleral strain

and axial length, the results of human myopia experiments are conflicting. Cross

sectional studies examining IOP and myopia in children report mixed findings.

ii)) CCrroossss sseeccttiioonnaall ssttuuddiieess

Edwards and Brown (1993) examined the clinical records myopic and non-myopic

Chinese children and found a significant difference in IOP between the two groups.

However, due to the retrospective nature of the study, variables such as level of

accommodation or direction of gaze during tonometry were not controlled.

Subsequently, Edwards et al (1993) conducted a prospective cross-sectional study

investigating IOP in young Chinese children and controlled for accommodation and

fixation. Myopic children had a higher mean IOP than non-myopic children;

however the difference was not statistically significant. There was also no

significant correlation between IOP and refractive error, but children with one

myopic parent had significantly higher IOP than children with two non-myopic

parents. This study suffered from a lack of myopic children (n = 13) in comparison

to non-myopic control group (n = 93).

Chapter 1

45

Quinn et al (1995) also conducted a cross sectional analysis examining IOP and

myopia in a wider range of children (age 1 month - 19 years). Myopia was

significantly associated with age, IOP and a family history of myopia. The authors

hypothesised that IOP may be higher in myopic subjects due to limbal stretching

distorting the aqueous outflow pathways. In some cases, presumably young

infants, IOP was measured with the subject in a supine position. The influence of

posture on IOP has been reported previously (Buchanan and Williams 1985) and

may have influenced the results of this study.

Other cross sectional studies have found no association between IOP and myopia.

Schmid et al (2003b) examined twenty myopic and non-myopic children aged 8-12

years and found no significant difference between the two cohorts for IOP, scleral

stress or ocular rigidity. In a much larger sample of 636 Chinese children aged 9-11

years, Lee et al (2004) found no significant difference in IOP between high myopes,

low myopes and emmetropes. The authors also reported no significant correlations

between IOP and spherical equivalent or axial length.

iiii)) LLoonnggiittuuddiinnaall ssttuuddiieess

Longitudinal studies following children (myopic and emmetropic) offer the best

opportunity to establish a causal link between IOP and axial length. However, the

results from a variety of studies do not reveal a clear correlation between the two

variables.

Chapter 1

46

Jensen (1992) monitored IOP and axial length in 51 Danish myopes aged 9-12 every

six months over a two-year period. Subjects were categorised into two groups

according to their baseline IOP with respect to the mean IOP of the entire group (16

mmHg). The high IOP group (> 16 mmHg) experienced a significantly higher rate of

axial elongation and myopic progression in comparison to the low IOP group ( 16

mmHg). These findings suggest that IOP may influence the rate of myopic

progression, although the division of the two groups at 16 mmHg was somewhat

arbitrary.

Similarly, Edwards and Brown (1996) and Goss and Caffey (1999) followed cohorts

of young children over two and three year periods respectively. Both studies

reported an increase in IOP does not occur prior to the onset of myopia in children,

but rather afterwards. Goss and Caffey (1999) conceded that due to the substantial

interval between follow up examinations (6 months) an increase or fluctuation in

IOP for a short period of time (up to 5-6 months) prior to myopia onset cannot be

entirely dismissed.

Recently, Manny et al (2008) examined a cohort of myopic children over a five-year

period. They found no significant relationship between IOP and baseline measures

of refractive error and axial length, or the changes observed in these measurements

over time. As this analysis was part of a larger myopia study there was no control

emmetropic group to compare these findings. IOP was measured using a variety of

Chapter 1

47

instruments (NCT and GAT) throughout the study which may have influenced the

results.

11..33..22..33 IInnttrraaooccuullaarr pprreessssuurree aanndd mmyyooppiiaa iinn aadduullttss

Studies examining the relationship between IOP and refractive error in adult

populations typically report a positive correlation between myopia and IOP. These

cross sectional studies give no information regarding causality, but highlight

possible trends or associations.

Tomlinson and Phillips (1970) reported a significant difference in IOP and axial

length measurements for both myopes and hyperopes when compared to

emmetropes. They also observed a small but significant correlation between axial

length and IOP (r = 0.37, p < 0.002).

Abdalla and Hamdi (1970) reported similar findings of higher IOP in myopes

compared to emmetropes in a much larger cohort (n = 760). However, the

relationship between IOP and refractive error was not consistent over each age

group examined. Subjects in this study with an IOP below 10 or above 20 mmHg

were excluded from analysis, which would have influenced the results.

Chapter 1

48

David et al (1985) also found an incremental increase in IOP with change in

refractive status. This relationship remained evident, although less significant, after

controlling for age and gender. Similarly, in the Beaver Dam Eye Study, Wong et al

(2003) reported a highly significant positive correlation between IOP and myopia

when controlling for age and gender. The results of both studies may be influenced

by other variables, such as blood pressure (affecting IOP) or ocular disease (e.g.

cataract affecting refraction), but demonstrate a clear association between IOP and

refractive status in a large population. Nomura et al (2004) also observed similar

trends after controlling for a range of variables including; blood pressure,

cardiovascular disease and central corneal thickness. Although this study employed

a different system of refractive error classification and IOP measurement technique

(NCT), the relationship between IOP and refractive error remains relatively

consistent in comparison to other studies.

In contrast, Puell-Marin et al (1997) found no association between IOP and

refractive status in a sample of 528 young university students. The noticeable

difference between this study and the others discussed above is the age of the

subjects. This suggests the relationship between IOP and refractive status in older

population cohorts may simply be an artefact of age. However, since most studies

have controlled for age and gender in their statistical analyses, the results of this

Spanish study are at odds with previous studies.

Chapter 1

49

Recently, Leydolt et al (2008) reported significant increases in axial length in human

eyes in vivo, following short periods of induced IOP elevation (through a suction cap

technique). Previously this had only been observed in animal models. The authors

reported a significant correlation between IOP increase and axial elongation (r =

0.66, p < 0.005). Read et al (2011) also reported that a small elevation in IOP,

induced through mechanical means (swimming goggles) for a short period of time

was correlated with a small but statistically significant axial elongation of the eye (in

both myopes and emmetropes). These results support the theory that increases in

IOP may be related to axial length changes causing myopia.


Mechanical forces associated with IOP, convergence and accommodation have

been suggested as potential factors which may promote axial elongation and

myopia development. However, studies comparing these mechanical factors in

cohorts of myopes and emmetropes during ocular development and during near

work tasks have produced conflicting results.

Chapter 1

50

11..44 NNoonn--aammbbllyyooppiicc aanniissoommeettrrooppiiaa

Anisometropia is a difference in refractive error between fellow eyes which is

typically due to an interocular difference in axial lengths, in particular the vitreous

chamber (Sorsby et al 1962b). The prevalence of anisometropia varies according to

the method of calculation (e.g. a between eye difference in spherical/cylindrical

component of refraction, spherical equivalent (SEq) or refraction in one meridian)

and the magnitude of the refractive difference used to define the condition (e.g. 1

or 2 D). In population studies, the prevalence of anisometropia ranges from 1-20%

depending on the above criteria used and the age distribution of the sample. In a

general clinical population, the prevalence of spherical equivalent anisometropia of

1 D or more is approximately 10% (Laird 1991).

Hyperopic anisometropia that persists during early childhood is often associated

with amblyopia and strabismus due to the disruption of normal visual development

(Abrahamsson and Sjostrand 1996). However, in myopic anisometropia, in which

the more myopic eye may still receive a clear image during close viewing,

amblyopia and strabismus are less likely to develop (Tanlamai and Goss 1979).

Non-amblyopic myopic anisometropia represents unequal eye growth or stretch

within a visual system which has presumably received the same visual input.

Anisometropia may therefore be of experimental use in refractive error research.

Examination of the two eyes from one subject presumably allows for greater

control of various potential confounding variables (such as genetic and

environmental influences).

Chapter 1

51

Previous animal studies have shown that manipulation of the focus of the retinal

image results in compensatory eye growth to minimise the imposed defocus

(WIldsoet 1997). The changes observed in axial length are due to enlargement or

reduction in the size of the vitreous chamber due to changes in the sclera and

choroid (Wallman et al 1995, Nickla et al 1997). Animal studies employing

monocular visual manipulation suggest that the two eyes are regulated

independently in response to visual stimuli. A high degree of interocular symmetry

in the anterior segment, but an asymmetry in the length of the posterior segment

suggests that anisometropia may develop due to a local mechanism in response to

an altered retinal image in the more myopic eye. In this section we examine

previous research in non-amblyopic (primarily myopic) anisometropia.

11..44..11 GGeenneettiicc iinnfflluueennccee

Although few studies have examined the influence of genetics on the development

of anisometropia, several case studies suggest genetics may play a role in the

aetiology of severe myopic anisometropia.

In a study of 48 children with unilateral axial myopia, Weiss (2003) reported that 3

female patients had a family history of high myopia and suggested that an x-linked

recessive inheritance pattern existed in cases of high anisometropia. However,

Ohguro et al (1998) examined the pedigree of a young male with 20 D of myopic

anisometropia and observed an autosomal dominant inheritance pattern.

Chapter 1

52

Several case studies have reported mirror or directly symmetric high anisometropia

in monozygotic twins (De Jong et al 1993, Cidis et al 1997, Okamoto et al 2001) and

non-twin siblings (Park et al 2010). Several of these cases were associated with

abnormal ocular development in the affected eye such as optic nerve or macula

hypoplasia. These reports suggest that severe myopic anisometropia may be

genetically determined.

A high degree of persistent anisometropia (greater than approximately 5-10 D)

present from a young age appears to be a result of genetic rather than

environmental influences. Severe cases of anisometropia are often associated with

a unilateral structural ocular abnormality resulting in excessive axial elongation.

11..44..22 LLoonnggiittuuddiinnaall ssttuuddiieess

Parssinen (1990) followed the change in refraction of 238 myopic children aged 9-

11 years over a 3 year period and found that anisometropia remained stable in

67%, increased in 27% and decreased in 6% of subjects. As myopia increased over

time (mean spherical equivalent -1.43 to -3.06D), the magnitude of spherical

equivalent anisometropia increased from 0.30 to 0.51 D. The initial refractive error,

magnitude or axes of astigmatism were not related to the change in anisometropia.

The changes observed in anisometropia were also not related to spectacle wear.

Chapter 1

53

Yamashita et al (1999) also observed that spherical anisometropia determined by

cycloplegic refraction remained relatively stable over a five year period (mean

approximately 0.25 D) in 350 Japanese schoolchildren aged 6-11 years. Over the

study period, anisometropia remained stable in 84% of children, while in 16% the

magnitude increased or decreased with age. The interocular difference in the

magnitude of astigmatism was also stable over time (mean approximately 0.32 D)

and there was a significant correlation between the amount of spherical and

astigmatic anisometropia.

Pointer and Gilmartin (2004) retrospectively examined the longitudinal change in

refraction of a slightly older population aged 6-19 years. They compared the rate of

refractive change in 21 unilateral myopic anisometropes (one eye myopic, fellow

eye emmetropic) in comparison to an age matched control group of bilateral

myopes. The rate of progression in the myopic eye of anisometropes was not

significantly different to the rate of progression in bilateral myopes.

In a large study of 1979 children aged 7 to 9 years, Tong et al (2006) annually

examined the change in refraction and axial length over a 3-year period. Mean

spherical equivalent anisometropia increased slightly over time; 0.29 D at baseline

and 0.44 D at study completion. Less than 4% of children had anisometropia of 1.0

D or more at baseline. Of these children with 1.0 D or more of anisometropia, 5.1%

had an increase in anisometropia by at least 0.5 D, whereas 3.4% had a decrease of

Chapter 1

54

at least 0.5D. The change in anisometropia correlated with the change in inter-eye

axial length. Compared with isometropic children, each eye of the anisometropic

children had a higher rate of myopia progression, but the change in anisometropia

over time was similar between the two cohorts.

Throughout childhood non amblyopic anisometropia may increase or decrease, but

such changes are small in magnitude. Changes in anisometropia during childhood

correlate with changes in axial length. Evidence regarding the rate of myopic

progression in anisometropic eyes compared to isometropic eyes is conflicting.

11..44..33 BBiioommeettrriicc ssttuuddiieess

Logan et al (2004) investigated the interocular symmetry of biometrics in a cohort

of non-amblyopic myopic anisometropes. There was a strong correlation between

the amount of anisometropia and the between-eye asymmetry in axial length. In

particular, the vitreous chamber depth was significantly different between eyes,

with small insignificant interocular differences in corneal curvature, anterior

chamber depth and lens thickness.

Properties of the anterior segment, including the cornea and anterior chamber, and

the intraocular lens are highly symmetric between fellow eyes in anisometropia and

make minimal contribution to the interocular difference in axial length and

refractive power. Asymmetric axial elongation of the posterior vitreous chamber is

Chapter 1

55

the primary cause of anisometropia in populations with and without ocular

abnormalities.

Given the potential role of the choroid in the regulation of the refractive state and

emmetropisation it is of interest to examine the interocular symmetry of choroidal

thickness in anisometropic eyes. Although no studies have directly measured

choroidal thickness in anisometropic eyes, some studies have indirectly measured

the interocular symmetry of the choroidal blood flow using various techniques.

Shih et al (1991) measured the ocular pulse amplitude (OPA: generated by the

choroidal blood flow) in both eyes of 188 subjects using a pneumatic tonometer.

The ocular pulse amplitude decreased significantly with an increase in axial length

suggesting that choroidal circulation is reduced in high myopia. In addition, for

subjects with anisometropia greater than 3 D, there was a significant interocular

ocular difference in OPA (0.27 mmHg). For all subjects, the interocular difference in

refractive error and axial length was significantly correlated with the interocular

difference in OPA.

Similarly, Lam et al (2003) measured the OPA and pulsatile ocular blood flow (POBF)

in anisometropic subjects (> 2.0 D SEq) using a pneumatic tonometer. Both OPA

and POBF were significantly lower in the more myopic eye of axial anisometropes

and the interocular difference in OPA and POBF were both significantly correlated

Chapter 1

56

with the interocular difference in axial length. This study also suggests that reduced

choroidal blood flow is associated with increasing myopia, but the cross sectional

nature of these studies does not prove causality. The measurement of OPA may be

influenced by various factors including ocular rigidity, corneal curvature and IOP

and is considered an estimate of choroidal blood flow circulation rather than a

direct measure of choroidal thickness. OPA may also be directly influenced by

ocular volume and therefore changes associated with axial length may be an

artefact of eye size (James et al 1991).

11..44..44 TThheeoorriieess ooff aassyymmmmeettrriicc rreeffrraaccttiivvee eerrrroorr ddeevveellooppmmeenntt

While anisometropia may be a result of a genetic predisposition which initiates

unequal eye growth, the role of genetics in the development of lower, more

common, degrees of anisometropia is less clear. In this section we describe optical

and mechanical factors which may contribute to asymmetric refractive error

development.

11..44..44..11 OOppttiiccaall ffaaccttoorrss

If optical factors contribute to asymmetric eye growth, we would expect differences

in the optical properties of the two eyes in cases of anisometropia. Several studies

have compared the power of the cornea and lens, the magnitude of higher-order

aberrations and the accommodative response between the fellow eyes of

Chapter 1

57

anisometropes to determine a potential mechanism resulting is asymmetric blur

between the eyes.

ii)) CCoorrnneeaa

Weiss (2003) found no interocular difference in corneal power between the eyes of

24 children with unilateral high axial anisometropia (mean anisometropia 9 D)

associated with a range of ocular and systemic disorders. Similarly, Kwan et al

(2009) and Logan et al (2004) found no significant difference in mean corneal

power between the more and less myopic eyes in their cross sectional studies of

adult myopic anisometropes.

iiii)) CCrryyssttaalllliinnee lleennss

In an early study, Sorsby et al (1962b) examined the ocular components of 68

anisometropes (ranging from 2-15 D anisometropia in the vertical meridian) and

observed that the power and thickness of the crystalline lens was similar between

fellow eyes for the majority of subjects. In subjects with moderate anisometropia

(3-5 D), interocular differences in lens power contributed to the magnitude of

anisometropia in a small proportion of cases, however the differences in axial

length were still the primary cause of the difference in refraction. Similarly, in a

study of 28 myopic anisometropes (2-4 D) Logan et al (2004) found no significant

difference in lens thickness between fellow eyes using an ultrasound biometer.

Chapter 1

58

iiiiii)) HHiigghheerr--oorrddeerr aabbeerrrraattiioonnss

A high degree of interocular symmetry exists between fellow isometropic eyes for

both corneal (Wang et al 2003a, Lombardo et al 2006) and total ocular aberrations

(Thibos et al 2002, Wang et al 2003). However, few studies have examined this

relationship in anisometropic populations. Tian et al (2006) investigated the

interocular symmetry of ocular aberrations in ten myopic anisometropes (> 1.00D

SEq) and found no significant interocular differences in individual Zernike terms, 3rd,

4th and 5th order aberrations or total higher-order aberrations. Kwan et al (2009)

also examined the interocular symmetry and magnitude of total ocular aberrations

in myopic anisometropia (> 1.75 D SEq) during cycloplegia. The authors observed

significantly higher levels of aberrations in the less myopic eyes (total, 3rd order, 4th

order and spherical aberration) and a high level of symmetry between fellow eyes

for a range of Zernike terms.

iivv)) AAccccoommmmooddaattiioonn

Unequal accommodative responses between the fellow eyes may also result in

unequal retinal blur. In a theoretical paper, Charman (2004) proposed that the

simple act of reading across a page induces an unequal accommodative demand

between the eyes (when the eyes are not viewing directly along the midline), which

increases as the working distance to the text is decreased. However, if the eyes

remain relatively centred and stationary over the reading task, the defocus endured

in one eye will also be endured in the other eye in the opposite direction of gaze,

and each eye would receive the same amount of blur (averaged over time). When a

Chapter 1

59

head tilt or turn is adopted, or in fact any position in which the reading material is

not centred in front of the eyes, the accommodative demand for each eye will again

change. Charman (2004) suggests that at a working distance of 10cm (10D

accommodative demand) when reading on an A4 page the interocular difference in

accommodative demand at the end of a line of text may reach up to 2D. Thus,

viewing reading material at a short working distance (with a head tilt) may lead to

hyperopic defocus in one eye, assuming a consensual accommodative response to

the lower of the two demands. Asymmetric hyperopic defocus during near work

may be related to the development of anisometropia.

It is assumed that the accommodative response is consensual between fellow eyes

due to the dominant innervation to each ciliary body via the parasympathetic

pathway originating from a common neural origin. Early studies confirmed that in

normal subjects the accommodative response is symmetric between the eyes in

both monocular (Ball 1952) and binocular (Campbell 1960) viewing conditions.

However, there is an increasing amount of evidence that suggests the

accommodative response may differ between fellow eyes in certain circumstances.

Small amounts of aniso-accommodation (accommodating to different levels

between fellow eyes) in the order of 0.25 - 0.75 D may be possible during binocular

viewing. Flitcroft et al (1992) examined the dynamic accommodative response in 3

subjects when different stimuli were presented to each eye simultaneously. When

Chapter 1

60

accommodative targets were presented in counter phase (e.g. 1 D demand in the

right eye and 1 D relaxation in the left eye) the accommodative response of the

right eye appeared to be an average of the two demands. When an

accommodative stimulus was presented to one eye only the response of the right

eye was approximately equal to the stimulus requiring no accommodative effort

(irrespective of which eye was exposed to the stimulus). The authors suggested

that the reduced accommodative response observed when the two eyes are

presented with conflicting accommodative stimuli may represent a suppression

mechanism activated by interocular differences in image quality.

Koh and Charman (1998) examined the interocular symmetry of accommodation in

six normal adults when presented with fusible targets differing in accommodative

demand and controlling for convergence. For interocular differences in

accommodative demand of 0.5 and 3.0 D, both eyes tended to accommodate to the

target requiring the least accommodative effort. For example, when the right eye

was presented with a 3 D stimuli and the left eye with a 5 D stimuli, the average

accommodative response was 2.54 D and 2.42 D in the right and left eyes

respectively. The interocular difference in accommodation when presented with

anisometropic stimuli ranged from 0.02 to 0.64 D. However there was no

statistically significant difference in the accommodative response for each eye in all

subjects. This study suggests that when the eyes are presented with stimuli of

unequal accommodative demand, the eye which requires the least accommodative

Chapter 1

61

effort to maintain clear focus of the target will control the accommodative

response in both eyes.

Marran and Schor (1998) observed an unequal accommodative response (> 0.50 D)

in some subjects following a period of aniso-accommodative training. When

presented with unequal accommodative targets subjects demonstrated aniso-

accommodation to approximately one quarter of the interocular difference in

demands. At a stimulus difference of approximately 3 D there appeared to be a

suppression mechanism involved in eliminating the image from the eye with the

higher accommodation demand. While this experiment relied heavily on subjective

responses to confirm aniso-accommodation, in a second experiment the authors

objectively measured the accommodative response in each eye simultaneously

using a dual infra-red optometer. Beginning with equal accommodative stimuli, the

accommodative response was recorded continuously and after ten seconds, convex

lenses of various powers (+1.00, +1.50 and +2.00 DS) were introduced in front of

the right eye reducing the accommodative demand. When accommodative stimuli

differed between eyes by 1 D the response was symmetric. As the difference in

stimuli increased to 1.5 and 2.0 D, the average interocular difference in

accommodative response was 0.65 and 0.33 D respectively. The authors concluded

that small amounts of aniso-accommodation are possible and proposed that the

motor pathway involved in accommodation may have independent control over

fellow eyes to a small extent. One potential drawback to this study was that only

Chapter 1

62

subjects who demonstrated the ability to aniso-accommodate to some extent in

pilot studies were included in the experiment.

If humans have the ability to aniso-accommodate this may enable them the ability

to iso-emmetropise (or remain symmetric in refractive error development). If this

mechanism is defunct, the defocus induced from the inability to aniso-

accommodate may be a precursor to the development of anisometropia.

Hosaka et al (1971) measured the monocular amplitude of accommodation in each

eye of 98 anisometropes (interocular difference ≥ 1.00 D). The majority of subjects

(70%) had an interocular difference in accommodative amplitudes of less than 2 D;

25% of subjects had an interocular difference less than 0.5 D, 18%; 0.5 - 0.99 D and

27%; 1.0 - 1.99 D. The authors suggested that interocular differences of 0.5 D or

less were most probably due to a measurement error in the near point method

used. Of the subjects with an interocular accommodation difference greater than

0.5 D, the amplitude of accommodation was reduced in the more ametropic eye

70% of the time. There was no significant correlation between the interocular

difference in accommodative amplitude and the magnitude of anisometropia.

Since the accommodative amplitude was measured without the spectacle

correction in place, and amblyopic subjects were included in the analysis the results

of this study do not provide adequate information regarding the interocular

symmetry of accommodation in pure anisometropia.

Chapter 1

63

Miwa and Tokoro (1993) examined tonic accommodation in twenty hyperopic

anisometropic children and reported interocular equality. However, only 15

seconds was allowed for accommodation to regress to the natural resting state in

darkness. McBrien and Millodot (1987b) have shown that approximately 1-2

minutes are required for accommodation to revert to the resting state without

visual stimuli. Xu et al (2009) examined the interocular symmetry of the

accommodative response in twenty anisometropes with 2.50 - 7.00 D of spherical

anisometropia. The accommodation response was measured at 1, 2, 3 and 4 D

demands, using a binocular infrared optometer. The more myopic eyes of

anisometropes exhibited a larger accommodative lag compared to the less myopic

eyes for accommodation demands of 2, 3, and 4 D, however, these differences did

not reach statistical significance. To our knowledge these are the only previous

studies to directly examine the interocular symmetry of accommodation in

anisometropia. Furthermore, no studies have examined the interocular symmetry

of changes in biometrics or higher-order aberrations during accommodation in

myopic anisometropes.

11..44..44..22 MMeecchhaanniiccaall ffaaccttoorrss

If mechanical factors are primarily involved in anisometropic eye growth, then we

would expect differences in the mechanical (IOP) or biomechanical properties

(corneal thickness/hysteresis) between the fellow eyes.

Chapter 1

64

ii)) CCoorrnneeaall pprrooppeerrttiieess

In a contact lens study, Holden et al (1985) examined the interocular difference in

the thickness of the corneal epithelium and stroma in twenty anisometropic

subjects, the majority of which were unilateral myopic anisometropes, and found

no statistically significant differences between the more and less myopic eyes.

Chang et al (2009) examined corneal biomechanics in 63 children, 12 of whom had

anisometropia greater than 1.5 D. They reported a significant negative correlation

between corneal hysteresis (CH) and axial length. Longer eyes tended to have

lower hysteresis values, where lower hysteresis suggests a reduction in mechanical

corneal strength. They also observed a significant negative correlation between the

interocular difference in CH as a function of axial anisometropia. The authors

suggested that perhaps lower corneal hysteresis of more myopic eyes is

representative of interocular differences in corneal lamellae arrangement or a

weaker myopic sclera.

Xu et al (2010) compared biometric properties of the cornea between fellow eyes in

23 cases of high anisometropia (mean spherical equivalent anisometropia of

approximately 11 D). There were no statistically significant interocular differences

for measures of central corneal thickness or the corneal resistance factor (CRF);

however, on average the more myopic eyes had slightly lower corneal hysteresis

values (1 mmHg lower), which reached statistical significance. The authors

Chapter 1

65

suggested that the interocular difference in CH may be due to microstructural

corneal damage in high myopia or interocular discrepancies in collagen fibril

arrangement within the stroma. In a case study, Gatinel et al (2007) reported on

the corneal biomechanics of a myopic anisometrope (SEq anisometropia

approximately 10 D) undergoing a corneal surgical procedure. At two preoperative

examinations there were no statistically significant differences between the fellow

eyes for measures of CH or CRF. Even in cases of severe axial anisometropia,

corneal thickness, power and viscoelastic properties appear to be symmetric

between fellow eyes. Small interocular differences in corneal hysteresis in the

more myopic eye in anisometropes suggests that the cornea may be structurally

altered in high myopia.

iiii)) IInnttrraaooccuullaarr pprreessssuurree

Van Alphen (1986) proposed that axial length is determined by genetic growth and

ocular stretch is influenced by intraocular pressure (IOP) and scleral rigidity or

resistance. This hypothesis proposes that myopia may result from the mechanical

force of IOP, reduced scleral rigidity or a combination of the two. If a relationship

exists between IOP and axial elongation, we would expect that IOP would be higher

in the more myopic eye of anisometropes, at least during myopia development or

progression.

Chapter 1

66

To date, relatively few studies have examined the relationship between IOP and

refractive errors using anisometropic subjects. This group of subjects offers

advantages when attempting to control for potential confounding variables such as

age, blood pressure and gender with respect to IOP because each anisometropic

subject provides a test (more myopic) and control (less myopic or emmetropic) eye

for comparison. Table 1.2 summarises the findings of previous IOP studies of

anisometropic subjects.

Tomlinson and Phillips (1972) first used anisometropic children to explore the

relationship between IOP and refractive error. Although the criterion for

anisometropia was not specified, the authors found no significant interocular

difference in IOP between the less and more myopic eyes using Goldmann

applanation tonometry (GAT). Similarly, Lee and Edwards (2000) found no

significant difference in IOP between the two eyes of young myopic or hyperopic

anisometropes or antimetropes using non-contact tonometry (NCT). The authors

suggest that perhaps interocular differences in axial length may be due to

differences in scleral structure and elasticity rather than IOP.

Bonomi et al (1982) employed both GAT and Schiotz (indentation) tonometry when

measuring IOP in anisometropes. They reported significant interocular differences

when using the Schiotz method, but attribute this to the variability in the clinical

technique. There was a statistically significant difference in IOP (using GAT)

Chapter 1

67

Table 1.2: Studies of intraocular pressure in anisometropia.

Study

Subject

age

(years)

Anisometropia criteria (D)

IOP

method

Results

More myopic eye

IOP mmHg (mean ± SD)

Less/non myopic eye

IOP mmHg mean ± SD

Statistical significance

Tomlinson &

Phillips (1972)

8-16

Not specified (n=13)

GAT

14.0

13.3

p > 0.05

(Wilcoxon matched pairs)

Bonomi et al

(1982)

7-68

High myopia (SPH <-5.00 D)

vs EMM or HYP (n=42)

High myopia (SPH <-5.00 D) vs low myopia (-5.00 D < SPH < 0.00 D) (n=95)

GAT

Schiotz

GAT Schiotz

16.1 ± 2.6 18.3 ± 3.0

16.1 ± 2.5 17.8 ± 3.3

16.4 ± 2.4 17.2 ± 3.0

16.8 ± 2.3 17.1 ± 3.0

p > 0.05 p < 0.05

p < 0.05 p < 0.05

(Paired t-tests)

Lee & Edwards

(2000)

8-14

SPH difference 2.00D Astigmatism < 1.50D

NCT

16.08 ± 3.09 (-5.38 ± 2.71 D) n=24 15.20 ± 2.24 (+1.57 ± 1.23 D) n=15 16.86 ± 3.60 (-2.91 ± 2.13 D) n=28

16.21 ± 3.12 (-2.24 ± 2.48 D) n=24 14.93 ± 1.91 (+5.10 ± 1.53 D) n=15 17.11 ± 3.45 (+1.33 ± 2.08) n=28

p = 0.65 p = 0.45 p = 0.31

(Paired t-tests)

Lam et al

(2003)

20-34

SEq 2.00 D (n=31)

OBF

14.50 ± 2.85

14.27 ± 2.5

p = 0.41

(Paired t-test)

NCT (non contact tonometry), GAT (Goldmann applanation tonometry), OBF (ocular blood flow tonometry), SPH (spherical component), SEq (spherical equivalent), EMM

(emmetropia), HYP (hyperopia)

Chapter 1

68

between the fellow eyes in a cohort of myopic anisometropes; however, the

authors considered such a small mean interocular difference (0.7 mmHg) clinically

irrelevant. Lam et al (2003) also found no significant interocular difference in IOP

within a cohort of 31 young anisometropes. However the authors concede that the

pneumatic tonometer used for measuring IOP may have been influenced by corneal

curvature. The interocular symmetry of IOP and in anisometropia requires further

investigation using more sophisticated technology.

In summary, cross-sectional studies of IOP in anisometropic subjects using both

applanation and non-contact techniques have shown no significant differences

between the more and less myopic eyes. These studies suggest that a mechanical

IOP inflation and axial elongation mechanism may not be involved in the

development of axial anisometropia or myopia (except for the study of Bonomi et al

1982). However, recently, Xu et al (2010) observed a slightly higher IOP (mean 1.8

mmHg higher) in the more myopic eyes of high myopic anisometropes when using a

non-contact technique (Ocular Response Analyzer) less affected by corneal

properties than previous tonometers, which approached statistical significance.

11..44..44..33 OOtthheerr ffaaccttoorrss

ii)) OOccuullaarr ddoommiinnaannccee

Ocular sighting dominance refers to the preference for the visual input from one

eye when binocularly viewing or aligning a distant target and is potentially

Chapter 1

69

influenced by genetics, environmental and cognitive factors. Recently, authors

have examined the relationship between ocular dominance and refractive error in

an attempt to elucidate the mechanisms governing myopia development.

Mansour et al (2003) examined the symmetry of refractive error between eyes and

found, on average, right eyes to be significantly more myopic than the left.

Although this retrospective analysis did not incorporate ocular dominance, the

authors proposed that as the majority of the population are right eye dominant, the

dominant eye may often be the more myopic eye. They hypothesised that

excessive accommodation in the dominant fixating eye at near may account for this

relative increase in myopia in right eyes.

Two studies have investigated the association between ocular sighting dominance

and myopic anisometropia. Cheng et al (2004a) measured ocular dominance in 55

adult myopic anisometropes (≥ 0.50 D interocular difference in spherical

equivalent) using the hole-in-the-card test. Dominant sight eyes were significantly

larger (25.15 ± 0.96 mm) and more myopic (-5.27 ± 2.45 D) compared to non-

dominant eyes (24.69 ± 1.17 mm, -3.94 ± 3.10 D) and when the degree of

anisometropia exceeded 1.75 D, the dominant eye was always the more myopic

eye. The authors suggested that an aniso-accommodative response (due to an

unequal accommodative demand during reading) may be responsible for the

dominant eye becoming more myopic.

Chapter 1

70

Chia et al (2007) also measured ocular dominance in a large cohort of children (age

12-13 years) using the hole-in-the-card-test. When including all children with an

identifiable dominant eye (n = 477), there was no significant difference between

the dominant and non-dominant eyes for spherical equivalent refractive error or

axial length. However, dominant eyes had significantly less astigmatism (0.88 ±

0.80 D) compared to non-dominant eyes (1.00 ± 0.92 D). The authors speculated

that the eye with less astigmatism may become the dominant eye during

development due to the better unaided vision. In contrast to the findings of CY.

Cheng et al (2004), when anisometropia exceeded 1.50 D (n = 25), the more myopic

eye was the dominant eye in only 56% of subjects.

The interocular symmetry of accommodation in response to various tasks requires

further investigation. In particular, there is limited research concerning the

accommodative response in anisometropes. Ocular characteristics such as

astigmatism and accommodation in anisometropia require further investigation and

are of interest with respect to the mechanisms underlying the development of

refractive error and ocular dominance.

iiii)) OOccuullaarr ddoommiinnaannccee aanndd aaccccoommmmooddaattiioonn

It has been suggested that the dominant eye (traditionally the preferred eye for

distant sighting) may exhibit different accommodative responses to the fellow non-

dominant eye. In amblyopia, the non-dominant (amblyopic) eye shows impaired

Chapter 1

71

accommodation following abnormal visual experience (Hokoda and Ciuffreda 1982,

Hung et al 1983, Ciuffreda et al 1983, Ciuffreda et al 1984) however few studies

have examined the role of ocular dominance and accommodation in non-amblyopic

subjects.

Ibi (1997) examined the accommodative response in the dominant and non-

dominant eyes of young isometropic subjects and observed that the dominant eye

showed a slight myopic shift at both distance and near fixation following

accommodation. The author speculated that the static tonus of the ciliary muscle is

increased in the dominant eye, which may explain why the dominant eye is often

the more myopic eye in non-amblyopic anisometropia. However, if the dominant

eye shows a slight lead of accommodation following near work, this myopic defocus

would slow eye growth, based on the theory of retinal image mediated eye growth.

Yang and Hwang (2010) compared the interocular equality of the accommodative

response in children with intermittent exotropia, without amblyopia or

anisometropia. Ocular dominance was determined by fixation preference during

cover testing and the accommodative response was measured during binocular and

monocular fixation of a 3 D stimulus using a Shin-Nippon NVision-K 5001

autorefractor. During monocular viewing, the dominant and non-dominant eyes of

intermittent exotropes both showed a small lag of accommodation. However,

during binocular fixation, a significant number of subjects displayed a greater lag of

Chapter 1

72

accommodation in the non-dominant eye compared to the fellow dominant eye.

The authors suggest that during binocular viewing, interocular rivalry may lead to

suppression and an accommodative lag in the non-dominant eye. On the other

hand, the reduced accommodative response in the non-dominant eye during

binocular viewing may be a result of reduced fusional convergence in exotropia

which may result in a diminished accommodative response. Although this study

excluded amblyopic subjects, it supports previous research which suggests that the

accommodative response is diminished in eyes following abnormal visual

experience.


Non-amblyopic anisometropia is primarily due to an interocular difference in axial

length. While genetics appears to play a role in the development of severe forms of

anisometropia associated with pathology and amblyopia, the role of genetics in the

development of lower degrees of non-amblyopic anisometropia is less clear.

Throughout childhood the magnitude of non-amblyopic anisometropia remains

relatively stable. Small changes in anisometropia observed during childhood

correlate with changes in axial length. Comparing the fellow eyes in anisometropic

subjects may be of use in studies of refractive error development as this allows for

greater control of potential confounding inter-subject variables. Several factors

have been suggested that may promote unequal axial elongation including optical

factors such as an asymmetry in accommodation or higher-order aberrations and

mechanical factors such as an interocular difference in IOP. However, studies which

Chapter 1

73

have investigated these hypotheses have not identified a single cause of

asymmetric axial elongation.

Chapter 1

74

11..55 AAmmbbllyyooppiiaa aassssoocciiaatteedd aanniissoommeettrrooppiiaa

Anisometropia associated with amblyopia, strabismus or ocular malformations

appears to have a strong genetic component. Case studies have reported mirror or

directly symmetric high anisometropia in monozygotic twins (De Jong et al 1993,

Cidis et al 1997, Okamoto et al 2001) and non-twin siblings (Park et al 2010)

associated with abnormal ocular development in the affected eye. These reports

suggest that severe anisometropia may be genetically determined. Congenital

strabismus which presents from birth to 6 months of age is also thought to be of

genetic aetiology while strabismus which develops later in childhood is thought to

be multifactorial. For later onset esotropia, although the presence of strabismus in

a parent or family member are significant risk factors, birth weight, refractive error

and accommodation-vergence ability also play a role (Griffin et al 1979). Family

studies suggest that the risk of strabismus is 3-5 times greater if a first degree

relative has a history of strabismus (Crone and Velzeboer 1956, Podgor et al 1996).

11..55..11 EEmmmmeettrrooppiissaattiioonn iinn aammbbllyyooppiicc eeyyeess

This section summarises the finding from both prospective and retrospective

studies of refractive error changes in refractive and strabismic amblyopia during

childhood.

Chapter 1

75

11..55..11..11 RReeffrraaccttiivvee aammbbllyyooppiiaa

Abrahamsson et al (1990) followed 310 astigmatic one year old infants (≥ 1.00 D in

one eye) over a 3 year period. Fifty-six percent of infants with anisometropia >1 D

became isometropic. Five percent of isometropic infants developed anisometropia.

Anisometropia persisted in 46% of the anisometropic infants throughout the study

period, and approximately 25% of these children developed amblyopia.

In another study, Abrahamsson and Sjostrand (1996) retrospectively examined the

change in refraction of 20 children with marked anisometropia ≥ 3 D at age 1, from

age 3 to 10. Thirty percent of the children experienced an increase in the

magnitude of their anisometropia (mean 1.4 D) and developed amblyopia.

Anisometropia decreased in the remaining children over time. Half of these

children had a significant decrease in anisometropia (mean 3 D) and did not

develop amblyopia. The other half of the diminishing anisometropes experienced a

mild decrease in anisometropia (mean 1.2 D) and all these children developed

amblyopia.

Atilla et al (2009) retrospectively examined the change in refraction of young 132

non-strabismic amblyopic anisometropes (≥ 1.00 D sphere or cylinder) aged 5-8

years over a 3 year period. They compared the refractive changes in children who

had been prescribed spectacles with those prescribed a regime of patching

(occlusion of the sound eye) in addition to spectacle wear. The more and less

Chapter 1

76

ametropic eyes appeared to emmetropise at a similar rate irrespective of the

treatment received. There was a reduction in hyperopia over time, whereas the

amount of astigmatism remained relatively stable. Similar changes were observed

in both amblyopic and normal eyes and both treatment groups. This study suggests

that occlusion therapy to improve the visual acuity of the amblyopic eye does not

influence the change in refraction during emmetropisation.

11..55..11..22 SSttrraabbiissmmiicc aammbbllyyooppiiaa

Lepard (1975) retrospectively examined the change in refractive error between the

amblyopic and sound eye of 55 young patients with unilateral esotropia and an age

matched control group with normal visual acuity in both eyes. Over a period of

over twenty years, eyes with normal visual acuity (the fixating eye in the strabismic

group and both eyes of the control group) underwent a myopic shift (mean

approximately 3 D), whereas the refractive error of the amblyopic eyes remained

relatively stable.

Nastri et al (1984) also reviewed the change in refraction of 21 young unilateral

hyperopic amblyopes. Over a ten year period, the fixating eye underwent a

significantly larger myopic shift (mean 1.67 D) compared to the amblyopic eye

(mean 0.61 D). Burtolo et al (2002) also observed a significantly larger myopic shift

towards emmetropia in the fixating eyes of 20 young strabismics, compared to the

fellow amblyopic eyes over a 3 year period. However, in a cohort of ten myopic

Chapter 1

77

children with strabismus, they observed the opposite trend. The fixating eye had a

relatively stable refraction, whereas the amblyopic eye underwent a large myopic

shift away from emmetropia. These studies suggest that eyes with reduced visual

acuity do not emmetropise or are underdeveloped in comparison to their fellow

eyes with normal visual acuity and highlight the importance of clear vision in

emmetropisation.

Conversely, Rutstein and Corliss (2004) reported that the refractive error of

amblyopic and fellow eyes undergo a myopic shift similar in magnitude during

development. The authors examined the evolution of refraction in 61 amblyopes

reviewed over a minimum period of 4 years. In strabismic patients, during the

review period, the amblyopic eye underwent a mean myopic shift of 1.70 D

compared to 1.27 D (SEq) in the fellow normal eye. The shorter follow-up period

and the lower level of hyperopia at the initial presentation may have contributed to

the different pattern of refractive development observed in this study compared to

earlier retrospective analyses.

Ingram et al (2003) compared the change in anisometropia of ‘normal’ non-

strabismic and strabismic infants (age 5-7 months) over a 42 month period. At the

beginning of the study 4% of normal infants were anisometropic (≥ 1.00 D SEq)

compared to 15% of infants with strabismus. In the normal cohort, the majority of

isometropic infants remained isometropic, with only 2% developing anisometropia.

Chapter 1

78

Also, 92% of anisometropic normals became isometropic during the study. In the

strabismic cohort, 26% of the isometropes developed anisometropia and 53% of

the anisometropes experienced an increase in the magnitude of anisometropia.

The change in refraction during emmetropisation differed between strabismic and

non-strabismic children. During ocular development, a higher proportion of

strabismic children developed anisometropia compared to the majority of non-

strabismic children who approached isometropia over time.

Caputo et al (2001) retrospectively reviewed the change in cycloplegic refractions of

forty-six young myopic anisometropes age 1-9 over a minimum of two years. More

than half of these patients had strabismus or an eye movement disorder. The

authors observed that the less myopic eye at the initial examination became more

myopic over time, whereas the more myopic eye had a relatively stable refraction

during development. Throughout the review period, anisometropia decreased in

65% of subjects, remained stable in 22% and increased in 13% when defined as a 1

D difference in spherical equivalent.

Fujikado et al (2010) retrospectively examined the change in refractive errors of

young children undergoing strabismus surgery to correct esotropia and exotropia.

Approximately five years following surgery, the average amount of anisometropia

increased significantly from 0.36 to 0.98 D. The development of anisometropia was

not related to the postoperative strabismus (i.e. residual esotropia or exotropia)

Chapter 1

79

but the proportion of patients with central fusion was significantly higher in

patients with less than 2.0 D of anisometropia. This study suggests that reduced

binocularity associated with amblyopia and strabismus may play a role in the

development of myopic anisometropia.

In summary, the refractive error of amblyopic eyes remains relatively stable over

time, whereas fellow normal eyes tend to undergo a myopic shift during youth.

This suggests that clear vision is required for emmetropisation and potentially

myopia development. Few studies have prospectively examined the change in

anisometropia associated with amblyopia and strabismus. Retrospective studies

suggest that large amounts of anisometropia may arise or diminish during

emmetropisation and that children with strabismus are more likely to develop

anisometropia compared to non-strabismic children. A small amount of hyperopic

anisometropia (as little as 1.25 D) that persists or develops during childhood almost

always results in amblyopia. Although patching of the sound eye significantly

improves the visual acuity of the amblyopic eye over time, this treatment does not

appear to alter the emmetropisation process.

11..55..22 BBiioommeettrriicc ssttuuddiieess ooff aammbbllyyooppiiaa

11..55..22..11 CCoorrnneeaa

Several studies have reported a high degree of interocular symmetry in both

corneal curvature and thickness of monocular amblyopes. Holden et al (1985)

Chapter 1

80

reported that the corneal thickness was similar between the fellow eyes of 27 adult

anisometropes including subjects with amblyopia. Weiss (2003) found that the

mean interocular difference in corneal power of 24 young patients with unilateral

high myopia (5 - 20 D) was 0.1 ± 0.1D. In a larger study of 85 amblyopes, Zaka-ur-

Rab et al (2006) observed that the mean interocular difference in corneal power

was 0.61 D for hyperopes and 0.55 D for myopes. There was no correlation

between the interocular difference in corneal power and the magnitude of

anisometropia in either refractive error cohort. Patel et al (2010) observed that

corneal astigmatism and corneal diameter were similar between the fellow eyes in

a small group of children with severe anisometropia and mild to moderate

amblyopia. Excluding children with astigmatic (meridional) amblyopia, interocular

differences in corneal astigmatism were within 0.5 - 1.0 D.

11..55..22..22 AAxxiiaall lleennggtthh

While numerous studies have examined the relationship between refractive error

and visual acuity in amblyopia, few studies have investigated the optical and

biometric properties of amblyopic eyes in detail.

Sorsby et al (1962b) calculated the axial length of anisometropes based on values of

refraction, power of the cornea, depth of the anterior chamber and curvatures and

thickness of the intraocular lens. The interocular difference in axial length was

found to be the main predictor of the anisometropia, with small interocular

Chapter 1

81

differences in corneal and lens power having a contributory or counteracting effect

in a small number of cases. As 37% of subjects in this study were bilateral

hyperopes, presumably this population included a moderate proportion of

refractive amblyopes. Weiss (2003) investigated the cause of anisometropia in

children with unilateral high myopia (5-18 D myopic anisometropia). All children

examined, except one, had a unilateral ocular disease or structural abnormality

such as optic nerve hypoplasia, retinopathy of prematurity or glaucoma, in the

highly myopic eye which explained the anisometropia. The magnitude of

anisometropia was highly correlated with the interocular difference in axial length

measured with A-scan ultrasonography, with negligible interocular differences in

corneal power. In a study of adult patients with high myopic anisometropia (6 - 17

D) which presumably included some amblyopic subjects, Xu et al (2010) also

observed a strong correlation between the magnitude of anisometropia and the

interocular difference in axial length.

Lempert (2008) compared the axial length and retinal characteristics between the

amblyopic and sound eye of hyperopic amblyopes and a control group of non-

amblyopic eyes. Not only were amblyopic eyes significantly shorter and more

hyperopic compared to eyes with normal visual acuity, but the size of the optic disc

and retina were significantly reduced. The author proposed that in some cases, the

reduction of acuity in amblyopic eyes may be a result of fewer retinal

photoreceptors and optic nerve fibres due to a reduction in eye size rather than

interrupted development of the visual cortex during youth.

Chapter 1

82

Zaka-Ur-Rab et al (2006) reported that the interocular difference in axial length was

significantly correlated with the magnitude of anisometropia in cases of untreated

amblyopia, more so in myopes (r = 0.67) than hyperopes (r = 0.61). Cass and

Tromans (2008) investigated the interocular differences of biometric parameters in

fellow eyes of paediatric amblyopes including subgroups of strabismic and

refractive amblyopes. Corneal curvature and lens thickness were not significantly

different between fellow eyes. However, amblyopic eyes exhibited shorter anterior

and vitreous chambers and greater crystalline lens power compared to fellow eyes.

In terms of percentage contribution to overall axial length, the lens thickness in

strabismic amblyopes was disproportionately large compared to the fellow normal

eye. The authors hypothesised that the crystalline lens may play a role in the

development of strabismic amblyopia due to alteration of the eyes optics (i.e. an

increase in power). However, the onset of strabismic amblyopia may also interfere

with the normal emmetropisation process during which the crystalline lens thins

and undergoes a reduction in curvature.

Patel et al (2010) examined the interocular differences in axial length and corneal

curvature in a small cohort of 13 young unilateral amblyopes without strabismus

(minimum 3 D anisometropia in spherical equivalent or cylinder) using the

IOLMaster. In hyperopic subjects, the amblyopic eye was significantly shorter than

the fellow eye. In myopes, the amblyopic eye was significantly longer compared to

the unaffected eye. Other anterior eye biometrics were not significantly different

between the fellow eyes including; anterior chamber depth, corneal astigmatism

Chapter 1

83

and corneal diameter. However, one subject had an interocular difference of more

than two dioptres of corneal astigmatism between the fellow eyes, which appeared

to be the primary cause of amblyopia, given a relatively small interocular difference

in axial length.

11..55..33 OOppttiiccaall ffaaccttoorrss

11..55..33..11 HHiigghheerr--oorrddeerr aabbeerrrraattiioonnss iinn aammbbllyyooppiiaa

Due to their potential role in altering retinal image quality, higher-order aberrations

may play a role in the development of refractive errors and amblyopia. However,

Levy et al (2005) has observed that eyes with unaided vision better than 6/5 may

demonstrate moderate levels of aberrations, which suggests that relatively high

levels of aberrations may be required to reduce vision below normal levels.


Plech et al (2010) examined the interocular differences in corneal higher-order

aberrations in unilateral and bilateral amblyopes without strabismus. Unilateral

amblyopes had significantly higher levels of corneal astigmatism and astigmatic

RMS in the amblyopic eye compared to the unaffected eye. However, there were

no statistically significant differences between fellow eyes for other corneal

aberrations including primary spherical aberration and primary coma RMS.

Bilateral amblyopes were compared to a control group and no significant

differences were observed between the amblyopic and normal eyes for any corneal

Chapter 1

84

parameters including astigmatism or higher-order aberrations. The authors

suggested that corneal astigmatism is a key factor in the development of unilateral

amblyopia.


In an early study of the optical quality in amblyopic eyes, Hess and Smith (1977)

examined the influence of ocular aberrations on contrast sensitivity and visual

acuity in three strabismic subjects. They used psychophysical tests to examine the

contrast sensitivity of amblyopic eyes when by-passing the optics of the eye and

found that the level of contrast sensitivity loss was similar. These results suggest

that the reduction in contrast sensitivity and visual acuity in strabismic eyes is due

to a neural rather than an optical cause. Although this study confirms that vision

loss in strabismus has a neural basis, it does not rule out the possibility that higher-

order aberrations may influence the development of refractive errors or contribute

towards amblyopia during periods of eye growth in childhood.

Prakash et al (2007) presented a case report of a young male with idiopathic

amblyopia (amblyopia in the absence of refractive error, strabismus, anisometropia

or an identifiable cause) which they attributed to asymmetric higher-order

aberrations. In the eye with reduced visual acuity, the levels of 3rd order coma,

trefoil and higher-order RMS were significantly higher compared to the fellow

normal eye. The authors suggested that asymmetric image degradation due to

Chapter 1

85

ocular aberrations may potentially cause amblyopia, but also acknowledged that

the patient may have had anisometropia at a young age which caused the

amblyopia, which resolved to isometropia over time. In addition, this case report

opens the possibility that the correction of higher-order aberrations may improve

visual acuity or binocular function. Cases of monocular diplopia associated with

increased levels of corneal aberrations in one eye have been reported in the

literature and laser surgery to decrease these aberrations may result in improved

visual function (Melamud et al 2006).

Kirwan and O’Keefe (2008) examined the higher-order aberrations of fellow eyes

during cycloplegia in thirty children with unilateral amblyopia. Fifteen children

were strabismic and the remaining children had hyperopic anisometropia.

Amblyopic eyes displayed higher levels of total higher-order RMS, and higher levels

of individual Zernike terms up to the 6th radial order; however these interocular

differences did not reach statistical significance. This trend was observed when

analyzing all subjects in one cohort, or separating them into strabismic and

anisometropic amblyopes. Based on these findings the authors concluded that

higher-order aberrations are unlikely to play a role in the development of

amblyopia.

In a follow up study to their earlier case report, Prakash et al (2011) examined the

interocular symmetry of higher-order aberrations in seventeen children diagnosed

with idiopathic amblyopia. These subjects had minimal anisometropia (less than

Chapter 1

86

0.75 D SEq) and no interocular differences in corneal astigmatism. No significant

differences were observed between the normal and amblyopic eyes for the mean

values of the Zernike coefficients from the 3rd to 5th order. These findings do not

support the theory that higher-order aberrations play a role in idiopathic

amblyopia.

Zhao et al (2010) examined higher-order aberrations in a large cohort of 262

children recruited from a hospital amblyopia clinic. Rather than examine the

symmetry between fellow eyes, children were classified as either; emmetropic

(refractive error -0.25 to +0.50 D), corrected amblyopes (visual acuity 6/6 following

patching), refractive amblyopes (visual acuity 6/7.5 - 6/9 following patching) and

amblyopes (visual acuity worse than 6/9) and comparisons were made between

these groups. RMS values for 3rd, 4th and total higher-order aberrations were larger

in amblyopic eyes compared to emmetropic eyes, but did not reach statistical

significance. In addition, the refractive amblyopes and the amblyope group

typically exhibited higher levels of higher-order RMS compared to the emmetropic

and corrected amblyope groups. Using a multivariate linear regression, the authors

observed a significant negative correlation between C(3,-1) vertical coma and best

corrected visual acuity in the refractive amblyopes (r = -0.59, p = 0.009) and

amblyopes group (r = -0.58, p = 0.012). This trend suggests primary vertical coma

may play a significant role in reduced visual acuity in some children with amblyopia.

Chapter 1

87

11..55..33..22 AAccccoommmmooddaattiioonn iinn aammbbllyyooppiiaa

Altered accommodative function has been reported in the amblyopic eye, including

reduced accommodative amplitude and increased lag of accommodation,

particularly for larger stimulus values (Ciuffreda et al 1983, Hokoda and Ciuffreda

1982). This is thought to be due to abnormal visual experience during the

development of the visual pathway and neural input associated with

accommodation. Reduced sensitivity to a defocused retinal image (which typically

triggers accommodation) would be expected to result in reduced accommodative

responses. Other factors which are thought to influence accommodation in

amblyopic eyes include the depth of focus, which is typically greater in amblyopic

eyes and may allow the amblyopic eyes to function with a reduced accommodative

response and eccentric fixation (i.e. non-foveal monocular viewing) which is

thought to diminish the accommodative response with increase in eccentricity of

fixation.

Ciuffreda et al (1983) compared the accommodative response of normal eyes,

amblyopic eyes (mostly strabismic subjects) and amblyopic eyes which had

undergone patching and orthoptic training. Amblyopic eyes exhibited reduced

amplitude of accommodation and a greater lag of accommodation compared to

normal eyes (up to 2 D interocular difference), particularly as the stimulus to

accommodation increased (up to 6 D). Former amblyopic eyes which had

undergone treatment still exhibited slightly reduced accommodative response (0.5 -

1.0 D) compared to the fellow normal eye. Hung et al (1983) also observed a

Chapter 1

88

reduced accommodative response in the amblyopic eye of four subjects of

approximately 1 to 2 D when the accommodative stimulus exceeded 3 D. When the

stimulus to accommodation was less than 3 D the fellow eyes displayed a similar

response.

Ukai et al (1986) examined the accommodative response over a wide range of

stimuli in the affected and fellow normal eyes of young amblyopes and former

amblyopes using an autorefractor (Nidek AR-2000) and a Badal lens system. There

was a larger amount of accommodative microfluctuations in amblyopic eyes. The

amplitude of accommodation was also significantly reduced in amblyopic eyes (7.7

± 1.8 D) compared to fellow normal eyes (9.3 ± 1.1 D). Former amblyopic eyes

displayed a slightly reduced amplitude of accommodation (8.9 ± 1.8 D) compared to

the fellow sound eye (9.4 ± 1.6 D), but this was not statistically significant. The

accommodative response of the amblyopic eye (expressed as the ratio of

accommodative response to the accommodative stimulus) was significantly

correlated with the level of visual acuity (r = 0.68, p < 0.001). This appears to be the

first study to correlate the reduction in visual acuity with the reduced

accommodative response. Small but non-statistically significant differences were

observed in the accommodative response between anisometropic and strabismic

amblyopes, however these differences were not specified. The authors suggested

that reduced visual acuity results in diminished ability to detect a change in contrast

at higher spatial frequencies, explaining the reduced accommodative response in

amblyopic eyes. The authors also speculated that the amblyopic eye may have the

Chapter 1

89

potential to exhibit normal accommodation responses by presenting a stimulus to

the sound fellow eye.

Hokoda and Ciuffreda (1982) examined the degree of consensually driven

accommodative amplitude in three amblyopic subjects. While stimulating the

normal eye, the accommodative response of the fellow eye was assessed using

dynamic retinoscopy. The accommodative response of the amblyopic eye (when

stimulating the sound eye) was similar (within 1 D) to the response of the normal

eye, suggesting that the afferent accommodation pathway is the affected portion in

amblyopia.

Recently Hurwood and Riddell (2010) used a more sophisticated technique to

examine the accommodative response in both eyes simultaneously of a 4 year old

with anisometropic amblyopia. Using a plusoptiX SO4 videorefractor set,

continuous recordings of refraction and pupil size for each eye were measured for

accommodation demands of 0.5 and 4 D. With the refractive error uncorrected,

both eyes displayed symmetric convergence and pupil constriction during

accommodation. However, the eyes exhibited independent accommodation

responses. The normal eye had a stable lag of accommodation (approximately 1 D)

at all viewing distances (average response 2.32 D of accommodation for a 3 D

demand) whereas the amblyopic eye “anti-accommodated” i.e. relaxed

accommodation (average response 2.12 D of relaxation for a 3 D demand).

Chapter 1

90

Following four months of occlusion therapy the subject was reexamined while

wearing the full refractive correction. The aniso-accommodative response was

drastically reduced under binocular viewing conditions. When the normal eye was

presented with a near target, both eyes accommodated in a similar fashion

although the response of the amblyopic eye lagged behind that of the normal eye

as the accommodative demand increased. However, when the amblyopic eye was

presented with accommodative stimuli, the response was the same (approximately

1.5 D accommodation) for all levels of accommodation demand. In addition, no

response was observed in the normal eye. This study suggests that the

accommodative response is impaired in the amblyopic eye, even following a period

of occlusion therapy, compared to the fellow normal eye under monocular

conditions. In binocular viewing conditions, the normal eye may trigger a

consensual accommodative response in the amblyopic eye, but not vice versa. This

finding supports the hypothesis that the reduced accommodative response in

amblyopic eyes is due to sensory rather than a motor deficit.

Tonic accommodation (TA) is the resting level of accommodation in the absence of

accommodative stimuli and is thought to represent the balance between the

sympathetic and parasympathetic inputs to the ciliary muscle. Previous studies

have found no consistent relationship between refractive error and TA, however,

TA is typically reduced in myopia compared to emmetropia and hyperopia (McBrien

and Millodot 1987b). Miwa and Tokoro (1993) measured TA in 20 young hyperopic

anisometropes (> 2 D interocular difference) including 7 children with unilateral

Chapter 1

91

amblyopia (6/9 or worse in the affected eye). TA was calculated by subtracting the

cycloplegic refraction from the non-cycloplegic refraction measured after 15

seconds of dark adaptation using the Nidek AR1600 autorefractor. Tonic

accommodation was similar between the fellow eyes of both pure and amblyopic

anisometropes. However, levels may differ in older children or adults when

accommodation is reduced, or following a longer period of dark adaptation which

may result in higher levels of TA.


Anisometropia associated with ocular pathology, strabismus or amblyopia appears

to have a genetic component. As for non-amblyopic anisometropia, an interocular

difference in axial length correlates well with the magnitude of anisometropia,

except in cases of meridional astigmatic amblyopia. The refractive error of

amblyopic eyes remains relatively stable over time, whereas fellow normal eyes

tend to undergo a myopic shift during youth. This suggests that clear vision is

required for emmetropisation and potentially myopia development. While large

amounts of anisometropia may diminish during ocular development, a small

amount of hyperopic anisometropia (as little as 1.25 D) that persists throughout

childhood almost always results in amblyopia. While the impaired accommodative

system of amblyopic eyes has been investigated in detail, few studies have

examined higher-order aberrations in monocular amblyopes. To date most studies

have reported similar or slightly higher levels of aberrations in the amblyopic eye

compared to the non-amblyopic eye which do not reach statistically significance.

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11..66 RRaattiioonnaallee

Previous studies of both animals and humans have shown that refractive error is

largely determined by axial length and that ocular growth is influenced by visual

experience. While there is evidence to suggest a genetic influence in the

development of refractive errors, environmental factors such as near work may also

play a significant role. Numerous studies have investigated the optical and

mechanical ocular changes associated with near work in different refractive error

groups. While there is some evidence to suggest an altered accommodative

response is associated with myopia, there is no single theory which adequately

explains the mechanism underlying axial elongation and myopia development.

Cohort studies which compare different refractive error groups (i.e. emmetropes,

myopes, and hyperopes) may be influenced by a range of confounding variables

such as age, gender, time spent reading or outdoors. The use of anisometropic

subjects in refractive error research may potentially allow for more control of such

confounding variables and also inter-subject variations genetic and environmental

factors. In addition, any mechanical or image-mediated theory of myopia

development should be able to explain the refractive condition of anisometropia.

Some biometric studies have examined the interocular symmetry of moderate to

high degrees of anisometropia including subjects with amblyopia. There appears to

be a genetic component in cases of high anisometropia associated with ocular

Chapter 1

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abnormalities. However, the mechanism behind the development of lower, more

common levels of anisometropia (particularly myopic anisometropia) is not fully

understood.

We examined the interocular differences in the more and less myopic eyes of axial

myopic anisometropes without amblyopia, strabismus or ocular disease for a

comprehensive range of biometric, biomechanical and optical parameters. Given

the association between myopia and near work, we hypothesised that the more

myopic eyes may exhibit biometric or optical differences in comparison to their

fellow less myopic eyes during or following a period of accommodation. The

identification of such interocular differences may provide insight into the

mechanism underlying the development of myopic anisometropia. We also

investigated the interocular symmetry of a range of ocular parameters in amblyopic

subjects with a history of asymmetric visual experience during childhood. The

identification of interocular differences in optical or biomechanical properties in

subjects with a pronounced interocular asymmetry in visual development may also

improve our understanding of factors which influence eye growth and asymmetric

refractive development.

Chapter 2

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22..11 IInnttrroodduuccttiioonn

Although genetic and environmental links to the development of myopia are well

established, there is no theory which adequately explains the mechanisms

underlying refractive error development. Commonly proposed hypotheses include

those where mechanical or optical factors promote excessive axial eye growth. Any

mechanical or image-mediated theory of myopia development should also be able

to explain the refractive condition of anisometropia.

Anisometropia is a condition characterised by a difference in refractive error

between fellow eyes which is typically due to an interocular difference in axial

lengths, in particular the depth of the vitreous chamber (Sorsby 1962). Hyperopic

anisometropia that persists during early childhood is often associated with

amblyopia and strabismus due to the disruption of normal visual development

(Abrahamsson and Sjostrand 1996). However, in myopic anisometropia, in which

the more myopic eye may still receive a clear image during close viewing,

amblyopia and strabismus are less likely to develop (Tanalmai and Goss 1979).

Anisometropia may be used as an experimental paradigm in refractive error

research. Comparing the more and less ametropic eyes of the same anisometropic

subject allows for greater control of confounding inter-subject variables such as age

or gender and potentially numerous other environmental and genetic factors.

Chapter 2

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If mechanical factors are primarily involved in anisometropic eye growth, then we

would expect differences in the biomechanical properties between the fellow eyes

(such as corneal thickness, corneal hysteresis or IOP). Previous research has

confirmed that corneal thickness is similar between the fellow eyes of

anisometropes (Holden et al 1985) however recent studies have shown that the

more myopic eyes of anisometropes have slightly lower values of corneal hysteresis

(Chang et al 2009, Xu et al 2010) suggesting a reduction in mechanical strength of

the cornea.

Cross-sectional studies of IOP in anisometropic subjects using both contact and

non-contact applanation techniques have shown no significant differences between

the more and less ametropic eyes (Tomlinson and Phillips 1972, Bonomi et al 1982,

Lee and Edwards 2000, Lam et al 2003). These studies suggest that axial elongation

due to a simple IOP induced expansion of the globe is unlikely to be involved in the

development of axial anisometropia or myopia. However, recently, Xu et al (2010)

observed a slightly higher IOP (mean 1.8 mmHg higher) which approached

statistical significance in the more myopic eyes of high myopic anisometropes when

using a non-contact technique less affected by corneal properties than previous

tonometer. If a relationship does exist between IOP and axial elongation, we might

expect that IOP would be higher in the more myopic eye of anisometropes, at least

during myopia development or progression.

Chapter 2

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If optical factors contribute to asymmetric eye growth, we might anticipate

differences in the optical properties of the two eyes. However, previous studies

have found no significant difference between the fellow eyes of anisometropes for

corneal (Weiss 2003, Logan et al 2004, Kwan et al 2009) or crystalline lens power

(Sorsby 1962, Logan 2004). Tian et al (2006) investigated the interocular symmetry

of ocular aberrations in ten myopic anisometropes (> 1.00 D spherical equivalent

[SEq]) and found no significant interocular differences in individual Zernike terms,

3rd, 4th and 5th order aberrations or total higher-order aberrations. Kwan et al

(2009) also examined the interocular symmetry and magnitude of total ocular

aberrations in myopic anisometropia (> 1.75 D SEq) during cycloplegia. The authors

observed a high level of symmetry between fellow eyes for a range of Zernike terms

but significantly higher levels of aberrations in the less myopic eyes (total, 3rd order

and 4th order RMS and spherical aberration C(4,0)).

Recently, two studies have investigated the association between ocular sighting

dominance (the preference for the visual input from one eye when binocularly

viewing) and myopic anisometropia. In a cohort of adult subjects Cheng et al

(2004a) found that when the degree of anisometropia exceeded 1.75 D, the

dominant eye was always the more myopic eye and suggested that an aniso-

accommodative response (due to unequal accommodative demand during reading)

may be responsible for the dominant eye being more myopic. However, in a large

study of children, Chia et al (2007) observed that when anisometropia was greater

than 1.50 D, the dominant eye was more myopic in only 56% of subjects.

Chapter 2

97

Previous biometric studies have examined the interocular symmetry of moderate to

high degrees of anisometropia including subjects with amblyopia, structural ocular

abnormalities or pathology. In this study we examined the interocular differences

in both eyes of myopic anisometropes without amblyopia, strabismus or ocular

disease for a comprehensive range of biometric, biomechanical and optical

parameters. We assumed that non-amblyopic myopic anisometropia represents

unequal eye growth in fellow eyes with identical genetic make-up exposed to

similar environmental factors (e.g. near work, sunlight exposure). Our hypothesis

was that the more and less myopic eyes may exhibit biometric or optical differences

which may provide insight into the mechanism underlying asymmetric refractive

error development. Since this was a cross sectional study and not longitudinal, we

could not be certain if differences between the eyes represent a possible cause or

consequence of myopic eye growth.

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Thirty-four young, healthy adult subjects aged between 18 and 34 years (mean age

23.9 ± 4.3 years) with a minimum of 1.00 D of spherical-equivalent myopic

anisometropia were recruited for the study (mean anisometropia 1.70 ± 0.74 D).

The subjects were primarily recruited from the staff and students of QUT

(Queensland University of Technology, Brisbane, Australia) and HKPU (Hong Kong

Polytechnic University, Hong Kong, PR China). The subjects’ mean spherical

equivalent refraction was -5.35 2.74 D for the more myopic eye and -3.64 ± 2.61 D

Chapter 2

98

for the less myopic eye. Twenty-two of the 34 subjects were female and 31 of the

subjects were of East Asian descent, with the remaining three subjects of Caucasian

ethnicity.

Before testing, subjects underwent a screening examination to determine

subjective refraction, binocular vision and ocular health status. Ocular sighting

dominance was assessed using a forced choice method (a modification of the hole-

in-the-card test) (Miles 1929). The subject’s formed a triangular aperture with their

hands through which a distant target could be aligned while their arms were

outstretched. All subjects were free of significant ocular or systemic disease and

had no history of ocular surgery or significant trauma. In addition, subjects with

visual acuity worse than 0.10 logMAR, strabismus, unequal visual acuities

(interocular difference of greater than 0.10 logMAR) or a history of rigid contact

lens wear were excluded from the study. Fourteen soft contact lens wearers were

included in the study, but ceased contact lens wear for 36 hours prior to

participation. Approval from both the QUT and HKPU human research ethics

committees was obtained before commencement of the study and subjects gave

written informed consent to participate (Appendix 1). All subjects were treated in

accordance with the tenets of the Declaration of Helsinki.

22..22..22 DDaattaa ccoolllleeccttiioonn pprroocceedduurreess

A range of biometric and optical measurements were collected from the more and

less myopic eye of each subject including; axial length, corneal topography, corneal

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99

thickness and biomechanics, ocular aberrations, intraocular pressure and digital

images of the anterior eye during primary and downward gaze. Table 2.1 provides

an overview of the instruments used and the parameters measured throughout the

experiment following the screening process.

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Axial length (defined as the distance from the anterior corneal surface to the retinal

pigment epithelium) was measured using the IOLMaster (Carl Zeiss Meditec, Inc.,

Jena; Germany). The IOLMaster is a non-contact instrument based on the principle

of partial coherence laser interferometry and has been found to provide precise,

repeatable measurements of axial length in children (Carkeet 2004) and adults (Lam

et al 2001, Sheng et al 2004). Five measures of axial length with a signal-to-noise

ratio of greater than 2.0 were taken and averaged for each eye.

22..22..22..22 CCoorrnneeaall ttooppooggrraapphhyy

Corneal topography was measured using the E300 videokeratoscope (Medmont

Pty. Ltd., Victoria, Australia). This instrument is based on the Placido disc principle

and has been shown to exhibit a high level of accuracy and precision for spherical

and aspheric test surfaces (Tang et al 2000) as well as a high level of repeatability in

human subjects (Cho et al 2002) including children (Chui and Cho 2005). Four

measurements, captured according to manufacturer recommendations were

performed on each eye.

Chapter 2

100

Table 2.1: Overview of instruments used and parameters measured in experiment 1.

Instrument Parameters measured

FujiFilm Fine Pix S9500 digital camera Anterior eye morphology*

Oculus Pentacam HR System Corneal thickness

Anterior and posterior corneal astigmatism Anterior chamber depth and volume

Medmont E-300 Corneal Topographer Anterior corneal astigmatism

Corneal shape factor (Q value) Corneal aberrations*

Reichart Ocular Response Analyzer IOPg, IOPcc

Corneal resistance factor Corneal hysteresis

Wavefront Sciences COAS wavefront aberrometer Total ocular aberrations*

Zeiss IOLMaster Axial length

* Data analysed using custom software, IOPg - Goldmann correlated intraocular

pressure, IOPcc - corneal compensated intraocular pressure.

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101

Simulated keratometry readings and corneal asphericity values (Q) were recorded

for the principal corneal meridians. The Q value defines an elliptical shape and is

used to indicate how far the corneal shape departs from a perfect sphere. A sphere

has a Q value of zero, with prolate shapes (most corneas are prolate) having

negative values, while oblate shapes have positive values. The Medmont E300

software calculates the best fit ellipse at a specified chord (6 mm diameter was

chosen).

Following data collection, corneal refractive power and height data were exported

from the videokeratoscope. Topography maps that displayed poor focus or local

irregularities such as tear film instability were excluded from analysis. Topography

data were analysed using customised software. Refractive power maps and corneal

height data were averaged using an established technique (Buehren et al 2001)

assuming a corneal refractive index of 1.376. This technique involved interpolation

of the videokeratoscope data to an equal point spacing maintaining a semi-

meridian format, and an average value at each point was then calculated. This

analysis was conducted for right and left eye data, taking into account midline

symmetry (enantiomorphism).

A best-fit sphero-cylinder was calculated from each subject’s mean refractive power

maps (Maloney et al 1993). The sphero-cylindrical analysis was calculated around

the line of sight. Corneal height data were used to calculate the corneal wavefront

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102

error using a ray tracing procedure described by Buehren et al (2003). Zernike

wavefront polynomials were fitted to the wavefront error (up to and including the

eighth radial order) and expressed using the double index notation (OSA

convention) (Thibos 2000). The image plane was at the circle of least confusion and

the chosen wavelength used was 555 nm. The wavefront was centred on the line of

sight by using the pupil offset value from the pupil detection function in the

Medmont videokeratoscope as the reference axis for the wavefront. This

procedure was conducted for 4 measurements per eye and the mean and standard

deviations were calculated. Corneal diameters of 4 and 6 mm were chosen for

analysis purposes to approximate mean pupil sizes in photopic and mesopic

conditions respectively (Shaw et al 2008).

Anterior eye biometrics were also measured using the Pentacam HR system (Oculus

Inc., Wetzlar, Germany). The Pentacam HR system uses a non-contact rotating

Scheimpflug camera and has excellent repeatability for measuring central corneal

thickness (Barkana et al 2005, Lackner et al 2005a, O’Donnell and Maldonado-

Codina 2005) and anterior chamber depth (Rabsilber et al 2006, Lackner et al

2005b). The 50-picture, 3-D scan mode was used for all measurements. Five scans

were performed on each eye. Measurements labelled as unreliable by the

instrument’s quality specification were excluded from analysis. The mean central

corneal thickness (CCT; centred on the corneal apex), anterior chamber depth (ACD;

the axial distance from the corneal endothelium to the anterior lens surface), and

anterior chamber volume (ACV; calculated for a 12-mm diameter around the

Chapter 2

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corneal apex) was calculated for each eye.

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Corneal biomechanics and intraocular pressure were measured using the Ocular

Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo, New York,

USA). The ORA is a non-contact tonometer that uses an air impulse to take two

pressure measurements; one while the cornea is moving inward, and the other as

the cornea returns. The average of these two pressure values provides a

Goldmann-correlated IOP measurement (IOPg). The difference between these two

pressure values is corneal hysteresis (CH), or the viscoelasticity of the corneal tissue

(Luce 2005). The CH measurement also allows the calculation the corneal-

compensated intraocular pressure (IOPcc), which is less affected by corneal

properties than other methods of applanation tonometry (Lam et al 2007). The

ORA also provides a measure of the corneal resistance to deformation, the corneal

resistance factor (CRF). IOPg measurements obtained using the ORA are

comparable to those obtained using Goldmann applanation tonometry (Lam et al

2007), and show good short-term repeatability in normal volunteers (Kynigopoulos

et al 2008). Four measurements were performed and the mean for each parameter

was calculated for each eye.

22..22..22..44 OOccuullaarr aabbeerrrraattiioonnss

Total ocular aberrations of each eye were measured using a Complete Ophthalmic

Analysis System (COAS) wavefront aberrometer (Wavefront Sciences, New Mexico,

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104

USA). The system was modified to allow fixation of an external target at 6 metres

via a beam splitter between the eye and the wavefront sensor. The subject’s

distance prescription was inserted into a lens holder outside of the path of the

COAS beam (after taking into account the change in vertex distance) to allow a clear

view of the fixation target. The instrument’s internal fixation target was turned off

during all wavefront measurements. The fixation target at the 6 metre stimulus

distance was a 0.4 logMAR letter in the centre of a high contrast Bailey-Lovie

logMAR chart. The beam splitter could be adjusted to enable the alignment of the

letter in the centre of the chart with the measurement axis of the instrument (i.e.,

the instrument’s measurement beam).

Subjects had natural pupil sizes without pharmacological dilation during the COAS

measurements. The room illumination was kept in the mesopic range to maximize

the pupil size during measurements. The eye not being measured was covered with

a patch. One hundred wavefront measurements (4 x 25 frames) were taken for

each eye. The wavefront data was fitted with an 8th order Zernike expansion and

exported for further analysis. Using customised software, the 100 wavefront

measurements were rescaled to set pupil diameters of 4, 5 and 6 mm using the

method of Schwiegerling (2002) and then the Zernike polynomials were averaged.

This analysis was conducted for right and left eye data, taking into account

enantiomorphism.

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A Fujifilm FinePix S9500 digital camera (Fuji, Tokyo, Japan) (10.7x optical zoom, 9.0

megapixels) positioned on a mount was used to capture the morphology of the

anterior eye in primary and 25 degree downward gaze. A similar experimental

setup has been described elsewhere (Read et al 2006); however, we positioned the

subjects in a chin rest to accurately control the downward gaze angle and limit head

tilt.

At the HKPU Optometry Clinic, the same camera (Fujifilm FinePix S9500) was

mounted on an adjustable tripod rather than the custom made mount used at QUT.

Subjects were positioned in a chin/head rest and the camera height was adjusted so

the cross hairs within the view finder were aligned with the subjects eyes during

primary gaze. A spirit level was used to ensure the camera was not tilted. For

photographs in downward gaze, the tripod height was lowered and the camera

angle adjusted such that subjects had to adopt a downward gaze of 25 degrees to

maintain fixation of the centre of the camera lens. A protractor was mounted on

the side of the head rest adjacent to the subjects right outer canthus to ensure the

angle of downward gaze was 25 degrees below horizontal. The following

methodology and analysis was employed for examination of the morphology of the

palpebral fissure at both testing sites.

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Both eyes were included in each photograph and the in-built camera flash was used

to ensure illumination was constant between the two eyes. The distance from the

subject’s eye to the camera lens was approximately 500 mm. Subjects were asked

to fixate on the centre of the camera lens, but not specifically focus on it, in an

attempt to maintain natural eyelid position and avoid forceful squinting. Since

uncorrected myopes may squint to improve their unaided vision during fixation,

photographs were taken both with and without subjects wearing their habitual

spectacles. A scale of known length was positioned in each photograph (both with

and without habitual correction in place) to allow calibration during later analysis.

Each digital image of the anterior eye in primary and 25 degree downward gaze was

analysed using custom written software to approximate the morphometry of the

limbus, pupil and upper and lower eyelids (Iskander et al 2004, Read et al 2006). All

left eye images were transposed to account for midline symmetry. For the limbus

and pupil outlines, 16 and 8 points respectively were used for the ellipse functions

fitted to the outlines. For the upper and lower eyelid margin, 8 points were

selected. These were then fit with a polynomial function with respect to the limbus

centre (Y = AX2 + BX + C) (Malbouisson et al 2000) (Figure 2.1). These terms

describe different aspects of the eyelid with coefficient A being the curvature,

coefficient B the angle or tilt and coefficient C the distance from the geometric

corneal centre. Four images were processed for each eye and condition (primary

and downward gaze, with and without spectacles) and mean and standard

deviations were calculated for a range of biometric parameters describing the

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Figure 2.1: Eyelid margin contour fit with polynomial function (Y = AX2 + BX + C)

Coefficients A, B and C describe different aspects of the eyelid. Coefficient A being

the curvature (larger A, steeper curve), coefficient B the angle or tilt (positive B,

downward slant) and coefficient C the height of the eyelid above or below the

geometric corneal centre.

X

Y

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morphology of the palpebral fissure and anterior eye. These parameters included;

horizontal eyelid fissure width, angle of the horizontal eyelid fissure, average limbus

diameter, average pupil diameter, vertical palpebral aperture width and the terms

which describe the upper and lower eyelids shape (outlined above).

22..22..33 SSttaattiissttiiccaall aannaallyyssiiss

Two tailed paired t-tests were used to assess the statistical significance of the mean

interocular difference between the more and less myopic eyes of the anisometropic

subjects. Pearson’s correlation coefficient was used to quantify the degree and

statistical significance of the correlation between the more and less myopic eyes. A

t-test was used to compare the slope of the linear regression (more vs less myopic

eye) with a theoretical slope of 1 (indicating perfect symmetry). In addition,

Pearson’s correlation coefficient was used to examine the relationship between the

magnitude of refractive anisometropic (more - less myopic eye) and the interocular

difference (more minus less myopic eye) for a range of parameters. To reduce the

probability of type I statistical errors associated with repeated statistical tests we

chose an alpha value of 0.01. Chi-square tests of independence were used to

examine the distribution of proportions between “high” and “low” anisometropia

cohorts (defined below).

Chapter 2

109

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22..33..11 OOvveerrvviieeww

The mean components of refraction, visual acuity and axial length of the

anisometropic subjects are presented in Table 2.2. There were statistically

significant differences between the more and less myopic eyes for the spherical

component and spherical equivalent of the refractive error, but, the magnitude of

refractive astigmatism (cylinder) was similar between the two eyes. Mean visual

acuity was not significantly different between fellow eyes. The magnitude of

anisometropia was significantly correlated with the interocular difference in axial

length between fellow eyes (R2 = 0.66, p < 0.001) (Figure 2.2).

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In this cohort of anisometropes, the more myopic eye was the sighting dominant

eye in 22 subjects (65%). However, when the level of anisometropia was greater

than 1.75 D (the approximate mean amount of anisometropia in the subject group),

the more myopic eye was the dominant eye in 90% of subjects (Table 2.3, Figure

2.3). Although two thirds of the subjects had anisometropia ≤ 1.75 D, there was a

statistically significant difference in the proportion of more myopic dominant eyes

between the “low” and “high” anisometropia groups (p = 0.002). The more myopic

eye was always the dominant sighting eye when the level of anisometropia

exceeded 2.25 D (5 subjects).

Chapter 2

110

Table 2.2: Overview of the more and less myopic eyes of the non-amblyopic myopic

anisometropes.

More myopic eyes Less myopic eyes Paired t-test

Variable Mean ± SD Range Mean ± SD Range p

Sphere (D) -4.87 ± 2.59 -11.8, -0.25 -3.18 ± 2.49 -9.50, +0.75 < 0.0001

Cylinder (D) -0.95 ± 0.85 -3.75, 0 -0.96 ± 0.82 -3.50, 0 0.85

SEq (D) -5.35 2.74 -12, -0.875 -3.64 ± 2.61 -9.75, +0.625 < 0.0001

VA (logMAR) -0.01 ± 0.04 -0.0, 0.10 0.00 ± 0.04 -0.08, 0.10 0.26

AxL (mm) 25.57 ± 0.89 23.37, 27.57 25.00 ± 0.95 22.77, 27.35 < 0.0001

SEq - Spherical equivalent refractive error, VA - visual acuity, AxL - Axial length

Chapter 2

111

Due to the significantly higher proportion of more myopic dominant sighting eyes in

the high anisometropia cohort, we also examined the interocular symmetry

between the dominant and non-dominant eyes of both the low and high

anisometropia groups. Characteristics of the low and high anisometropia groups

are described in Table 2.4. Seventy-nine percent of all subjects were right eye

dominant. However, there was a significantly higher proportion of right eye

dominance in the high anisometropia group (90%) compared to the lower

anisometropia group (58%) (Table 2.5).

On average, right eyes were slightly more myopic with a greater axial length

compared to left eyes, but not to a statistically significant level in any subject group

(Table 2.6). There were no significant differences in visual acuity between the

dominant and non-dominant eyes. Dominant eyes were more myopic with longer

axial lengths, and this was most evident for the high anisometropia group (p <

0.0001) (Table 2.7).

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112

Figure 2.2: Correlation between spherical equivalent anisometropia (D) and

interocular difference in axial length (mm) in non-amblyopic myopic anisometropia.

Figure 2.3: Scatter plot of sighting dominant eyes with respect to level of myopic

anisometropia. Dashed line 1.75 D anisometropia. Solid line 2.25 D anisometropia.

y = -0.30x + 0.06 R

2 = 0.66

Chapter 2

113

Table 2.3: Distribution of sighting dominant eyes in more and less myopic eyes of

anisometropes.

Anisometropia SEq (D)

Sighting dominant eye Χ2

More myopic Less myopic p

≤ 1.75 (low) 13 11 0.002

> 1.75 (high) 9 1

Table 2.4: Characteristics of the low and high anisometropia groups.

Group SEq Anisometropia (D) Anisometropia Mean ± SD (D)

Low (n = 24) ≤ 1.75 1.30 ± 0.26

High (n = 10) > 2.00 2.53 ± 0.74

Table 2.5: Distribution of right and left eye dominance in the low and high

anisometropia groups.

Anisometropia group Dominant right eyes Dominant left eyes Χ2 (p)

Low 14 10 < 0.0001

High 9 1

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Table 2.6: Characteristics of right and left eyes in the low and high anisometropia

groups.

Parameter Subjects Right eyes

(Mean ± SD) Left eyes

(Mean ± SD) Paired t-test

(p)

Visual acuity (logMAR)

All 0.00 ± 0.04 0.00 ± 0.04 0.65

Low -0.01 ± 0.04 0.00 ± 0.04 0.23

High 0.01 ± 0.05 0.00 ± 0.05 0.38

SEq (D)

All -4.72 ± 2.58 -4.27 ± 3.00 0.16

Low -4.11 ± 2.38 -3.91 ± 2.64 0.76

High -5.98 ± 2.63 -5.03 ± 3.67 0.42

Axial length (mm)

All 25.39 ± 0.94 25.19 ± 0.98 0.06

Low 25.36 ± 1.07 25.25 ± 1.05 0.65

High 25.43 ± 0.62 25.05 ± 0.83 0.23

SEq - spherical equivalent refractive error

Table 2.7: Characteristics of dominant and non-dominant eyes in the low and high

anisometropia groups.

Parameter Subjects Dominant eyes

(Mean ± SD) Non-dominant eyes


(p)

Visual acuity (logMAR)

All -0.01 ±0.04 0.00 ± 0.04 0.11

Low -0.01 ±0.04 0.00 ± 0.04 0.08

High 0.00 ± 0.05 0.00 ± 0.05 0.82

SEq (D)

All -4.86 ± 2.80 -4.13 ± 2.77 0.02

Low -4.09 ± 2.48 -3.95 ± 2.46 0.64

High -6.70 ± 2.77 -4.56 ± 3.51 < 0.0001

Axial length (mm)

All 25.42 ± 1.01 25.15 ± 0.90 0.01

Low 25.31 ± 1.13 25.25 ± 0.97 0.57

High 25.69 ± 0.57 24.93 ± 0.71 < 0.0001

SEq - spherical equivalent refractive error

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22..33..33 MMoorrpphhoommeettrryy ooff tthhee ppaallppeebbrraall ffiissssuurree

There were no statistically significant differences between measurements of the

palpebral fissure taken with and without the subjects’ refractive correction in place.

Subsequently, the results presented here are for the analysis conducted without

spectacle correction.

There was a high degree of symmetry between the fellow eyes for a range of

biometric measures during both primary and 25 degree downward gaze (Table 2.8,

Figure 2.4). Statistical analysis revealed significant correlations between the more

and less myopic eyes (Pearson’s correlation coefficient) with the slopes of the

regression lines close to 1. However the small interocular difference in pupil size

approached significance (p = 0.09) with larger pupils (3.53 ± 0.55 mm) in the more

myopic eyes compared with the less myopic eyes (3.48 ± 0.57 mm).

There were several small but significant correlations between the interocular

difference in morphological variables in primary gaze and the magnitude of

anisometropia (Table 2.10). As the magnitude of anisometropia increased, the

interocular asymmetry in upper and lower eyelid shape factors A (curvature) and C

(distance from the corneal centre) also increased. These correlations were

influenced by an outlying data point and became weaker and statistically

insignificant when the data was analysed excluding this one subject. In addition,

these correlations were not significant for downward gaze analysis. There was also

Chapter 2

116

a weak but significant correlation between the interocular difference in limbus

diameter and the magnitude of anisometropia. Although the group means for

limbus diameter were similar between the more and less myopic eyes (11.48 ± 0.63

and 11.50 ± 0.64 mm respectively), as the degree of anisometropia increased, the

more myopic eye tended to have a slightly larger limbus in comparison to the fellow

eye. This trend was strongest for the primary gaze analysis.

The morphology of the palpebral aperture changed significantly during downward

gaze with a vertical narrowing of the aperture and an increase in downward slant.

The contour of the upper and lower eyelids (term A) remained relatively stable

during primary and downward gaze. The angle or tilt of the upper and lower

eyelids (term B) increased slightly (i.e. became more downward slanted). However,

the magnitudes of these changes were similar between the more and less myopic

eyes.

There were no statistically significant differences between the dominant and non-

dominant eyes for measures of vertical palpebral aperture or pupil diameter during

primary gaze. Dominant eyes had smaller mean values of vertical PA and pupil

diameter (9.66 ± 1.25 and 3.47 ± 0.51 mm respectively) compared to non-dominant

eyes (9.77 ± 1.25 and 3.54 ± 0.50 mm) but these differences were not statistically

significant (p = 0.14 and 0.10 respectively). This trend was not evident in the

analysis of downward gaze images.

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Table 2.8: Mean anterior eye morphology measurements in primary and downward gaze for the more and less myopic eyes.

PRIMARY GAZE DOWN GAZE

Parameter MORE LESS Paired t-test

Pearson’s Correlation (More vs Less)

MORE LESS Paired t-test

Pearson’s Correlation (More vs Less)

AVG ± SD AVG ± SD p r p AVG ± SD AVG ± SD p r p

HEF 25.42 ± 2.06 25.61 ± 1.82 0.29 0.87 < 0.0001 25.63 ± 2.01 25.88 ± 2.20 0.37 0.74 < 0.0001

theta_HEF * -6.20 ± 3.81 -6.26 ± 2.98 0.94 0.20 0.26 1.01 ± 2.42 1.35 ± 2.99 0.61 0.02 0.91

Limbus diameter 11.48 ± 0.63 11.50 ± 0.64 0.28 0.89 < 0.0001 11.50 ± 0.64 11.56 ± 0.70 0.27 0.78 < 0.0001

Pupil diameter * 3.53 ± 0.55 3.48 ± 0.57 0.09 0.86 < 0.0001 3.64 ± 0.53 3.62 ± 0.69 0.65 0.86 < 0.0001

Upper Eyelid

A * -0.03 ± 0.01 -0.03 ± 0.01 0.52 0.90 < 0.0001 -0.03 ± 0.00 -0.03 ± 0.01 0.43 0.75 < 0.0001

B * -0.05 ± 0.06 -0.04 ± 0.05 0.48 0.22 0.21 0.03 ± 0.04 0.04 ± 0.06 0.69 0.19 0.28

C * 3.65 ± 0.83 3.62 ± 0.75 0.70 0.79 < 0.0001 3.19 ± 0.66 3.11 ± 0.61 0.31 0.69 < 0.0001

Lower Eyelid

A * 0.02 ± 0.00 0.02 ± 0.00 0.21 0.65 < 0.0001 0.02 ± 0.00 0.02 ± 0.01 0.85 0.77 < 0.0001

B * 0.06 ± 0.06 0.06 ± 0.06 0.71 0.26 0.14 0.10 ± 0.04 0.09 ± 0.06 0.33 0.17 0.34

C * -6.12 ± 0.85 -6.11 ± 0.80 0.88 0.91 < 0.0001 -4.71 ± 0.59 -4.70 ± 0.73 0.92 0.78 < 0.0001

PA * 9.73 ± 1.27 9.70 ± 1.24 0.64 0.93 < 0.0001 7.88 ± 0.98 7.79 ± 1.15 0.53 0.71 < 0.0001

All measurements in mm, except theta_HEF measured in degrees. *Indicates significant change with down gaze

Table 2.9: Explanation of the anterior eye measurements and abbreviations used in Table 2.8.

ABBREVIATION EXPLANATION DEFINITION

HEF Horizontal eyelid fissure The horizontal distance between the nasal and temporal canthi

theta_HEF Theta horizontal eyelid fissure The angle between the temporal and nasal canthus (a positive angle indicates the nasal canthus is higher than the temporal canthus)

Limbus Diameter Average limbus diameter Average of the vertical and horizontal diameter of the ellipse fitted to the limbus outline

Pupil Diameter Average pupil diameter Average of the vertical and horizontal diameter of the ellipse fitted to the pupil outline

Eyelid margin terms A Eyelid curve The curvature of the eyelid (a larger A term indicates a steeper curve)

B Eyelid tilt The angle of the eyelid (a positive B term indicates a downward slant)

C Eyelid height The height of the eyelid above or below the corneal centre

PA Palpebral aperture The vertical distance between the upper and lower lid measured through the pupil centre

Chapter 2

118

Figure 2.4: Graphical representation of the morphology of the palpebral aperture of the more and less myopic eyes during primary and

downward gaze. The origin represents the geometric centre of the limbus.

Chapter 2

119

Table 2.10: Correlation analysis for the interocular differences in anterior eye

morphology and spherical equivalent anisometropia (D).

PRIMARY GAZE DOWN GAZE

Pearson’s Correlation

(Interocular difference vs anisometropia)

Parameter r p r p

HEF -0.06 0.73 -0.18 0.31

theta_HEF 0.35 0.05 0.24 0.17

Limbus diameter -0.41 0.02 -0.30 0.08

Pupil diameter -0.04 0.81 0.08 0.66

Upper Eyelid

A -0.36 0.04 -0.14 0.81

B 0.08 0.67 0.31 0.08

C 0.41 0.02 0.04 0.44

Lower Eyelid

A -0.38 0.03 0.09 0.73

B 0.13 0.48 0.23 0.20

C 0.66 < 0.0001 0.06 0.60

PA -0.07 0.70 0.00 1.00

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22..33..44 OOccuullaarr bbiioommeecchhaanniiccss

Three subjects were excluded from this analysis, as valid measurements could not

be obtained using the Ocular Response Analyzer due to poor fixation or eyelash

interference. For the remaining 31 anisometropes, we observed similar mean

values between the fellow eyes for measures of intraocular pressure and corneal

biomechanics (Table 2.11, Figures 2.5 and 2.6). There were no significant

correlations between the degree of myopia (spherical equivalent or axial length)

and intraocular pressure or measures of corneal resistance. In addition, there were

no statistically significant correlations between the degree of anisometropia and

the interocular difference in IOPg (r = 0.12), IOPcc (r = 0.19), CRF (r = -0.16) and CH

(r = -0.16) (p > 0.05 for all parameters).

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Table 2.11: Mean and standard deviation of intraocular pressure and corneal

biomechanics in myopic anisometropia.

Variable More myopic eyes Less myopic eyes Paired t-test Pearson correlation

(More vs Less)

(mmHg) Mean ± SD Mean ± SD p r p

IOPg 15.60 ± 2.98 15.66 ± 2.86 0.83 0.87 < 0.0001

IOPcc 15.05 ± 2.20 15.15 ± 2.14 0.66 0.66 < 0.0001

CRF 11.25 ± 1.80 11.11 ± 1.60 0.52 0.76 < 0.0001

CH 11.35 ± 1.37 11.30 ± 1.41 0.68 0.68 < 0.0001

Figure 2.5: Interocular symmetry of intraocular pressure in myopic anisometropia.

Figure 2.6: Interocular symmetry of corneal biomechanics in myopic anisometropia.

Chapter 2

122

22..33..55 AAnntteerriioorr eeyyee bbiioommeettrriiccss

Various anterior eye biometrics were measured using the Pentacam HR system. Six

subjects were excluded from the Pentacam analysis, due to poor fixation during

measurements. The group mean and standard deviations for the more and less

myopic eyes are displayed in Table 2.12.

On average, the more myopic eyes had slightly deeper anterior chambers

compared to the less myopic eyes, but this difference was only significantly

different in terms of anterior chamber volume (interocular difference of 4 mm3).

Average corneal thickness measured over the pupil centre was not significantly

different between fellow eyes.

22..33..66 CCoorrnneeaall ooppttiiccss

We captured various measures of corneal shape using the Medmont E300

videokeratoscope and the Pentacam HR system. One subject was excluded from

the Medmont data analysis due to substantial missing data from eyelash

interference and reduced palpebral aperture size. The group mean and standard

deviations for the more and less myopic eyes are displayed in Table 2.12. There

was a strong correlation between the fellow eyes for all the corneal parameters

that were measured and linear regression revealed a high degree of interocular

symmetry with the slope of the best fit regression line for each parameter close to

1. The magnitude of anterior and posterior refractive corneal astigmatism was not

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123

Table 2.12: Mean values for corneal and anterior chamber parameters in myopic

anisometropia.

More

myopic eyes

Less

myopic eyes

Paired

t-test

Pearson’s Correlation

(More vs Less)

Instrument Parameter Mean ± SD Mean ± SD p r p

Medmont

(n = 33)

Flat K (D) 42.91 ± 1.30 42.77 ± 1.30 0.03 0.96 < 0.0001

Steep K (D) 44.52 ± 1.78 44.32 ± 1.69 0.06 0.95 < 0.0001

Mean K (D) 43.72 ± 1.51 43.55 ± 1.43 < 0.01 0.98 < 0.0001

Anterior astigmatism (D) -1.61 ± 0.81 -1.55 ± 0.93 0.70 0.71 < 0.0001

Flat Q -0.46 ± 0.17 -0.44 ± 0.15 0.21 0.92 < 0.0001

Steep Q -0.19 ± 0.12 -0.14 ± 0.09 0.001 0.71 < 0.0001

Mean Q -0.32 ± 0.13 -0.29 ± 0.10 < 0.001 0.91 <0.0001

Pentacam

(n = 28)

Posterior astigmatism (D) 0.48 ± 0.19 0.47 ± 0.18 0.75 0.67 0.0001

ACD (mm) 3.71 ± 0.36 3.69 ± 0.38 0.12 0.99 < 0.0001

ACV (mm3) 198 ± 31 194 ± 28 0.03 0.96 < 0.0001

CCT (PC) (microns) 567 ± 32 567 ± 32 0.76 0.97 < 0.0001

K - Corneal power, Q - corneal asphericty (for 6 mm chord), ACD - anterior chamber depth, ACV -

anterior chamber volume, CCT (PC)- Central corneal thickness measured over the pupil centre

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124

statistically different between the more and less myopic eyes, although on average

the more myopic eyes had a slightly higher level of anterior corneal astigmatism.

Examination of the principal corneal meridians revealed that on average, the more

myopic eyes were slightly more powerful in both the flattest and steepest corneal

meridians, when compared to fellow eyes. The average interocular difference

between the more and less myopic eyes was 0.19 ± 0.57 D for the steepest

meridian (p = 0.06), 0.15 ± 0.37 D for the flattest meridian (p = 0.03) and 0.17 ± 0.32

D for the average of the two principal meridians (p < 0.01). Average corneal

asphericity (Q) values were slightly more prolate (greater peripheral flattening) in

the more myopic eyes in both the steepest and flattest meridians. This interocular

difference was statistically significant for the mean Q value (average of the steepest

and flattest meridians) and for the steepest corneal meridian, with Q values of -0.14

± 0.09 in the less myopic eyes and -0.19 ± 0.12 in the more myopic eyes (p = 0.001).

The group mean and standard deviations for corneal refractive power vectors M

(spherical corneal power), J0 (90/180 astigmatic power) and J45 (45/135 oblique

astigmatic power) in the more and less myopic eyes are displayed in Table 2.13.

The more myopic eyes had a significantly higher M for both 4 and 6 mm corneal

diameters, however, the mean astigmatic vectors were similar between the more

and less myopic eyes.


dominant eyes for corneal M, J0 and J45 over a 4 or 6 mm corneal diameter. Here

Chapter 2

125

we report the values for the 6 mm analysis, which were slightly larger than 4 mm

analysis values. Dominant eyes had slightly steeper M values (49.21 ± 1.73 D)

compared to non-dominant eyes (49.17 ± 1.74 D). Dominant and non- dominant

eyes of the high anisometrope group (49.88 ± 1.61 and 49.84 ±1.61 D respectively)

had steeper M values in comparison to the low anisometrope group (48.90 ± 1.70

and 48.86 ± 1.75 D). Dominant eyes had higher levels of J45 in comparison to non-

dominant eyes in the high anisometrope group (0.15 ± 0.32 and 0.06 ± 0.32 D), but

not in the low anisometrope group (0.06 ± 0.24 and 0.08 ± 0.25 D).

22..33..77 CCoorrnneeaall hhiigghheerr--oorrddeerr aabbeerrrraattiioonnss

Given that the predominant higher-order corneal aberrations are third and fourth

order terms (Wang et al 2003), the analysis here has concentrated on these corneal

aberrations. On average, the less myopic eyes had larger third, fourth and higher-

order RMS values compared to the more myopic eyes, however, these differences

did not reach statistical significance (Table 2.14). Non-dominant eyes had larger

RMS values for third, fourth and higher-order aberrations, compared to the

dominant eyes in each anisometropic cohort examined, however, these interocular

differences were not statistically significant. As expected, RMS values were

significantly larger for the 6 mm compared to the 4 mm corneal diameter analysis.

There was a high degree of interocular symmetry for corneal higher-order

aberrations up to the fourth order, in particular within the larger 6 mm analysis

diameter (Table 2.15).

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126

There were few significant correlations between the interocular difference in

corneal aberrations for individual Zernike coefficients up to the fourth order and

the degree of spherical equivalent anisometropia. The strongest correlations were

observed for fourth order Zernike terms C(4,-2) secondary astigmatism (r = -0.35, p

= 0.06) and C(4,-4) tetrafoil along 22.5˚ (r = 0.41, p = 0.03) over a 4 mm corneal

diameter. These correlations were relatively weak for the 4 mm diameter and were

weaker for the 6 mm analysis diameter. In addition, correlation analysis for

spherical aberration revealed no significant relationship between the interocular

difference in the Zernike coefficient C(4,0) and the degree of anisometropia.

Chapter 2

127

Table 2.13: Mean corneal refractive power vectors M, J0 and J45 (D) for the more

and less myopic eyes (4 and 6 mm corneal diameters).

More myopic Less myopic

DIAMETER 4 mm 6 mm 4 mm 6 mm

M (D) 49.21 ± 1.8 * 49.60 ± 2.13 ** 49.06 ± 1.78 49.43 ± 2.06

J0 (D) 0.87 ± 0.48 0.94 ± 0.55 0.85 ± 0.53 1.05 ± 0.56

J45 (D) 0.09 ± 0.24 0.14 ± 0.14 0.06 ± 0.29 0.12 ± 0.35

Sphero-cylinder (D) 50.08/-1.75 x 3 50.55/-1.90 x 4 49.91/-1.70 x 2 50.49/-2.11 x 3

All values are Mean ± SD

Paired t test (More v less myopic eyes) * p < 0.01, ** p < 0.001

Table 2.14: Corneal RMS values for the more and less myopic eyes (4 and 6 mm

corneal diameters).

RMS value (microns)

4mm corneal diameter 6 mm corneal diameter

More myopic Less myopic t-test

(p) More myopic Less myopic

t-test (p)

3rd order 0.106 ± 0.043 0.132 ± 0.109 0.14 0.379 ± 0.279 0.435 ± 0.586 0.24

4th order 0.055 ± 0.016 0.076 ± 0.079 0.16 0.266 ± 0.164 0.359 ± 0.455 0.10

Higher-order 0.130 ± 0.040 0.171 ± 0.151 0.12 0.498 ± 0.370 0.636 ± 0.845 0.13

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128

Table 2.15: Interocular symmetry of corneal aberrations (Zernike coefficients) in

myopic anisometropia (4 and 6 mm corneal diameters).

4mm corneal diameter 6mm corneal diameter

C r p r p

(3,-3) 0.36 0.05 0.86 < 0.0001

(3,-1) 0.18 0.33 0.74 < 0.0001

(3,1) 0.21 0.26 0.59 < 0.001

(3,3) 0.60 < 0.001 0.76 < 0.0001

(4,-4) -0.07 0.71 0.83 < 0.0001

(4,-2) -0.01 0.96 0.53 < 0.01

(4,0) 0.04 0.83 0.85 < 0.0001

(4,2) 0.02 0.91 0.89 < 0.0001

(4,4) 0.06 0.75 0.94 < 0.0001

RMS Sphere 0.42 0.02 0.76 < 0.0001

RMS Astigmatism 0.75 < 0.0001 0.77 < 0.0001

RMS 3rd Order 0.46 < 0.01 0.91 < 0.0001

RMS 4th Order 0.01 0.96 0.93 < 0.0001

RMS Higher-order 0.35 0.05 0.97 < 0.0001

RMS Total 0.55 < 0.01 0.67 < 0.0001

Chapter 2

129

22..33..88 TToottaall ooccuullaarr mmoonnoocchhrroommaattiicc aabbeerrrraattiioonnss

Valid data was obtained for 31 anisometropic subjects. Due to inter-subject

variation in natural pupil sizes during data collection, some subjects were excluded

from analysis when examining aberrations over larger pupil diameters. Here we

present data for 31 subjects over a 4 mm pupil diameter, 30 subjects for a 5 mm

pupil diameter and 19 for 6 mm. Similar trends were observed for the 4, 5 and 6

mm analyses.

The interocular correlations of total monochromatic aberrations up to the fourth

order are displayed in Table 2.16. The anisometropic subjects displayed a high

degree of interocular symmetry of Zernike coefficients between more and less

myopic eyes over all pupil sizes analysed. There were no statistically significant

differences between mean Zernike coefficients for the more and less myopic

groups. The less myopic eyes had slightly greater mean RMS values of 3rd, 4th and

total higher-order aberrations compared to more myopic eyes. However, these

interocular differences were small in magnitude and did not reach statistical

significance (Table 2.17). There were no significant correlations between the

interocular difference in individual Zernike coefficients up to the 4th order and the

magnitude of anisometropia (Table 2.18). Similarly, dominant eyes had slightly

lower levels of total higher-order RMS compared to non- dominant eyes (except for

the high anisometropia group 6 mm pupil analysis). However, these differences did

not reach statistical significance.

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130

Table 2.16: Interocular symmetry of total monochromatic aberrations (Zernike

coefficients) in myopic anisometropia (4, 5 and 6 mm pupil diameters).

Pupil diameter (mm) 4 (n = 31) 5 (n = 30) 6 (n = 19)

Zernike Term r p r p r p

(2,-2) 0.4 < 0.05 0.48 < 0.01 0.42 0.07

(2,0) 0.96 < 0.0001 0.96 < 0.0001 0.98 < 0.0001

(2,2) 0.68 < 0.0001 0.66 < 0.0001 0.81 < 0.0001

(3,-3) 0.67 < 0.0001 0.69 < 0.0001 0.54 < 0.05

(3,-1) 0.72 < 0.0001 0.69 < 0.0001 0.71 < 0.001

(3,1) 0.19 0.31 0.41 <0.05 0.53 < 0.05

(3,3) 0.48 <0.01 0.5 <0.01 0.27 0.26

(4,-4) 0.27 0.14 0.45 < 0.05 0.27 0.26

(4,-2) 0.04 0.83 0.37 < 0.05 0.61 < 0.01

(4,0) 0.7 < 0.0001 0.82 < 0.0001 0.92 < 0.0001

(4,2) 0.41 <0.05 0.29 0.12 0.54 < 0.05

(4,4) 0.28 0.13 0.26 0.17 0.49 < 0.05

3rd order RMS 0.51 < 0.01 0.57 < 0.01 0.43 0.07

4th Order RMS 0.52 < 0.01 0.63 < 0.001 0.78 < 0.0001

Total HO RMS 0.56 < 0.01 0.59 < 0.001 0.48 < 0.05

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131

Table 2.17: Total monochromatic aberrations (Zernike coefficients and RMS values) for the more and less myopic eyes (4, 5 and 6 mm pupil

diameters).

Pupil size 4 mm (n = 31) 5 mm (n = 30) 6 mm (n = 19)

Z Term More (Mean ± SD) Less (Mean ± SD) T test (p) More (Mean ± SD) Less (Mean ± SD) T test (p) More (Mean ± SD) Less (Mean ± SD) T test (p)

(2,-2) -0.056 ± 0.171 -0.075 ± 0.182 0.57 -0.143 ± 0.275 -0.119 ± 0.297 0.67 -0.166 ± 0.415 0.297 ± 0.451 0.68

(2,0) 3.052 ± 1.433 2.267 ± 1.530 < 0.001 4.863 ± 2.327 3.605 ± 2.428 < 0.001 6.768 ± 3.138 2.428 ± 3.449 < 0.001

(2,2) -0.291 ± 0.320 -0.308 ± 0.406 0.74 -0.487 ± 0.525 -0.495 ± 0.634 0.92 -0.731 ± 0.752 0.634 ± 0.819 0.97

(3,-3) 0.004 ± 0.054 -0.014 ± 0.056 0.03 -0.003 ± 0.091 -0.023 ± 0.107 0.16 -0.030 ± 0.118 0.107 ± 0.121 0.71

(3,-1) -0.005 ± 0.062 0.009 ± 0.070 0.14 0.000 ± 0.108 0.015 ± 0.141 0.43 0.037 ± 0.130 0.141 ± 0.117 0.29

(3,1) -0.003 ± 0.035 -0.004 ± 0.038 0.96 -0.014 ± 0.055 -0.011 ± 0.059 0.82 -0.034 ± 0.087 0.059 ± 0.101 0.53

(3,3) 0.007 ± 0.041 0.023 ± 0.049 0.09 0.021 ± 0.075 0.051 ± 0.086 0.07 0.041 ± 0.097 0.086 ± 0.110 0.21

(4,-4) 0.007 ± 0.013 0.008 ± 0.020 0.78 0.022 ± 0.028 0.023 ± 0.036 0.81 0.025 ± 0.038 0.036 ± 0.051 0.15

(4,-2) -0.004 ± 0.012 -0.003 ±0.014 0.70 -0.013 ± 0.022 -0.010 ± 0.025 0.54 -0.020 ± 0.033 0.025 ± 0.043 0.67

(4,0) 0.018 ± 0.025 0.016 ± 0.027 0.67 0.053 ± 0.058 0.046 ± 0.059 0.28 0.110 ± 0.140 0.059 ± 0.123 0.91

(4,2) -0.001 ± 0.022 -0.002 ± 0.020 0.87 -0.010 ± 0.035 -0.004 ± 0.031 0.47 -0.030 ± 0.065 0.031 ± 0.063 0.70

(4,4) 0.006 ± 0.015 0.004 ± 0.020 0.70 0.018 ± 0.026 0.017 ± 0.035 0.87 0.043 ± 0.046 0.035 ± 0.048 0.38

3rd order RMS 0.045 ± 0.021 0.048 ± 0.028 0.56 0.082 ± 0.047 0.090 ± 0.070 0.39 0.105 ± 0.047 0.107 ± 0.055 0.93

4th Order RMS 0.019 ± 0.009 0.020 ± 0.009 0.26 0.077 ± 0.038 0.087 ± 0.060 0.28 0.083 ± 0.038 0.087 ± 0.035 0.50

Total HOA RMS 0.115 ± 0.048 0.121 ± 0.052 0.49 0.206 ± 0.079 0.224 ± 0.112 0.30 0.313 ± 0.085 0.328 ± 0.113 0.55

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132

Table 2.18: Correlation analysis for the interocular difference of total

monochromatic aberrations (Zernike coefficients and RMS values) and spherical

equivalent anisometropia (D) (4, 5, and 6 mm pupil diameters).

Pupil diameter (mm) 4 (n = 31) 5 (n = 30) 6 (n = 19)


(2,-2) 0.30 0.10 0.25 0.18 -0.18 0.46

(2,0) -0.73 < 0.0001 -0.79 < 0.0001 -0.72 < 0.0001

(2,2) 0.36 0.05 0.35 0.06 -0.31 0.20

(3,-3) 0.13 0.49 0.17 0.37 -0.14 0.57

(3,-1) 0.44 0.01 0.40 0.03 0.11 0.65

(3,1) -0.09 0.63 0.00 1.00 -0.20 0.41

(3,3) 0.06 0.75 0.04 0.83 -0.21 0.39

(4,-4) 0.12 0.52 0.04 0.83 -0.01 0.97

(4,-2) 0.24 0.19 0.13 0.49 0.03 0.90

(4,0) -0.21 0.26 -0.12 0.53 -0.32 0.18

(4,2) -0.08 0.67 0.06 0.75 0.01 0.97

(4,4) -0.21 0.26 -0.05 0.79 -0.36 0.13

3rd order RMS 0.00 1.00 0.16 0.40 0.21 0.39

4th Order RMS -0.10 0.59 0.10 0.60 -0.04 0.87

Total HO RMS -0.25 0.17 0.05 0.79 -0.02 0.94

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133

22..44 DDiissccuussssiioonn

This study provides a comprehensive examination of the optical and biomechanical

properties of anisometropic eyes not associated with pathology, amblyopia or

strabismus. We observed a high degree of interocular symmetry in myopic

anisometropia. Aside from the interocular difference in axial length, there were

few significant differences between the more and less myopic fellow eyes for a

range of ocular parameters. But interestingly, for higher levels of anisometropia (>

1.75 D), the more myopic eye was typically the ocular sighting dominant eye.

The anisometropia in our subjects can be primarily attributed to the interocular

difference in the length of the posterior segment (anterior lens surface to the

retinal pigment epithelium). Presumably this is due to the difference in vitreous

chamber lengths, however without lens thickness data we cannot comment with

certainty. However, corneal thickness and anterior chamber depth were highly

symmetric between fellow eyes and previous studies have reported symmetry in

lens thickness between fellow eyes in most cases of anisometropia (Sorsby et al

1962b, Logan et al 2004). We examined the interocular symmetry of a range of

other biometric and optical measurements to improve our understanding of

asymmetric axial elongation.

There was a high degree of interocular symmetry in our cohort of anisometropes

who were primarily of East Asian ethnicity, for measures of eyelid contour,

Chapter 2

134

palpebral aperture dimensions, and corneal shape and pupil size during primary and

downward gaze. Cartwright et al (1994) observed a high degree of mirror

symmetry between fellow eyes for upper eyelid and eyebrow dimensions in healthy

subjects (of unspecified refractive errors). Lam et al (1995) also found a high

degree of interocular symmetry for vertical palpebral aperture in a Caucasian

population.

Differences in eyelid position between the two eyes could potentially promote

anisometropic eye growth. Congenital unilateral ptosis (interocular asymmetry in

eyelid position) may result in amblyopic anisometropia (Beneish et al 1983,

Hornblass et al 1995, Gusek-Schneider and Martus 2000). Form deprivation

associated with partial eyelid closure in humans (O’Leary and Millodot 1979) and lid

suturing in animal models of refractive error development (Langford et al 1998)

typically leads to axial myopia and astigmatism with amblyopia. However, in our

population of young adult myopic anisometropes, eyelid parameters were largely

symmetrical. We observed no correlation between interocular differences in eyelid

shape or position or vertical palpebral aperture size and the magnitude of

anisometropia.

In addition, asymmetry in pupil size (anisocoria) or an interocular difference in the

quality and size of the fundus reflex is often used as a screening technique for

interocular differences in refractive errors or ocular misalignment in children

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135

(Tongue and Cibis 1981). In our cohort of non-amblyopic subjects, pupil dimensions

were highly symmetrical between the more and less myopic eyes. Although the

difference between the more and less myopic eyes approached significance, there

was no correlation between the degree of physiological anisocoria and

anisometropia. Anterior eye biometrics were highly correlated between fellow

eyes and the more myopic eyes were indistinguishable by external examination of

the ocular adnexae.

A high degree of symmetry exists between fellow eyes for corneal power, corneal

thickness and anterior chamber depth in both isometropic (Myrowitz et al 2005)

and anisometropic eyes (Holden et al 1985, Weiss 2003, Logan et al 2004, Kwan et

al 2009). We observed no significant differences between the fellow eyes of our

anisometropic subjects with respect to corneal thickness and anterior chamber

depth, although there was a small (4 mm3) interocular difference in mean anterior

chamber volume between the more and less myopic eyes which reached statistical

significance.

A high degree of symmetry exists between fellow eyes for corneal power in both

isometropic eyes measured with slit scanning topography (Myrowitz et al 2005) and

anisometropic eyes measured with keratometry (Holden et al 1985, Weiss 2003,

Logan et al 2004, Kwan et al 2009). Although there is significant variability in

corneal power in emmetropia and myopia (Sorsby et al 1962), several studies have

Chapter 2

136

shown greater corneal power (Grosvenor and Scott 1991, Scott and Grosvenor

1993, Goss et al 1997) and a less prolate corneal shape (Davis et al 2005) (less

peripheral flattening) in myopes compared to emmetropes. In our population of

anisometropes, our corneal measures with videokeratoscopy revealed, small

interocular differences between the flat and steep corneal meridians of fellow eyes.

The more myopic eyes exhibited more prolate corneas (flattening more rapidly in

the periphery), which is in contrast to previous studies which have shown that

corneas tend to become less prolate with increasing levels of myopia (Carney et al

1997, Horner et al 2000). Also, the mean refractive corneal power (average of the

steep and flat corneal meridians) was significantly greater (steeper) in the more

myopic eyes. To our knowledge, this has not been observed in previous biometric

studies of anisometropic subjects.”

Animal models have also shown that peripheral optics may play a role in the

regulation of eye growth and refractive error development (Smith et al 2005, Smith

et al 2009). Buehren et al (2007) hypothesised that altered mid-peripheral corneal

shape and optics due to lid pressure during reading might be a potential trigger for

refractive error development. Temporary corneal distortion resulting in hyperopic

retinal defocus may lead to compensatory axial elongation. A similar mechanism

could be proposed in the development of myopic anisometropia. A greater amount

of peripheral corneal flattening in one eye (observed in our cohort of

anisometropes) could result in peripheral hyperopic defocus triggering asymmetric

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137

axial elongation. However, such a hypothesis would also need to account for the

steeper central cornea of the more myopic eye.

Asymmetries in retinal contour have also been reported between the two eyes of

myopic anisometropes (Logan et al 2004). There is increasing evidence that

orthokeratology, which focuses light centrally at the fovea but induces peripheral

myopic blur, slows the rate of axial elongation during myopia development (Cheung

et al 2004, Cho et al 2005, Walline et al 2009). This experiment was limited to on-axis

measurements of higher order aberrations which were similar between the fellow

eyes (both corneal and total aberrations). However given the potential role of

peripheral optics in refractive error development, and the interocular differences

observed in corneal power and peripheral shape, investigations of peripheral optics

in anisometropia may be worthy of future study.

It could also be argued that altered corneal shape may be a result of vision-

dependent eye growth. Kee and Deng (2008) reported significant changes in

corneal astigmatism following various visual manipulations in young chicks

including form deprivation, hyperopic and myopic defocus. Small corneal

differences observed between the eyes of our anisometropic subjects may be

attributed to axial elongation (rather than cause it) and subsequent alterations in

scleral structure which could potentially impact upon the cornea at the limbus.

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138

If this were the case we might expect to observe interocular differences in

measures of corneal biomechanics. However, there were no significant differences

between the fellow eyes with respect to group mean corneal resistance and

hysteresis and no correlation between the interocular difference in these

parameters and the degree of anisometropia.

Hysteresis is positively correlated with central corneal thickness and is reduced in

conditions associated with corneal thinning such as advanced keratoconus, Fuch’s

endothelial dystrophy and the post LASIK cornea (Luce 2005). Shen et al (2008)

observed significantly lower levels of hysteresis in high myopes (-9.00 D) compared

to a control group of emmetropes and low myopes with similar corneal thickness

and suggested that corneal collagen structure may be altered in higher levels of

myopia as axial length increases. In addition, Xu et al (2010) observed a small but

statistically significant reduction in corneal hysteresis in the more myopic eye

compared to the fellow eye in a study of high myopic anisometropia. A stretched or

weakened sclera, may be related to these lower values of corneal hysteresis in high

myopia. We found no such relationship in our cohort of anisometropes, possibly

due to the difference in the magnitude of anisometropia in our population of

subjects (mean 1.70 D) compared to Xu et al (2010) (mean 10.82 D).

The measurement of intraocular pressure may be influenced by variables such as

age, blood pressure, gender, corneal thickness and curvature and diurnal variation.

Chapter 2

139

We measured IOP using an air impulse technique that was less influenced by

corneal characteristics in comparison to applanation tonometry. We compared the

more and less myopic eyes of axial anisometropes to control for individual

variations, which may influence results in cohort studies.

Our findings were similar to those of previous studies examining IOP in

anisometropia using applanation or non-contact tonometry (Tomlinson and Phillips

1972, Bonomi et al 1982, Lee and Edwards 2000, Lam et al 2003). We found no

significant differences in IOP between the more and less myopic eyes and no

correlation between the interocular difference in IOP and the magnitude of

anisometropia. Our results do not support a simple mechanical model of increased

IOP leading to axial elongation and myopia. However, it is possible that

anisometropia may develop through an IOP dependant mechanical mechanism with

symmetrical IOPs, if there are interocular differences in scleral biomechanics. Lee

and Edwards (2000) calculated that the stress upon the sclera was significantly

higher in the more myopic eyes of anisometropes compared to the fellow eye. The

authors proposed that an interocular difference in scleral thickness due to different

rates of collagen formation may result in asymmetric axial elongation and the

development of axial anisometropia in the presence of symmetrical intraocular

pressures.

This hypothesis suggests that there should be differential growth rates between

anisometropic eyes. However, Tong et al (2006) observed that the rate of change in

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140

spherical equivalent refractive error and axial length in young Singaporean

anisometropes was similar between the fellow eyes, although anisometropic eyes

grew at a faster rate than isometropic counterparts. This suggests that a

mechanical IOP inflation and axial elongation mechanism may not be involved in

the development of axial anisometropia or myopia. The findings from our study

and previous studies of IOP in anisometropia are cross sectional in nature, which

leaves open the possibility that short term (e.g. diurnal variations) or longer term

fluctuations in IOP may vary with anisometropia.

To our knowledge this study is the first to report the interocular symmetry of

corneal aberrations in anisometropic eyes without amblyopia or strabismus. Plech

et al (2010) observed that corneal higher-order aberrations were similar between

fellow eyes in cases of unilateral amblyopia including isometropic and

anisometropic refractive errors. We found a high degree of interocular symmetry

for corneal higher-order aberrations, which increased as the corneal analysis

diameter increased. This suggests that the optical quality of the cornea is similar

for the two eyes of myopic anisometropes. These findings are in agreement with

previous studies of between eye symmetry of corneal aberrations in isometropic

populations (Wang et al 2003, Lombardo et al 2006).

Buehren et al (2007) hypothesised that increased levels of corneal aberrations

following near work may temporarily alter retinal image quality and stimulate axial

elongation. In this study we found no evidence of increased corneal aberrations in

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141

the more myopic eyes, which does not support a model of corneal aberration

driven myopia development. However, these measurements were not taken

following near work, which has been shown to alter corneal optics due to eyelid

pressure (Buehren et al 2003, Buehren et al 2005, Collins et al 2006a, Collins et al

2006b, Shaw et al 2008).

A high degree of interocular symmetry exists for total higher-order aberrations

after correcting for enantiomorphism in various isometropic populations (Liang and

Williams 1997, Thibos et al 2002, Marcos and Burns 2000). We observed a high

level of symmetry between the fellow eyes of anisometropes for Zernike

coefficients up to the fourth order. Kwan et al (2009) also noted significant

symmetry of higher-order aberrations, however they also noted significantly higher

levels of third order and total higher-order aberrations in the less myopic eye of

anisometropes (> 2.00 D SEq). Tian et al (2006) investigated the interocular

symmetry of ocular aberrations in ten myopic anisometropes (> 1.00 D SEq) similar

to the cohort in our study and found no significant interocular differences in

individual Zernike terms, 3rd order, 4th order and 5th order aberrations or total

higher-order aberrations. Our findings do not support the hypothesis that

increased aberrations (and hence reduced retinal image quality) in the

unaccommodated eye play a role in the development of myopic anisometropia.

However, this does not rule out the possibility that higher-order aberrations play a

role in the development of myopia or anisometropia following near work or during

accommodation (examined in Chapters 3 and 4 respectively), or that the sign of the

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142

aberrations (relative hyperopic versus myopic focus i.e. the distribution of power

across the entrance pupil) may play a role.

We observed that as the degree of anisometropia increased, the sighting dominant

eye was more often the more myopic of the two eyes. When anisometropia

exceeded 1.75 D (n = 10), the more myopic eye was the dominant eye in 90% of

subjects. When greater than 2.25 D, the more myopic eye was always the

dominant eye. Our findings are in agreement with those of Cheng et al (2004a)

who examined ocular dominance in 55 adults with spherical equivalent

anisometropia ranging from 0.5 - 5.5 D and reported a threshold level of

anisometropia (1.75 D), beyond which the more myopic eye was always the

dominant sighting eye. The authors hypothesised that during or following

sustained near work, the dominant eye may have a larger lag of accommodation in

comparison to the non-dominant eye, resulting in greater axial elongation in the

dominant eye.

Similarly, the right eye was the dominant sighting eye in 90% of the subjects in the

high anisometropia group. The proportion of right eye dominance in our cohort of

subjects (79%) was higher than those reported in previous studies of myopic adults

(64%) (Cheng et al 2004a) and children (58%) (Chia et al 2007) using a similar

technique to assess dominance. Since the right eye, the more myopic eye and the

dominant sighting eye are inter-related we cannot discount that laterality (a

Chapter 2

143

preference for the right or left side) may play a role in the development of ocular

dominance. However, we have presented our results with respect to myopia and

anisometropia (rather than laterality) for comparison with previous studies (Cheng

et al 2004a, Chia et al 2007) and to investigate potential factors associated with

refractive error and sighting dominance.

Charman (2004) proposed that reading creates an unequal accommodative demand

due to unequal target distances between the two eyes. However, due to the

consensual nature of the accommodative system, substantial levels of aniso-

accommodation are not possible. In theory, the level of accommodation in both

eyes would be limited to the lower of the two demands, resulting in relative blur in

the other eye (with the higher accommodative demand). However, Marran and

Schor (1998) reported that when the interocular difference in accommodative

demand is less than approximately 3 D, with training, some adults are able to

demonstrate aniso-accommodation. Ibi (1997) examined the accommodative

response in the dominant and non-dominant eyes of young isometropic subjects

and observed that the dominant eye showed a slight myopic shift at both distance

and near fixation following accommodation. The author speculated that the static

tonus of the ciliary muscle is increased in the dominant eye, which may explain why

the dominant eye is often the more myopic eye in non-amblyopic anisometropia.

However, if the dominant eye shows a slight lead of accommodation following near

work, this myopic defocus would slow eye growth, based on the theory of retinal

image mediated eye growth.

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144

In anisometropic amblyopia, the dominant sighting eye is typically the eye with

better visual acuity, although there may be exceptions in some cases with

intermittent strabismus (Rutstein and Swanson 2007). We found no significant

difference in visual acuity between dominant and non-dominant eyes (mean inter-

eye difference ≤ 0.01 logMAR), or when dividing our subjects into low and high

anisometropia cohorts. If visual acuity influenced ocular dominance in myopic

anisometropia, we might expect to see a significant difference in acuity between

the fellow eyes for the myopes with anisometropia greater than 1.75 D (in which

the more myopic eye was typically the dominant sighting eye) and no significant

difference between the fellow eyes for the myopes with a lower degree of

anisometropia (in which the spread of ocular dominance was fairly even between

the more and less myopic eyes). However, there were no significant differences in

visual acuity between the fellow eyes for either group. Furthermore, we compared

the higher order monochromatic aberrations between the dominant and non-

dominant eyes to examine if subtle optical differences (which may alter the retinal

image, but not significantly reduce visual acuity) between the eyes might somehow

influence ocular dominance. However, the dominant and non-dominant eyes

displayed similar RMS values. Near visual acuity may have provided some more

interesting information regarding the relationship between acuity and ocular

dominance. Given our subjects were established anisometropes (not developing

anisometropia), we cannot rule out that visual acuity (or some aspect of the quality

of vision) during anisometropia development plays a role in determining sighting

dominance.

Chapter 2

145

The proportion of right eye dominance in all of our subjects (79%) and in particular

the high anisometropes > 1.75 D (90%) was higher than that of normal populations

(65-70%) (Miles 1929, Zoccolotti 1978, Reiss and Reiss 1997) and a cohort of

anisometropes (64%) (Cheng et al 2004a). Although the right eyes of subjects were

on average slightly longer and more myopic than left eyes, these interocular

differences did not reach statistical significance. We also examined the interocular

difference between dominant and non-dominant eyes for a selection of optical and

biometric parameters including; vertical palpebral aperture and pupil size in

primary and down gaze, corneal power vectors M, J0 and J45 and corneal and total

higher-order aberration RMS values. Whilst some trends were observed for

differences in ocular optics (e.g. higher levels of 3rd, 4th and higher-order corneal

RMS values in non-dominant eyes) and biometrics (e.g. larger palpebral apertures

and pupil diameters in non-dominant eyes) between the dominant and non-

dominant eyes, limited differences of statistical significance were found. These

data do not point to an obvious underlying optical or biomechanical reason for the

more myopic eye typically being the dominant eye for higher levels of

anisometropia. The association between ocular sighting dominance and

anisometropia requires further investigation given the findings of this study and

those of Cheng et al (2004a).

The association between ocular sighting dominance and anisometropia requires

further investigation given the findings of this study and those of Cheng et al

(2004a). A more precise technique of measuring sensory ocular dominance,

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146

described by Li et al (2010) may provide a clearer insight into this association.

While this experiment has examined the association between refractive error and

ocular dominance, we do not discount the possibility that laterality may be an

important factor. The correlation between right and left handedness and ocular

dominance may provide information regarding cortical input to sighting dominance.

Beyond a certain degree of anisometropia, the more myopic eye may be favoured

for near work during binocular vision due to the reduced ocular accommodative

demand relative to the fellow eye and thus dominates during binocular viewing.

Studies of ocular changes of both eyes simultaneously during near tasks with

binocular viewing may provide insight into characteristics which influence ocular

dominance. Ocular changes such as accommodative response and axial length

changes of dominant and non-dominant eyes during monocular accommodation

tasks are reported in Chapter 4.

A longitudinal study into the ocular changes of dominant and non-dominant eyes

during refractive error development may also provide further insight into the

potential causal nature of this relationship. Characteristics of the dominant eye

during binocular near work may help explain the underlying mechanism, if ocular

dominance influences the development of myopic anisometropia.

Chapter 2

147

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Aside from an interocular difference in axial length, due to asymmetry in the

posterior vitreous chamber, anisometropic eyes display a high degree of interocular

symmetry for a range of biometric and optical characteristics. Unlike previous

anisometropia studies, we observed that the more myopic eye had, on average, a

significantly steeper cornea in comparison to the fellow eye. The findings from our

study do not support a single mechanical (IOP expansion) or retinal image mediated

(corneal or total monochromatic aberrations) mechanism in the unaccommodated

eye in the development of myopic anisometropia. There is a threshold level of

anisometropia, above which the more myopic eye is typically the dominant sighting

eye. The role of ocular sighting dominance in the development of myopia and

anisometropia requires further investigation.

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148

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In Chapter 2, we observed a high degree of symmetry between the more and less

myopic eyes of myopic anisometropes for a range of biometric, biomechanical and

optical parameters. In this chapter, we describe the interocular symmetry of

changes in axial length, corneal optics and the total ocular wavefront following a

short period of near work in the same cohort of anisometropic subjects.

There is a reported association between near work and myopia (Morgan and Rose

2005). However, the mechanism underlying this association is not fully understood.

Mechanical and optical changes which occur during near work temporarily alter

certain optical and biometric properties of the eye and may provide insight into the

mechanism linking near work and refractive error development.

When near work is performed the eyes typically converge and accommodate in

order to maintain clear, single binocular vision of near targets. Forces exerted by

the extraocular muscles during convergence are thought to have the potential to

lead to changes in axial length (Greene 1980). Bayramlar et al (1999) concluded

that transient axial elongation associated with near work was a result of

convergence rather than accommodation after observing significant vitreous

chamber elongation measured with ultrasound biometry in young subjects

Chapter 3

149


(2009) reported that axial length as measured with partial coherence

interferometry appears largely unchanged in adults both during and following a

period of sustained convergence. Ciliary muscle contraction has also been found to

be associated with small but significant increases in the eye’s axial length (Drexler

et al 1998, Mallen et al 2006). Various studies have documented transient changes

in axial length using highly precise non-contact instruments during or following

periods of accommodation. Drexler et al (1998) observed small increases in axial

length, slightly larger in magnitude in emmetropes compared to myopes during a

short period of maximum accommodation. Mallen et al (2006) also examined axial

length changes during accommodation but controlled for the accommodative

demand between emmetropic and myopic cohorts. Axial elongation was greater in

myopic eyes compared to emmetropes, and correlated positively with the level of

accommodation. Read et al (2010) also observed an increase in axial elongation

during accommodation which increased with higher levels of accommodation, but

found no significant difference in the magnitude of axial elongation between

myopic and emmetropic cohorts. Woodman et al (2011) examined the change in

axial length following a prolonged (30 minute) reading task and observed greater

axial elongation in myopes compared to emmetropes. Ten minutes after the

reading task, axial length measures were not significantly different from baseline

measurements suggesting that axial length changes associated with near work are

transient in nature.

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150

Animal models have shown that manipulation of the retinal image results in

predictable compensatory eye growth to produce emmetropia in a variety of

species (Wildsoet 1997). Therefore it is possible that altered retinal image quality

in humans during or following near work could play a role in axial elongation and

the development of myopia.

The accommodation response in various refractive error groups has been

investigated in detail (Chen et al 2003). Typically, greater lags of accommodation

(under accommodation during near work) have been reported in myopes compared

to emmetropes (McBrien and Millodot 1986, Rosenfield and Gilmartin 1987,

Rosenfield and Gilmartin 1988, Gwiazda et al 1993). The hyperopic defocus

associated with a lag of accommodation may provide a cue to eye growth and

myopic development. Higher-order aberrations, optical imperfections within the

eye which degrade retinal image quality, may also influence eye growth. Although

the unaccommodated eyes of myopes and emmetropes exhibit similar levels of

aberrations (He et al 2002, Carkeet et al 2002), during or following near work

myopes tend to have higher levels of aberrations in comparison to their

emmetropic counterparts (Buehren et al 2003, Buehren et al 2005, Buehren et al

2006). Recent studies suggest this may be due to differences in corneal

aberrations.

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151

Buehren et al (2003) examined the change in corneal optics following sixty minutes

of reading in adult subjects. The most common change in the shape of the corneal

wavefront following near work was a “wave-like” distortion accompanied by an

increase in against-the-rule corneal astigmatism. In another study, Buehren et al

(2005) observed that the magnitude of corneal aberration changes due to near

work were significantly larger in myopes compared to emmetropes due to smaller

palpebral apertures during reading. These changes in corneal aberrations due to

sustained eyelid pressure (Buehren et al 2003, Shaw et al 2008) may have the

potential to initiate compensatory eye growth resulting in myopia and with the rule

astigmatism (Buehren et al 2007).

While some studies have examined higher-order aberrations in anisometropic

populations (Tian et al 2006, Kwan et al 2009) no study has examined the

interocular symmetry of optical or biometric parameters in anisometropes during

or following a period of near work. Given the strong association between myopia

and near work, we investigated the changes in the fellow eyes of myopic

anisometropes following a short reading task to control for potential confounding

inter-subject variables inherent in cohort studies.

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152



The subjects recruited for this study and the screening procedures are the same as

those reported in Chapter 2. The methodology for capturing and analysing the

measurements of corneal topography, ocular aberrations, axial length, morphology

of the palpebral fissure and corneal biomechanics have also been described in

Chapter 2. The following section describes the experimental procedure for this

experiment involving a near work task and any modifications to the techniques

outlined in the previous experiment.


To examine the potential influence of near work on the optical and biometric

characteristics of anisometropic eyes, corneal topography, ocular aberrations and

axial length were measured before and immediately following (within

approximately 10 seconds) a ten minute reading task. For each parameter, the

right eye was measured first followed by the left eye. Because ocular changes may

dissipate quickly following a reading task (Collins et al 2005), subjects performed

the reading task three times, once for each parameter being examined. This

experimental procedure is outlined in Figure 3.1. The order in which each

parameter was examined was randomised and a 30 minute washout period was

used between post and pre reading measurements to allow any ocular changes as a

result of the previous reading task to return to baseline levels. Collins et al (2005)

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153

Task Time Parameter measured

Baseline measures 1 ↓ Axial length

Reading task 10 minutes

Post reading measures 1 ↓ Axial length

Washout period 30 minutes

Baseline measures 2 ↓ Corneal topography


Post reading measures 2 ↓ Corneal topography

Washout period 30 minutes

Baseline measures 3 ↓ Ocular aberrations


Post reading measures 3 ↓ Ocular aberrations

Figure 3.1: Example of experimental procedure. Measurements taken before and

after a short near work task with washout periods following reading.

Chapter 3

154

reported that following a ten minute reading task, the regression of the maximum

change in corneal power to baseline levels takes approximately 30 minutes, with

the majority of the recovery occurring within the first ten minutes following

reading. During the washout periods, subjects refrained from near work and

maintained distance fixation.

Subjects were positioned in a headrest to ensure consistency of eye and head

position during the reading task. Six lines of n 11 text were visible on a computer

monitor at a distance of approximately 40 cm from the spectacle plane and 25

degrees below horizontal (the average angle of downward gaze adopted during

reading (Hill et al 2005, Read et al 2006). This setup minimised the amount of

vertical eye movements. Subjects could read continuously by scrolling the mouse

and were instructed to blink naturally while reading.

To highlight changes occurring following reading, difference maps were calculated

by subtracting the average pre-reading refractive power map from the average

post-reading refractive power map. For each data point on the difference map a 2-

tailed paired t-test was performed. This provided the statistical significance (p-

values) of the differences between the maps at each point.

Corneal biomechanics were measured only at the end of the testing session (rather

than pre and post reading task, approximately five minutes after all other

Chapter 3

155

measurements were completed) to ensure the air puff from the ORA did not

influence the measurement of corneal topography.


Two tailed paired t-tests were used to assess the statistical significance of the

difference between pre-task and post-task measurements in the more and less

myopic eyes of the anisometropic subjects. Pearson’s correlation coefficient was

used to quantify the degree and statistical significance of the interocular symmetry

between the post-near work change in the more and less myopic eyes. Pearson’s

correlation coefficient was also used to examine the relationship between the

magnitude of change in the variable of interest and various potential predictors

(e.g. magnitude of change in corneal sphere as a function of corneal hysteresis).

Chapter 3

156


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There was no statistically significant change in axial length for more or less myopic

eyes following the ten minute reading task (Table 3.1). The group mean axial length

change following reading was -1 ± 20 microns for the more myopic eyes and 0 ± 20

microns for the less myopic eyes. There was no correlation between spherical

equivalent refractive error or axial length and the magnitude of axial length change

following reading. Although dominant eyes were significantly longer than non-

dominant eyes, there was no statistically significant change in axial length following

reading for either the dominant or non-dominant eyes (Table 3.2). Figures 3.2 and

3.3 display the change in axial length for each subject following reading for the

more and less myopic eyes and the dominant and non-dominant eye respectively.

Chapter 3

157

Table 3.1: Mean axial length (mm) pre and post reading task for the more and less

myopic eyes in myopic anisometropia.

More myopic Less myopic Paired t-test

Axial length (mm) Mean ± SD Mean ± SD p

Pre-reading 25.57 0.89 25.00 0.95 < 0.0001

Post-reading 25.56 0.91 24.99 0.96 < 0.0001

Difference (Post - Pre) -0.001 0.02 0.000 0.02 0.89

Table 3.2: Mean axial length (mm) pre and post reading task for the dominant and

non-dominant eyes in myopic anisometropia.

Dominant Non-dominant Paired t-test

Axial length (mm) Mean ± SD Mean ± SD p

Pre-reading 25.42 1.00 25.15 0.90 0.01

Post-reading 25.42 1.01 25.15 0.90 0.01

Difference (Post - Pre) -0.001 0.02 0.000 0.02 0.87

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158

Figure 3.2: Change in axial length following reading for more and less myopic eyes.

Figure 3.3: Change in axial length following reading for dominant and non-

dominant eyes.

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159


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Corneal power vectors M (spherical corneal power), J0 (90/180 astigmatic power)

and J45 (45/135 oblique astigmatic power) were calculated from the average pre-

reading and post-reading refractive power maps. The mean corneal power vectors

for the more and less myopic eyes are shown in Table 3.3 along with the change

following the reading task. The more myopic eyes had a significantly higher M

before and after the reading task for both 4 and 6 mm corneal diameters.

Following the reading task there were small reductions in mean M, J0 and J45 in

both the more and less myopic eyes over both corneal diameters (except J45 for

the 6 mm analysis diameter which increased slightly). The mean decrease in J0 was

statistically significant over 4 and 6 mm diameters for the more myopic eyes but did

not reach statistical significance for the less myopic eyes. The magnitude of change

in corneal vector J0 was significantly greater in the more myopic eyes (-0.04 ± 0.04

D) compared to the less myopic eyes (-0.02 ± 0.06 D) over the 6 mm corneal

diameter, however, the changes in M and J45 were similar between eyes. The

magnitude of change in M, J0 or J45 was not correlated with pre-reading M, J0, J45

values, or spherical equivalent refractive error. The interocular differences in

corneal change were not correlated with the magnitude of anisometropia.

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Figure 3.4 displays the refractive power topography maps for subject 22 before and

after the reading task for each eye. The difference maps (Post - Pre reading)

highlight areas of corneal change following reading. The p-value maps highlight

statistically significant areas of corneal change following reading. In this example,

both eyes shows a distinct band of corneal change (a decrease in corneal refractive

power or hyperopic defocus) which appears to correlate with the position of the

upper eyelid during downward gaze. On average, fellow eyes displayed a

symmetrical change in corneal topography (Figure 3.5), due to the high degree of

interocular symmetry in palpebral aperture characteristics, discussed in Chapter 2.

The mean change in corneal spherocylinder was +0.03/-0.11 x 101 and +0.02/-0.07

x 107 for more and less myopic eyes respectively over a 4 mm diameter. Over a 6

mm diameter, the mean group changes were +0.02/-0.11 x 113 and +0.02/-0.06 x

68 for the more and less myopic eyes respectively. Figure 3.5 shows the mean

group refractive change following the reading task for the more and less myopic

eyes. The more and less myopic eyes both show a horizontal band of negative

refractive change (hyperopic defocus) corresponding to the approximate position of

the upper eyelid during downward gaze.

The same analysis was carried out for the dominant and non-dominant eyes before

and after the reading task (Table 3.4, Figure 3.5). There were no statistically

significant differences between the dominant and non-dominant eyes for corneal

Chapter 3

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vectors M, J0 or J45 before or after the reading task for either corneal diameter

analysed. Both the dominant and non-dominant eyes had a slight reduction in J0

following reading over both corneal diameters, however this change only reached

statistical significance in the dominant eyes.

Pre-reading and post-reading corneal root mean square error (RMSE) values from

the best fit refractive power spherocylinder (which represent the higher-order

corneal aberrations) are shown in Table 3.5. RMSE values increased following the

reading task for both the less and more myopic eye groups for both corneal

diameters. Although changes were less than 0.1 D for all analysis diameters, these

were statistically significant increases from mean baseline levels. The more myopic

eyes had slightly higher levels of corneal RMSE before and after the reading task for

each pupil diameter in comparison to the less myopic group, however these

differences were not statistically significant.

Chapter 3

162

Subject

22

MORE LESS SCALE

-9.25/-2.50 x 2 -7.25/-2.50 x 168 P

RE

TASK

PO

ST T

ASK

DIF

FER

ENC

E

(PO

ST –

PR

E)

P V

ALU

E

25

DEG

REE

DO

WN

WA

RD

GA

ZE

Figure 3.4: Refractive power maps for one subject (subject 22). The refractive

power maps and digital image of the left (less myopic) eye have been transposed to

right eyes using customised software to account for mirror symmetry.

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163

Table 3.3: Mean corneal vectors M, J0 and J45 (D) before and after reading for the more and less myopic eyes (4 and 6 mm corneal diameters).

MORE MYOPIC LESS MYOPIC

Corneal diameter (mm)

TIME M J0 J45 Spherocyl M J0 J45 Spherocyl

4

Pre-task 49.21 ± 1.80 * 0.87 ± 0.48 0.09 ± 0.24 50.08/-1.75 x 3 49.06 ± 1.78 0.85 ± 0.53 0.06 ± 0.29 49.91/-1.70 x 2

Post-task 49.18 ± 1.77 * 0.81 ± 0.46 0.06 ± 0.25 49.99/-1.63 x 3 49.04 ± 1.78 0.82 ± 0.52 0.04 ± 0.28 49.86/-1.64 x 1

Change (Post-Pre)

-0.02 ± 0.08 -0.05 ± 0.06 ^ -0.02 ± 0.08 +0.03/-0.11 x 101 -0.02 ± 0.06 -0.03 ± 0.15 -0.02 ± 0.07 +0.02/-0.07 x 107

6

Pre-task 49.60 ± 2.13 * 0.94 ± 0.55 0.14 ± 0.14 50.55/-1.90 x 4 49.43 ± 2.06 1.05 ± 0.56 0.12 ± 0.35 50.49/-2.11 x 3

Post-task 49.57 ± 2.09 * 0.91 ± 0.54 0.11 ± 0.33 50.49/-1.83 x 3 49.41 ± 2.04 1.02 ± 0.53 0.14 ± 0.33 50.44/-2.06 x 4

Change (Post-Pre)

-0.04 ± 0.07 -0.04 ± 0.04 *^ -0.04 ± 0.07 +0.02/-0.11 x 113 -0.01 ± 0.06 -0.02 ± 0.06 0.02 ± 0.05 +0.02/-0.06 x 68

All values are Mean ± SD in Dioptres. * p < 0.01 Paired t-test (More v less myopic eyes). ^ p < 0.01 Paired t-test (Pre v post-task)

Table 3.4: Mean corneal vectors M, J0 and J45 before and after reading for the dominant and non-dominant eyes (4 and 6 mm corneal diameters).

DOMINANT EYES NON-DOMINANT EYES


TIME M J0 J45 Spherocyl M J0 J45 Spherocyl

4

Pre-task 49.00 ± 1.70 0.84 ± 0.45 0.05 ± 0.25 49.85/-1.69 x 2 48.97 ± 1.74 0.85 ± 0.51 0.04 ± 0.26 49.82/-1.71 x 1

Post-task 48.98 ± 1.69 0.79 ± 0.45 0.05 ± 0.27 49.77/-1.58 x 2 48.94 ± 1.71 0.83 ± 0.53 0.02 ± 0.26 49.77/-1.67 x 1

Change (Post-Pre)

-0.03 ± 0.11 -0.05 ± 0.10 * ^^ -0.01 ± 0.07 +0.03/-0.10 x 93 -0.03 ± 0.09 -0.04 ± 0.09 0.00 ± 0.07 0.00/-0.05 x 115

6

Pre-task 49.21 ± 1.73 0.84 ± 0.44 0.09 ± 0.26 50.06/-1.70 x 3 49.17 ± 1.75 0.85 ± 0.50 0.07 ± 0.27 50.02/-1.71 x 3

Post-task 49.18 ± 1.72 0.80 ± 0.45 0.09 ± 0.27 49.99/-1.61 x 3 49.14 ± 1.72 0.83 ± 0.52 0.06 ± 0.26 49.98/-1.66 x 2

Change (Post-Pre)

-0.03 ± 0.14 -0.02 ± 0.11 ^ -0.02 ± 0.06 +0.02/-0.09 x 92 -0.02 ± 0.11 -0.02 ± 0.09 -0.02 ± 0.06 0.00/-0.05 x 110

All values are Mean ± SD in Dioptres. * p <0.05 Paired t-test (Dominant v non-dominant eyes). ^ p < 0.05, ^^ p < 0.001 Paired t-test (Pre v post-task)

Chapter 3

164

More myopic eyes

Mean refractive change

after ten minutes reading

Less myopic eyes



Scale

(D)

Dominant eyes



Non-dominant eyes



Scale

(D)

Figure 3.5: Mean refractive change (post – pre-reading) for more and less myopic

eyes (top) and dominant and non-dominant eyes (bottom) after ten minutes of

reading. Inner circle 4 mm diameter, outer circle 6 mm diameter (n = 34 subjects).

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165

Table 3.5: Pre and post-reading corneal RMSE values (D) for the more and less

myopic eyes (4 and 6 mm corneal diameters).

RMSE MEAN ± SD (D)


Measurement More myopic eyes LESS myopic eyes

4

Pre-task 0.51 ± 0.14 0.49 ± 0.19

Post-task 0.57 ± 0.18 0.55 ± 0.20

Change (Post-Pre) 0.06 ± 0.12* 0.06 ± 0.10**

6

Pre-task 0.86 ± 0.18 0.83 ± 0.10

Post-task 0.95 ± 0.20 0.90 ± 0.13

Change (Post-Pre) 0.09 ± 0.09** 0.07 ± 0.08**

Significant changes over time * p < 0.05, ** p < 0.01

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33..33..22..22 CCoorrnneeaall rreeffrraaccttiivvee cchhaannggeess aanndd ppaallppeebbrraall aappeerrttuurree mmoorrpphhoollooggyy

We also examined the correlation between the magnitude of corneal change

following reading and anterior eye biometrics. The relationship between the

morphology of the anterior eye and corneal optical changes following reading were

similar between fellow eyes. There was a weak correlation between vertical

palpebral aperture size during downward gaze and the change in M which

approached statistical significance for the less myopic eyes (r = 0.32, p = 0.07) and

just reached statistical significance for the more myopic eyes (r = 0.39, p = 0.03).

Narrower palpebral apertures tended to be associated with a greater reduction in

corneal M (Figure 3.6). Figure 3.7 shows the relationship between the position of

the upper and lower eyelid during downward gaze and the magnitude of the

change in M. The closer the upper or lower eyelid was to the pupil centre during

down gaze the greater the decrease in M. This was a weak correlation which just

reached statistical significance for the upper eyelid (p = 0.05 for the more and less

myopic eyes). Similar trends were observed for changes in J0 and vertical palpebral

aperture during down gaze, but did not reach statistical significance. There were no

significant associations between eyelid curvature or tilt with the magnitude of

corneal astigmatic refractive changes J0 or J45.

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167

Figure 3.6: Change in corneal vector M (D) following reading vs vertical palpebral

aperture in downward gaze (mm).

Figure 3.7: Change in corneal vector M (D) following reading vs vertical distance

from pupil centre to eyelid margin (mm).

Chapter 3

168

33..33..22..33 CCoorrnneeaall rreeffrraaccttiivvee cchhaannggeess aanndd ccoorrnneeaall bbiioommeecchhaanniiccss

We also investigated the correlation between the magnitude of change in corneal

vectors M, J0 and J45 with the biomechanical measures of corneal hysteresis and

corneal resistance factor. There was no association between the magnitude of

change in M with either biomechanical measure. For the less myopic eyes, there

were small but statistically significant correlations between the magnitude of

change in corneal astigmatism vectors J0 and J45 with corneal biomechanical

measures CRF and CH (J0; CRF (r = 0.48, p = 0.008), CH (r = 0.46, p = 0.01), J45; CRF

(r = -0.47, p = 0.01), CH (r = -0.40, p = 0.03). Lower values of CRF and CH (i.e. less

corneal resistance) were associated with a greater negative change in J0 and a

larger positive change in J45. This trend was not evident in the more myopic eyes.

Figure 3.8 shows the relationship between the magnitude of change in corneal J0

(right panels) and J45 (left panels) following reading as a function of CRF for the

more and less myopic groups (top panel) and both groups combined (bottom

panels).

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169

Figure 3.8: Change in corneal astigmatism following reading vs corneal resistance factor. Left panels: Change in vector J0 vs corneal resistance

factor. Right panels: Change in vector J45 vs corneal resistance factor.

Chapter 3

170

33..33..22..44 CCoorrnneeaall aabbeerrrraattiioonnss

The magnitude of change in corneal aberrations following reading did not differ

significantly between the more and less myopic eyes for any Zernike terms up to

the fourth order. Figure 3.9 shows the group mean change in corneal RMS

following reading for more and less myopic eyes over 4 and 6 mm corneal

diameters. Apart from RMS astigmatism, the less myopic eyes had a slightly higher

increase in the other RMS values compared to the more myopic eyes over the 6mm

corneal diameter after 10 minutes of reading. However, these interocular

differences did not reach statistical significance.

There was a significant correlation between the magnitude of change in corneal

aberrations C(3,-3) trefoil along 30 and C(3,-1) primary vertical coma following the

reading task in both the less and more myopic eyes (Figure 3.10) over a 4 and 6 mm

corneal diameter.

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171

Figure 3.9: Group mean change in corneal RMS following reading for more and less

myopic eyes over 4 mm and 6 mm corneal diameters.

Figure 3.10: Correlation between change in corneal Zernike coefficients C(3,-3) and

C(3,-1) following reading over 4 mm corneal diameter.

Chapter 3

172


Due to intersubject variation in natural pupil sizes during data collection, some

subjects were excluded from analysis when examining aberrations over larger pupil

diameters. Here we present data for 31 subjects over a 4 mm pupil diameter, 30

subjects for a 5 mm pupil diameter and 19 subjects for a 6 mm diameter.

Pre-reading values of the less myopic eyes had slightly greater mean RMS values of

3rd, 4th and total higher-order aberrations compared to the more myopic eyes.

However, these interocular differences were small in magnitude and did not reach

statistical significance (Table 3.6). Post-reading RMS values were also similar

between the more and less myopic eyes, except for 4th order RMS (6 mm pupil

diameter) which was significantly higher in the more myopic eyes (0.097 ± 0.042

microns) compared to the less myopic eyes (0.084 ± 0.044 microns) (p = 0.01).


dominant eyes before or after the reading task for 3rd, 4th or total higher-order RMS

values over all pupil diameters (Table 3.7).

There were no statistically significant differences between the individual Zernike

coefficients for the more and less myopic groups before or after reading. The mean

change in the individual Zernike coefficients following the reading task are

displayed in Table 3.8. The less myopic eyes had slightly larger negative shifts in

Zernike terms C(3,-3) trefoil along 30, C(3,-1) primary vertical coma and C(4,0)

spherical aberration following the reading task compared to the more myopic eyes

Chapter 3

173

(for 4 and 6 mm pupil diameters). However, these interocular differences did not

reach statistical significance.

In Chapter 2 we observed slightly larger average pupil diameters in the more

myopic eyes compared to fellow eyes during primary gaze in photopic conditions

(3.53 ± 0.53 and 3.48 ± 0.57 mm respectively) which approached statistical

significance (p = 0.09). Prior to the reading task the average mesopic pupil

diameter was 6.15 ± 0.67 and 6.08 ± 0.74 mm for the more and less myopic eyes

respectively, as measured by the pupil detection software within the COAS. For

post-reading task measurements, the average pupil size was slightly larger for the

less myopic eyes (6.15 ± 0.68 mm) compared to the more myopic eyes (6.07 ± 0.71

mm). These interocular differences in mesopic pupil size did not reach statistical

significance for pre (p = 0.34) or post-reading task (p = 0.18) measurements.

Dominant eyes had slightly larger mesopic pupil diameters compared to non-

dominant eyes before (6.18 ± 0.68 and 6.05 ± 0.73 mm) and after the reading task

(6.14 ± 0.64 and 6.09 ± 0.74 mm), however these interocular differences did not

reach statistical significance.

Since pupil size may also influence retinal image quality, analysis of total

aberrations was also conducted using the natural pupil size of each subject in

addition to the fixed pupil size analysis. There were no significant differences

between the more and less myopic eyes, or the dominant and non-dominant eyes

Chapter 3

174

Table 3.6: Total monochromatic aberrations (RMS values) before and after reading for the more and less myopic eyes (various pupil diameters).

3rd Order aberration

Mean RMS ± SD (microns) 4th Order aberration

Mean RMS ± SD (microns) Total HOA

Mean RMS ± SD (microns)

Pupil Task More Less p More Less p More Less p

4 mm (n = 31)

Pre 0.045 ± 0.021 0.048 ± 0.028 0.56 0.019 ± 0.009 0.020 ± 0.009 0.26 0.115 ± 0.048 0.121 ± 0.052 0.49

Post 0.043 ± 0.023 0.045 ± 0.030 0.58 0.020 ± 0.009 0.019 ± 0.009 0.76 0.115 ± 0.037 0.121 ± 0.053 0.39

5 mm (n = 30)

Pre 0.082 ± 0.047 0.090 ± 0.070 0.39 0.077 ± 0.038 0.087 ± 0.060 0.28 0.206 ± 0.079 0.224 ± 0.112 0.30

Post 0.044 ± 0.017 0.048 ± 0.040 0.55 0.043 ± 0.016 0.042 ± 0.018 0.88 0.222 ± 0.082 0.244 ± 0.164 0.42

6 mm (n = 19)

Pre 0.105 ± 0.047 0.107 ± 0.055 0.93 0.083 ± 0.038 0.087 ± 0.035 0.50 0.313 ± 0.085 0.328 ± 0.113 0.55

Post 0.099 ± 0.043 0.099 ± 0.065 0.98 0.097 ± 0.042 0.084 ± 0.044 0.01* 0.313 ± 0.075 0.299 ± 0.121 0.57

Natural pupils

(n = 31)

Pre 0.136 ± 0.070 0.142 ± 0.076 0.68 0.096 ± 0.046 0.100 ± 0.070 0.59 0.389 ± 0.148 0.415 ± 0.212 0.46

Post 0.143 ± 0.071 0.150 ± 0.098 0.72 0.098 ± 0.054 0.100 ± 0.056 0.82 0.414 ± 0.174 0.429 ± 0.199 0.72

p - p value for paired t-test (more v less myopic eyes)

Table 3.7: Total monochromatic aberrations (RMS values) before and after reading for the dominant and non-dominant eyes (various pupil diameters).

3rd Order aberration

Mean RMS ± SD (microns) 4th Order aberration

Mean RMS ± SD (microns) Total HOA

Mean RMS ± SD (microns)

Pupil Task Dominant Non-dominant p Dominant Non-dominant p Dominant Non-dominant p

4 mm (n = 31)

Pre 0.044 ± 0.022 0.047 ± 0.027 0.39 0.019 ± 0.007 0.021 ± 0.009 0.28 0.114 ± 0.049 0.119 ± 0.049 0.45

Post 0.048 ± 0.028 0.042 ± 0.025 0.29 0.020 ± 0.010 0.021 ± 0.007 0.81 0.121 ± 0.052 0.115 ± 0.042 0.75

5 mm (n = 30)

Pre 0.080 ± 0.045 0.084 ± 0.055 0.59 0.040 ± 0.015 0.045 ± 0.019 0.08 0.209 ± 0.091 0.221 ± 0.103 0.47

Post 0.092 ± 0.066 0.080 ± 0.052 0.22 0.049 ± 0.041 0.043 ± 0.015 0.36 0.247 ± 0.159 0.218 ± 0.090 0.30

6 mm (n = 19)

Pre 0.111 ± 0.052 0.101 ± 0.049 0.41 0.083 ± 0.036 0.087 ± 0.038 0.51 0.321 ± 0.100 0.322 ± 0.101 0.95

Post 0.109 ± 0.058 0.090 ± 0.051 0.18 0.095 ± 0.045 0.086 ± 0.041 0.08 0.322 ± 0.106 0.290 ± 0.093 0.21

Natural pupils

(n = 31)

Pre 0.137 ± 0.063 0.141 ± 0.082 0.79 0.096 ± 0.053 0.101 ± 0.066 0.58 0.392 ± 0.146 0.412 ± 0.214 0.58

Post 0.156 ± 0.097 0.137 ± 0.071 0.27 0.104 ± 0.058 0.093 ± 0.051 0.24 0.439 ± 0.200 0.404 ± 0.171 0.40

p - p value for paired t-test (dominant v non-dominant eyes)

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175

Table 3.8: Mean change in total monochromatic aberrations (individual Zernike

term coefficients) following reading for the more and less myopic eyes (4, 5 and 6

mm pupil diameters).

More myopic eyes (Mean change ± SD) (microns) Less myopic eyes (Mean change ± SD) (microns)

C 4 mm 5 mm 6 mm 4 mm 5 mm 6 mm

(2,-2) 0.002 ± 0.083 0.024 ± 0.121 0.026 ± 0.155 0.025 ± 0.088 0.026 ± 0.111 0.021 ± 0.092

(2,0) 0.036 ± 0.176 -0.001 ± 0.209 0.034 ± 0.228 0.062 ± 0.169 0.093 ± 0.297 0.127 ± 0.414

(2,2) 0.018 ± 0.088 0.040 ± 0.131 0.025 ± 0.174 0.011 ± 0.093 -0.006 ± 0.152 0.018 ± 0.122

(3,-3) 0.002 ± 0.029 0.002 ± 0.051 0.012 ± 0.039 0.013 ± 0.036* 0.010 ± 0.059 0.028 ± 0.068

(3,-1) -0.006 ± 0.033 -0.009 ± 0.062 -0.018 ± 0.047 -0.014 ± 0.053 -0.005 ± 0.109 -0.032 ± 0.059*

(3,1) -0.002 ± 0.021 -0.004 ± 0.027 0.003 ± 0.028 0.002 ± 0.015 0.000 ± 0.015 0.005 ± 0.017

(3,3) -0.003 ± 0.024 -0.011 ± 0.042 -0.020 ± 0.057 -0.005 ± 0.033 -0.009 ± 0.057 -0.017 ± 0.042

(4,-4) 0.001 ± 0.014 -0.002 ± 0.020 0.002 ± 0.018 0.003 ± 0.012 0.000 ± 0.020 -0.006 ± 0.022

(4,-2) -0.002 ± 0.010 -0.002 ± 0.015 -0.002 ± 0.014 0.000 ± 0.012 -0.001 ± 0.021 -0.002 ± 0.016

(4,0) 0.002 ± 0.014 -0.003 ± 0.026 0.001 ± 0.027 -0.003 ± 0.020 0.007 ± 0.055 -0.012 ± 0.049

(4,2) -0.006 ± 0.016 -0.002 ± 0.025 -0.011 ± 0.026*^ -0.002 ± 0.024 -0.018 ± 0.067 0.012 ± 0.059

(4,4) -0.001 ± 0.013 -0.004 ± 0.024 0.005 ± 0.022 0.001 ± 0.021 0.009 ± 0.062 -0.003 ± 0.036

* significant change following reading (p < 0.05)

^ significant difference between more and less myopic eyes (p < 0.05)

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176

for any of the individual Zernike coefficients up to the 4th order before or after the

reading task (except for C(2,0)) or 3rd, 4th or total higher-order RMS values over

natural pupil diameters.


Overall, the more and less myopic eyes and the dominant and non-dominant eyes

of myopic anisometropes, displayed a high degree of interocular symmetry before

and after a short reading task. There was no significant change in axial length

following a short reading task in the more or less myopic eyes or the dominant and

non-dominant sighting eyes of our anisometropic subjects. Previous studies have

reported a significant increase in axial length during accommodation in both

myopes and emmetropes, which increases proportionately with the

accommodation demand (Drexler et al 1998, Mallen et al 2006, Read et al 2010b).

Our protocol measured the change in axial length following near work rather than

during active accommodation. In contrast to our findings, Woodman et al (2011)

reported axial elongation in both myopes (0.020 ± 0.020 mm) and emmetropes

(0.010 ± 0.015 mm) following a 30 minute reading task (5 D accommodation

demand). Given that both studies used the IOLMaster to measure changes in axial

length, the difference between our results is most likely due to the differences in

accommodation demand and task duration between protocols (2.5 D and 10

minutes duration in our study). While a longer duration near task or a higher

accommodation demand would have resulted in larger changes in axial length, the

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177

primary goal of this experiment was to examine the between eye symmetry of

ocular changes induced during near work.

Drexler et al (1998) observed symmetrical axial length elongation between the

fellow eyes of isometropic subjects during accommodation. Although we did not

observe a significant change in axial length following reading in our subjects, this

does not rule out the involvement of axial elongation during accommodation in the

development of anisometropia. Axial length changes may be significantly larger, or

potentially differ between fellow eyes with longer periods of near work at higher

levels of accommodation.

The magnitude of corneal refractive change and regression time following near

work is affected by; the type (Collins et al 2006a) and duration of the task (Buehren

et al 2003, Collins et al 2005), the angle of downward gaze (Shaw et al 2008) and

the amount of horizontal eye movements (Buehren et al 2003, Collins et al 2006b).

In our study we controlled these variables between subjects by employing a chin

and head rest to limit head movements and maintain the angle of downward gaze.

The number of horizontal eye movements may have differed between subjects (i.e.

different reading speeds between subjects); however, as our analysis investigated

the interocular symmetry of corneal changes, we assumed an equal amount of

horizontal eye movements between the fellow eyes of individuals due to the yoked

nature of the extraocular muscles. We chose a specific duration for the near work

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178

task (10 minutes) based on the work of Collins et al (2005), who reported that the

corneal changes following ten minutes of near work can take up to 30 minutes to

regress. While a longer duration near task would produce larger changes in corneal

and total aberrations, we were interested to examine the interocular symmetry in

the changes in the more and less myopic eyes of our anisometropic cohort.

We observed small changes in corneal refractive power and aberrations following a

short reading task. The magnitude of these changes correlated weakly with certain

aspects of upper eyelid position and vertical palpebral aperture size during

downward gaze, with smaller apertures resulting in a larger hyperopic shift in

average corneal power. Buehren et al (2005) also observed that subjects with

smaller palpebral apertures during reading had significantly higher increases in

corneal aberrations compared to subjects with wider apertures. Shaw et al (2008)

reported a significant correlation between the change in corneal vector J45

following a fifteen minute reading task (40 degree downward gaze) with the angle

of tilt of the lower eyelid in downward gaze. We did not observe a similar

relationship in our study potentially due to a shorter duration reading task (ten

minutes) and a lesser angle of downward gaze (25 degrees). Weak but statistically

significant correlations were observed between the magnitude of astigmatic

corneal change following reading and measures of corneal biomechanics (CRF and

CH). This is interesting since corneal changes due to eyelid pressure are probably

limited to the superficial layers of the corneal epithelium (Buehren et al 2003),

whereas the Ocular Response Analyzer is thought to provide a measure of stromal

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179

corneal biomechanics (Luce 2005). These findings suggest a possible association

between eyelid induced epithelial changes and the stroma (i.e. epithelial cells which

are not as strongly adhered to the stroma are more susceptible to deformation

resulting in refractive changes as a result of eyelid pressure).

In addition to eyelid morphology (examined in Chapter 2) and corneal biomechanics

discussed in this chapter, the magnitude and distribution of the pressure exerted

upon the cornea by the eyelids may also contribute to changes in corneal curvature

and optics following reading. Unilateral eyelid malformations have been associated

with significant changes in astigmatism which diminish when the cause is removed

(Nisted and Hofstetter 1974). Although the measurement of eyelid pressure was

beyond the scope of this experiment, future research examining the magnitude of

eyelid pressure in anisometropic subjects or different ethnic groups (during primary

and downward gaze) may provide further information on the relationship between

the eyelids, cornea and myopia development.

There was a strong correlation between the magnitude of change in corneal

aberrations vertical trefoil C(3,-3) and vertical coma C(3,-1) following reading. This

change in the corneal wavefront has been described previously as a wave-like

distortion and is thought to be associated with the effect of pressure from the

upper eyelid during downward gaze (Buehren et al 2003). This correlation was

evident in both the more and less myopic eyes.

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180

On average, the corneal refractive changes we observed following reading were not

statistically different between the fellow eyes. Although the magnitude of corneal

change would no doubt increase with a longer duration reading task, or increased

angle of downward gaze, the interocular symmetry would most probably remain

constant due to the high degree of interocular symmetry in anterior eye

morphology and corneal biomechanics we observed in our subjects (discussed in

Chapter 2).

To our knowledge, this is the first study to examine the interocular symmetry of

total monochromatic aberrations in a cohort of anisometropes before and after a

short period of near work. The interocular symmetry of total aberrations prior to

the reading task has been described in the previous chapter.

Following ten minutes of reading, the change in higher-order aberrations was

relatively small and symmetrical between the more and less myopic eyes and also

the dominant and non-dominant sighting eyes. Third, fourth and total higher-order

RMS values typically decreased following reading which differs from the findings of

Buehren et al (2005) who observed increases in RMS values following 1 and 2 hours

of reading in myopes and emmetropes. Over a 6 mm pupil diameter, the mean

fourth order RMS value increased in the more myopic eyes following the near task

and was significantly higher compared to the less myopic eyes. Examination of the

changes in individual Zernike terms between the more and less myopic eyes

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181

revealed no consistent trends. The less myopic eyes exhibited larger shifts in some

third order (trefoil and vertical coma) and fourth order terms (spherical aberration)

compared to the more myopic eyes, but these differences were small in magnitude

and did not reach statistical significance.

Several studies have reported higher levels of aberrations in myopes compared to

emmetropes during or following accommodation, suggesting that retinal image blur

during near work may be linked to myopia development (Buehren et al 2003,

Buehren et al 2005, Buehren et al 2007). If higher-order aberrations influence

myopia development, we would expect higher levels of aberrations in the more

myopic eyes of anisometropes. However, previous studies of anisometropic eyes

during distance fixation have found little difference in aberrations between fellow

eyes, or lower levels in the more myopic eyes (Tian et al 2006, Kwan et al 2009).

Similarly, our findings suggest that following a short period of near work, the more

and less myopic eyes of myopic anisometropes exhibit similar levels of higher-order

aberrations. These findings do not support the hypothesis that increased

aberrations following near work (of short duration and relatively low

accommodation demand) play a role in myopia development. However, the

interocular symmetry of monochromatic aberrations may differ following longer

periods of near work requiring higher levels of accommodation. The interocular

symmetry in ocular optics during reading may also differ during reading. During

distance fixation, the magnitude of higher-order RMS was greater in the more

myopic eyes, but this difference did not reach statistical significance. A high degree

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of symmetry in Zernike wavefront coefficients was observed between the more and

less myopic eyes before and after the reading task.


The biometric and optical characteristics of anisometropic eyes displayed a high

degree of interocular symmetry before and after a short period of near work. The

findings from our study do not support a mechanical or retinal image mediated

mechanism during near work in the development of myopic anisometropia.

However, we cannot rule out the possibility that longer periods of near work, or

tasks requiring higher levels of accommodation may contribute to asymmetric

refractive error development through a mechanical or optically mediated

mechanism. The interocular symmetry of the accommodative response in myopic

anisometropes requires further investigation.

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In the studies described in Chapters 2 and 3 we observed a high degree of

interocular symmetry between the fellow eyes of myopic anisometropes for a

range of optical and biometric measurements during distance fixation and following

a short reading task. Since the influence of near work on eye growth is likely to be

most obvious during, rather than following near tasks, in this chapter, we describe

an investigation of the interocular symmetry of the biometric and optical changes

during accommodation in myopic anisometropia.

Near work has previously been found to be associated with myopia development;

however the underlying mechanism remains unclear. It is thought that the

hyperopic defocus associated with a lag of accommodation may be an optical factor

that promotes axial elongation in humans (Gwiazda et al 2004). The forces exerted

by the ciliary body during accommodation have also been proposed as a potential

mechanical mechanism of myopia development (Greene 1980, Bayramlar et al

1999). When near work is performed the eyes typically converge and

accommodate in order to maintain clear, single binocular vision. This results in a

number of ocular biometric and optical changes which lead to an increase in the

refractive power of the eye. During accommodation there is a steeping in curvature

of the anterior and posterior crystalline lens surfaces, an increase in lens thickness

and a concomitant decrease in anterior chamber depth (Drexler et al 1997, Bolz et

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al 2007). The magnitudes of these anterior biometric changes are directly

proportional to the accommodative demand.

Optical changes associated with accommodation not only include an increase in

total ocular refractive power, but typically also involve a negative shift in spherical

aberration, which is proportional to the accommodative demand (Atchison et al

1995). Higher-order comatic terms also change with accommodation, but the

magnitude and direction of change is less predictable (Cheng et al 2004b). Given

the association between near work and myopia development, numerous studies

have compared the biometric and optical ocular changes during or following

accommodation in different refractive error groups to determine a potential link

between accommodation and axial elongation.

Forces exerted by the extraocular muscles during convergence are thought to have

the potential to lead to changes in axial length (Greene 1980). Bayramlar et al

(1999) concluded that transient axial elongation associated with near work was a

result of convergence rather than accommodation after observing significant

vitreous chamber elongation measured with ultrasound biometry in young subjects


(2009) reported that axial length (measured using partial coherence interferometry)

appears largely unchanged in adults following a period of sustained convergence.

New interferometry techniques have been used to show that accommodation is

associated with small but significant increases in the axial length of the eye (Drexler

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et al 1998, Mallen et al 2006, Read et al 2010b). While the magnitude of axial

elongation appears to be proportional to the accommodative demand, there are

conflicting results regarding the influence of refractive error on these changes.

These studies suggest that accommodation causes transient increases in axial

length which dissipate quickly when accommodation is relaxed (Woodman et al

2011). Such changes in axial length are thought to be a result of the mechanical

effects of the contraction of the ciliary muscle and choroidal tension during

accommodation.

The accommodation response in refractive error groups has been investigated in

detail (Chen et al 2003). Typically, greater lags of accommodation have been

reported in myopes compared to emmetropes and it has been hypothesised that

the hyperopic defocus associated with a lag of accommodation may provide a cue

to eye growth and myopia development. Higher-order aberrations, which may

potentially degrade retinal image quality or induce hyperopic defocus, may also

influence eye growth. Although the unaccommodated eyes of myopes and

emmetropes exhibit similar levels of aberrations (He et al 2002), during or following

near work myopes tend to have higher levels of aberrations in comparison to their

emmetropic counterparts (Buehren et al 2003, Buehren et al 2005, Buehren et al

2006).

The refractive condition of anisometropia may present a unique opportunity to

minimize the influence of confounding factors such as age, gender and

environmental factors in the study of accommodation. In an early study, Hosaka et

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al (1971) measured the monocular amplitude of accommodation in a large cohort

of anisometropes (interocular difference ≥ 1.00 D) including some amblyopes. Of

the subjects with an interocular difference in accommodation greater than 0.5 D,

the amplitude of accommodation was reduced in the more myopic eye 70% of the

time. However there was no significant correlation between the interocular

difference in accommodative amplitude and the magnitude of anisometropia.

More recently, Xu et al (2009) used an infrared optometer to measure the

interocular symmetry of the accommodative response in twenty anisometropes

with 2.50 - 7.00 D of spherical anisometropia at a range of accommodative

demands up to 4 D. The more myopic eyes exhibited a larger accommodative lag

compared to the less myopic eyes for accommodation demands of 2, 3, and 4 D,

however, these differences did not reach statistical significance. To our knowledge

these are the only previous studies to directly examine the interocular symmetry of

accommodation in anisometropia. This may be due to previous research which has

shown a symmetric accommodative response between the eyes of normal subjects

during monocular (Ball 1952) and binocular (Campbell 1960) viewing. Furthermore,

no studies have examined the interocular symmetry of changes in biometrics or

higher-order aberrations during accommodation in myopic anisometropes.

Given the potential confounding factors associated with cohort studies (such as the

inter-subject variations in genetic and environmental factors) and the limited

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research in this area, we examined the interocular symmetry of the optical and

mechanical changes during accommodation in a small group of myopic

anisometropes.



Eleven young, healthy adult subjects aged between 18 and 32 years (mean age 24 ±

4 years) with a minimum of 1.00 D of spherical-equivalent myopic anisometropia

were recruited for this study. The subjects were primarily recruited from the staff

and students of QUT (Queensland University of Technology, Brisbane, Australia).

Six of these subjects participated in the experiments conducted in Chapters 2 and 3.

Nine of the 11 subjects were female and 8 of the subjects were of Asian descent,

with the remaining 3 subjects of Caucasian ethnicity.


subjective refraction, binocular vision and ocular health status. Ocular sighting

dominance was assessed using a forced choice method (a modification of the hole-

in-the-card test) (described in Chapter 2). The swinging plus test was also used to

assess dominance. While binocularly viewing a row of letters (6/12 at 6 m) with

best sphero-cylindrical correction, a +2.00 D lens was alternated between the right

and left eye. The preferred binocular view was noted for each subject and the

dominant sighting eye was recorded as the ‘non-blurred’ eye. Monocular

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amplitude of accommodation was assessed using the push up test, and all subjects

exhibited more than 7 D of accommodation in each eye. All subjects were free of

ocular or systemic disease and had no history of ocular surgery or trauma. In

addition, subjects with visual acuity worse than 0.10 logMAR, strabismus, unequal

visual acuities (interocular difference of greater than 0.10 logMAR) or a history of

rigid contact lens wear were excluded from the study. Four soft contact lens

wearers were included in the study, but ceased contact lens wear for 36 hours prior

to participation. Approval from the QUT human research ethics committee was

obtained before commencement of the study and subjects gave written informed

consent to participate (Appendix 1). All subjects were treated in accordance with

the tenets of the declaration of Helsinki.


Following the screening procedure, biometric and optical measurements were

taken during three different levels of accommodation for each eye (0, 2.5 and 5 D,

in that order). The order of testing was randomised so that half of the subjects had

the more myopic eye measured first. All measurements were collected through the

subjects’ natural pupils without pharmacological dilation, and the room illumination

was kept at a mesopic range to maximize pupil size. During measurements the eye

not being measured was occluded with a patch. Between each measurement,

subjects maintained distance fixation for two minutes as per the protocol employed

by Read et al (2010b).

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Ocular biometrics were measured using the Lenstar LS 900 instrument (Haag Streit

AG, Koeniz, Switzerland). This instrument is a reliable and highly precise

noncontact optical biometer (Buckhurst et al 2009) based on the principle of low

coherence reflectometry that provides a range of axial biometric measurements

including; central corneal thickness (CCT, distance from the anterior to posterior

cornea), anterior chamber depth (ACD, distance from the posterior cornea to

anterior lens), lens thickness (LT, distance from the anterior lens to posterior lens)

and axial length (AXL, distance from the anterior cornea to the retinal pigment

epithelium) simultaneously. The anterior segment length (ASL, distance from the

anterior corneal surface to the posterior lens surface) and the vitreous chamber

depth (VCD, distance from the posterior lens surface to the retinal pigment

epithelium) can also be calculated from the Lenstar data. Five repeated biometric

measurements were performed on each eye of all subjects for the three different

levels of accommodative stimuli. While in previous chapters we have used the

IOLMaster to measure axial length, in this experiment, we used the Lenstar in order

to obtain additional biometric measures such as LT during accommodation, which

are not provided by the IOLMaster.

The total ocular aberrations of each eye were also measured at the three levels of

accommodation using a Complete Ophthalmic Analysis System (COAS) wavefront

aberrometer (Wavefront Sciences, New Mexico, USA). One hundred wavefront

measurements (4 x 25 frames) were taken for each eye at each session. The

wavefront data was fitted with an 8th order Zernike expansion and exported for

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further analysis. Using customised software, the 100 wavefront measurements

were rescaled to set pupil diameters of 3 mm using the method of Schwiegerling

(2002) and then the Zernike polynomials were averaged.

To allow measurements to be performed while subjects were accommodating at

various levels, we used an experimental system consisting of a back illuminated

high-contrast target (N8 print, luminance 237 cd/m2) viewed through a pellicle

beamsplitter (92% transmittance) and a 12 D Badal lens mounted in front of the

Lenstar or COAS (Figure 4.1). Astigmatic refractive errors greater than 0.5 D were

corrected using an auxiliary cylindrical lens placed between the Badal lens and the

moveable target, correcting for vertex distance. Before measurements were

performed care was taken to align a letter at the centre of the target as viewed

through the beamsplitter to be coincident with the instrument’s measurement

beam. Subjects were instructed to keep the target in sharp focus throughout the

measurement procedures. Lenstar measurements were taken first, followed by

COAS measurements.

Prior to data collection we confirmed that the introduction of the beamsplitter in

front of the Lenstar did not result in significant changes in biometric measurements

on a model eye and the right eye of five human subjects. The mean CCT (533 ± 13

μm without and 535 ± 12 μm with beamsplitter), ACD (3.06 ± 0.37 mm without and

3.06 ± 0.37 mm with beamsplitter), LT (3.68 ± 0.15 mm without and 3.67 ± 0.16 mm

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Figure 4.1: Diagram of the experimental setup to allow measurement of ocular

biometrics or ocular aberrations during accommodation.

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with beamsplitter) and AXL (24.26 ± 0.87 mm without and 24.26 ± 0.87 mm with

beamsplitter) showed no statistically significant change when measurements were

taken through the beamsplitter.

Prior to measurements involving accommodation, we captured cross sectional

chorio-retinal images of both eyes of each subject using the SOCT Copernicus HR

(Optopol, Zawiercie, Poland) (a static measurement without an accommodation

task). This instrument is a spectral domain optical coherence tomographer (OCT)

that uses a super luminescent diode (wavelength 850 nm) to obtain 3D cross

sectional images of the retina. The instrument has an axial resolution of 3 microns,

transverse resolution of 12-18 μm and a scanning speed of 52,000 A-scans per

second. We used the ‘animation’ scan; a 5 mm horizontal raster scan comprising of

50 B-scans (with each B-scans consisting of 1200 A-scans) centred on the fovea.

Four images were captured for each eye.

44..22..33 DDaattaa aannaallyyssiiss

Like the IOLMaster used in previous chapters, the Lenstar also uses an average

ocular refractive index to convert optical length to geometric length in axial length

calculations. Because the eye’s average refractive index increases during

accommodation as lens thickness increases, axial length measurements obtained

during accommodation may overestimate the true axial length (Atchison and Smith,

2004). We have used the technique described by Atchison and Smith (2004) (using

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the Gullstrand no 3 model eye shell lens) to calculate the potential error associated

with the axial length measurements obtained during the 2.5 and 5 D

accommodation tasks. We used the formula Error = OPLa/nave - Lu, where OPLa

represents the optical path length of the accommodated eye, nave is the average

refractive index of the unaccommodated eye and Lu is the geometric length of the

unaccommodated eye. The optical path lengths used in the equation to calculate

the errors were calculated using the biometric measures from each subject’s

individual Lenstar measurements. The potential error was used to calculate a

corrected axial length measurement for each subject.

Custom written software was used to improve the signal to noise ratio of OCT

images and measure the retinal and choroidal thickness at the fovea in each eye

(Alonso-Caneiro et al 2011) (Figure 4.2). In brief, the inner limiting membrane (ILM)

was detected in each individual B-Scan. The foveal pit of the inner limiting

membrane was used as a reference point to align the 50 B-scans within each

animation scan. After the automated removal of outlying individual B-Scans, eight

points were manually selected to fit a function to the curve of both the posterior

edge of the retinal pigment epithelium (RPE) and the choroidal/scleral interface.

The distance between the ILM and the RPE (retinal thickness) and the RPE and the

choroid (choroidal thickness) was then automatically calculated along a vertical line

through the centre of the fovea. Of the four images captured for each eye, the

image which gave the best visualisation of the choroid-sclera interface was used for

analysis. OCT images were analysed by two experienced independent masked

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1. 50 B-scans averaged 2. Outliers filtered

3. Automated ILM, manual RPE 4. Contrast enhanced

5. Manual choroid 6. Automated biometry through fovea

Figure 4.2: Flow chart of the procedure used to improve the signal to noise ratio of

OCT images and measure the retinal and choroidal thickness at the fovea in each

eye. ILM - inner limiting membrane, RPE - retinal pigment epithelium.

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observers. The results from each observer for the retinal and choroidal thickness

were used to calculate the mean measurement.


For each of the ocular parameters examined during accommodation we conducted

a repeated measures analysis of variance using a within-subjects factor (level of

accommodation) and a between subjects factor (more or less myopic eye) to

examine changes with accommodation and between the more and less myopic

eyes. Paired t-tests were used to assess the between eye differences in retinal and

choroidal thickness between the fellow eyes derived from the OCT measurements

collected with relaxed accommodation. Pearson’s correlation coefficient was used

to calculate the degree and statistical significance of associations where

appropriate.


The subject’s mean spherical equivalent refraction was -4.31 1.91 D for the more

myopic eye and -2.84 ± 1.76 D for the less myopic eye. The mean spherical

equivalent anisometropia was 1.47 ± 0.50 D and the mean interocular difference in

axial length was 0.52 ± 0.13 mm.

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44..33..11..11 BBiioommeettrriiccss

All anterior segment biometrics (CCT, ACD, LT and ASL) were not significantly

different between the more and less myopic eyes at any level of accommodation (p

> 0.05) (Table 4.1). There were no significant correlations between the interocular

difference in any of the measures of the anterior segment and the magnitude of

anisometropia at any level of accommodation (p > 0.05). VCD and AXL were

significantly larger in the more myopic eyes compared to the less myopic eyes at all

levels of accommodation. There was a significant correlation between the

magnitude of spherical equivalent anisometropia and the interocular difference in

VCD (r = 0.77, p = 0.006) and AXL (r = 0.82, p = 0.002) (0 D accommodation level).

Accommodation resulted in significant changes in the majority of ocular parameters

measured using the Lenstar. Table 4.1 displays the mean biometric parameters for

the more and less myopic eyes at three different accommodation levels. Excluding

CCT, all anterior segment biometrics showed significant changes with

accommodation. During accommodation, an increase in LT was accompanied with

a decrease in ACD and increase in ASL (p < 0.001).

For the 2.5 D stimulus, there was a mean increase in lens thickness of 0.12 ± 0.06

mm and 0.12 ± 0.04 mm for the more and less myopic eyes respectively. For the 5

D stimulus, there was mean increase in lens thickness of 0.33 ± 0.06 mm (more

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Table 4.1: Mean biometric parameters from the Lenstar for the more and less

myopic eyes during three levels of accommodation.

Biometric parameter (mm) P-value

Eye 0 D 2.5 D 5.0 D Accomm Accomm *

Eye Eye

CCT More 0.528 ± 0.030 0.528 ± 0.030 0.528 ± 0.030

0.47 0.17 0.95 Less 0.528 ± 0.028 0.527 ± 0.028 0.527 ± 0.028

ACD More 3.38 ± 0.31 3.28 ± 0.31 3.12 ± 0.27

< 0.001 0.39 0.94 Less 3.36 ± 0.32 3.26 ± 0.32 3.12 ± 0.32

LT More 3.46 ± 0.23 3.58 ± 0.24 3.79 ± 0.24

< 0.001 0.12 0.95 Less 3.48 ± 0.23 3.60 ± 0.23 3.77 ± 0.25

ASL More 7.37 ± 0.32 7.39 ± 0.29 7.44 ± 0.28

< 0.001 0.35 0.95 Less 7.37 ± 0.33 7.39 ± 0.32 7.41 ± 0.34

VCD More 17.77 ± 0.59 17.77 ± 0.60 17.73 ± 0.61

0.05 0.53 0.06 Less 17.25 ± 0.60 17.24 ± 0.61 17.22 ± 0.62

AXL measured More 25.14 ± 0.64 25.16 ± 0.65 25.17 ± 0.65

< 0.001 0.70 0.07 Less 24.62 ± 0.65 24.63 ± 0.64 24.64 ± 0.64

AXL corrected More 25.14 ± 0.64 25.15 ± 0.65 25.15 ± 0.66

0.02 0.87 0.07 Less 24.62 ± 0.65 24.63 ± 0.64 24.63 ± 0.64

CCT – central corneal thickness, ACD – anterior chamber depth, LT – lens thickness,

ASL – anterior segment length, VCD – vitreous chamber depth, AXL– axial length,

More - more myopic eyes, Less - less myopic eyes. p-values from repeated

measures ANOVA for within subjects effect of accommodation (Accomm) and

‘between subjects’ group of more or less myopic eye (Eye).

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myopic) and 0.29 ± 0.05 mm (less myopic). The increase in LT also resulted in a

significant decrease in ACD and a significant increase in ASL during accommodation

(p < 0.001). For the 2.5 D stimulus there was a mean decrease in ACD of 0.11 ± 0.14

mm and 0.10 ± 0.03 mm for the more and less myopic eyes respectively. For the 5

D stimulus, the mean decrease was 0.26 ± 0.08 mm (more myopic) and 0.24 ± 0.02

mm (less myopic). The mean increase in ASL was 0.02 ± 0.04 mm (more myopic)

and 0.02 ± 0.03 mm (less myopic) for 2.5 D stimulus and 0.07 ± 0.07 mm (more

myopic) and 0.04 ± 0.06 mm (less myopic) for the 5 D stimulus. The magnitude of

these biometric changes was similar between the fellow eyes for both levels of

accommodation (p > 0.05).

Axial length underwent a small but statistically significant increase with

accommodation (p < 0.001 and p = 0.02 for the measured and corrected axial

lengths respectively). Post-hoc analysis (paired t-tests) for the measured and

corrected axial lengths revealed that the more myopic eyes underwent significant

elongation at both the 2.5 D (p = 0.001) and 5.0 D stimuli (p < 0.001). However, for

the less myopic eyes the magnitude of axial elongation only reached statistical

significance at the 5 D stimuli (p < 0.01). Figures 4.3 and 4.4 display the mean

change in axial length for the more and less myopic eyes for the measured and

corrected axial lengths respectively. The more myopic eyes underwent a mean

increase in measured axial length of 18 ± 13 μm and 30 ± 19 μm for the 2.5 and 5 D

stimulus respectively compared to 15 ± 30 μm (2.5 D) and 26 ± 29 μm (5 D) for the

less myopic eyes. A similar trend was observed for the corrected axial length. The

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more myopic eyes displayed a mean increase of 13 ± 13 μm for the 2.5 D stimulus

and 15 ± 18 μm for the 5 D stimulus compared to 10 ± 30 μm (2.5 D) and 13 ± 30

μm (5.0 D) for the less myopic eyes. Although more myopic eyes displayed greater

levels of axial elongation during accommodation for both the 2.5 and 5 D stimuli

(for both the measured and corrected axial length) this interocular difference did

not reach statistical significance (p > 0.05). The sighting dominant eyes displayed

greater axial elongation during accommodation compared to the non-dominant

eyes during both levels of accommodation (corrected axial length measure:

dominant: 17 ± 17 μm (2.5 D) and 19 ±23 μm (5.0 D), non-dominant: 6 ± 27 μm (2.5

D) and 8 ± 25 μm (5.0 D)), however as for the more and less myopic eyes these

interocular differences did not reach statistical significance (p > 0.05). The

magnitude of axial elongation during both levels of accommodation was also similar

between high (> 1.75 D) and low (≤ 1.75 D) anisometropes.

The sighting dominant eyes displayed greater axial elongation during

accommodation compared to the non-dominant eyes during both levels of

accommodation (corrected axial length measure: dominant: 17 ± 17 μm (2.5 D) and

19 ±23 μm (5.0 D), non-dominant: 6 ± 27 μm (2.5 D) and 8 ± 25 μm (5.0 D)),

however as for the more and less myopic eyes these interocular differences did not

reach statistical significance (p > 0.05). The magnitude of axial elongation during

both levels of accommodation was also similar between high (> 1.75 D) and low (≤

1.75 D) anisometropes.

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Figure 4.3: Mean change in measured axial length during accommodation for the

more and less myopic eyes. Error bars represent the standard error of the mean.

* statistically significant change from 0 D stimulus (p < 0.05).

Figure 4.4: Mean change in corrected axial length during accommodation for the

more and less myopic eyes. Error bars represent the standard error of the mean.

* statistically significant change from 0 D stimulus (p < 0.05).

*

* *

*

* *

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Estimates of retinal and choroidal thickness from the two independent observers

correlated closely with correlation coefficients of 0.95 for retinal thickness and 0.94

for choroidal thickness. The mean retinal thickness was not significantly different

between the more (210 ± 13 μm) and less myopic (208 ± 12 μm) eyes (p = 0.29).

However, the interocular difference in choroidal thickness approached statistical

significance (p = 0.06). The mean choroidal thickness of the more myopic eyes was

slightly thinner (283 ± 38 μm) compared to the less myopic eyes (314 ± 31 μm).

No significant correlations were observed between the spherical equivalent

refractive error or axial length and choroidal thickness for the more (SEq: r = 0.29,

AXL: r = -0.43) and less myopic eyes (SEq: 0.29, AXL: -0.15) (p > 0.05). However, the

interocular difference in choroidal thickness (more minus less myopic eye) showed

a moderate correlation with both the interocular difference in axial length (r = -

0.57, p = 0.07) and the magnitude of spherical equivalent anisometropia (r = 0.61, p

= 0.05) (Figures 4.5 and 4.6).

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Figure 4.5: Correlation between the interocular difference in axial length (mm) and

the interocular difference in choroidal thickness (microns). Interocular difference

calculated as the more minus the less myopic eye.

Figure 4.6: Correlation between spherical equivalent anisometropia (D) and the

interocular difference in choroidal thickness (microns). Interocular difference and

anisometropia calculated as the more minus the less myopic eye.

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We analysed the total ocular aberrations with both the natural pupil size and a

fixed pupil diameter of 3 mm. We have restricted our analysis to third and fourth

order terms as they are the predominant higher-order aberrations (Wang et al

2003). There were no significant differences between the fellow eyes for natural

pupil diameters (as measured by the COAS) at any level of accommodation (p >

0.05) (Table 4.2). As expected, the spherical component of refraction and

spherocylinder M were significantly different between the more and less myopic

eyes at all levels of accommodation (p < 0.01). There were few interocular

differences in higher-order aberrations between the fellow eyes. For the 0 D

stimulus level there were no significant interocular differences for any third or

fourth order Zernike coefficients. The less myopic eyes displayed higher (more

positive) levels of C(3,1) primary horizontal coma and C(4,2) secondary astigmatism

at all levels of accommodation, which reached statistical significance for the 2.5 D

stimuli (coma; -0.011 ± 0.073 μm more myopic and 0.048 ± 0.087 μm less myopic,

secondary astigmatism; -0.006 ± 0.024 μm more myopic and 0.015 ± 0.027 μm less

myopic)(p < 0.05). Similar trends were observed for the analysis conducted over a 3

mm pupil diameter. The spherical component of refraction and spherocylinder M

were significantly different between the fellow eyes at all levels of accommodation.

Less myopic eyes displayed more positive horizontal coma C(3,1) at all levels of

accommodation compared to the more myopic eyes, which reached statistical

significance for the 2.5 D stimulus (-0.011 ± 0.028 μm more myopic and 0.016 ±

0.033 μm less myopic) (p < 0.05).

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For the natural pupil analysis, pupil diameter decreased significantly with increasing

levels of accommodation for both the more and less myopic eyes (p < 0.001). The

spherical component of refraction and spherocylinder M also underwent a

significant change with increasing levels of accommodation. We have used the

change in the spherical component of refraction to calculate the accommodative

response for each stimulus level. The accommodative response was not

significantly different between fellow eyes at both accommodation levels, with the

more and less myopic eyes exhibiting a small lag of accommodation which was

greatest for the 2.5 D stimulus. For the 2.5 D stimulus the mean accommodative

response was 1.80 ± 0.60 D and 1.64 ± 0.52 D for the more and less myopic eyes

respectively (i.e. a lag of accommodation of 0.70 ± 0.60 D and 0.86 ± 0.52 D for the

more and less myopic eyes) (p > 0.05). For the 5 D stimulus, the mean

accommodative response was 4.74 ± 1.05 D and 4.77 ± 0.74 D for the more and less

myopic eyes respectively (i.e. a lag of accommodation of 0.26 ± 1.05 D and 0.23 ±

0.74 D for the more and less myopic eyes) (p > 0.05).

The mean interocular difference in the accommodative response (more minus less

myopic eye) was -0.16 ± 0.55 D (range -1.15 D lead to 0.84 D lag) for the 2.5 D

stimulus and 0.03 ± 0.71 D (range -0.80 D lead to 1.79 D lag) for the 5 D stimulus.

For each individual subject, the asymmetry in accommodation between the fellow

eyes was similar at both levels of accommodation (r = 0.89, p < 0.001) (Figure 4.7).

There was no significant correlation between the interocular difference in the

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accommodation response and the magnitude of anisometropia for either level of

accommodation (p > 0.05).

Several higher-order aberrations also underwent significant changes during

accommodation. Trefoil along 30˚ C(3,-3)and secondary astigmatism along 45˚ C(4,-

2) increased significantly in the positive direction with increasing levels of

accommodation, while spherical aberration C(4,0) shifted in the negative direction

(Table 4.2, Figure 4.8). Higher-order RMS values also decreased significantly with

accommodation. These changes occurred in both the more and less myopic eyes

and are most likely due to the decrease in pupil size with increasing levels of

accommodation.

For the fixed 3 mm pupil analysis, similar trends were observed for the changes in

spherical component of refraction, M and spherical aberration. However, the

changes observed in C(3,-3) and C(4,-2) for the natural pupil analysis were not

observed over a fixed pupil diameter (Table 4.3). There was an increase observed in

higher-order RMS with increasing levels of accommodation, which may be a result

of the fixed pupil size; however these changes were similar between the fellow

eyes.

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44..33..22 OOccuullaarr ddoommiinnaannccee

The more myopic eye was the dominant sighting eye in seven of the eleven subjects

using the hole-in-the-card test. Sensory dominance was determined in nine

subjects; however two subjects reported no preference during the swinging plus

test. The sensory dominant eye was the more myopic eye in four subjects, and the

less myopic eye in six subjects. For six subjects the sighting and sensory dominant

eye were the same eye (three subjects more myopic, three subjects less myopic),

while for three subjects the sighting and sensory dominant eyes differed.

Based on sighting dominance, there were no statistically significant differences in

the accommodative response between the dominant and non-dominant eyes at

either the 2.5 (dominant 1.73 ± 0.71 D, non-dominant 1.71 ± 0.37 D) or 5 D

accommodation stimuli (dominant 4.68 ± 1.08, non-dominant 4.83 ± 0.68 D) (p >

0.05). For the 5 D accommodation stimuli, four subjects showed a greater

accommodative response with their sighting dominant eye (mean anisometropia

1.84 ± 0.67 D), while seven subjects showed a greater response with their non-

dominant eye (mean anisometropia 1.25 ± 0.20 D). The difference in the

magnitude of anisometropia between these two groups approached statistical

significance (unpaired t-test, p = 0.05). Table 4.4 shows the distribution of subjects

with respect to the magnitude of spherical equivalent anisometropia (high and low

anisometropia as defined in Chapter 2) and the eye which showed the greater

accommodative response for the 5 D accommodation stimuli.

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Table 4.2: Mean ocular parameters from COAS analysis for the more and less myopic eyes during three levels of accommodation (natural pupil

diameter).

Natural pupil analysis Biometric parameter (μm unless labelled otherwise) P-value

Eye 0 D 2.5 D 5.0 D Accommodation Acc * Eye Eye

Pupil diameter (mm) More 5.29 ± 0.81 4.44 ± 0.71 3.76 ± 0.75

0.000 0.35 0.82 Less 5.17 ± 0.54 4.55 ± 0.77 3.95 ± 0.65

Sphere (D) More -3.97 ± 1.62 -5.77 ± 1.94 -8.71 ± 2.36

0.000 0.94 0.12 Less -2.71 ± 1.73 -4.35 ± 1.66 -7.48 ± 2.05

M (D) More -4.51 ± 1.97 -6.37 ± 2.41 -9.40 ± 2.72

0.000 0.90 0.18 Less -3.27 ± 1.90 -4.95 ± 1.89 -8.21 ± 2.27

HO RMS More 0.300 ± 0.127 0.197 ± 0.075 0.207 ± 0.146

0.02 0.63 0.63 Less 0.263 ± 0.109 0.188 ± 0.078 0.200 ± 0.087

C(3,-3) More -0.087 ± 0.086 -0.046 ± 0.052 -0.034 ± 0.064

0.004 0.62 0.38 Less -0.075 ± 0.064 -0.031 ± 0.059 -0.002 ± 0.062

C(3,-1) More -0.013 ± 0.152 0.003 ± 0.109 0.065 ± 0.177

0.77 0.07 0.70 Less 0.043 ± 0.074 -0.025 ± 0.096 -0.014 ± 0.125

C(3,1) More -0.032 ± 0.153 -0.011 ± 0.073 -0.012 ± 0.034

0.49 0.98 0.11 Less 0.014 ± 0.098 0.048 ± 0.087 0.035 ± 0.082

C(3,3) More 0.037 ± 0.058 0.007 ± 0.046 0.012 ± 0.054

0.75 0.12 0.43 Less -0.011 ± 0.063 0.019 ± 0.031 0.006 ± 0.037

C(4,-4) More 0.031 ± 0.040 0.011 ± 0.031 0.016 ± 0.030

0.12 0.88 0.73 Less 0.032 ± 0.040 0.016 ± 0.019 0.021 ± 0.024

C(4,-2) More -0.027 ± 0.028 -0.015 ± 0.021 -0.004 ± 0.021

0.004 0.80 0.11 Less -0.009 ± 0.033 -0.002 ± 0.026 0.011 ± 0.026

C(4,0) More 0.117 ±0.080 0.028 ± 0.042 -0.032 ± 0.053

0.000 0.50 0.36 Less 0.080 ± 0.069 0.022 ± 0.069 -0.042 ± 0.042

C(4,2) More -0.015 ± 0.047 -0.006 ± 0.024 -0.007 ± 0.037

0.61 0.73 0.23 Less 0.003 ± 0.043 0.015 ± 0.027 0.004 ± 0.044

C(4,4) More 0.014 ± 0.055 0.007 ± 0.032 0.003 ± 0.036

0.43 0.54 0.47 Less 0.005 ± 0.050 0.002 ± 0.039 0.004 ± 0.040

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Table 4.3: Mean ocular parameters from COAS analysis for the more and less myopic eyes during three levels of accommodation (3 mm pupil

diameter).

Fixed 3 mm pupils Biometric parameter (μm unless labelled otherwise) P-value

Eye 0 D 2.5 D 5.0 D Accommodation Acc * Eye Eye

Sphere (D) More -3.75 ± 1.58 -5.69 ± 1.96 -8.77 ± 2.32

0.000 0.87 0.11 Less -2.54 ± 1.68 -4.29 ± 1.64 -7.50 ± 2.04

M (D) More -4.28 ± 1.90 -6.31 ± 2.42 -9.48 ± 2.67

0.000 0.87 0.18 Less -3.12 ± 1.85 -4.88 ± 1.86 -8.25 ± 2.26

HO RMS More 0.070 ± 0.037 0.078 ± 0.040 0.117 ± 0.055

0.000 0.85 0.61 Less 0.063 ± 0.029 0.071 ± 0.029 0.107 ± 0.056

C(3,-3) More -0.020 ± 0.029 -0.011 ± 0.021 -0.016 ± 0.048

0.28 0.56 0.16 Less -0.008 ± 0.019 0.001 ± 0.024 0.007 ± 0.031

C(3,-1) More 0.001 ± 0.046 -0.007 ± 0.043 0.006 ± 0.073

0.75 0.44 0.56 Less -0.001 ± 0.031 -0.016 ± 0.033 -0.014 ± 0.049

C(3,1) More -0.012 ± 0.028 -0.011 ± 0.028 -0.006 ± 0.026

0.58 0.96 0.06 Less 0.002 ± 0.026 0.016 ± 0.033 0.009 ± 0.049

C(3,3) More -0.002 ± 0.015 0.006 ± 0.022 0.003 ± 0.022

0.45 0.85 0.66 Less 0.001 ± 0.010 0.011 ± 0.014 0.004 ± 0.024

C(4,-4) More 0.001 ± 0.009 0.002 ± 0.020 0.004 ± 0.012

0.88 0.14 0.58 Less 0.007 ± 0.008 0.005 ± 0.008 0.003 ± 0.014

C(4,-2) More 0.000 ± 0.007 -0.002 ± 0.012 -0.002 ± 0.015

0.49 0.16 0.23 Less 0.001 ± 0.007 0.001 ± 0.008 0.007 ± 0.011

C(4,0) More 0.022 ± 0.018 0.010 ± 0.015 0.002 ± 0.027

0.02 0.59 0.61 Less 0.017 ± 0.018 0.016 ± 0.018 -0.010 ± 0.038

C(4,2) More -0.005 ± 0.010 -0.001 ± 0.010 -0.004 ± 0.020

0.92 0.88 0.61 Less -0.003 ± 0.014 0.004 ± 0.007 -0.003 ± 0.028

C(4,4) More 0.001 ± 0.009 -0.001 ± 0.013 -0.001 ± 0.018

0.63 0.85 0.91 Less 0.004 ± 0.014 -0.004 ± 0.015 0.003 ± 0.018

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209

Table 4.4: Distribution of subjects according to the dominant or non-dominant eye

displaying a greater accommodative response for the 5 D stimuli.

Eye with greater accommodative response for 5 D stimuli (Mean ± SD anisometropia (D))

Dominant (1.84 ± 0.67)

Non-dominant (1.25 ± 0.20)

Low anisometropia (≤ 1.75 D) 2 7

High anisometropia (> 1.75 D) 2 0

Figure 4.7: Correlation between the interocular differences accommodation (more

myopic minus less myopic eye) at 2.5 and 5.0 D stimuli.

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210

Figure 4.8: Higher-order RMS and spherical aberration C(4,0) (microns) at 0, 2.5 and

5.0 D accommodation demands (natural pupil diameter). Error bars represent the

standard deviation.

Chapter 4

211


In previous chapters we have shown that the magnitude of anisometropia is

significantly correlated with the interocular difference in axial length. We have

confirmed this again in a smaller group of non-amblyopic anisometropes in this

chapter. However, since the Lenstar was used to measure axial biometrics

including lens thickness in this experiment we were able to calculate vitreous

chamber depths for these subjects. The similarity between fellow eyes for

measures of CCT, ACD, and LT confirm that the major contributor to anisometropia

is the interocular difference in vitreous chamber depth, which also showed a

significant correlation with the magnitude of anisometropia. We found no

interocular difference in retinal thickness measured with the OCT; however, the

average choroidal thickness was thinner in the more myopic eyes and this

difference approached statistical significance. While numerous studies have

reported choroidal thinning with increasing myopia and axial length, in our subjects

choroidal thickness was poorly correlated with axial length and the magnitude of

myopia in both the more and less myopic eyes. This may be due to the relatively

small sample size in our study (restricted to myopic anisometropes), with a much

narrower range of refractive error, axial length and choroidal thickness. However,

the interocular difference in choroidal thickness was moderately correlated with

the interocular difference in magnitude of spherical equivalent and axial

anisometropia.

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212

Although no studies have directly measured choroidal thickness in anisometropic

eyes, some studies have measured the interocular symmetry of choroidal blood

flow using various techniques. Shih et al (1991) measured the intraocular pulse

amplitude (generated by the choroidal blood flow) in both eyes of 188 subjects

using a pneumatic tonometer. The ocular pulse amplitude decreased significantly

with increasing axial length, suggesting that choroidal circulation is reduced in high

myopia (however, this may be an artefact associated with increased axial length

(James et al 1991)). In addition, for subjects with anisometropia greater than 3 D,

there was a significant interocular ocular difference in OPA (0.27 mmHg). For all

subjects, the interocular difference in refractive error and axial length was

significantly correlated with the interocular difference in OPA.

Similarly, Lam et al (2003) measured the OPA and pulsatile ocular blood flow (POBF)

in anisometropic subjects (> 2.0 D SEq) using a pneumatic tonometer. Both OPA

and POBF were significantly lower in the more myopic eye of axial anisometropes

and the interocular difference in OPA and POBF were both significantly correlated

with the interocular difference in axial length. This study also suggests that reduced

choroidal blood flow is associated with increasing myopia. Although these studies

suggest an interocular difference in choroidal thickness in anisometropia, OPA and

POBF may be influenced by various factors including IOP (Kaufmann et al 2006) and

are considered estimates of choroidal blood flow circulation rather than a direct

measure of choroidal thickness. Singh et al (2006) used magnetic resonance

imaging to measure ocular volume and axial length and characterize the 3-D shape

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213

of the globe in a small group of subjects. They observed a large variation in globe

shape (sphericity) between subjects and regional asymmetries within subjects (i.e.

nasal and temporal). While choroidal thickness was not measured, the authors

postulated that ocular volume and regional variations in the posterior segment

contour may influence choroidal blood flow.

All of the anterior biometric parameters measured (except for CCT) underwent a

significant change during accommodation. Of particular interest is the change in

lens thickness and axial length during accommodation. While previous studies have

reported lens thickness to be similar between the fellow eyes of anisometropes

during relaxed accommodation (or cycloplegia), our results show that lens thickness

remains similar between the fellow eyes during up to 5 D of monocular

accommodation, suggesting a similar accommodative response between the eyes

(which was also confirmed with the objective spherocylindrical refractive power

data from the COAS). However, for the 5 D stimulus, the magnitude of increase in

LT compared with the 0 D stimulus, was slightly greater in the more myopic eyes

and approached statistical significance. Overall, there were no significant

interocular differences in the magnitude of change between the more and less

myopic eyes.

Transient axial length changes associated with near work may be linked to

permanent axial length changes and refractive error development. Recent studies

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214

suggest that accommodation causes transient increases in axial length proportional

to the magnitude of accommodation, which dissipate quickly when accommodation

is relaxed (Drexler et al 1998, Mallen et al 2006, Read et al 2010b, Woodman et al

2011). These changes in axial length may be a result of the mechanical effects of

the contraction of the ciliary muscle and choroidal tension during accommodation.

However, there is conflicting evidence regarding the magnitude of axial length

changes during accommodation between different refractive error groups.

We observed a greater amount of axial elongation during accommodation in the

more myopic eyes of myopic anisometropes; however this asymmetry in axial

elongation did not reach statistical significance. In a cohort of 7 isometropes,

Drexler et al (1998) also found no significant interocular difference in axial

elongation during a short period of accommodation. The mechanism involved in

axial elongation during accommodation is unknown, but it is hypothesised to be a

mechanical stretching of the globe. Since the changes in lens thickness during

accommodation were similar between the fellow eyes in our experiment, we would

assume the forces generated were also similar between the eyes. However,

between eye differences in choroidal/scleral thickness may be associated with the

greater axial elongation observed in the more myopic eyes if more axial elongation

is possible with a thinner choroid. But we found no correlation between choroidal

thickness and the magnitude of axial elongation, so the association between these

factors may not be causal.

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215

If ciliary body forces or choroidal tension during accommodation are the causes of

such axial length changes, we might expect ciliary body thickness to be larger in

myopes compared to emmetropes or larger in the more myopic eye of

anisometropes relative to the fellow eye. This finding has been reported previously

in children (Bailey et al 2008) and cases of unilateral high myopia (mean

anisometropia 8 D) (Muftuoglu et al 2009). However, a recent study of low myopic

anisometropes (mean anisometropia 2.25 D) reported that ciliary muscle size was

greater in the less myopic eye (Kuchem et al 2010). Factors other than ciliary body

size may also influence the amount of force transmitted to the choroid and sclera

during accommodation such as structural and biomechanical properties of the

sclera. In our study we have only examined the choroidal thickness at the fovea

since our measures of axial length during accommodation were taken along the

visual axis. However, choroidal thickness may vary with eccentricity away from the

fovea (Esmaeelpour et al 2010, Manjunath et al 2010) and regional variations may

influence the axial length changes during accommodation.

The more and less myopic eyes of our anisometropic subjects underwent similar

changes in pupil size, spherical component of refraction, spherocylinder M and

higher-order aberrations at both 2.5 and 5.0 D of accommodation. On average,

both eyes displayed a small lag of accommodation which was greatest for the 2.5 D

stimuli. Subjects exhibited small interocular differences in accommodative

response, which were consistent at both levels of accommodation. The interocular

difference in accommodative response was not correlated with the magnitude of

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216

anisometropia. Our results differ to those of Xu et al (2009), who observed that as

accommodative demand increased, the more myopic eye of anisometropes

displayed a greater lag of accommodation compared to the less myopic eye,

although these interocular differences in accommodation did not reach statistical

significance. Our cohort of subjects (mean anisometropia 1.47 ± 0.50 D) differed to

those of Xu et al (2009) (spherical anisometropia 2.5 - 7.0 D), leaving open the

possibility that for larger degrees of anisometropia, the accommodative response

between the eyes may differ. Our study designs also differed in that Xu et al (2009)

measured the accommodative response of each eye in free space, during binocular

viewing (corrected with soft contact lenses) using a Grand Seiko WV 500

autorefractor. Off-axis measurements with this instrument have been shown to

result in small inaccuracies in refractive error measurement (Wolffsohn et al 2004),

which may have influenced the findings in the study of Xu et al (2009) as subjects

converged. However, such inaccuracies in the measurement technique would

presumably affect each eye equally.

It has also been suggested that the dominant eye (traditionally the preferred eye

for distant sighting) may exhibit different accommodative responses to the fellow

non-dominant eye. In amblyopia, the non-dominant (amblyopic) eye shows

impaired accommodation following abnormal visual experience (Hokoda and

Ciuffreda 1982, Hung et al 1983, Ciuffreda et al 1984); however, few studies have

examined the role of ocular dominance and accommodation in non-amblyopic

subjects. Given the potential association between accommodation and myopia

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217

development, the characteristics of accommodation between the dominant and

non-dominant eyes are of interest with respect to refractive error development.

There was no statistically significant difference in the accommodative response

between the dominant and non-dominant eyes in our population of anisometropes.

However, we observed that in the majority of subjects the non-dominant eye

showed a slightly greater accommodative response for both the 2.5 and 5 D stimuli.

As the magnitude of anisometropia increased, there was a trend towards the

dominant eye being the eye with the greater accommodative response. Ibi (1997)

examined the accommodative response in the dominant and non-dominant eyes of

young isometropic subjects and observed that the dominant eye showed a slight

myopic shift at both distance and near fixation following accommodation. The

author speculated that the static tonus of the ciliary muscle is increased in the

dominant eye, which may explain why the dominant eye is often the more myopic

eye in non-amblyopic anisometropia. However, if the dominant eye shows a slight

lead of accommodation following near work, this myopic defocus would slow eye

growth, based on the theory of retinal image mediated eye growth.

Yang and Hwang (2010) compared the interocular equality of the accommodative

response in children with intermittent exotropia, without amblyopia or

anisometropia. Ocular dominance was determined by fixation preference during

cover testing and the accommodative response was measured during binocular and

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218

monocular fixation of a 3 D stimulus using an open field autorefractor. During

monocular viewing, the dominant and non-dominant eyes of intermittent

exotropes both showed a small lag of accommodation. However, during binocular

fixation, a significant number of subjects displayed a greater lag of accommodation

in the non-dominant eye compared to the fellow dominant eye.

In Chapter 2 we observed that the more myopic eye tended to be the dominant

sighting eye for higher levels of anisometropia (greater than 1.75 D), a finding which

has been reported previously (Cheng et al 2004a). Cheng et al (2004a) also

reported that as anisometropia increased, the preferred eye for near viewing

tended to be the more myopic eye. In this chapter, we observed that as the

magnitude of anisometropia increases; the dominant eye tends to show a greater

accommodation response. However, a much larger pool of subjects would be

required to investigate the relationship between the accommodative response and

ocular dominance.

One limitation of this study is that we have only examined the accommodative

response under monocular viewing conditions during a brief period of

accommodation. In order to simulate natural conditions more closely, ideally we

would measure the accommodative response in each eye simultaneously under

binocular viewing conditions. It is assumed that the accommodative response is

consensual between fellow eyes due to the dominant innervation to each ciliary

Chapter 4

219

body via the parasympathetic pathway originating from a common neural origin.

Early studies confirmed that in normal subjects the accommodative response is

symmetric between the eyes in both monocular (Ball 1952) and binocular

(Campbell 1960) viewing conditions. However, there is some evidence that

suggests the accommodative response may differ between fellow eyes in certain

circumstances. Koh and Charman (1998) reported that during binocular viewing,

when the eyes are presented with stimuli of unequal accommodative demand, the

eye which requires the least accommodative effort to maintain clear focus of the

target will control the accommodative response in both eyes. Marran and Schor

(1998) observed that when presented with unequal accommodative targets

subjects demonstrated aniso-accommodation to approximately one quarter of the

interocular difference in demands. At a stimulus difference of approximately 3 D

there appeared to be a suppression mechanism involved in eliminating the image

from the eye with the higher accommodation demand.

In Chapters 2 and 3, we observed that the more and less myopic eyes of

anisometropes displayed similar levels of higher-order aberrations during distance

fixation and following a short reading task. In this chapter we examined the

interocular symmetry of total ocular aberrations between the fellow eyes during

accommodation. There was a high degree of symmetry between the fellow eyes

for higher-order aberrations, at all levels of accommodation. The less myopic eyes

displayed higher (more positive) levels of C(3,1) primary horizontal coma and C(4,2)

secondary astigmatism at all levels of accommodation, which reached statistical

Chapter 4

220

significance for the 2.5 D stimuli. The high degree of symmetry between the fellow

eyes during accommodation is not surprising given the symmetry observed during

distance fixation in these subjects, and the similar changes in lens thickness and

ocular biometry during accommodation. Our results do not show an obvious

between eyes difference in higher-order aberrations during accommodation and do

not support an aberration driven model of axial length elongation and myopia or

anisometropia development. However, we do not discount the possibility that

interocular differences in accommodation or higher-order aberrations may be

present in subjects with larger degrees of anisometropia, during tasks of greater

accommodation demands performed for longer periods of time, or during binocular

viewing. Given the cross sectional nature of the study it is also possible that at

some point of time during refractive development the more myopic eye endured

higher levels of aberrations or blur which influenced anisometropic growth which

has since regressed to isometropic levels.


During monocular accommodation tasks at 2.5 and 5.0 D stimuli, the fellow eyes of

myopic anisometropes underwent a range of biometric and optical changes that

were similar in magnitude. The more myopic eyes exhibited a slightly larger

amount of axial elongation during accommodation, which may be related to the

thinner choroid observed in the more myopic eyes.

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221

CChhaapptteerr 55:: OOccuullaarr cchhaarraacctteerriissttiiccss iinn aassyymmmmeettrriicc vviissuuaall eexxppeerriieennccee


In the previous chapters we examined the interocular symmetry in myopic

anisometropes without amblyopia to investigate various biometric, mechanical and

optical factors that may be associated with unequal eye growth between the two

eyes of an individual. In this chapter, we examine the interocular differences

between fellow eyes which have a history of asymmetric visual experience during

development resulting in unequal visual acuities.

Amblyopia is defined as a unilateral or bilateral decrease in visual acuity in the

absence of ocular pathology. Disruption of the retinal image during early life due to

uncorrected refractive error or form deprivation (e.g. cataract, ptosis) or binocular

inhibition due to strabismus inhibits the normal development of the visual pathway.

This results in a range of visual deficits in addition to reduced visual acuity in the

amblyopic eye including, reduced accommodation (Hokoda and Ciuffreda 1982,

Hung et al 1983, Ciuffreda et al 1984), contrast sensitivity and depth perception

(McKee et al 2003). Hyperopic anisometropia is the most common cause of

refractive amblyopia and an interocular difference of +1.00 D may result in

amblyopia in the more hyperopic eye (Abrahamsson and Sjostrand 1996).

Amblyopia as a result of myopic anisometropia is less common, since the myopic

eye may still receive clear vision at close working distances.

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222

Higher-order aberrations (HOA’s) may also degrade the retinal image and

potentially influence eye growth. Numerous studies have hypothesised that HOA’s

may play a role in the development of myopia. The changes in aberrations during

(Collins et al 1995, Collins et al 2006c) or following accommodation tasks (Buehren

et al 2005) or as a result of eyelid forces acting upon the cornea during downward

gaze (Buehren et al 2003, Collins et al 2006a) have been investigated in various

refractive error groups. However, few studies have examined the optics of

amblyopic eyes, possibly due to early research which suggested that vision loss in

amblyopia is primarily neural and not influenced by HOAs (Hess and Smith 1977).

Prakash et al (2007) recently proposed that interocular differences in HOA’s may

explain the reduced visual acuity observed in cases of idiopathic amblyopia

(reduced visual acuity in the absence of any identifiable cause or amblyogenic

factor) a refractive entity which Agarwal et al (2009) termed ‘aberropia’. The few

studies examining HOA’s in amblyopes have typically shown similar levels of corneal

(Plech et al 2010) and total aberrations (Kirwan and O’Keefe 2008) between fellow

eyes. However, recent studies of HOAs in animals (Coletta et al 2010) and humans

(Zhao et al 2010) suggest that HOA’s such as trefoil and coma may be linked with

form deprivation myopia and reduced visual acuity in amblyopia.

It is well known that during accommodation the eye undergoes a range of optical

changes including an increase in overall power and a shift from positive to negative

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223

spherical aberration. Given the link between near work and myopia development,

a range of studies have examined the accommodative response and change in

aberrations during accommodation in myopes and emmetropes. Although altered

accommodative responses in amblyopic eyes have been well documented, the

nature of HOA’s in amblyopic subjects during accommodation has not been

reported. Additionally, few studies have examined the biometrics of amblyopic

eyes in detail. Nathan et al (1985) and Du et al (2005) retrospectively examined the

association between refractive error type and a range of different ocular conditions

resulting in low vision, but did not have access to biometric data. Excluding studies

of growth patterns following surgery for congenital cataract, only a small number of

studies have examined axial length asymmetry in amblyopic eyes (Weiss 2003,

Zaka-Ur-Rab 2006, Cass and Tromans 2008, Lempert et al 2008, Patel et al 2010).

In this study, we have examined a large range of optical and biometric ocular

parameters in subjects with unequal visual acuity following asymmetric visual

experience. We hypothesised that optical or biomechanical properties may

contribute to or be altered during disrupted emmetropisation. However, since this

was a cross sectional study and not longitudinal, we cannot be certain if the

differences between the eyes represent a possible cause or consequence of altered

visual development. Nonetheless, the differences between amblyopic and fellow

non-amblyopic eyes may provide useful information regarding the development of

asymmetric eye growth and refractive error development.

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224



Twenty one healthy subjects aged between 14 and 55 years (mean age 30 ± 11

years) with a history of asymmetric visual experience were included in this study.

The subjects were primarily recruited from the staff and students of QUT

(Queensland University of Technology, Brisbane, Australia) and HKPU (Hong Kong

Polytechnic University, Hong Kong, PR China). Thirteen of the 21 subjects were

female and the majority of subjects were Caucasian with 4 subjects of Asian

descent. Eight subjects had refractive amblyopia, 11 had strabismic amblyopia (7

esotropes, 2 exotropes and 2 with vertical deviations) and two had form

deprivation amblyopia (corneal scar and congenital cataract). All subjects had

unilateral amblyopia with an interocular difference in best-corrected visual acuity of

0.10 logMAR or greater.


subjective refraction, binocular vision and ocular health status. All subjects

exhibited central fixation in both eyes, which was assessed monocularly using the

internal graticule target of a direct ophthalmoscope. All subjects were free of

significant ocular or systemic disease. Fourteen subjects had a prior history of

amblyopia therapy (penalisation or occlusion) for at least one month and six had a

history of strabismus surgery. One subject had undergone surgery for the removal

of congenital cataract. No subjects were rigid contact lens wearers. Six soft contact

lens wearers were included in the study but ceased lens wear for 36 hours prior to

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225

participation. Approval from both the QUT and HKPU human research ethics

committees was obtained before commencement of the study and subjects gave

written informed consent to participate (Appendix 1). All subjects were treated in

accordance with the tenets of the Declaration of Helsinki.


We collected a range of biometric and optical measurements from the amblyopic

and non-amblyopic eye of each subject including; axial length, corneal topography,

corneal thickness and biomechanics, ocular aberrations during distance and near

fixation (2.5 D accommodation demand – for subjects under 40 years of age),

intraocular pressure and digital images of the anterior eye during primary gaze. The

data collection procedures for each of these measurements have been described in

Chapters 2 and 3.


Two tailed paired t-tests were used to assess the statistical significance of the mean

interocular difference between the non-amblyopic and amblyopic eye of each

subject. Pearson’s correlation coefficient was used to quantify the degree and

statistical significance of the interocular symmetry between the fellow eyes and the

association between the magnitude of anisometropia or amblyopia and the

interocular difference in the variable of interest.

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55..33.. RReessuullttss

55..33..11 OOvveerrvviieeww

Table 5.1 provides an overview of the mean refraction, visual acuity and axial length

of the amblyopic subjects studied. On average, amblyopic eyes were significantly

shorter in axial length and more hyperopic in comparison to fellow eyes. There

were statistically significant differences between the fellow eyes for both the

spherical component and spherical equivalent of the refractive error. The

magnitude of refractive astigmatism (cylinder) was slightly greater in the amblyopic

eyes but this difference did not reach statistical significance. Visual acuity and axial

length were significantly different between fellow eyes. The magnitude of

anisometropia was highly correlated with the interocular difference in axial length

between fellow eyes (r = -0.96, p < 0.0001) (Figure 5.1) and moderately correlated

with the magnitude of amblyopia (i.e. the interocular difference in visual acuity) (r =

0.55, p < 0.01). Table 5.2 provides the same overview of subject characteristics for

strabismic and refractive amblyopes separately. Similar trends were observed in

both cohorts.

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Table 5.1: Overview of the amblyopic and non-amblyopic eyes in all subjects (n = 21).

Amblyopic eye Non-amblyopic eye Paired t-test

Variable Mean ± SD Range Mean ± SD Range p

Sphere (D) +1.81 ± 3.94 -10.00, +8.75 +0.14 ± 3.11 -8.25, +7.00 < 0.01

Cylinder (D) -1.00 ± 0.95 -3.00, 0.00 -0.76 ± 0.60 -2.00, 0.00 0.12

SEq (D) +1.31 ± 4.11 -11.50, +8.75 -0.24 ± 3.25 -9.25, +7.00 < 0.01

VA (logMAR) 0.35 ± 0.41 0.00, 1.68 -0.02 ± 0.06 -0.14, 0.10 < 0.001

AxL (mm) 22.98 ± 1.61 20.67, 28.22 23.56 ± 1.32 21.18, 27.36 < 0.01

Table 5.2: Overview of the amblyopic and non-amblyopic eyes in the strabismic (n = 11) and refractive (n = 8) amblyopes.

Strabismic amblyopes (n = 11) Refractive amblyopes (n = 8)

Amblyopic eye Non-amblyopic eye Paired t-test Amblyopic eye Non-amblyopic eye Paired t-test

Variable Mean ± SD Range Mean ± SD Range p Mean ± SD Range Mean ± SD Range p

Sphere (D) +1.98 ± 2.89 -2.50, +7.00 +0.39 ± 1.93 -2.00, +4.50 0.06 +1.50 ± 5.63 -10.00, +8.75 -0.06 ± 4.68 -8.25, +7.00 0.02

Cylinder (D) -1.07 ± 1.04 -3.00, 0.00 -0.68 ± 0.59 -1.75, 0.00 0.15 -1.00 ± 0.97 -3.00, 0.00 -0.81 ± 0.69 -2.00, 0.00 0.20

SEq (D) +1.44 ± 2.76 -2.63, +5.50 +0.05 ± 1.96 -2.63, +4.25 0.08 +1.00 ± 6.06 -11.50, +8.75 -0.47 ± 4.91 -9.25, +7.00 0.04

VA (logMAR) 0.43 ± 0.50 0.00, 1.68 -0.01 ± 0.03 -0.10, 0.02 0.01 0.28 ± 0.33 0.00, 1.00 -0.01 ± 0.09 -0.14, 0.10 0.02

AxL (mm) 22.87 ± 1.09 21.15, 24.71 23.40 ± 0.97 21.55, 24.77 0.07 23.21 ± 2.36 20.67, 28.22 23.74 ± 1.88 21.18, 27.36 0.05

SEq - Spherical equivalent refractive error, VA - visual acuity, AxL - Axial length

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interocular difference in axial length (mm) for all amblyopic subjects (n = 21).

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55..33..22 MMoorrpphhoollooggyy ooff tthhee ppaallppeebbrraall ffiissssuurree

There was a high degree of symmetry between the fellow eyes for a range of

biometric measures of the anterior eye and palpebral fissure during primary gaze

(Table 5.3, Figure 5.2). Amblyopic eyes had slightly smaller mean vertical palpebral

apertures (9.19 ± 1.62 mm) compared to fellow non-amblyopic eyes (9.48 ± 1.52

mm) (p < 0.05). This was primarily due to the interocular difference in upper eyelid

position (on average 0.18 mm lower in the amblyopic eyes), although there was

also a small difference in lower eyelid position (on average 0.10 mm higher in the

amblyopic eyes). There were no significant correlations between the magnitude of

anisometropia or the magnitude of amblyopia and the interocular differences in

morphology variables (p > 0.05).

55..33..33 OOccuullaarr bbiioommeecchhaanniiccss

Three subjects were excluded from this analysis, as valid measurements could not

be obtained using the Ocular Response Analyzer due to poor fixation (two form

deprivation amblyopes) or eyelash interference. For the remaining 18 subjects, we

observed a moderate degree of symmetry between the fellow eyes for all measures

of intraocular pressure and corneal biomechanics (Table 5.5). There were no

significant correlations between the degree of ametropia (spherical equivalent or

axial length) and intraocular pressure or measures of corneal biomechanics. In

addition, there were no statistically significant correlations between the degree of

anisometropia and the interocular difference in; IOPg (r = 0.08), IOPcc (r = 0.33),

CRF (r = -0.31) and CH (r = -0.36) (all p > 0.05).

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Figure 5.2: Graphical representation of the morphology of the palpebral aperture of

the amblyopic and non-amblyopic eyes during primary gaze. The origin represents

the geometric centre of the limbus.

.

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231

Table 5.3: Mean anterior eye morphology measurements in primary gaze for amblyopic and non-amblyopic eyes.

Parameter Amblyopic Non-amblyopic Paired t-test

Pearson’s Correlation Interocular symmetry

Pearson’s Correlation IOD vs anisometropia

Mean ± SD Mean ± SD p r p r p

HEF 26.29 ± 2.77 26.57 ± 2.85 0.36 0.89 < 0.0001 0.03 0.90

theta_HEF -4.86 ± 4.41 -5.16 ± 3.86 0.79 0.20 0.38 0.10 0.67

Limbus diameter 11.67 ± 1.04 11.65 ± 1.07 0.85 0.95 < 0.0001 -0.12 0.60

Pupil diameter 3.49 ± 0.46 3.52 ± 0.52 0.48 0.90 < 0.0001 0.27 0.24

Upper Eyelid A -0.03 ± 0.01 -0.03 ± 0.01 0.16 0.05 0.83 -0.14 0.55

B 0.00 ± 0.11 -0.02 ± 0.07 0.36 0.37 0.10 0.00 1

C 3.58 ± 1.08 3.80 ± 1.05 0.06 0.89 < 0.0001 0.21 0.36

Lower Eyelid A 0.02 ± 0.00 0.02 ± 0.01 1 0.77 < 0.0001 0.26 0.26

B 0.04 ± 0.08 0.04 ± 0.06 0.82 -0.32 0.16 0.00 1

C -5.64 ± 1.02 -5.70 ± 0.95 0.39 0.94 < 0.0001 0.21 0.36

PA 9.19 ± 1.62 9.48 ± 1.52 0.04 0.93 < 0.0001 0.14 0.55

PC_UL 3.39 ± 1.13 3.57 ± 1.07 0.08 0.92 < 0.0001 0.22 0.34

PC_LL -5.81 ± 0.98 -5.91 ± 0.90 0.18 0.94 < 0.0001 0.08 0.73

All measurements in mm, except theta_HEF measured in degrees. IOD: interocular difference.

Table 5.4: Explanation of anterior eye measurements and abbreviations used.

ABBREVIATION EXPLANATION DEFINITION

HEF Horizontal eyelid fissure The horizontal distance between the nasal and temporal canthi theta_HEF Theta horizontal eyelid fissure The angle between the temporal and nasal canthus (a positive angle indicates a higher nasal canthus)

Limbus diameter Limbus diameter Average of the vertical and horizontal diameter of the ellipse fitted to the limbus Pupil diameter Pupil diameter Average of the vertical and horizontal diameter of the ellipse fitted to the pupil

Eyelid margin terms A Eyelid curve The curvature of the eyelid (a larger A term indicates a steeper curve) B Eyelid tilt The angle of the eyelid (a positive B term indicates a downward slant) C Eyelid height The height of the eyelid above or below the corneal centre

PA Palpebral aperture The vertical distance between the upper and lower lid measured through the pupil centre PC_UL Pupil centre to upper eyelid The vertical distance from the pupil centre to the upper eyelid PC_LL Pupil centre to lower eyelid The vertical distance from the pupil centre to the lower eyelid

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We captured a range of measures of corneal shape and anterior chamber

morphology using the Medmont E300 videokeratoscope and the Pentacam HR

system. One subject was excluded from the Medmont data analysis due to

extensive missing data from eyelash interference and reduced palpebral aperture

size. The group mean and standard deviations for the amblyopic and normal eyes

are displayed in Table 5.6.

There was a high degree of interocular symmetry for all parameters measured.

Amblyopic eyes had a greater level of anterior corneal astigmatism compared to

fellow eyes for both Medmont (-1.35 ± 0.81 D amblyopic, -0.92 ± 0.65 D non-

amblyopic) and Pentacam values (-1.09 ± 0.87 D amblyopic, -0.87 ± 0.73 D non-

amblyopic). This interocular difference in anterior astigmatism was statistically

significant for the Medmont data (p < 0.01). Posterior corneal astigmatism was also

slightly greater in the amblyopic eyes (0.24 ± 0.26 D amblyopic, 0.19 ± 0.25 D non-

amblyopic) however the difference was not statistically significant (p > 0.05).

Average corneal asphericity values (Q values, Medmont data) were slightly more

prolate (greater peripheral flattening) in the amblyopic eyes in the flattest meridian

and slightly less prolate in the steepest meridian. This interocular difference was

statistically significant for the flattest corneal meridian, with mean Q values of -0.49

± 0.15 in the amblyopic eyes and -0.41 ± 0.16 in the fellow eyes (p = 0.02).

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Table 5.5: Mean and standard deviation of intraocular pressure and corneal

biomechanics in the amblyopic and non-amblyopic eyes.

Variable Amblyopic Non-amblyopic Paired t-test Pearson correlation

coefficient Interocular symmetry

(mmHg) Mean ± SD Mean ± SD p r p

IOPg 12.92 ± 2.65 13.28 ± 2.69 0.31 0.85 < 0.0001

IOPcc 12.67 ± 2.61 12.89 ± 3.33 0.64 0.82 < 0.0001

CRF 10.49 ± 1.58 10.67 ± 2.05 0.58 0.76 < 0.001

CH 11.40 ± 1.48 11.50 ± 2.22 0.79 0.76 < 0.001

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On average, the non-amblyopic eyes had slightly deeper anterior chambers

compared to the amblyopic eyes; however this difference only approached

statistical significance in terms of anterior chamber volume (interocular difference

of 5 mm3). The average corneal thickness measured over the pupil centre was not

significantly different between fellow eyes.

The group mean and standard deviations for corneal power vectors M (spherical

corneal power), J0 (90/180 astigmatic power) and J45 (45/135 oblique astigmatic

power) in the amblyopic and non-amblyopic eyes are displayed in Table 5.7. The

mean astigmatic vectors were similar between the eyes, however the cylindrical

component was significantly greater in the amblyopic eyes over a 6 mm analysis

diameter (p < 0.05). On average the J45 power vectors were of small magnitude

compared to the J0 vectors in both amblyopic and non-amblyopic eyes, indicative

that the corneal astigmatism was primarily ‘with the rule’ in nature. For all of these

parameters obtained from the Medmont and Pentacam data (excluding higher-

order corneal aberrations discussed later), similar trends were observed between

both the strabismic and refractive amblyope groups.

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235

Table 5.6: Mean values for corneal and anterior chamber parameters in the

amblyopic and non-amblyopic eyes.

Amblyopic Non-amblyopic Paired t test

Pearson’s correlation Interocular symmetry

Instrument Parameter Mean ± SD Mean ± SD p r p

Medmont (n = 20)

Flat K (D) 42.88 ± 1.48 43.01 ± 1.30 0.31 0.93 < 0.0001

Steep K (D) 44.23 ± 1.52 43.93 ± 1.16 0.06 0.91 < 0.0001

Mean K (D) 43.56 ± 1.45 43.47 ± 1.19 0.47 0.94 < 0.0001

Anterior astigmatism (D) -1.35 ± 0.81 -0.92 ± 0.65 < 0.01 0.69 < 0.001

Flat Q -0.49 ± 0.15 -0.41 ± 0.16 0.02 0.58 < 0.01

Steep Q -0.26 ± 0.20 -0.34 ± 0.21 0.10 0.60 < 0.01

Mean Q -0.38 ± 0.11 -0.38 ± 0.13 0.99 0.58 < 0.01

Pentacam (n = 21)

Flat K (D) 42.77 ± 1.32 42.90 ± 1.25 0.21 0.94 < 0.0001

Steep K (D) 43.86 ± 1.39 43.78 ± 1.17 0.43 0.94 < 0.0001

Anterior astigmatism (D) -1.09 ± 0.87 -0.87 ± 0.73 0.07 0.79 < 0.0001

Posterior astigmatism (D)

0.24 ± 0.26 0.19 ± 0.25 0.43 0.46 < 0.05

ACD (mm) 2.92 ± 0.39 2.96 ± 0.36 0.23 0.93 < 0.0001

ACV (mm3) 160 ± 30 165 ± 28 0.05 0.94 < 0.0001

CCT (PC) (microns) 553 ± 33 554 ± 33 0.94 0.86 < 0.0001

K - Corneal power, Q - corneal asphericty, ACD - anterior chamber depth, ACV - anterior chamber volume, CCT (PC)- Central

corneal thickness measured over the pupil centre

Table 5.7: Mean corneal vectors M, J0 and J45 (D) in the amblyopic and non-

amblyopic eyes (4 and 6 mm corneal diameters).

Amblyopic (Mean ± SD) Non-amblyopic (Mean ± SD)

DIAMETER 4 mm 6 mm 4 mm 6 mm

M 48.50 ±1.42 48.68 ± 1.45 48.49 ± 1.25 48.70 ± 1.29

J0 0.31 ± 0.75 0.32 ± 0.77 0.26 ± 0.58 0.26 ± 0.55

J45 0.02 ± 0.36 0.07 ±0.31 0.01 ± 0.25 -0.01 ± 0.23

Spherocyl 49.23/-1.45 x 13 49.41/-1.45 x 178 49.05/-1.12 x 165 49.23/-1.05 x 178

All values are Mean ± SD in Dioptres.

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55..33..55 CCoorrnneeaall aassttiiggmmaattiissmm aanndd ppaallppeebbrraall aappeerrttuurree mmoorrpphhoollooggyy

We also examined the correlation between the corneal refractive power vectors M,

J0 and J45 and various anterior eye biometrics for the non-amblyopic and

amblyopic eyes (Table 5.8). A number of significant associations were observed

between measures of palpebral aperture morphology and the corneal power

vectors. Correlations were similar for the two corneal analysis diameters of 4 and 6

mm. Here we present the 6 mm corneal diameter analysis. Significant correlations

between palpebral aperture parameters and M and J0 were also found to be similar

between fellow eyes.

For the non-amblyopic eyes, M was moderately associated with the position of the

lower eyelid. Significant correlations were observed with lower eyelid height (term

C) (r = 0.67, p < 0.001), distance from the pupil centre to the lower lid (PC_LL) (r =

0.63, p < 0.01) and vertical palpebral aperture size (r = -0.58, p < 0.01) (Figure 5.3).

Similar correlations were observed for the amblyopic eyes; lower eyelid height

(term C) (r = 0.69, p < 0.001), PC_LL (r = 0.67, p < 0.001) and vertical palpebral

aperture (r = -0.62, p < 0.01).

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Table 5.8: Correlation analysis of corneal vectors M, J0 and J45 (D) with various

palpebral aperture biometrics (mm) (6 mm corneal diameter).

Pearson’s correlation coefficient (p value)

Corneal vector M J0 J45

Parameter Amblyopic Non-amblyopic Amblyopic Non-amblyopic Amblyopic Non-amblyopic

Upper Eyelid

A -0.38 (0.09) -0.35 (0.12) -0.12 (0.60) 0.34 (0.13) -0.09 (0.70) -0.11 (0.64)

B -0.52 (0.02) -0.39 (0.08) -0.14 (0.55) -0.18 (0.43) -0.09 (0.70) 0.11 (0.64)

C -0.23 (0.32) -0.36 (0.11) 0.55 (< 0.01)* 0.54 (0.01)* 0.00 (1.00) -0.52 (0.02)*

Lower Eyelid

A -0.06 (0.79) 0.14 (0.55) 0.07 (0.76) -0.06 (0.79) -0.18 (0.43) -0.14 (0.55)

B -0.03 (0.90) -0.45 (0.05) 0.03 (0.90) -0.26 (0.26) 0.10 (0.67) 0.43 (0.05)

C 0.69 (< 0.001)* 0.67 (< 0.001)* 0.19 (0.41) -0.20 (0.38) 0.59 (< 0.01)* 0.00 (1.00)

PC_UL [mm] -0.29 (0.20) -0.27 (0.24) 0.32 (0.16) 0.38 (0.09) -0.15 (0.52) -0.36 (0.11)

PC_LL [mm] 0.67 (< 0.001)* 0.63 (< 0.01)* 0.16 (0.49) -0.08 (0.73) 0.36 (0.11) -0.14 (0.55)

PA [mm] -0.62 (< 0.01)* -0.58 (< 0.01)* 0.12 (0.60) 0.32 (0.16) -0.33 (0.14) -0.17 (0.46)

* p < 0.01

Table 5.9: Correlation analysis of interocular difference in corneal vectors M, J0 and

J45 (D) with interocular difference in palpebral aperture biometrics (6 mm corneal

diameter).

Pearson’s correlation coefficient (p value)

Interocular difference M J0 J45

Upper Eyelid A -0.14 (0.55) -0.14 (0.55) -0.17(0.46)

B -0.25 (0.27) -0.18 (0.43) -0.31 (0.17)

C -0.01 (0.97) 0.25 (0.27) -0.03 (0.90)

Lower Eyelid A -0.47 (< 0.05) 0.07 (0.76) -0.16 (0.49)

B -0.08 (0.73) -0.10 (0.67) 0.33 (0.14)

C 0.13 (0.57) -0.46 (< 0.05) 0.14 (0.55)

PC_UL [mm] 0.18 (0.43) 0.34 (0.13) -0.31 (0.17)

PC_LL [mm] 0.34 (0.13) -0.33 (0.14) 0.58 (< 0.01)*

PA [mm] -0.07 (0.76) 0.44 (< 0.05) -0.57 (< 0.01)*

* p < 0.01

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Figure 5.3: Correlation between corneal vectors M (D) and J0 (D) and parameters

describing anterior eye morphology (mm).

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239

J0 was moderately correlated with upper eyelid height (C) for both non-amblyopic

(r = -0.55, p = 0.01) and amblyopic eyes (r = -0.55, p < 0.01) (Figure 5.3). J45 was

also correlated with upper eyelid height (C) for non-amblyopic eyes (r = -0.52, p =

0.02), whereas for the amblyopic eyes J45 was significantly correlated with lower

eyelid height (C) (r = 0.59, p < 0.01). We also investigated the correlation between

the interocular difference in palpebral aperture and eyelid parameters and the

interocular differences in corneal vectors M, J0 and J45 (Table 5.9). Significant

correlations were observed for the interocular differences in J45 and PC_LL (r =

0.58, p < 0.01) and J45 and vertical palpebral aperture (r = -0.57, p < 0.01).

55..33..66 CCoorrnneeaall aabbeerrrraattiioonnss

There was a moderate degree of interocular symmetry for corneal aberrations up to

the fourth order, more so over the larger 6 mm analysis diameter. When all

subjects were included in the analysis (n = 20 for the Medmont data) amblyopic

eyes typically had slightly greater amounts of third and higher-order RMS values

compared to the fellow eyes, however, these differences did not reach statistical

significance (Tables 5.10 and 5.11). Examination of the refractive amblyopes

separately (n= 8) revealed a similar trend; greater amounts of third, fourth and

higher-order RMS values in the amblyopic eyes, which reached statistical

significance for 4th and total higher-order RMS over the 6 mm analysis diameter.

Strabismic amblyopes (n = 11) displayed a different trend, with greater third, fourth

and total higher-order RMS values in the non-amblyopic eye over both analysis

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240

diameters. These interocular RMS differences did not reach statistical significance

for the strabismic amblyopes.

Examination of individual Zernike terms used to describe the corneal wavefront

revealed several small but statistically significant differences between fellow eyes.

Figure 5.4 displays the Zernike wavefront coefficients of the third and fourth order

terms for the amblyopic and non-amblyopic eyes. For the 6 mm corneal diameter

(all amblyopes), there were significant differences between fellow eyes for

horizontal coma C(3,1) and trefoil C(3,3). Strabismic subjects displayed a similar

interocular difference in corneal aberrations with a significantly higher level of

horizontal coma C(3,1) in the amblyopic eye. Refractive amblyopes did not exhibit

the same interocular differences in third order terms, rather, they displayed

significant interocular differences in fourth order terms C(4,2) secondary

astigmatism, C(4,-2) secondary astigmatism along 45 degrees and C(4,0) spherical

aberration. The amblyopic eyes of the refractive amblyopes had significantly more

positive spherical aberration and significantly less (greater negative values) of the

secondary astigmatic terms. These interocular differences in Zernike coefficients

observed for all amblyopes, strabismic amblyopes and refractive amblyopes were

consistent over 4 and 6 mm corneal diameters.

The correlation between the interocular difference in corneal aberrations for each

Zernike coefficient up to the fourth order and the degree of spherical equivalent

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241

anisometropia are presented in Table 5.12. The strongest correlations were

observed for third order Zernike term C(3,1) horizontal coma for the analysis of all

amblyopes and strabismic amblyopes over both 4 and 6 mm corneal diameters

(Figure 5.5). However, there was no correlation between the interocular difference

in horizontal coma and the magnitude of amblyopia for all amblyopes (r = 0.32, p =

0.16) or strabismic amblyopes (r = 0.36, p = 0.11).

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242

Figure 5.4: Third and fourth order mean Zernike corneal wavefront coefficients

(microns) for the amblyopic and non-amblyopic eyes (6 mm analysis). Error bars

represent the standard deviation of the mean. * Statistically significant interocular

differences (p < 0.05). (Note: “All amblyopes” includes n = 1 form deprivation

amblyope not included in Strabismic or Refractive amblyope plots).

* * * * * *

All amblyopes Strabismic amblyopes Refractive amblyopes

(n = 20) (n = 11) (n = 8)

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Table 5.10: Corneal aberrations (Zernike coefficients) for the amblyopic and non-amblyopic eyes (4 mm analysis).

All amblyopes (n = 20) Strabismic amblyopes (n = 11) Refractive amblyopes (n = 8)

Z Term Amblyopic

(Mean ± SD) Non-amblyopic

(Mean ± SD) Paired

t-test (p) Symmetry Amblyopic


(Mean ± SD) Paired



(Mean ± SD) Paired

t-test (p) Symmetry

r p r p r p

(3,-3) 0.019 ± 0.102 0.014 ± 0.042 0.82 0.15 0.53 -0.007 ± 0.039 0.014 ± 0.039 0.09 0.59 0.07 0.003 ± 0.048 0.013 ± 0.053 0.61 0.46 0.25

(3,-1) -0.048 ± 0.130 -0.052 ± 0.046 0.89 0.12 0.61 -0.013 ± 0.056 -0.060 ± 0.054 0.03 0.46 0.18 -0.034 ± 0.039 -0.043 ± 0.041 0.65 0.03 0.94

(3,1) -0.049 ± 0.063 -0.028 ± 0.055 0.11 0.51 0.02 -0.044 ± 0.051 -0.034 ± 0.052 0.64 0.32 0.37 -0.062 ± 0.039 -0.037 ± 0.044 0.17 0.38 0.35

(3,3) 0.014 ± 0.043 -0.011 ± 0.064 0.03* 0.64 < 0.01 0.010 ± 0.046 -0.030 ± 0.082 0.07 0.70 0.02 0.015 ± 0.037 0.007 ± 0.034 0.52 0.57 0.14

(4,-4) 0.002 ± 0.030 0.006 ± 0.016 0.61 0.09 0.71 -0.007 ± 0.007 0.011 ± 0.018 0.01 0.12 0.74 0.000 ± 0.021 0.000 ± 0.014 0.94 0.59 0.12

(4,-2) -0.010 ± 0.027 0.000 ± 0.012 0.09 0.30 0.20 -0.002 ± 0.013 -0.003 ± 0.010 0.96 0.21 0.56 -0.006 ± 0.021 0.006 ± 0.015 0.06 0.38 0.35

(4,0) 0.041 ± 0.015 0.039 ± 0.021 0.62 0.71 < 0.001 0.047 ± 0.013 0.046 ± 0.019 0.83 0.65 0.04 0.032 ± 0.014 0.024 ± 0.011 0.08 0.66 0.07

(4,2) -0.005 ± 0.023 -0.002 ± 0.028 0.56 0.55 0.01 -0.008 ± 0.025 -0.013 ± 0.027 0.59 0.47 0.17 0.003 ± 0.019 0.015 ± 0.026 0.06 0.79 0.02

(4,4) 0.008 ± 0.026 -0.003 ± 0.016 0.10 0.10 0.67 0.006 ± 0.014 0.000 ± 0.014 0.16 0.62 0.06 -0.001 ± 0.011 -0.009 ± 0.018 0.33 0.04 0.93

3rd order RMS 0.136 ± 0.141 0.111 ± 0.055 0.49 -0.14 0.56 0.106 ± 0.026 0.127 ± 0.061 0.36 -0.24 0.50 0.104 ± 0.033 0.093 ± 0.051 0.58 0.31 0.45

4th Order RMS 0.062 ± 0.038 0.058 ± 0.026 0.59 0.38 0.10 0.061 ± 0.017 0.063 ± 0.022 0.77 0.33 0.35 0.048 ± 0.012 0.046 ± 0.030 0.85 0.51 0.20

Total HOA RMS 0.160 ± 0.147 0.136 ± 0.059 0.51 -0.06 0.80 0.134 ± 0.028 0.154 ± 0.062 0.41 -0.21 0.56 0.120 ± 0.028 0.113 ± 0.058 0.74 0.17 0.69

Greyed cells - Zernike terms displaying significant between eye differences for either all amblyopes, strabismic amblyopes or refractive amblyopes. Bold cells - interocular difference p < 0.05

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Table 5.11: Corneal aberrations (Zernike coefficients) for the amblyopic and non-amblyopic eyes (6 mm analysis).


Z Term Amblyopic


(Mean ± SD) Paired



(Mean ± SD) Paired



(Mean ± SD) Paired

t-test (p) Symmetry

r p r p r p

(3,-3) 0.043 ± 0.168 0.050 ± 0.137 0.89 0.04 0.87 0.018 ± 0.096 0.065 ± 0.160 0.49 -0.21 0.56 0.016 ± 0.144 0.058 ± 0.121 0.16 0.86 < 0.01

(3,-1) --0.202 ± 0.369 -0.177 ± 0.192 0.78 0.13 0.58 -0.135 ± 0.201 -0.210 ± 0.254 0.38 0.38 0.28 -0.144 ± 0.085 -0.164 ± 0.098 0.67 0.06 0.89

(3,1) -0.180 ± 0.194 -0.105 ± 0.167 0.04* 0.65 0.002 -0.163 ± 0.158 -0.113 ± 0.144 0.26 0.62 0.06 -0.231 ± 0.139 -0.159 ± 0.136 0.21 0.44 0.28

(3,3) 0.048 ± 0.140 -0.033 ± 0.179 0.005* 0.76 < 0.001 0.041 ± 0.139 -0.091 ± 0.232 0.009* 0.88 < 0.001 0.016 ± 0.102 -0.001 ± 0.056 0.37 0.94 < 0.01

(4,-4) 0.011 ± 0.045 0.007 ± 0.048 0.68 0.56 0.01 0.003 ± 0.004 0.007 ± 0.060 0.76 0.58 0.08 0.018 ± 0.048 0.003 ± 0.039 0.21 0.77 < 0.05

(4,-2) -0.058 ± 0.120 -0.003 ± 0.027 0.05 0.34 0.14 -0.030 ± 0.042 -0.004 ± 0.023 0.11 0.11 0.76 -0.033 ± 0.033 0.006 ± 0.027 0.001* 0.80 < 0.05

(4,0) 0.182 ± 0.068 0.184 ± 0.108 0.90 0.73 < 0.001 0.178 ± 0.083 0.202 ± 0.124 0.43 0.68 0.03 0.169 ± 0.042 0.130 ± 0.045 0.0002* 0.94 < 0.01

(4,2) -0.015 ± 0.080 -0.001 ± 0.122 0.57 0.49 0.03 0.008 ± 0.071 -0.023 ± 0.115 0.46 0.57 0.09 -0.13 ± 0.055 0.049 ± 0.063 0.006* 0.73 < 0.05

(4,4) 0.014 ± 0.065 -0.007 ± 0.081 0.27 0.38 0.10 -0.004 ± 0.066 -0.018 ± 0.114 0.66 0.51 0.13 0.013 ± 0.020 0.001 ± 0.026 0.29 0.13 0.76

3rd order RMS 0.440 ± 0.341 0.371 ± 0.163 0.97 0.36 0.12 0.381 ± 0.131 0.448 ± 0.175 0.46 -0.61 0.06 0.353 ± 0.070 0.294 ± 0.123 0.12 0.65 0.08

4th Order RMS 0.249 ± 0.113 0.250 ± 0.108 0.97 0.36 0.12 0.249 ± 0.048 0.301 ± 0.111 0.26 -0.40 0.25 0.196 ± 0.032 0.166 ± 0.033 0.05 0.36 0.38

Total HOA RMS 0.534 ± 0.357 0.474 ± 0.194 0.53 -0.04 0.87 0.493 ± 0.134 0.573 ± 0.216 0.45 -0.64 0.05 0.417 ± 0.066 0.355 ± 0.110 0.04* 0.78 < 0.05

Greyed cells - Zernike terms displaying significant between eye differences for either all amblyopes, strabismic amblyopes or refractive amblyopes. Bold cells - interocular difference p < 0.05

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Table 5.12: Correlation analysis of interocular difference in corneal aberrations

(Zernike coefficients) (microns) and the magnitude of spherical equivalent

anisometropia (D).


Corneal diameter 4 mm 6 mm 4 mm 6 mm 4 mm 6 mm

Zernike term r p r p r p r p r p r p

(3,-3) 0.33 0.15 0.31 0.18 -0.42 0.23 -0.06 0.87 0.38 0.35 0.50 0.21

(3,-1) -0.29 0.21 -0.41 0.07 0.40 0.25 -0.07 0.85 -0.23 0.58 -0.58 0.13

(3,1) -0.54 0.01* -0.55 0.01* -0.57 0.07 -0.54 0.09 -0.30 0.47 -0.39 0.34

(3,3) -0.07 0.77 0.29 0.21 -0.16 0.66 0.05 0.89 -0.29 0.49 0.14 0.74

(4,-4) 0.29 0.21 0.09 0.71 0.28 0.43 0.03 0.93 -0.39 0.34 -0.27 0.52

(4,-2) -0.29 0.21 -0.34 0.14 0.33 0.35 0.09 0.80 -0.39 0.34 -0.25 0.55

(4,0) -0.05 0.83 -0.31 0.18 0.16 0.66 -0.26 0.47 -0.08 0.85 0.08 0.85

(4,2) -0.38 0.10 0.05 0.83 -0.28 0.43 0.39 0.27 -0.31 0.45 -0.66 0.07

(4,4) 0.42 0.07 -0.04 0.87 -0.01 0.98 -0.42 0.23 0.44 0.28 0.18 0.67

RMS 3rd order 0.37 0.11 0.36 0.12 0.19 0.60 -0.07 0.85 -0.03 0.94 0.62 0.10

RMS 4th order 0.31 0.18 0.15 0.53 0.48 0.16 -0.02 0.96 -0.51 0.20 -0.32 0.44

RMS Higher-order 0.38 0.10 0.35 0.13 0.35 0.32 0.02 0.96 -0.15 0.72 0.50 0.21


interocular difference in corneal wavefront Zernike coefficient of primary horizontal

coma C(3, 1) (microns) (6 mm analysis).

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Valid data was obtained for 21 amblyopic subjects during distance fixation and 11

subjects (5 strabismic and 6 refractive amblyopes) during near fixation. Zernike

wavefront coefficients and RMS values for the amblyopic and non-amblyopic eyes

are presented in Table 5.13 along with the interocular symmetry correlation

coefficients, averaged over a 4 mm pupil diameter for both distance and near

fixation measurements. There was a moderate degree of symmetry for Zernike

coefficients between the fellow eyes. There were no statistically significant

differences between mean Zernike coefficients for the amblyopic and non-

amblyopic eyes, however, 4th order RMS values were significantly greater in the

amblyopic eyes (0.025 ± 0.011 μm) compared to fellow eyes (0.021 ± 0.008 μm) (p =

0.02). In a similar fashion to the corneal aberrations, amblyopic eyes displayed

higher levels of trefoil C(3,3) which approached statistical significance for the

analysis including all subjects (p = 0.09) and strabismic amblyopes alone (p = 0.05).

The correlations between the interocular difference in individual Zernike

coefficients up to the 4th order and the magnitude of anisometropia are displayed

in Table 5.14. For the analysis including all subjects, the interocular difference in

spherical aberration, 3rd, 4th and higher-order RMS increased in direct proportion

with the magnitude of anisometropia (p ≤ 0.05). The same trend for spherical

aberration was observed in the strabismic subjects, but there were no significant

correlations between interocular differences in Zernike coefficients and

anisometropia in the refractive amblyope cohort. There were no significant

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correlations between the interocular differences in Zernike coefficients and the

magnitude of amblyopia.

During near fixation (2.5 D accommodative demand) the spherical component of

refraction and spherical aberration C(4,0) changed significantly from distance

fixation levels in both the amblyopic and fellow eyes of the subjects (Table 5.15).

On average, spherical aberration shifted in the negative direction in both amblyopic

(-0.013 ± 0.017 microns) and non-amblyopic eyes (-0.020 ± 0.024 microns). This

magnitude of change was not statistically different between fellow eyes. The

change in the spherical component of refraction and best sphere M was

significantly different between the fellow eyes. Although both eyes displayed a lag

of accommodation for a 2.5 D stimulus, non-amblyopic eyes exhibited a significantly

larger accommodative response (change in spherical component) (1.76 ± 0.71 D)

compared to amblyopic eyes (1.04 ± 1.11 D) (p < 0.05). There was a moderate

correlation between the interocular difference in accommodative response with

the magnitude of spherical equivalent anisometropia which approached statistical

significance (r = -0.52, p = 0.10). The between eye difference in accommodative

response was significantly correlated with the magnitude of amblyopia (r = -0.69, p

= 0.02) (Figure 5.6).

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Table 5.13: Total monochromatic aberrations for the amblyopic and non-amblyopic eyes (distance fixation) (4 mm pupil diameter).


Z Term Amblyopic



Symmetry Amblyopic (Mean ± SD)

Non-amblyopic (Mean ± SD)

Paired t-test

Symmetry Amblyopic (Mean ± SD)

Non-amblyopic (Mean ± SD)

Paired t-test

Symmetry

r p r p r p

(3,-3) 0.004 ± 0.065 0.003 ± 0.047 0.94 0.49 0.02 -0.011 ± 0.060 0.007 ± 0.059 0.30 0.60 0.05 0.009 ± 0.049 -0.002 ± 0.037 0.38 0.72 < 0.05

(3,-1) -0.031 ± 0.050 -0.028 ± 0.052 0.81 0.41 0.06 -0.028 ± 0.056 -0.040 ± 0.047 0.48 0.48 0.14 -0.031 ± 0.040 -0.015 ± 0.063 0.46 0.43 0.29

(3,1) -0.006 ± 0.059 0.013 ± 0.060 0.19 0.42 0.06 0.006 ± 0.032 0.019 ± 0.061 0.55 -0.13 0.70 -0.023 ± 0.047 -0.011 ± 0.052 0.18 0.90 < 0.01

(3,3) 0.032 ± 0.069 0.005 ± 0.059 0.09 0.41 0.06 0.029 ± 0.043 -0.004 ± 0.072 0.05 0.74 < 0.01 0.008 ± 0.030 0.010 ± 0.045 0.92 0.38 0.35

(4,-4) -0.005 ± 0.020 0.002 ± 0.013 0.18 -0.19 0.41 -0.006 ± 0.021 0.004 ± 0.014 0.30 -0.71 < 0.05 0.000 ± 0.017 -0.001 ± 0.014 0.80 0.78 0.02

(4,-2) -0.002 ± 0.018 -0.001 ± 0.011 0.82 0.03 0.90 -0.003 ± 0.014 -0.001 ± 0.010 0.66 -0.26 0.44 0.004 ± 0.021 -0.002 ± 0.015 0.53 0.20 0.63

(4,0) 0.031 ± 0.028 0.029 ± 0.024 0.59 0.74 < 0.001 0.030 ± 0.021 0.030 ± 0.022 0.94 0.47 0.14 0.033 ± 0.040 0.026 ± 0.031 0.27 0.92 0.001

(4,2) -0.005 ± 0.027 -0.001 ± 0.021 0.44 0.49 0.02 -0.013 ± 0.027 -0.013 ± 0.016 0.95 0.70 < 0.05 0.005 ± 0.027 0.019 ± 0.009 0.25 -0.31 0.46

(4,4) 0.017 ± 0.017 0.012 ± 0.013 0.26 0.18 0.43 0.017 ± 0.015 0.019 ± 0.010 0.70 0.54 0.09 0.011 ± 0.008 0.005 ± 0.014 0.30 0.04 0.93

3rd order RMS 0.053 ± 0.036 0.052 ± 0.020 0.92 -0.21 0.36 0.048 ± 0.020 0.058 ± 0.022 0.25 0.09 0.79 0.042 ± 0.016 0.046 ± 0.016 0.67 -0.33 0.42

4th Order RMS 0.025 ± 0.011 0.021 ± 0.008 0.02 0.59 < 0.01 0.024 ± 0.009 0.021 ± 0.008 0.27 0.49 0.13 0.026 ± 0.012 0.021 ± 0.008 0.09 0.77 0.03

Total HOA RMS 0.132 ± 0.068 0.128 ± 0.039 0.80 -0.14 0.55 0.121 ± 0.035 0.140 ± 0.038 0.16 0.35 0.29 0.113 ± 0.038 0.116 ± 0.039 0.87 0.11 0.80

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Table 5.14: Correlations analysis for the interocular difference in total

monochromatic aberrations (Zernike coefficients) (microns) and spherical

equivalent anisometropia (D) (4 mm pupil diameter).



(3,-3) 0.10 0.67 -0.50 0.12 0.54 0.17

(3,-1) 0.21 0.36 0.82 < 0.01 -0.19 0.65

(3,1) -0.03 0.90 0.36 0.28 -0.04 0.93

(3,3) 0.44 0.05 0.39 0.24 -0.02 0.96

(4,-4) -0.05 0.83 0.17 0.62 -0.23 0.58

(4,-2) -0.27 0.24 -0.23 0.50 0.00 1.00

(4,0) 0.45 < 0.05 0.90 < 0.001 -0.04 0.93

(4,2) -0.10 0.67 -0.60 0.05 0.02 0.96

(4,4) 0.04 0.86 -0.43 0.19 -0.24 0.57

3rd order RMS 0.45 < 0.05 0.51 0.11 -0.12 0.78

4th Order RMS 0.43 0.05 0.49 0.13 0.00 1.00

Total HO RMS 0.45 < 0.05 0.57 0.07 -0.04 0.93

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Table 5.15: Lower (D) and higher-order monochromatic aberrations (microns) during distance and near fixation for the amblyopic and

non-amblyopic eyes (n = 11) (4 mm pupil diameter).

Distance fixation Near fixation (2.5 D demand) Change from distance fixation Magnitude of change

between eyes #

Z Term Amblyopic

(Mean ± SD)

Non-amblyopic

(Mean ± SD)

Paired t-test

Amblyopic (Mean ± SD)

Non-amblyopic

(Mean ± SD)

Paired t-test

Amblyopic (Mean ± SD)

Paired t-test

Non-amblyopic

(Mean ± SD)

Paired t-test

Paired t-test

Sphere 1.71 ± 2.87 -0.12 ± 2.07 0.02 0.67 ± 3.30 -1.89 ± 2.33 0.01 -1.04 ± 1.11 0.01 -1.76 ± 0.71 < 0.0001* 0.04*

Cyl -0.99 ± 0.71 -0.79 ± 0.26 0.35 -0.96 ± 0.73 -0.72 ± 0.32 0.26 0.03 ± 0.10 0.38 0.07 ± 0.11 0.07 0.39

M 1.22 ± 2.87 -0.52 ± 2.09 0.01* 0.19 ± 3.23 -2.25 ± 2.33 0.01* -1.02 ± 1.09 0.01 -1.73 ± 0.70 < 0.0001* 0.05

(3,-3) 0.023 ± 0.064 0.002 ± 0.047 0.33 0.021 ± 0.056 0.005 ± 0.044 0.41 -0.002 ± 0.014 0.71 0.004 ± 0.016 0.47 0.46

(3,-1) -0.048 ± 0.049 -0.027 ± 0.051 0.23 -0.055 ± 0.048 -0.041 ± 0.048 0.47 -0.007 ± 0.026 0.39 -0.015 ± 0.024 0.07 0.44

(3,1) 0.001 ± 0.068 0.017 ± 0.046 0.42 -0.002 ± 0.071 0.000 ± 0.032 0.89 -0.004 ± 0.017 0.49 -0.016 ± 0.024 0.04* 0.17

(3,3) 0.046 ± 0.086 0.011 ± 0.056 0.19 0.040 ± 0.091 0.013 ± 0.051 0.25 -0.005 ± 0.014 0.23 0.002 ± 0.025 0.77 0.40

(4,-4) 0.000 ± 0.016 0.006 ± 0.007 0.19 -0.002 ± 0.017 0.007 ± 0.007 0.21 -0.001 ± 0.010 0.64 0.001 ± 0.010 0.66 0.51

(4,-2) -0.005 ± 0.018 -0.001 ± 0.008 0.42 -0.005 ± 0.016 0.002 ± 0.010 0.15 -0.000 ± 0.006 0.87 0.002 ± 0.008 0.36 0.43

(4,0) 0.020 ± 0.029 0.026 ± 0.030 0.23 0.007 ± 0.031 0.006 ± 0.038 0.93 -0.013 ± 0.017 0.03 -0.020 ± 0.024 0.02* 0.34

(4,2) -0.002 ± 0.019 0.002 ± 0.020 0.62 -0.001 ± 0.019 -0.001 ± 0.014 0.99 0.001± 0.008 0.67 -0.003 ± 0.013 0.40 0.40

(4,4) 0.018 ± 0.021 0.008 ± 0.010 0.20 0.018 ± 0.029 0.014 ± 0.016 070 0.000 ± 0.012 0.93 0.005 ± 0.011 0.14 0.29

3rd order RMS 0.058 ± 0.047 0.047 ± 0.019 0.49 0.057 ± 0.051 0.045 ± 0.018 0.45 -0.001 ± 0.009 0.63 -0.002 ± 0.012 0.51 0.81

4th Order RMS 0.021 ± 0.010 0.019 ± 0.009 0.42 0.022 ± 0.009 0.019 ± 0.010 0.34 0.001 ± 0.006 0.70 -0.001 ± 0.011 0.88 0.62

Total HOA RMS 0.133 ± 0.092 0.113 ± 0.033 0.53 0.136 ± 0.096 0.111 ± 0.025 0.44 0.003 ± 0.019 0.60 -0.001 ± 0.023 0.86 0.52

* statistically significant change, # Paired t-test comparing the magnitude of change between fellow eyes.

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Figure 5.6: Correlation between the interocular difference in accommodative

response (D) and spherical equivalent anisometropia (D) (top panel) and magnitude

of amblyopia (logMAR) (bottom panel). Interocular differences calculated as

amblyopic minus non-amblyopic eye.

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This study provides a comprehensive examination of the optical and biomechanical

properties of amblyopic and their fellow non-amblyopic eyes which have

experienced asymmetric visual input during development. We examined the

interocular symmetry of a range of other biometric and optical measurements to

improve our understanding of asymmetric eye growth. We observed a moderate

degree of interocular symmetry between the fellow eyes; however there were also

significant differences between the fellow eyes for several ocular parameters.

The magnitude of anisometropia was strongly correlated with the interocular

difference in axial length in our cohort of subjects. Given the symmetry of the

anterior segment biometrics, this suggests that an interocular difference in the

length of the posterior eye is the primary cause of asymmetric refractive errors in

anisometropic amblyopia. The amblyopic eye was typically shorter than the fellow

non-amblyopic eye suggesting that the disruption of visual input resulted in axial

retardation rather than excessive axial elongation. Our findings show a higher

correlation between interocular axial length difference and anisometropia (r = 0.96)

compared to a previous study of untreated amblyopes (Zaku-Ur-Rab 2006). Zaku-

Ur-Rab (2006) reported correlations of r = 0.61 and 0.67 for the association

between interocular difference in axial length and magnitude of anisometropia in

hyperopic and myopic amblyopes respectively. This may be due to the different

amblyopic populations studied; the mean interocular difference in visual acuity for

our subjects was 0.37 ± 0.39 logMAR compared to a larger difference in visual

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acuity of 0.64 ± 0.36 logMAR for the hyperopes and 0.42 ± 0.22 logMAR for the

myopes in the populations studied by Zaka-Ur-Rab (2006). As the magnitude of

amblyopia increases, interocular differences in other parameters such as corneal or

intraocular lens power may potentially make a greater contribution to the

magnitude of anisometropia. However, in our cohort of amblyopes, although

anterior corneal astigmatism was, on average, greater in amblyopic eyes, there

were no significant correlations between the magnitude of amblyopia and

interocular differences in corneal power, shape or biometric measures such as

corneal thickness.

There was a high degree of interocular symmetry in our cohort of amblyopic

subjects for measures of palpebral aperture dimensions, corneal diameter and pupil

size during primary gaze. Upper eyelid shape factors were not as highly correlated

between fellow eyes compared to the descriptors of lower eyelid shape. A high

degree of mirror symmetry between fellow eyes has been reported in various

populations of unspecified refractive errors (Lam et al 1995, Cartwright et al 1994)

and also in our cohort of non-amblyopic anisometropes in Chapter 3.

We observed a significant difference between vertical palpebral aperture size of

amblyopic and non-amblyopic eyes primarily due to the interocular difference in

upper lid position. Differences in eyelid position between the two eyes could

potentially promote asymmetric eye growth. Congenital unilateral ptosis

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(interocular asymmetry in eyelid position) may result in amblyopic anisometropia

(Beneish et al 1983, Hornblass et al 1995, Gusek-Schneider and Martus 2000). Form

deprivation associated with partial eyelid closure in humans (O’Leary and Millodot

1979) and lid suturing in animal models of refractive error development (Langford

et al 1998) typically leads to axial myopia and astigmatism with amblyopia. The

visual effects of the narrower palpebral aperture in the amblyopic eyes however

are likely to be small given that the magnitude of difference in lid position between

the amblyopic and non-amblyopic eyes was small (~ 0.3 mm). This could potentially

be a result of a reduction in central (higher order) input to the eyelids as a result of

mal-development of the visual pathway, similar to abnormalities in pupil size and

accommodation reported in some amblyopic patients.

Although we found no correlation between the interocular differences of any of the

eyelid morphological dimensions and the magnitude of anisometropia or

amblyopia, we did observe significant correlations between the interocular

difference in anterior eye morphology and interocular differences in the corneal

refractive power vectors M, J0 and J45 which have been observed previously in

normal populations (Shaw et al 2008, Read et al 2007). However, the lack of

association with the magnitude of anisometropia and amblyopia suggests that the

interocular differences in eyelid parameters we observed may be a consequence

rather than a cause of asymmetric refractive error development.

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Asymmetry in pupil size (anisocoria) or an interocular difference in the quality and

size of the fundus reflex is often used as a screening technique for interocular

differences in refractive errors or ocular misalignment in children (Tongue and Cibis

1981). In our cohort of amblyopic subjects, pupil dimensions were highly

symmetrical between the amblyopic and non-amblyopic eyes. Overall, anterior eye

biometrics were highly correlated between fellow eyes and the only distinguishable

feature between the amblyopic and fellow non-amblyopic eyes by external

examination of the ocular adnexae was, on average, a slightly narrower vertical

palpebral aperture width in the amblyopic eye (0.18 mm).

A high degree of symmetry exists between fellow eyes for corneal power, corneal

thickness and anterior chamber depth in amblyopic eyes (Holden et al 1985, Weiss

2003). We observed no significant differences between the fellow eyes of our

amblyopic subjects with respect to corneal thickness and anterior chamber depth,

although there was a small (5 mm3) interocular difference in mean anterior

chamber volume between the fellow eyes which approached statistical significance.

This suggests that the asymmetric visual input experienced by our subjects during

development primarily alters posterior eye growth. Manipulation of visual

experience in animal models has been shown to alter corneal astigmatism, and the

increase in astigmatism has been shown to correlate well with the magnitude of

change in spherical ametropia (Kee et al 2008). We also found that the magnitude

of anterior corneal astigmatism was significantly greater in amblyopic eyes

compared to fellow eyes which is in agreement with the findings of Plech et al

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256

(2010). However, studies of children with severe anisometropia have also shown

that corneal power is relatively similar between the amblyopic and fellow eye,

when excluding cases of meridional (astigmatic) amblyopia (Weiss 2003, Patel et al

2010). We observed no correlation between the interocular difference in corneal

power (for either meridian) or corneal astigmatism and the magnitude of

anisometropia or amblyopia which has been reported in a larger study of myopic

and hyperopic monocular amblyopes (Zaka-Ur-Rab 2006).

Corneal astigmatism has been shown to be correlated with various eyelid

parameters in normal populations (Read et al 2007) and subjects with eyelid or

palpebral aperture abnormalities (Haugen et al 2001) which supports a potential

mechanical influence of the eyelids on the cornea contributing to corneal

astigmatism. In our amblyopic subjects, we found significant correlations between

certain parameters of eyelid morphology and corneal refractive power vectors.

Smaller palpebral apertures and a lower eyelid position closer to the pupil centre

were associated with steeper values of corneal M. An upper eyelid position closer

to the pupil centre was associated with a more positive J0 value. These correlations

were observed in both non-amblyopic and amblyopic eyes. J45 was associated with

lower eyelid position for the amblyopic eyes and upper eyelid position for the non-

amblyopic eyes. In a large study of young adults, Read et al (2007) observed similar

relationships between corneal vector M and vertical palpebral aperture height and

J45 and lower eyelid position but did not observe any correlation between J0 and

anterior eye morphology.

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Given the higher magnitude of anterior corneal astigmatism and the greater

amount of upper eyelid ptosis in the amblyopic eyes, we might expect a difference

in the correlations between M, J0 or J45 and upper eyelid term C (eyelid height

above the corneal centre) for the amblyopic and non-amblyopic eyes. However,

correlations involving the upper and lower lid were similar between fellow eyes.

Interestingly, although we observed no significant difference in lower eyelid

position between the fellow eyes (lower eyelid term C and PC_LL), the interocular

difference in lower lid position (along with vertical palpebral aperture) correlated

with the interocular asymmetry in corneal parameters suggesting that asymmetries

in palpebral aperture morphology may play a role in, or be caused by, asymmetric

refractive error development.

There was a high degree of interocular symmetry for measures of corneal

biomechanics. There were no significant differences between the fellow eyes with

respect to group mean corneal resistance and hysteresis and no correlation

between the interocular difference in these parameters and the degree of

anisometropia or amblyopia. Unilateral reduced corneal hysteresis has been

observed previously in cases of high myopic anisometropia (mean 10.82 D

anisometropia) (with or without amblyopia) (Xu et al 2010), however our

amblyopes were primarily hyperopic anisometropes with a lower degree of

anisometropia (mean 1.55 D anisometropia).

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While it has been hypothesised that IOP may play a role in the development of

myopia, to our knowledge, no studies have specifically examined the interocular

symmetry of IOP in an amblyopic population. We measured IOP using an air

impulse technique that is reported to be less influenced by corneal characteristics

in comparison to other applanation tonometry techniques (Medeiros and Weinreb

2006) and compared the fellow eyes of monocular amblyopes to control for

individual variables. We found no significant differences in IOP between the

amblyopic and non-amblyopic eyes and no correlation between the interocular

difference in IOP and the magnitude of anisometropia or amblyopia. Lee and

Edwards (2000) examined the between eye difference in IOP in a cohort of young

anisohyperopes (mean anisometropia 3.5 D) (some of which may have been

amblyopic since visual acuity data was not reported) and also found no significant

difference between the two eyes.

Previous studies have reported a high degree of interocular symmetry of corneal

aberrations in isometropic populations (Wang et al 2003, Lombardo et al 2006) and

also in our cohort of anisometropes in Chapter 2. Plech et al (2010) examined the

interocular differences in corneal higher-order aberrations in unilateral amblyopes

without strabismus and found significantly higher levels of corneal astigmatism in

the amblyopic eye compared to the fellow eye. They observed no statistically

significant differences between fellow eyes for other corneal aberrations including

primary spherical aberration; however the interocular difference in primary coma

RMS approached statistical significance, with higher levels of coma in the non-

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amblyopic eye. They concluded that corneal astigmatism rather than higher-order

corneal aberrations may play a role in the development of refractive amblyopia.

We observed a moderate degree of interocular symmetry for most corneal higher-

order aberrations, which tended to increase as the corneal analysis diameter

increased. Like Plech et al (2010), we observed greater amounts of corneal

astigmatism in the amblyopic eye however, we also found some significant

interocular differences in corneal aberrations between the fellow eyes. Refractive

amblyopes displayed greater amounts of third, fourth and higher-order corneal

RMS values in the amblyopic eyes, whereas strabismic subjects had greater third,

fourth and total higher-order RMS values in the non-amblyopic eye.

Analysis including all subjects revealed significant differences between fellow eyes

for horizontal coma C(3,1) and trefoil C(3,3). Examination of the strabismic subjects

only revealed a similar trend with a significantly higher level of positive horizontal

coma in the amblyopic eye compared to the fellow eye. Refractive amblyopes did

not exhibit the same interocular differences in third order terms but displayed

significant interocular differences in fourth order terms C(4,2) secondary

astigmatism, C(4,-2) secondary astigmatism along 45 degrees and C(4,0) spherical

aberration. These findings suggest that the interocular asymmetry in corneal

aberrations of monocular amblyopes may differ depending on the cause of

amblyopia.

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We undertook additional analyses to investigate whether the interocular

differences observed in primary horizontal coma of the strabismic amblyopes was

due to differences in fixation during the measurement of corneal topography. If

strabismic subjects were fixating eccentrically during topography measurements,

one might expect a larger amount of coma due to the rotation of the eye (visual

axis) relative to the videokeratoscope (measurement axis). We compared the

average horizontal pupil offsets from the Medmont data (the horizontal distance

between the pupil centre and the geometric centre of the cornea) between the

amblyopic and non-amblyopic eye after accounting for enantiomorphism.

Horizontal pupil offsets were not significantly different between the fellow eyes for

strabismic (interocular difference 0.08 ± 0.17 mm) or refractive amblyopes

(interocular difference 0.11 ± 0.23 mm). This supports the assumption that fixation

was controlled in the amblyopic eyes during measurement procedures and

confirms the central monocular fixation found with direct ophthalmoscopy in the

subject screening process. In addition, no significant correlations were found

between the horizontal pupil offset and the amount of primary horizontal coma or

trefoil for the amblyopic and non-amblyopic eyes of both refractive and strabismic

subjects. These findings suggest the interocular differences observed in the

strabismic amblyopes were not an artefact of eccentric fixation in the amblyopic

eye.

It has been reported previously that extraocular muscle tension may influence

refractive astigmatism (Bagheri et al 2003). To investigate the potential role of

extraocular muscle tension producing changes in corneal topography and larger

Chapter 5

261

amounts of coma in the amblyopic eye of the strabismic subjects, we examined the

relationship between the magnitude of horizontal deviation strabismus (measured

by prism cover test) and the amount of primary horizontal corneal coma; however

the correlation was not statistically significant (r = -0.07, p >0.05). In addition, we

observed no significant difference in the magnitude of third or fourth order

aberrations in the amblyopic eyes of strabismic subjects who had undergone

strabismus surgery and those who had not (p > 0.05, unpaired t-test). Given the

lack of association between the interocular difference in corneal aberrations and

the magnitude of amblyopia in our subjects, it is likely that between eye differences

in corneal aberrations is a result of asymmetric eye growth rather than a cause.

A moderate degree of interocular symmetry was also observed between the fellow

eyes for total monochromatic aberrations. There were no statistically significant

differences between mean Zernike coefficients for the amblyopic and non-

amblyopic eyes, however, as for the corneal aberrations, amblyopic eyes displayed

higher levels of trefoil C(3,3) which approached statistical significance. Similarly,

Kirwan and O’Keefe (2008) reported that in children with unilateral amblyopia, the

affected eye displayed higher levels of total higher-order RMS, and higher levels of

individual Zernike terms up to the 6th radial order; however these interocular

differences did not reach statistical significance. This trend was observed when

analysing all subjects, or separating them into strabismic and refractive amblyopes

as we have in our aberration analysis. In a study of children with idiopathic

amblyopia Prakash et al (2011) also found no significant differences between the

Chapter 5

262

non-amblyopic and amblyopic eyes for the mean values of the Zernike coefficients

from the 3rd to 5th order.

When including all subjects we also observed significant correlations between the

interocular difference in spherical aberration, 3rd, 4th and higher-order RMS and the

magnitude of anisometropia. When examining the strabismic subjects separately,

this trend was observed only for Zernike terms C(3,-1) and C(4,0). These significant

correlations suggest that subtle interocular differences in ocular aberrations may be

associated with asymmetric refractive errors, more so in strabismic than refractive

amblyopes. Recently, Coletta et al (2010) reported that form deprived eyes of

marmosets had significantly higher levels of trefoil C(3,-3) and 5th and 7th order RMS

compared to their fellow control eyes. In addition, the magnitude of anisometropia

induced following form deprivation was significantly correlated with the interocular

difference in RMS values for 5th and 6th order aberrations. While several chick

studies using a monocular deprivation paradigm have demonstrated an increase in

aberrations following monocular altered visual experience (Garcia de la Cera et al

2006, Kisilak et al 2006, Tian and Wildsoet 2006), the study of Coletta et al (2010) is

the first to report an association between the magnitude of induced anisometropia

and the interocular difference in higher-order aberrations. We observed a similar

trend in our experiment for both corneal (positive coma) and total (trefoil along

30˚) aberrations. In a large study of children, Zhao et al (2010) also suggested that

comatic aberrations may be associated with amblyopia. Although the interocular

difference in total aberrations was not addressed, the authors observed a

significant negative correlation between C(3,-1) and best corrected visual acuity in

Chapter 5

263

refractive amblyopes (r = -0.59, p = 0.009) suggesting that primary vertical coma

may contribute to the reduction of visual acuity in children with refractive

amblyopia.

Given that animal studies have shown an increase in higher order aberrations

following altered visual experience, it is likely that the variations we observed in the

aberration profile associated with amblyopia type and magnitude are a result of

abnormal eye growth rather than a cause. However, future studies of ocular

changes in response to alterations in higher order aberrations (without altering

lower order terms) using customised contact lenses, or laser assisted ablation in

animal models, may provide additional information regarding the potential causal

nature of the relationship.

We also measured the total aberrations of the amblyopic and fellow eye during

near fixation in a small subgroup of the amblyopes. Overall, higher-order

aberrations did not change significantly during accommodation, except for spherical

aberration which underwent a negative shift of similar magnitude in both

amblyopic and non-amblyopic eyes. To our knowledge, the change or interocular

symmetry of higher-order aberrations during accommodation in amblyopic eyes

has not been investigated previously.

Chapter 5

264

We also observed a significant asymmetry in the lag of accommodation for a 2.5 D

stimulus. While studies have suggested that a lag of accommodation may be

associated with the development of myopia due to hyperopic retinal defocus

(Gwiazda et al 1993, Gwiazda et al 1995b), we observed a greater lag in the

amblyopic (more hyperopic) eyes (mean lag 1.46 ± 1.11 D) compared to the fellow

non-amblyopic eyes (mean lag 0.74 ± 0.71 D). The reduced accommodative

response in amblyopic eyes has been investigated in detail previously and is

thought to be a result of abnormal visual experience during the development of the

visual pathway which affects the neural input associated with accommodation.

Reduced sensitivity to a defocused retinal image (which typically triggers

accommodation) is also thought to result in reduced accommodative response. Of

interest was the finding that the asymmetry in the accommodative response

between fellow eyes was moderately correlated with the magnitude of

anisometropia and significantly associated with the magnitude of amblyopia. Ukai

et al (1986) reported a similar finding in an early study of accommodation in

amblyopia in which the authors observed a correlation between the

accommodative response and the visual acuity of the amblyopic eye.

Chapter 5

265


In subjects with a history of asymmetric visual experience, the interocular

difference in axial length is the primary cause of refractive anisometropia and also

correlates with the magnitude of amblyopia. While anterior eye biometrics

including corneal thickness and biomechanical properties are moderately

symmetric between the fellow eyes, the magnitude of corneal astigmatism is

typically greater in amblyopic eyes and may be a consequence of refractive error

development or due to eyelid pressure and position. Overall, corneal and total

higher-order aberrations were similar between fellow eyes, but higher levels of

trefoil and coma in the amblyopic eye suggest that non-rotationally symmetric

aberrations may be associated with asymmetric eye growth.

Chapter 6

266

CChhaapptteerr 66:: CCoonncclluussiioonnss

To improve our understanding of factors which influence eye growth and

asymmetric refractive development we have examined the differences between the

fellow eyes of anisometropes (with and without amblyopia). A comprehensive

range of parameters were investigated including biometric, biomechanical and

optical factors (summarised in Figure 6.1).

66..11 SSuummmmaarryy aanndd mmaaiinn ffiinnddiinnggss

66..11..11 MMyyooppiicc aanniissoommeettrrooppiiaa -- ooccuullaarr ddoommiinnaannccee

In Chapter 2 we observed a high degree of symmetry between the fellow eyes of

non-amblyopic myopic anisometropes for a range of biometric, optical and

biomechanical measurements. A key finding in this chapter was that when the

magnitude of myopic anisometropia exceeded 1.75 D, the more myopic eye was

almost always the dominant eye. Although this finding has been reported

previously (Cheng et al 2004a), we undertook further investigations into the optical

and biometric properties of the dominant and non-dominant eyes to determine any

related factors. However, we observed no significant interocular differences

between the dominant and non-dominant eyes for best-corrected visual acuity, or

corneal and total ocular aberrations during relaxed accommodation (Chapter 2) or

following a period of near work (Chapter 3). In Chapter 4, we observed that for

higher levels of anisometropia, the dominant sighting eye showed a slightly greater

accommodative response compared to the fellow non-dominant

Chapter 6

267

Myopic non-amblyopic anisometropia Amblyopic anisometropia (form deprivation example)

Summary of ocular characteristics examined for interocular symmetry:

A: Palpebral aperture morphology, corneal biometrics and biomechanics, corneal optics including higher-order aberrations (Chapters 2-5)

B: Crystalline lens biometrics, accommodative response (Chapter 4)

C: Total ocular higher-order aberrations (Chapters 2-5)

D: Intraocular pressure (Chapters 2 and 5)

Figure 6.1: Diagram of ocular characteristics examined in non-amblyopic and amblyopic anisometropia which may be associated with asymmetric growth.

A B

V

C

D

Axial elongation

Chapter 6

268

eye during a monocular accommodation task. Although this was a small group of

subjects, accommodation and ocular dominance may be related to refractive error

development.

The fact that the more myopic eye is typically the dominant eye in higher levels of

myopic anisometropia seems counterintuitive. In amblyopic eyes, the dominant

eye is the eye with better visual acuity which has experienced normal

emmetropisation and has a lower degree of ametropia. Conversely, in non-

amblyopic myopic anisometropia, the dominant eye tends to be the eye with the

greater refractive error further from emmetropia. However in both amblyopic and

non-amblyopic anisometropia the more myopic eye was typically the dominant eye.

From our study we cannot determine whether ocular dominance influences

anisometropic development, or vice versa. Theories explaining the association

between ocular dominance and myopic anisometropia are outlined in Table 6.1.

One explanation may be that ocular dominance is predetermined genetically

(Zoccolotti 1978). The eye which is then favoured for near work (as genetically

determined) may endure greater amounts of optical blur or mechanical stress

resulting in greater axial elongation and myopia in the dominant eye causing

anisometropia. If this were the case, we might expect to see a greater lag of

accommodation in the dominant eyes of anisometropes. However, we observed a

greater lead of accommodation (Chapter 4). Myopic defocus or a lead of

Chapter 6

269

accommodation should slow myopic progression rather than promote axial

elongation, according to the theory of hyperopic defocus and myopia development

(Gwiazda et al 1995a). Perhaps a larger accommodative response in the more

dominant eye results in a greater amount of force exerted by the ciliary body upon

the eye leading to greater axial elongation. In Chapter 4 we observed slightly

greater axial elongation in dominant eyes compared to non-dominant eyes during

accommodation, however, the magnitude of axial elongation was similar between

high and low anisometropes.

An alternative explanation may be that ocular dominance is influenced by the

development of anisometropia. Beyond a certain degree of anisometropia, the

more myopic eye may be favoured for near work during binocular vision due to the

reduced ocular accommodative demand relative to the fellow eye and thus

dominates during binocular viewing.

In addition, laterality (a preference for the right or left side) may play a role in the

determination of ocular dominance. In Chapter 2 we observed that the right eye

was typically the dominance sighting eye (79% of subjects) and as the magnitude of

anisometropia increased the proportion of right eye dominance also increased

significantly (the same trend observed for the more myopic eye). While we have

focussed our discussion on the relationship between refractive error and ocular

Chapter 6

270

dominance, we do not discount the possibility that laterality may be an important

factor.

66..11..22 MMyyooppiicc aanniissoommeettrrooppiiaa -- nneeaarr wwoorrkk aanndd aaccccoommmmooddaattiioonn

The results of our first experiment did not provide support for an optical or

mechanical association with asymmetric refractive error development. Given the

high degree of symmetry observed between the eyes during distance viewing in

Chapter 2 and the strong association previously reported between near work and

myopia development (Adams and McBrien 1992, Parssinen and Lyyra 1993), we

decided to investigate the symmetry between the fellow eyes of myopic

anisometropes following a period of near work (Chapter 3) and during

accommodation (Chapter 4). A summary of the results of Chapters 2, 3 and 4 are

provided in Table 6.2.

The high degree of symmetry between the fellow eyes for measures of anterior eye

morphology, and corneal biomechanics resulted in symmetrical changes in corneal

and total ocular aberrations following a short reading task. These changes were

related to eyelid shape and position during downward gaze, similar to previous

studies (Buehren et al 2003, Shaw et al 2008). However, this experiment is the first

to report the symmetrical nature of near work induced changes in corneal optics.

While Buehren et al (2005) found greater eyelid effects in myopes compared to

emmetropes and proposed that the associated retinal image degradation may be

Chapter 6

271

Table 6.1: Hypotheses explaining the association between ocular dominance and non-amblyopic myopic anisometropia.

MODEL TYPE GENETICS NEAR WORK OUTCOME

CAUSE

(initially isometropic)

Ocular dominance predetermined1

Dominant eye favoured for distance and near tasks.

Greater accommodative

response in dominant compared to

non-dominant eye.2

Greater ciliary body forces and axial elongation in dominant eye during accommodation (Chapter 4)

Dominant eye becomes more myopic than non-

dominant eye

Lead of accommodation (or less lag) in dominant eye

(Chapter 4)

This should inhibit myopia development

based on retinal defocus theory3

Dominant eye becomes less myopic than non-

dominant eye (not observed)

EFFECT

(initially anisometropic)

Predisposition for anisometropic

growth

Lower ocular accommodative demand in

the more myopic eye of anisometrope

More myopic eye favoured in binocular viewing (less accommodative effort)

Beyond a threshold level of anisometropia, the more myopic eye is

the dominant eye.4 (Chapter 2)

References for Table 6.1:

1. Reiss M, Reiss G. Ocular dominance: some family data. Laterality 1997; 2(1):7-16.

2. Ibi K. Characteristics of dynamic accommodation responses: comparison between the dominant and non-dominant eyes. Ophthalmic Physiol Opt 1997; 17 (1):44-54.

3. Gwiazda J, Bauer J, Thorn F, Held R. A dynamic relationship between myopia and blur-driven accommodation in school-aged children. Vision research 1995; 35(9):1299-304.

4. Cheng CY, Yen MY, Lin HY, Hsia WW, Hsu WM. Association of ocular dominance and anisometropic myopia. Invest Ophthalmolol Vis Sci 2004; 45(8):2856-60.

Chapter 6

272

involved in axial elongation (Buehren et al 2007), we found no significant

differences in the optical quality between the fellow eyes of myopic anisometropes

following a short reading task (due to highly symmetric anterior segments).

In Chapter 3 we also investigated the interocular symmetry of the accommodative

response in a small group of anisometropic subjects and observed that the more

myopic eye displayed a greater lag of accommodation. In Chapter 4 we explored

the interocular symmetry of the optical and biometric changes during

accommodation for 11 myopic anisometropes. The changes in anterior eye

biometrics associated with accommodation were similar between the eyes,

resulting in symmetrical changes in the optical characteristics. However, the more

myopic eyes exhibited slightly greater amounts of axial elongation during

accommodation (although this interocular difference did not reach statistical

significance). Axial elongation during accommodation may be related to the force

exerted by the ciliary body and may contribute to more permanent axial elongation

and myopia development. The small asymmetry in axial elongation we observed

between the eyes may be related to interocular differences in posterior eye

structure, given that the accommodative response was equal between eyes.

Using OCT we observed a reduced average choroidal thickness in the more myopic

eyes compared to the less myopic eyes. The interocular difference in choroidal

thickness was correlated with the magnitude of spherical equivalent and axial

Chapter 6

273

Table 6.2: Hypotheses investigated of asymmetric refractive error development in non-amblyopic myopic anisometropia.

FACTOR GENETIC

INFLUENCE

ENVIRONMENTAL INFLUENCE: NEAR WORK

COMMENT Thesis

Chapter Mechanism Hypothesis Finding

OPTICAL DEFOCUS

Gen

etic

su

scep

tib

ility

to

myo

pia

or

anis

om

etro

pic

dev

elo

pm

ent

Accommodation Unequal ACC produces

asymmetric hyperopic defocus (unequal lags)

Greater lag more myopic eye (n = 3, 2.5 D stimuli)

Higher ACC demand, longer duration task, higher

magnitude anisometropia, binocular viewing conditions

may alter AC symmetry.

3

Equal lags (n = 11, 2.5 and 5 .0 D stimuli)

4

HOA

Corneal Asymmetries in morphology

of PA or corneal structure leads to asymmetric HOA

Symmetric corneal aberrations pre and post near

work

Longer and more demanding near work may produce

asymmetries, but unlikely with highly symmetric PA, anterior segment and ACC

response.

2,3

Total Asymmetry in HOA during or

following near work promotes aniso growth

Symmetric HOA during, pre and post near work

2,3,4

MECHANICAL FORCES

IOP Interocular difference in IOP results in asymmetric axial

stretch/elongation

Similar IOPg between fellow eyes (mmHg)

M: 15.60 ± 2.98 L: 15.66 ± 2.86

Symmetric IOP may still play a role, depending on posterior

eye rigidity (e.g. sclera).

2

Ciliary body forces

Greater accommodative response in one eye results in

larger mechanical force transmitted

Slightly greater axial elongation in more myopic eye during accommodation

(p > 0.05)

May reflect asymmetries in choroidal/scleral structure as

ACC response was equal between eyes.

4

HOA - higher-order aberration; PA - palpebral aperture; ACC - accommodation; IOP - intraocular pressure; IOPg - Goldmann correlated intraocular pressure

Chapter 6

274

anisometropia. Similar findings have been previously reported in isometropic subjects

where the magnitude of myopia is related to choroidal thickness (Esmaeelpour et al 2010,

Benavente et al 2010).

It has also been suggested that choroidal thickness varies in anisometropia using the ocular

pulse amplitude as an indirect measurement of choroidal blood flow and an approximation

of choroidal thickness (Shih et al 1991, Lam et al 2003). However, this is the first study to

show that the magnitude of anisometropia correlates with the interocular difference in

choroidal thickness.

Although the optics of the fellow eyes were similar during distance and near fixation and

following near work, we cannot discount that asymmetric blur may be present in different

circumstances such as higher accommodative demands, longer periods of near work or

during binocular viewing. In addition, asymmetric blur (such as an interocular difference in

accommodation or higher-order aberrations) may contribute to the development of

anisometropia at some time during refractive error development, which diminishes to

symmetric levels when the refractive error stabilises. The same argument could be applied

for any mechanical theory of asymmetric refractive development.

Chapter 6

275

66..11..33 AAssyymmmmeettrriicc vviissuuaall eexxppeerriieennccee -- aammbbllyyooppiicc aanniissoommeettrrooppiiaa

We were also interested to examine the symmetry in optics and biometrics between fellow

eyes which had endured significantly different visual development. In Chapter 5 we

investigated the influence of altered visual experience upon higher-order aberrations.

While previous studies have reported no significant interocular differences in higher-order

aberrations between the fellow eyes of amblyopes, we observed differences between the

fellow eyes, which varied according to the type of amblyopia (refractive or strabismic)

(Table 6.3). Refractive amblyopes displayed significantly higher levels of 4th order corneal

aberrations (spherical aberration and secondary astigmatism) in the amblyopic eye

compared to the fellow non-amblyopic eye. Strabismic amblyopes exhibited significantly

higher levels of trefoil, a third order aberration, in the amblyopic eye for both corneal and

total ocular aberrations. Analysis including all subjects revealed that the interocular

differences in both corneal horizontal coma and total ocular spherical aberration correlated

with the magnitude of anisometropia. A recent animal model of form deprivation myopia

reported a similar finding, where the interocular differences in some higher-order

aberrations (third and fifth order terms) correlated with magnitude of induced

anisometropia (Coletta et al 2010). The results of our study suggest that asymmetric visual

experience during development may lead to asymmetries in higher-order aberrations,

proportional to the magnitude of deprivation or amblyopia and dependent upon the

amblyogenic factor. This finding is of interest, since it suggests a direct link between the

development of higher-order optical characteristics of the human eye and visual feedback.

Chapter 6

276

Table 6.3: Summary of findings for amblyopic anisometropia as a result of asymmetric visual experience.

AMBLYOPIC ANISOMETROPIA

GENETIC INFLUENCE

AMBLYOGENIC MECHANISM

FINDINGS (Refractive and strabismic separate)

FINDINGS (Subjects combined)

COMMENT

REFRACTIVE AMBLYOPIA

Family history of amblyopia or strabismus1,2

Alt

ere

d v

isu

al e

xper

ien

ce d

uri

ng

ocu

lar

dev

elo

pm

ent

Op

tics

Co

rnea

l H

OA

Greater levels in amblyopic eye of: +ve spherical aberration C(4,0)

-ve secondary astigmatism C(4,-2) & C(4,2)

All subjects combined:

*Greater ptosis & reduced ACC response in amblyopic

eyes.

* IOD in ACC response correlates with magnitude

anisometropia and amblyopia

* IOD in corneal C(3,1) and total C(4,0) correlate with

magnitude of anisometropia.

Previous studies suggest no IOD in corneal5 or total6,7 HOA.

Asy

mm

etri

c vi

sual

exp

erie

nce

du

rin

g d

evel

op

men

t m

ay le

ad t

o

asym

met

ries

in H

OA

, pro

po

rtio

nal

to

th

e m

agn

itu

de

of

dep

riva

tio

n o

r am

bly

op

ia

Tota

l H

OA

Symmetric total HOA - no significant IOD’s

STRABISMIC AMBLYOPIA

Dis

rup

ted

b

ino

cula

r vi

sio

n

Co

rnea

l H

OA

Greater levels in amblyopic eye of: +ve trefoil C(3,3)

Tota

l H

OA

Greater levels in amblyopic eye of: +ve trefoil C(3,3)

UNILATERAL SEVERE MYOPIA

X-linked recessive3 or dominant

inheritance pattern4 Ocu

lar

pat

ho

logy

Not examined

Recent animal model of form deprivation myopia found

interocular difference in HOA correlates with magnitude of

anisometropia.8

HOA - higher-order aberration; IOD - interocular difference; ACC - accommodation.

Chapter 6

277

References for Table 6.3:

1. Crone RA, Velzeboer CM. Statistics on strabismus in the Amsterdam youth;

researches into the origin of strabismus. AMA Arch Ophthalmol 1956; 55(4):455-70.

2. Podgor MJ, Remaley NA, Chew E. Associations between siblings for esotropia

and exotropia. Arch Ophthalmol 1996; 114(6):739-44.

3. Weiss AH. Unilateral high myopia: optical components, associated factors, and

visual outcomes. Br J Ophthalmol 2003; 87(8):1025-31.

4. Ohguro H, Enoki T, Ogawa K, Suzuki J, Nakagawa T. Clinical Factors Affecting

Ocular Axial Length in Patients with Unilateral Myopia. In: Tokoro T, ed. Myopia

Updates: Proceedings of the 6th International Conference on Myopia. Tokyo:

Springer, 1998.

5. Plech AR, Pinero DP, Laria C, Aleson A, Alio JL. Corneal higher-order aberrations

in amblyopia. Eur J Ophthalmol 2010; 20(1):12-20.

6. Kirwan C, O'Keefe M. Higher-order aberrations in children with amblyopia. J

Pediatr Ophthalmol Strabismus 2008; 45(2):92-6.

7. Prakash G, Sharma N, Saxena R, Choudhary V, Menon V, Titiyal JS. Comparison of

higher order aberration profiles between normal and amblyopic eyes in children

with idiopathic amblyopia. Acta Ophthalmol 2011; 89(3): e257-e262.

8. Coletta NJ, Marcos S, Troilo D. Ocular wavefront aberrations in the common

marmoset Callithrix jacchus: effects of age and refractive error. Vision Res 2010;

50(23):2515-29.

Chapter 6

278

66..22 FFuuttuurree rreesseeaarrcchh ddiirreeccttiioonnss

The results from our experiments have shown that a high degree of symmetry

exists between the fellow eyes of myopic anisometropes for a range of

biomechanical, biometric and optical parameters. We have not identified a single

specific optical or mechanical factor that is consistently associated with asymmetric

refractive error development. However, the findings from these studies suggest

areas of potential interest that require further research.

There appears to be a strong association between ocular dominance and myopic

anisometropia. A longitudinal study into the ocular changes of dominant and non-

dominant eyes during myopic development may provide further insight into the

potential causal nature of this relationship. Characteristics of the dominant eye

during binocular near work may help explain the underlying mechanism, if ocular

dominance influences the development of myopic anisometropia.

We observed an asymmetry in choroidal thickness (along the visual axis) in a small

group of myopic anisometropes which increased proportionately with the

magnitude of anisometropia. Previous animal studies have shown an active

choroidal mechanism to emmetropise to imposed defocus (Wallman et al 1995,

Wildsoet and Wallman 1995) and evidence for a similar mechanism in humans has

recently been reported (Read et al 2010a). Whether the interocular difference in

choroidal thickness we observed is a result of choroidal accommodation to imposed

Chapter 6

279

anisometropic blur during development or simply a result of asymmetric axial

elongation remains unknown. Given that we observed this interocular difference in

choroidal thickness in a small number of subjects with a relatively low level of

anisometropia (mean 1.47 D SEq anisometropia), it would be of interest to explore

the interocular symmetry of choroidal thickness in different populations (i.e.

subjects with larger degrees of anisometropia with or without amblyopia).

Several studies have compared the retinal thickness between the fellow eyes of

amblyopic subjects (Huynh et al 2009, Repka et al 2009), however the symmetry of

choroidal thickness has not been investigated. In subjects who have been exposed

to asymmetric visual experience during development (in particular hyperopic

anisometropia) we might expect a thicker choroid in comparison to the non-

amblyopic eye.

It has been suggested that peripheral blur and peripheral higher-order aberrations

play a role in the regulation of refractive errors. While we have limited our studies

to the optics and biometrics measured along the visual axis, future studies

examining the interocular symmetry of peripheral optics and biometrics (including

choroidal thickness which may vary with eccentricity) may provide additional

information regarding the development of asymmetric refractive errors.

Chapter 6

280

Anisometropia is a unique ocular condition which is of experimental use in

refractive error research. Although a high degree of symmetry was observed

between the fellow eyes of anisometropes for a range of biometric and optical

measurements, differences were found with respect to ocular dominance and

choroidal thickness (non-amblyopic anisometropia) and higher order aberrations

(amblyopic anisometropia). The findings of this project open up a range of

potential future research directions which may help to improve the current

understanding of the mechanisms that influence asymmetric refractive

development.

References

281

RReeffeerreenncceess

Abbott ML, Schmid KL, Strang NC. Differences in the accommodation stimulus

response curves of adult myopes and emmetropes. Ophthalmic Physiol Opt 1998;

18(1):13-20.

Abdalla MI, Hamdi M. Applanation ocular tension in myopia and emmetropia. Br J

Ophthalmol 1970; 54(2):122-5.

Abrahamsson M, Fabian G, Andersson AK, Sjostrand J. A longitudinal study of a

population based sample of astigmatic children. I. Refraction and amblyopia. Acta

Ophthalmologica (Copenh) 1990; 68(4):428-34.

Abrahamsson M, Sjostrand J. Natural history of infantile anisometropia. Br J

Ophthalmol 1996; 80(10):860-3.

Abrahamsson M, Sjostrand J. Astigmatic axis and amblyopia in childhood. Acta

Ophthalmol Scand 2003; 81(1):33-7.

Adams DW, McBrien NA. Prevalence of myopia and myopic progression in a

population of clinical microscopists. Optom Vis Sci 1992; 69(6):467-73.

Adler D, Millodot M. The possible effect of undercorrection on myopic progression

in children. Clin Exp Optom 2006; 89(5):315-21.

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Zoccolotti P. Inheritance of ocular dominance. Behav Genet 1978; 8(4):377-9.

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AAppppeennddiicceess

AAppppeennddiixx 11:: EEtthhiiccss

Research ethics information sheets and consent forms used for experiments

conducted at the Queensland University of Technology and the Hong Kong

Polytechnic University.

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PARTICIPANT INFORMATION for QUT RESEARCH PROJECT


Research Team Contacts

Prof Michael Collins Stephen Vincent Phone: (07) 3138 5702 Phone: (07) 3138 5732

Email: [email protected] Email: [email protected]

Description

This project is being undertaken as part of a PhD project by Stephen Vincent.

The purpose of this project is to investigate ocular changes that occur during reading in human anisometropia. Anisometropia is a condition in which the two eyes have unequal refractive power. The ocular parameters that will be investigated include the shape of the front surface of the eye (cornea), the total optics of the eye, the length of the eye, the pressure within the eye and the position and shape of the eyelids.

We have contacted you as a potential participant in this project based on your previous attendance at the Optometry Clinic at QUT.

Participation Your participation in this project is voluntary. If you do agree to participate, you can withdraw from participation at any time during the project without comment or penalty. Your decision to participate will in no way impact upon your current or future relationship with QUT (for example your grades, employment or on going clinical care). Your participation will involve a series of measurements to determine the optical and biometric characteristics of your eyes. In this study, the shape of the front surface of your eye (cornea) will be measured using the Pentacam instrument and the Medmont instrument. A wavefront sensor will be used to measure the total optics of your eye, and the IOL master instrument will be used to measure the length of your eye. A digital camera will be used to photograph your eyes when looking straight ahead and in a reading position. We may also measure the pressure inside your eye (intraocular pressure) using a tonometer instrument. You will be asked to look into each of the instruments as they take their measurements. These measurements will be carried out before and after a ten minute reading task. The reading task requires you to read text on a computer screen with your head positioned on a chin and forehead rest. The Pentacam, Medmont, wavefront sensor, IOL master, tonometer and digital camera are all standard clinical instruments and pose no risk to the health of your eyes. Prior to the experiment, we will conduct a screening examination to determine your suitability for the study and ensure your eyes are healthy. All measurements will be conducted at the School of Optometry at QUT. The testing may require up to 2 hours of your time. Expected benefits It is expected that this project will not benefit you directly. However, data collected from this study are expected to improve our understanding of refractive error development and aid further research. Risks There are no greater risks in this study other than those associated with your routine eye examinations. The instruments used to measure the optical and biometric characteristics of your eye are standard clinical instruments.

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Confidentiality The research data we gather from the experiments will not personally identify you by name, or in any other way that allows you to be identified. Any publication of data arising from this research will use a code system which does not identify you personally. The data will be stored securely in the School of Optometry.

Consent to Participate We would like to ask you to sign a written consent form (enclosed) to confirm your agreement to participate. Questions / further information about the project Please contact the researcher team members named above to have any questions answered or if you require further information about the project. Concerns / complaints regarding the conduct of the project QUT is committed to researcher integrity and the ethical conduct of research projects. However, if you do have any concerns or complaints about the ethical conduct of the project you may contact the QUT Research Ethics Officer on 3138 2340 or [email protected]. The Research Ethics Officer is not connected with the research project and can facilitate a resolution to your concern in an impartial manner.

mailto:[email protected]

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CONSENT FORM for QUT RESEARCH PROJECT


Statement of consent By signing below, you are indicating that you:

have read and understood the information document regarding this project

have had any questions answered to your satisfaction

understand that if you have any additional questions you can contact the research team

understand that you are free to withdraw at any time, without comment or penalty

understand that you can contact the Research Ethics Officer on 3138 2340 or [email protected] if you have concerns about the ethical conduct of the project

agree to participate in the project

have discussed the project with your child and their requirements if participating

Name

Signature

Date / /

Statement of Child Consent

Your parent or guardian has given their permission for you to be involved in this research

project.

This form is to seek your agreement to be involved. By signing below, you are indicating that

the project has been discussed with you and you agree to participate in the project.

Name

Signature

Date / /

mailto:[email protected]

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The Hong Kong Polytechnic University

Faculty of Health and Social Studies

RReesseeaarrcchh pprrooggrraammmmee oonn mmyyooppiiaa

Information Sheet

Aim:

In Hong Kong, approximately 70% of young adults have myopia (or short-sightedness).

Previous studies have shown the contribution of both genetic and environmental factors to

myopia. We are interested in the influence of reading on the development of myopia. In

particular, we hope to examine subjects with anisometropia.

Anisometropia is a condition in which the two eyes have unequal refractive power due to

unequal eye growth. The purpose of this project is to investigate structural and optical

qualities in human anisometropia before and after a reading task. This may help improve

our understanding of myopia development.

The target subjects are those with anisometropia of at least 1 dioptre (spherical equivalent)

aged 10-35. Please think seriously before deciding to participate.

Method:

Each participant will be asked to give the necessary personal information (including sex,

medical history, etc.), and offered FREE eye examination (about 1-2 hours) all performed

by qualified personnel.

Eye examination.

The following measurements will be made using standard optometric procedures: refractive

status of the eye, the ocular aberration, the corneal curvature, the dimensions of the eyeball,

the intraocular pressure and digital photography of the anterior eye. Some of these

measurements will be repeated following a 10-minute reading task.

All ocular measurements will be performed in a non-invasive manner without using any

eyedrop.

You will be informed of your own results of the eye examination. All the information

collected will only be available to the investigators involved in this study. Otherwise, all

personal information collected will be kept confidential. Data from this study may be

published, but individuals will not be identified or identifiable. You may decline to take part

or withdraw should you change your mind.

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Potential risks:

All of the measurements carried out in the project are standard clinical

techniques/instruments and pose no substantive risk to the subjects.

Potential benefits:

The results of this research will provide a better understanding of the optical and anatomical

properties of human eyes in relation to reading and refractive error development.

For inquiry or booking, please contact our optometrist Mr. Percy Ng (9846 8353). If you

have any complaint, please contact the Principal Investigator Professor Maurice Yap (2766

6097) or the Human Subjects Ethics Subcommittee.

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The Hong Kong Polytechnic University

Faculty of Health and Social Studies

Research programme on myopia

INFORMED CONSENT

********************************************************

I understand all in the information as stated in the attached Information Sheet.

I have had enough opportunity to ask questions, and the queries were answered to

my satisfaction.

I have the right to withdraw from the study at any time without any penalty or

comment.

I also understand that all the information obtained from me will be dealt with the

strictest confidentiality. When data from the study are published, no individuals

will be identified or identifiable.

********************************************************

(For a participant aged 16 or above)

I, ___________________________ , agree to take part in the captioned research

programme.

Signature: ___________________________ Signature: _________________________

(Participant) (Witness)

Date: _________________________________

This study has been approved by the Ethics Committee of the Hong Kong Polytechnic

University. However, if you think there are procedures that seem to violate your welfare,

you may complain in writing to the Human Subjects Ethics Committee of the University.

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AAppppeennddiixx 22:: PPuubblliiccaattiioonnss aarriissiinngg ffrroomm tthhee tthheessiiss

Publications which have arisen from the work in this thesis:

Published abstracts:

Vincent SJ, Collins MJ, Read SA and Carney LG. Interocular symmetry in myopic

anisometropia. Optom Vis Sci. 2010; 87. E-Abstract 105273. Presented at the

American Academy of Optometry Meeting, San Francisco November 2010.

Peer reviewed papers:

Vincent SJ, Collins MJ, Read SA, Carney LG and Yap MKH. Interocular symmetry in

myopic anisometropia. Optom Vis Sci 2011; 88 (12):

DOI:10.1097/OPX.0b013e318233ee5f.

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