Ocular Characteristics of Anisometropia

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

Keywords

Anisometropia

Myopia

Asymmetry

Amblyopia

Aberrations

Dominance

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

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Abstract 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 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 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

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

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Contents

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

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Contents

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

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

3.2 Methods ...... 152

3.2.1 Subjects and screening ...... 152

3.2.2 Data collection procedures ...... 152

3.2.3 Statistical analysis ...... 155

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

4.2.1 Subjects and screening ...... 187

4.2.2 Data collection procedures ...... 188

4.2.3 Data analysis ...... 192

Contents

4.2.4 Statistical analysis ...... 195

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

5.2.1 Subjects and screening ...... 224

5.2.2 Data collection procedures ...... 225

5.2.3 Statistical analysis ...... 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

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Contents

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

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Contents

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

myopic anisometropia. 112

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

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Contents

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

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 194 thickness at the fovea.

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

Figure 4.6 Correlation between spherical equivalent anisometropia (D) and

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

Figure 5.1 Correlation between spherical equivalent anisometropia (D) and

interocular difference in axial length (mm) for all amblyopic

subjects (n = 21). 228

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Contents

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

Figure 5.5 Correlation between spherical equivalent anisometropia (D) and

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

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Contents

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

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Contents

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

myopic anisometropia. 123

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

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Contents

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

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

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Contents

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

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Contents

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

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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

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Statement of Authorship

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:

xxv

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.

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Chapter 1

Chapter 1: Literature Review

1.1 Refractive error development

1.1.1 Emmetropisation

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 evidence from both human and animal studies of refractive error development that visual experience regulates eye growth (Wildsoet 1997).

1.1.2 Biometric changes during emmetropisation

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 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.

1.1.3 Biometric basis of refractive errors

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 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).

1.1.4 Altered visual experience during emmetropisation

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 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).

1.1.4.1 Ocular pathology

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

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.

1.1.4.2 Refractive amblyopia

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

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).

1.1.4.3 Strabismic amblyopia

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

1.1.4.4 Form deprivation amblyopia

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.

1.1.4.5 Treatment of amblyopia

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).

1.1.5 Animal studies of refractive error development

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

(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 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 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.

1.1.6 Retinal image manipulation in humans

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.

1.1.6.1 Orthokeratology

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

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.

1.1.6.2 Bifocal contact lenses

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 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 elongation. However, manipulation of the retinal image in older presbyopic subjects does not show a consistent pattern of refractive change.

1.1.6.3 Monovision

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 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 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.

1.1.7 Summary

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 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

1.2 Myopia development - aetiological factors

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

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

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.

1.2.1 Myopia development - optical factors

1.2.1.1 Accommodation

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 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 near work, resulting in transient increases in distance myopic refractive errors following sustained near work.

1.2.1.2 Higher-order aberrations

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 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).

1.2.1.3 Variables that influence higher-order aberrations i) Age

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 ii) Pupil size

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.

iii) Retinal eccentricity

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.

iv) Accommodation

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 magnitude and direction of change is less predictable than that of spherical aberration (Cheng et al 2004b).

v) Ocular disease

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).

1.2.1.4 Interocular symmetry of higher-order aberrations

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

Right eye Left eye

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

Chapter 1 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.

i) Corneal aberrations

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

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

Total cohort demographic Age (years) N Significance Wavefront examined Study N Total Pupil size (mm) Interocular correlation examined Significant Correlations Sphere or SEq (D) Symmetry level Cylinder (D)

20-79

Each Zernike term coefficient (all subjects averaged) Terms 6-10, 12-14, 17 Corneal Wang (2003) 134 < ± 3.25 SEq 94 6.0 p < 0.002

Total HOA (all subjects averaged) r = 0.565 < 2.00

24-52

53% of px’s correlated Corneal Lombardo (2006) 30 -1.75 to -8.75 SEq 30 4.0 & 7.0 Total HOA (individual subjects averaged) p < 0.001

97% of px’s correlated NA

20-69

Internal Wang (2005) 114 -10.68 to +3.47D SEq 30 6.0 Each Zernike term coefficient (all subjects averaged) Terms 12 and 24 p < 0.002

21-38

Total Liang & Williams (1997) 9 < ± 3.00 Sphere 4 7.3 All Zernike term coefficients (all subjects averaged) “Slope close to 1” NA

< ± 3.00

22-58

Total Marcos & Burns (2000) 12 -6.50 to 0 Sphere 12 Unspecified (dilated) All Zernike term coefficients (all subjects averaged) r = 0.45 p < 0.0001

< 0.80

21-65

Total Porter (2001) 109 -12.00 to +6.00 Sphere 109 5.7 Each Zernike term coefficient (all subjects averaged) Terms 3-9, 12-17 p < 0.01

<3.00

20-30

Total Castejon-Mochon (2002) 59 Emmetropic 35 7.0 Each Zernike term coefficient (all subjects averaged) Terms 4-8, 12-15 p < 0.05

5-7

Total Carkeet (2003) 34 NA 33 5.0 Each Zernike term coefficient (all subjects) Terms 4-6, 12 p < 0.001

22-32 Each Zernike term coefficient (all subjects and nasal/temporal averaged) Horizontal peripheral total HOA’s up to ±40˚ Lundstrom et al (2011) 22 Emmetropes and myopes (-2.00 to -7.25 Sphere) 22 4.0 0 - 40˚ distance fixation Terms 3-5, 7-9, 11-13 p < 0.01 (distance and near fixation) ≤ 0.75 0 - 35˚ near fixation (4 D stimuli) Terms 3-9,11-13 p < 0.01

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

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.

ii) Total ocular aberrations

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

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

1.2.1.5 Compensatory mechanisms

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.

1.2.1.6 Higher-order aberrations and refractive error development

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

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.

i) Corneal aberrations

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 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.

ii) Total ocular aberrations

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 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.

iii) Peripheral aberrations

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

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 aberrations suggesting that the development of myopia may be related to peripheral retinal defocus during near work.

iv) Longitudinal studies of aberrations

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 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

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.

1.2.2 Summary

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

1.3 Myopia development - mechanical factors

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).

1.3.1 Mechanical changes during near work

1.3.1.1 Convergence

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

1.3.1.2 Ciliary body forces

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 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 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.

1.3.2 Intraocular pressure

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.

1.3.2.1 Animal models

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

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 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).

1.3.2.2 Intraocular pressure and myopia in children

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.

i) Cross sectional studies

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

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.

ii) Longitudinal studies

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

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 instruments (NCT and GAT) throughout the study which may have influenced the results.

1.3.2.3 Intraocular pressure and myopia in adults

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

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

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.

1.3.3 Summary

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

1.4 Non-amblyopic anisometropia

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

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.

1.4.1 Genetic influence

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

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.

1.4.2 Longitudinal studies

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

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 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.

1.4.3 Biometric studies

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 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.

Chapter 1 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).

1.4.4 Theories of asymmetric refractive error development

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.

1.4.4.1 Optical factors

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 anisometropes to determine a potential mechanism resulting is asymmetric blur between the eyes.

i) Cornea

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.

ii) Crystalline lens

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 iii) Higher-order aberrations

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.

iv) Accommodation

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 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 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 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 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

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.

1.4.4.2 Mechanical factors

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 i) Corneal properties

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 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.

ii) Intraocular pressure

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

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

Table 1.2: Studies of intraocular pressure in anisometropia.

Study Subject Anisometropia criteria (D) IOP Results method age More myopic eye Less/non myopic eye Statistical significance (years) IOP mmHg (mean ± SD) IOP mmHg mean ± SD

Tomlinson & 8-16 Not specified (n=13) GAT 14.0 13.3 p > 0.05 Phillips (1972) (Wilcoxon matched pairs)

Bonomi et al 7-68 High myopia (SPH <-5.00 D) GAT 16.1 ± 2.6 16.4 ± 2.4 p > 0.05 (1982) vs EMM or HYP (n=42) Schiotz 18.3 ± 3.0 17.2 ± 3.0 p < 0.05

High myopia (SPH <-5.00 D) GAT 16.1 ± 2.5 16.8 ± 2.3 p < 0.05 vs low myopia (-5.00 D < SPH < 0.00 D) (n=95) Schiotz 17.8 ± 3.3 17.1 ± 3.0 p < 0.05 (Paired t-tests)

Lee & Edwards 8-14 SPH difference 2.00D NCT 16.08 ± 3.09 (-5.38 ± 2.71 D) n=24 16.21 ± 3.12 (-2.24 ± 2.48 D) n=24 p = 0.65 (2000) Astigmatism < 1.50D 15.20 ± 2.24 (+1.57 ± 1.23 D) n=15 14.93 ± 1.91 (+5.10 ± 1.53 D) n=15 p = 0.45 16.86 ± 3.60 (-2.91 ± 2.13 D) n=28 17.11 ± 3.45 (+1.33 ± 2.08) n=28 p = 0.31 (Paired t-tests)

Lam et al 20-34 SEq 2.00 D (n=31) OBF 14.50 ± 2.85 14.27 ± 2.5 p = 0.41 (2003) (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 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.

1.4.4.3 Other factors i) Ocular dominance

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 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

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.

ii) Ocular dominance and accommodation

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 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 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.

1.4.5 Summary

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 have investigated these hypotheses have not identified a single cause of asymmetric axial elongation.

Chapter 1

1.5 Amblyopia associated anisometropia

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).

1.5.1 Emmetropisation in amblyopic eyes

This section summarises the finding from both prospective and retrospective studies of refractive error changes in refractive and strabismic amblyopia during childhood.

Chapter 1

1.5.1.1 Refractive amblyopia

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 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.

1.5.1.2 Strabismic amblyopia

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 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

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 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.

1.5.2 Biometric studies of amblyopia

1.5.2.1 Cornea

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 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.

1.5.2.2 Axial length

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 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

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 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.

1.5.3 Optical factors

1.5.3.1 Higher-order aberrations in amblyopia

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.

i) Corneal aberrations

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 parameters including astigmatism or higher-order aberrations. The authors suggested that corneal astigmatism is a key factor in the development of unilateral amblyopia.

ii) Total ocular aberrations

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 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

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

1.5.3.2 Accommodation in amblyopia

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 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 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

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 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.

1.5.4 Summary

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.

Chapter 1

1.6 Rationale

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 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

Chapter 2: Interocular symmetry in myopic anisometropia

2.1 Introduction

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

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

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

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

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.

2.2 Methods

2.2.1 Subjects and screening

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 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.

2.2.2 Data collection procedures

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

Chapter 2 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.

2.2.2.1 Axial length

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.

2.2.2.2 Corneal topography

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

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*

Corneal thickness Oculus Pentacam HR System Anterior and posterior corneal astigmatism Anterior chamber depth and volume

Anterior corneal astigmatism Medmont E-300 Corneal Topographer Corneal shape factor (Q value) Corneal aberrations*

IOPg, IOPcc Reichart Ocular Response Analyzer 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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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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Chapter 2 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

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2.2.2.3 Ocular biomechanics/biometrics

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.

2.2.2.4 Ocular aberrations

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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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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2.2.2.5 Morphology of the palpebral fissure

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.

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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).

2.2.3 Statistical analysis

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).

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2.3 Results

2.3.1 Overview

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).

2.3.2 Sighting ocular dominance

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).

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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

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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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y = -0.30x + 0.06 R2 = 0.66

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.

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

Sighting dominant eye Χ2 Anisometropia SEq (D) 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.

2 Anisometropia group Dominant right eyes Dominant left eyes Χ (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.

Right eyes Left eyes Paired t-test Parameter Subjects (Mean ± SD) (Mean ± SD) (p) All 0.00 ± 0.04 0.00 ± 0.04 0.65 Visual acuity Low -0.01 ± 0.04 0.00 ± 0.04 0.23 (logMAR) High 0.01 ± 0.05 0.00 ± 0.05 0.38 All -4.72 ± 2.58 -4.27 ± 3.00 0.16 SEq Low -4.11 ± 2.38 -3.91 ± 2.64 0.76 (D) High -5.98 ± 2.63 -5.03 ± 3.67 0.42 All 25.39 ± 0.94 25.19 ± 0.98 0.06 Axial length Low 25.36 ± 1.07 25.25 ± 1.05 0.65 (mm) 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.

Dominant eyes Non-dominant eyes Paired t-test Parameter Subjects (Mean ± SD) (Mean ± SD) (p) All -0.01 ±0.04 0.00 ± 0.04 0.11 Visual acuity Low -0.01 ±0.04 0.00 ± 0.04 0.08 (logMAR) High 0.00 ± 0.05 0.00 ± 0.05 0.82 All -4.86 ± 2.80 -4.13 ± 2.77 0.02 SEq Low -4.09 ± 2.48 -3.95 ± 2.46 0.64 (D) High -6.70 ± 2.77 -4.56 ± 3.51 < 0.0001 All 25.42 ± 1.01 25.15 ± 0.90 0.01 Axial length Low 25.31 ± 1.13 25.25 ± 0.97 0.57 (mm) High 25.69 ± 0.57 24.93 ± 0.71 < 0.0001

SEq - spherical equivalent refractive error

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2.3.3 Morphometry of the palpebral fissure

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

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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 Paired Pearson’s Correlation Paired Pearson’s Correlation Parameter MORE LESS MORE LESS t-test (More vs Less) t-test (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 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 Upper 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 Eyelid 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 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 Lower 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 Eyelid 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

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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.

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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

A -0.36 0.04 -0.14 0.81

Upper Eyelid B 0.08 0.67 0.31 0.08

C 0.41 0.02 0.04 0.44

A -0.38 0.03 0.09 0.73

Lower Eyelid 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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2.3.4 Ocular biomechanics

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.

Pearson correlation Variable More myopic eyes Less myopic eyes Paired t-test (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.

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2.3.5 Anterior eye biometrics

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.

2.3.6 Corneal optics

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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Table 2.12: Mean values for corneal and anterior chamber parameters in myopic anisometropia.

More Less Paired Pearson’s Correlation

myopic eyes myopic eyes t-test (More vs Less) Instrument Parameter Mean ± SD Mean ± SD p r p

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 Medmont Anterior astigmatism (D) -1.61 ± 0.81 -1.55 ± 0.93 0.70 0.71 < 0.0001 (n = 33) 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

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 Pentacam

(n = 28) 3 ACV (mm ) 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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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.

There were no statistically significant differences between the dominant and non- dominant eyes for corneal M, J0 and J45 over a 4 or 6 mm corneal diameter. Here

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2.3.7 Corneal higher-order aberrations

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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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.

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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).

4mm corneal diameter 6 mm corneal diameter RMS value (microns) t-test t-test More myopic Less myopic More myopic Less myopic (p) (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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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

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2.3.8 Total ocular monochromatic aberrations

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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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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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

131

Chapter 2

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)

Zernike Term r p r p r p

(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

132 Chapter 2

2.4 Discussion

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,

133 Chapter 2 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

134 Chapter 2

(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

135 Chapter 2 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

136 Chapter 2 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.

137 Chapter 2

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.

138 Chapter 2

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

139 Chapter 2 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

140 Chapter 2 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

141 Chapter 2 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

142 Chapter 2 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.

143 Chapter 2

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.

144 Chapter 2

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,

145 Chapter 2 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.

146 Chapter 2

2.5 Conclusions

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.

147 Chapter 3

Chapter 3: Ocular changes following near work in myopic anisometropia

3.1 Introduction

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

148 Chapter 3 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. 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.

149 Chapter 3

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.

150 Chapter 3

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.

151 Chapter 3

3.2 Methods

3.2.1 Subjects and screening

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.

3.2.2 Data collection procedures

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)

152 Chapter 3

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

Reading task 10 minutes

Post reading measures 2 ↓ Corneal topography

Washout period 30 minutes

Baseline measures 3 ↓ Ocular aberrations

Reading task 10 minutes

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.

153 Chapter 3 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

154 Chapter 3 measurements were completed) to ensure the air puff from the ORA did not influence the measurement of corneal topography.

3.2.3 Statistical analysis

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).

155 Chapter 3

3.3 Results

3.3.1 Axial length

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.

156 Chapter 3

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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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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3.3.2 Corneal optics

3.3.2.1 Corneal changes following near work

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

160 Chapter 3 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.

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Subject MORE LESS SCALE

22 -9.25/-2.50 x 2 -7.25/-2.50 x 168

PRE TASKPRE

POST TASK

PRE)

– DIFFERENCE

(POST (POST

P VALUE P

GAZE 25 DEGREE

DOWNWARD

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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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 TIME M J0 J45 Spherocyl M J0 J45 Spherocyl diameter (mm)

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

4 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 -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 (Post-Pre)

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

6 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 -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 (Post-Pre)

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

Corneal TIME M J0 J45 Spherocyl M J0 J45 Spherocyl diameter (mm)

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

4 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 -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 (Post-Pre)

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

6 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 -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 (Post-Pre)

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)

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More myopic eyes Less myopic eyes Scale Mean refractive change Mean refractive change (D) after ten minutes reading after ten minutes reading

Dominant eyes Non-dominant eyes Scale Mean refractive change Mean refractive change (D) after ten minutes reading after ten minutes reading

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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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) Corneal Measurement More myopic eyes LESS myopic eyes diameter (mm) Pre-task 0.51 ± 0.14 0.49 ± 0.19

4 Post-task 0.57 ± 0.18 0.55 ± 0.20

Change (Post-Pre) 0.06 ± 0.12* 0.06 ± 0.10**

Pre-task 0.86 ± 0.18 0.83 ± 0.10

6 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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3.3.2.2 Corneal refractive changes and palpebral aperture morphology

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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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).

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3.3.2.3 Corneal refractive changes and corneal biomechanics

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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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.

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3.3.2.4 Corneal aberrations

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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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.

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3.3.3 Total ocular monochromatic aberrations

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).

There were no statistically significant differences between the dominant and non- 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

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(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

173 Chapter 3 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 4th Order aberration Total HOA

Mean RMS ± SD (microns) Mean RMS ± SD (microns) Mean RMS ± SD (microns) Pupil Task More Less p More Less p More Less p

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 4 mm (n = 31) 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

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 5 mm (n = 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

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 6 mm (n = 19) 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 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 pupils (n = 31) 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 4th Order aberration Total HOA

Mean RMS ± SD (microns) Mean RMS ± SD (microns) Mean RMS ± SD (microns) Pupil Task Dominant Non-dominant p Dominant Non-dominant p Dominant Non-dominant p

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 4 mm (n = 31) 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

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 5 mm (n = 30) 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

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 6 mm (n = 19) 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 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 pupils (n = 31) 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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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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Chapter 3 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.

3.4 Discussion

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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Chapter 3 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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Chapter 3 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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Chapter 3 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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Chapter 3

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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Chapter 3 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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Chapter 3 of symmetry in Zernike wavefront coefficients was observed between the more and less myopic eyes before and after the reading task.

3.5 Conclusions

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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Chapter 4: Ocular changes during accommodation in myopic anisometropia

4.1 Introduction

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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Chapter 4 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 following near fixation with and without cycloplegia. Recently however, Read et al

(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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Chapter 4 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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Chapter 4 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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Chapter 4 research in this area, we examined the interocular symmetry of the optical and mechanical changes during accommodation in a small group of myopic anisometropes.

4.2 Methods

4.2.1 Subjects and screening

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.

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) (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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Chapter 4 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.

4.2.2 Data collection procedures

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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Chapter 4 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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Chapter 4 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.

4.2.3 Data analysis

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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Chapter 4 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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Chapter 4 observers. The results from each observer for the retinal and choroidal thickness were used to calculate the mean measurement.

4.2.4 Statistical analysis

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.

4.3 Results

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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4.3.1 Interocular symmetry

4.3.1.1 Biometrics

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 Accomm * Eye 0 D 2.5 D 5.0 D Accomm Eye Eye More 0.528 ± 0.030 0.528 ± 0.030 0.528 ± 0.030 CCT 0.47 0.17 0.95 Less 0.528 ± 0.028 0.527 ± 0.028 0.527 ± 0.028

More 3.38 ± 0.31 3.28 ± 0.31 3.12 ± 0.27 ACD < 0.001 0.39 0.94 Less 3.36 ± 0.32 3.26 ± 0.32 3.12 ± 0.32

More 3.46 ± 0.23 3.58 ± 0.24 3.79 ± 0.24 LT < 0.001 0.12 0.95 Less 3.48 ± 0.23 3.60 ± 0.23 3.77 ± 0.25

More 7.37 ± 0.32 7.39 ± 0.29 7.44 ± 0.28 ASL < 0.001 0.35 0.95 Less 7.37 ± 0.33 7.39 ± 0.32 7.41 ± 0.34

More 17.77 ± 0.59 17.77 ± 0.60 17.73 ± 0.61 VCD 0.05 0.53 0.06 Less 17.25 ± 0.60 17.24 ± 0.61 17.22 ± 0.62

More 25.14 ± 0.64 25.16 ± 0.65 25.17 ± 0.65 AXL measured < 0.001 0.70 0.07 Less 24.62 ± 0.65 24.63 ± 0.64 24.64 ± 0.64

More 25.14 ± 0.64 25.15 ± 0.65 25.15 ± 0.66 AXL corrected 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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Chapter 4 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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Chapter 4 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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4.3.1.2 Ocular coherence tomography

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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4.3.1.3 Optics

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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Chapter 4 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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4.3.2 Ocular dominance

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).

Biometric parameter (μm unless labelled otherwise) P-value Natural pupil analysis Eye 0 D 2.5 D 5.0 D Accommodation Acc * Eye Eye More 5.29 ± 0.81 4.44 ± 0.71 3.76 ± 0.75 Pupil diameter (mm) 0.000 0.35 0.82 Less 5.17 ± 0.54 4.55 ± 0.77 3.95 ± 0.65 More -3.97 ± 1.62 -5.77 ± 1.94 -8.71 ± 2.36 Sphere (D) 0.000 0.94 0.12 Less -2.71 ± 1.73 -4.35 ± 1.66 -7.48 ± 2.05 More -4.51 ± 1.97 -6.37 ± 2.41 -9.40 ± 2.72 M (D) 0.000 0.90 0.18 Less -3.27 ± 1.90 -4.95 ± 1.89 -8.21 ± 2.27 More 0.300 ± 0.127 0.197 ± 0.075 0.207 ± 0.146 HO RMS 0.02 0.63 0.63 Less 0.263 ± 0.109 0.188 ± 0.078 0.200 ± 0.087 More -0.087 ± 0.086 -0.046 ± 0.052 -0.034 ± 0.064 C(3,-3) 0.004 0.62 0.38 Less -0.075 ± 0.064 -0.031 ± 0.059 -0.002 ± 0.062 More -0.013 ± 0.152 0.003 ± 0.109 0.065 ± 0.177 C(3,-1) 0.77 0.07 0.70 Less 0.043 ± 0.074 -0.025 ± 0.096 -0.014 ± 0.125 More -0.032 ± 0.153 -0.011 ± 0.073 -0.012 ± 0.034 C(3,1) 0.49 0.98 0.11 Less 0.014 ± 0.098 0.048 ± 0.087 0.035 ± 0.082 More 0.037 ± 0.058 0.007 ± 0.046 0.012 ± 0.054 C(3,3) 0.75 0.12 0.43 Less -0.011 ± 0.063 0.019 ± 0.031 0.006 ± 0.037 More 0.031 ± 0.040 0.011 ± 0.031 0.016 ± 0.030 C(4,-4) 0.12 0.88 0.73 Less 0.032 ± 0.040 0.016 ± 0.019 0.021 ± 0.024 More -0.027 ± 0.028 -0.015 ± 0.021 -0.004 ± 0.021 C(4,-2) 0.004 0.80 0.11 Less -0.009 ± 0.033 -0.002 ± 0.026 0.011 ± 0.026 More 0.117 ±0.080 0.028 ± 0.042 -0.032 ± 0.053 C(4,0) 0.000 0.50 0.36 Less 0.080 ± 0.069 0.022 ± 0.069 -0.042 ± 0.042 More -0.015 ± 0.047 -0.006 ± 0.024 -0.007 ± 0.037 C(4,2) 0.61 0.73 0.23 Less 0.003 ± 0.043 0.015 ± 0.027 0.004 ± 0.044 More 0.014 ± 0.055 0.007 ± 0.032 0.003 ± 0.036 C(4,4) 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).

Biometric parameter (μm unless labelled otherwise) P-value Fixed 3 mm pupils Eye 0 D 2.5 D 5.0 D Accommodation Acc * Eye Eye More -3.75 ± 1.58 -5.69 ± 1.96 -8.77 ± 2.32 Sphere (D) 0.000 0.87 0.11 Less -2.54 ± 1.68 -4.29 ± 1.64 -7.50 ± 2.04 More -4.28 ± 1.90 -6.31 ± 2.42 -9.48 ± 2.67 M (D) 0.000 0.87 0.18 Less -3.12 ± 1.85 -4.88 ± 1.86 -8.25 ± 2.26 More 0.070 ± 0.037 0.078 ± 0.040 0.117 ± 0.055 HO RMS 0.000 0.85 0.61 Less 0.063 ± 0.029 0.071 ± 0.029 0.107 ± 0.056 More -0.020 ± 0.029 -0.011 ± 0.021 -0.016 ± 0.048 C(3,-3) 0.28 0.56 0.16 Less -0.008 ± 0.019 0.001 ± 0.024 0.007 ± 0.031 More 0.001 ± 0.046 -0.007 ± 0.043 0.006 ± 0.073 C(3,-1) 0.75 0.44 0.56 Less -0.001 ± 0.031 -0.016 ± 0.033 -0.014 ± 0.049 More -0.012 ± 0.028 -0.011 ± 0.028 -0.006 ± 0.026 C(3,1) 0.58 0.96 0.06 Less 0.002 ± 0.026 0.016 ± 0.033 0.009 ± 0.049 More -0.002 ± 0.015 0.006 ± 0.022 0.003 ± 0.022 C(3,3) 0.45 0.85 0.66 Less 0.001 ± 0.010 0.011 ± 0.014 0.004 ± 0.024 More 0.001 ± 0.009 0.002 ± 0.020 0.004 ± 0.012 C(4,-4) 0.88 0.14 0.58 Less 0.007 ± 0.008 0.005 ± 0.008 0.003 ± 0.014 More 0.000 ± 0.007 -0.002 ± 0.012 -0.002 ± 0.015 C(4,-2) 0.49 0.16 0.23 Less 0.001 ± 0.007 0.001 ± 0.008 0.007 ± 0.011 More 0.022 ± 0.018 0.010 ± 0.015 0.002 ± 0.027 C(4,0) 0.02 0.59 0.61 Less 0.017 ± 0.018 0.016 ± 0.018 -0.010 ± 0.038 More -0.005 ± 0.010 -0.001 ± 0.010 -0.004 ± 0.020 C(4,2) 0.92 0.88 0.61 Less -0.003 ± 0.014 0.004 ± 0.007 -0.003 ± 0.028 More 0.001 ± 0.009 -0.001 ± 0.013 -0.001 ± 0.018 C(4,4) 0.63 0.85 0.91 Less 0.004 ± 0.014 -0.004 ± 0.015 0.003 ± 0.018

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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 Dominant Non-dominant (Mean ± SD anisometropia (D)) (1.84 ± 0.67) (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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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.

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4.4 Discussion

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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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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Chapter 4 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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Chapter 4 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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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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Chapter 4 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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Chapter 4 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.

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Chapter 4 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

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Chapter 4 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

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Chapter 4 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.

4.5 Conclusions

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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Chapter 5: Ocular characteristics in asymmetric visual experience

5.1 Introduction

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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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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Chapter 5 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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5.2 Methods

5.2.1 Subjects and screening

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.

Before testing, subjects underwent a screening examination to determine 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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Chapter 5 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.

5.2.2 Data collection procedures

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.

5.2.3 Statistical analysis

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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5.3. Results

5.3.1 Overview

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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Figure 5.1: Correlation between spherical equivalent anisometropia (D) and interocular difference in axial length (mm) for all amblyopic subjects (n = 21).

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5.3.2 Morphology of the palpebral fissure

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).

5.3.3 Ocular biomechanics

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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Table 5.3: Mean anterior eye morphology measurements in primary gaze for amblyopic and non-amblyopic eyes.

Paired Pearson’s Correlation Pearson’s Correlation Parameter Amblyopic Non-amblyopic t-test Interocular symmetry 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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5.3.4 Corneal optics

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.

Pearson correlation Variable Amblyopic Non-amblyopic Paired t-test 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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Table 5.6: Mean values for corneal and anterior chamber parameters in the amblyopic and non-amblyopic eyes.

Paired Pearson’s correlation Amblyopic Non-amblyopic t test Interocular symmetry Instrument Parameter Mean ± SD Mean ± SD p r p

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 Medmont Anterior astigmatism (D) -1.35 ± 0.81 -0.92 ± 0.65 < 0.01 0.69 < 0.001 (n = 20) 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

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 Pentacam Posterior astigmatism 0.24 ± 0.26 0.19 ± 0.25 0.43 0.46 < 0.05 (n = 21) (D) 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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5.3.5 Corneal astigmatism and palpebral aperture morphology

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

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) Upper 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) Eyelid 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)*

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) Lower 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) Eyelid 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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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).

5.3.6 Corneal aberrations

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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Chapter 5 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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Chapter 5 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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All amblyopes Strabismic amblyopes Refractive amblyopes (n = 20) (n = 11) (n = 8)

* * * * * *

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).

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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) Amblyopic Non-amblyopic Paired Symmetry Amblyopic Non-amblyopic Paired Symmetry Amblyopic Non-amblyopic Paired Symmetry Z Term (Mean ± SD) (Mean ± SD) t-test (p) r p (Mean ± SD) (Mean ± SD) t-test (p) r p (Mean ± SD) (Mean ± SD) t-test (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).

All amblyopes (n = 20) Strabismic amblyopes (n = 11) Refractive amblyopes (n = 8) Amblyopic Non-amblyopic Paired Symmetry Amblyopic Non-amblyopic Paired Symmetry Amblyopic Non-amblyopic Paired Symmetry Z Term (Mean ± SD) (Mean ± SD) t-test (p) r p (Mean ± SD) (Mean ± SD) t-test (p) r p (Mean ± SD) (Mean ± SD) t-test (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).

All amblyopes (n = 20) Strabismic amblyopes (n = 10) Refractive amblyopes (n = 8) 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

Figure 5.5: Correlation between spherical equivalent anisometropia (D) and interocular difference in corneal wavefront Zernike coefficient of primary horizontal coma C(3, 1) (microns) (6 mm analysis).

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5.3.7 Total ocular monochromatic aberrations

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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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).

All amblyopes (n = 21) Strabismic amblyopes (n = 11) Refractive amblyopes (n = 8) Amblyopic Non-amblyopic Paired Symmetry Amblyopic Non-amblyopic Paired Symmetry Amblyopic Non-amblyopic Paired Symmetry Z Term (Mean ± SD) (Mean ± SD) t-test r p (Mean ± SD) (Mean ± SD) t-test r p (Mean ± SD) (Mean ± SD) t-test 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).

All amblyopes (n = 21) Strabismic amblyopes (n = 11) Refractive amblyopes (n = 8)

Zernike Term r p r p r p

(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).

Magnitude of change Distance fixation Near fixation (2.5 D demand) Change from distance fixation between eyes # Non- Non- Non- Amblyopic Paired Amblyopic Paired Amblyopic Paired Paired Z Term amblyopic amblyopic amblyopic Paired t-test (Mean ± SD) t-test (Mean ± SD) t-test (Mean ± SD) t-test t-test (Mean ± SD) (Mean ± SD) (Mean ± SD) 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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5.4 Discussion

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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Chapter 5 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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(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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Chapter 5 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

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Chapter 5 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

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Chapter 5 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

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Chapter 5 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.

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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.

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5.5 Conclusions

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.

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Chapter 6: Conclusions

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).

6.1 Summary and main findings

6.1.1 Myopic anisometropia - ocular dominance

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

266

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Myopic non-amblyopic anisometropia Amblyopic anisometropia (form deprivation example)

Axial elongation

C A B V D

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.

267

Chapter 6 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

268

Chapter 6 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

269

Chapter 6 dominance, we do not discount the possibility that laterality may be an important factor.

6.1.2 Myopic anisometropia - near work and accommodation

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

270

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Table 6.1: Hypotheses explaining the association between ocular dominance and non-amblyopic myopic anisometropia.

MODEL TYPE GENETICS NEAR WORK OUTCOME

Dominant eye favoured for Dominant eye becomes Greater ciliary body forces and axial elongation in distance and near tasks. more myopic than non- dominant eye during accommodation (Chapter 4) CAUSE dominant eye Ocular dominance Greater accommodative (initially predetermined1 response in dominant This should inhibit Dominant eye becomes isometropic) compared to Lead of accommodation (or myopia development less myopic than non- non-dominant eye.2 less lag) in dominant eye based on retinal dominant eye (Chapter 4) defocus theory3 (not observed)

Beyond a threshold EFFECT Lower ocular Predisposition for level of anisometropia, accommodative demand in More myopic eye favoured in binocular viewing anisometropic the more myopic eye is (initially the more myopic eye of (less accommodative effort) growth the dominant eye.4 anisometropic) anisometrope (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.

271

Chapter 6 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

272

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Table 6.2: Hypotheses investigated of asymmetric refractive error development in non-amblyopic myopic anisometropia.

ENVIRONMENTAL INFLUENCE: NEAR WORK GENETIC Thesis FACTOR COMMENT INFLUENCE Chapter Mechanism Hypothesis Finding

Greater lag more myopic eye Higher ACC demand, longer 3 Unequal ACC produces (n = 3, 2.5 D stimuli) duration task, higher Accommodation asymmetric hyperopic defocus magnitude anisometropia, Equal lags (unequal lags) binocular viewing conditions (n = 11, 2.5 and 4 may alter AC symmetry.

5 .0 D stimuli)

OPTICAL Asymmetries in morphology Symmetric corneal DEFOCUS Corneal of PA or corneal structure aberrations pre and post near Longer and more demanding 2,3 leads to asymmetric HOA work near work may produce asymmetries, but unlikely HOA with highly symmetric PA, Asymmetry in HOA during or Symmetric HOA during, pre anterior segment and ACC Total following near work promotes 2,3,4 and post near work response. aniso growth

Similar IOPg between fellow Symmetric IOP may still play a Interocular difference in IOP anisometropic development anisometropic eyes (mmHg) role, depending on posterior IOP results in asymmetric axial 2 Genetic susceptibility to myopia or myopia to susceptibility Genetic M: 15.60 ± 2.98 eye rigidity stretch/elongation MECHANICAL L: 15.66 ± 2.86 (e.g. sclera). FORCES Greater accommodative Slightly greater axial May reflect asymmetries in Ciliary body response in one eye results in elongation in more myopic choroidal/scleral structure as 4 forces larger mechanical force eye during accommodation ACC response was equal transmitted (p > 0.05) between eyes.

HOA - higher-order aberration; PA - palpebral aperture; ACC - accommodation; IOP - intraocular pressure; IOPg - Goldmann correlated intraocular pressure

273

Chapter 6 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.

274

Chapter 6

6.1.3 Asymmetric visual experience - amblyopic anisometropia

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.

275

Chapter 6

Table 6.3: Summary of findings for amblyopic anisometropia as a result of asymmetric visual experience.

AMBLYOPIC GENETIC AMBLYOGENIC FINDINGS FINDINGS COMMENT ANISOMETROPIA INFLUENCE MECHANISM (Refractive and strabismic separate) (Subjects combined)

All subjects combined:

Greater levels in amblyopic eye of:

+ve spherical aberration C(4,0)

HOA *Greater ptosis & reduced

Corneal -ve secondary astigmatism C(4,-2) & C(4,2) REFRACTIVE ACC response in amblyopic

AMBLYOPIA eyes.

Optics

Symmetric total HOA - no significant IOD’s * IOD in ACC response HOA Family history of Total correlates with magnitude amblyopia or anisometropia and amblyopia

strabismus1,2

Greater levels in amblyopic eye of: * IOD in corneal C(3,1) and HOA +ve trefoil C(3,3) STRABISMIC Corneal total C(4,0) correlate with

AMBLYOPIA magnitude of anisometropia.

Disrupted Disrupted Greater levels in amblyopic eye of:

binocular vision binocular

HOA Total +ve trefoil C(3,3) Previous studies suggest no amblyopia or deprivation IOD in corneal5 or total6,7 HOA.

Recent animal model of form X-linked recessive3 deprivation myopia found UNILATERAL or dominant ular Not examined interocular difference in HOA

SEVERE MYOPIA 4 ocular development during experience visual Altered asymmetries in HOA, proportional to the magnitude of magnitude the to proportional HOA, in asymmetries inheritance pattern Oc correlates with magnitude of pathology 8

anisometropia. to may lead development during experience visual Asymmetric

HOA - higher-order aberration; IOD - interocular difference; ACC - accommodation.

276

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6.2 Future research directions

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,

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278

Chapter 6 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.

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Chapter 6

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.

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Appendix 1

Appendices

Appendix 1: Ethics

Research ethics information sheets and consent forms used for experiments conducted at the Queensland University of Technology and the Hong Kong

Polytechnic University.

328

Appendix 1

PARTICIPANT INFORMATION for

QUT RESEARCH PROJECT

Ocular characteristics of anisometropia

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.

329

Appendix 1

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.

330

Appendix 1

CONSENT FORM for QUT RESEARCH PROJECT

Ocular characteristics of anisometropia

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 / /

331

Appendix 1

The Hong Kong Polytechnic University Faculty of Health and Social Studies Research programme on myopia 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.

332

Appendix 1

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.

333

Appendix 1

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.

334

Appendix 2

Appendix 2: Publications arising from the thesis

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.

335