TABLE OF CONTENTS

Introduction .........................................................................................................3 Ocular aberrations ................................................................................................5 Ocular aberrations and Myopia............................................................................8 Aberrations and Accommodation ......................................................................11 Myopia and Accommodation.............................................................................13 Optical interventions in myopia .........................................................................16

Rigid and Rigid Gas-Permeable (RGP) contact lenses................................16 Soft contact lenses.........................................................................................18 Bifocal Spectacle Lenses ...............................................................................19 Progressive addition lenses............................................................................20 Undercorrection of myopia ...........................................................................21 Overcorrection of myopia .............................................................................22 Orthokeratology............................................................................................22

Peripheral aberrations and myopia .....................................................................24 Aim.....................................................................................................................26 Material and methods ........................................................................................27

Subjects .........................................................................................................27 Experiment I............................................................................................27 Experiment II ..........................................................................................28 Experiment III.........................................................................................28 Experiment IV.........................................................................................28 Experiment V ..........................................................................................28

Ethics ............................................................................................................29 Instrumentation and experimental procedure ...............................................29

Aberrometry ............................................................................................29 Accommodation measurement................................................................32 Visual acuity and contrast sensitivity assessment.....................................34 Contact lenses..........................................................................................35

Experiments .......................................................................................................37 Experiment I .................................................................................................38

Experiment II ............................................................................................... 39 Introduction............................................................................................. 39 Materials and methods ............................................................................ 39 Results ..................................................................................................... 42 Discussion................................................................................................ 45

Experiment III .............................................................................................. 47 Experiment IV .............................................................................................. 48 Experiment V................................................................................................ 49

Discussion and conclusion ................................................................................. 50 Acknowledgements ............................................................................................ 52 References .......................................................................................................... 54

INTRODUCTION

Myopia is a major cause of vision loss throughout the world. High myopia is associated with severe eye diseases like maculopathy, retinal detachment and glaucoma [Saw et al. 2005]. The prevalence of myopia is increasing, and varies by country and by ethnic group. In some Asian populations the prevalence is 70%-80% [Edwards & Lam 2004;Lam, Goldschmidt, & Edwards 2004;Lin et al. 2001]. The causes of myopia and its progression in animals have been established by various studies. In humans, although studies have shown correlations between myopia and both genetic factors [Farbrother et al. 2004;Hammond et al. 2001;Hammond et al. 2004;Wong et al. 2000;Young et al. 1998]; and environmental factors such as near work [Allen & O'Leary

causes of myopia progression have not yet been fully elucidated. A variety of factors such as age of onset, ethnicity, gender and visual environment have been suggested to influence progression of myopia [Kleinstein et al. 2003;Morgan & Rose 2005;Zadnik et al. 2003]. Among the proposed environmental factors, near work has been linked to myopia development [Angle & Wissmann 1980;Kinge et al. 2000;Richler & Bear 1980]. Gwiazda et al. [1993] suggested that reduced accommodation at near causes retinal blur due to hyperopic defocus. This blur induces an increase in axial length, causing myopia. This theory is represented in the figure 1. The figure shows that for a near object (T), the best focus is behind the retina (inverted T), which is the hyperopic defocus due to decrease in accommodation. Since the best focus is behind the retina, the eye elongates backwards toward the best focus making it more myopic.

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2006;McBrien & Adams 1997;Mutti et al. 2002;Wong et al. 2000] the

Figure1 . Schematic representation of hyperopic defocus and axial elongation of the eye. The figure

shows that for a near object (T), the best focus is behind the retina (inverted T).

It has been shown in many species that severe retinal image degradation (either through using lens-induced defocus to render the eye very hypermetropic, or through some form of occlusion) acts as a stimulus to axial growth of the eye [Graham & Judge 1999;Norton 1999;O'Leary & Millodot 1979;Schaeffel, Glasser, & Howland 1988;Smith, III & Hung 1999;Wiesel & Raviola 1977;Wildsoet & Wallman 1995]. In a similar way, the presence of higher magnitude of ocular aberrations degrades the retinal image in humans which might cause axial myopia. It is not yet established whether the retinal defocus (as suggested by Gwiazda et al. [1993]) or the retinal image degradation (as shown by animal studies) causes elongation of the eyes leading to myopia.

4

OCULAR ABERRATIONS

In an optical system where there is deviation of light rays and a blurred image is formed instead of a diffraction-limited spot, the system is considered to have aberrations. With the use of Zernike aberration terminology [Atchison 2004;Navarro, Moreno, & Dorronsoro 1998;Thibos et al. 2002] the refractive errors (defocus, astigmatism) are referred to as lower-order aberrations and the other aberrations such as coma and spherical aberration are referred to as higher-order aberrations. The lower-order aberrations can be fully corrected either with spectacles or by contact lenses. The higher-order aberrations remain once the lower-order aberrations are corrected [Atchison 2004]. Aberrations can be divided into two groups: a) Monochromatic aberrations, the aberrations found when only one wavelength of the light is considered, b) Chromatic aberrations, the aberrations found when different wavelengths of

Aberrations can be represented as follows: (i) Wave aberration is the deviation of the wavefront from the ideal spherical wavefront and is measured at the exit pupil. It is measured in micrometers. (ii) Transverse aberration is the deviation of a ray from its ideal position at the

(iii) Longitudinal aberration is the deviation of the intersection of a ray with a reference axis such as the optic axis from its ideal intersection and is measured in millimeters or Dioptres. Zernike Polynomials Optical meteorologists found it convenient to express wavefront data in polynomial form. They used Zernike polynomials to interpret their results since these polynomials are made up of terms that are of the same form as the types of aberrations frequently seen in optical tests [Zernike 1934]. Zernike polynomials are a set of functions that are orthogonal over the unit circle.

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light are considered.

image surface and is measured in millimeters or minutes of arc.

Howland & Howland [1977] were the first people to use Zernike polynomials to describe the wavefront aberration of the human eye. In the last decade many other studies have also used these polynomials for human eyes [Applegate et al. 2003;Applegate, Sarver, & Khemsara 2002;Cheng et al. 2003a;He, Burns, & Marcos 2000;Llorente et al. 2003;McLellan et al. 2006;Zhu, Collins, & Robert 2004]. There are several ways of representing and numbering Zernike polynomials. In this thesis we used the ordering of the OSA standards reported by Thibos et al. [2002] and the order is given below in the figure 2

m = Meridional frequency

Figure 2. Representation of Zernike polynomials up to fourth-order

One of the most important higher-order aberrations in the eye is spherical aberration. Spherical aberration is a rotationally symmetrical aberration that occurs when the power of the eye is different for rays in the centre of the pupil

00

11

33

66

1100

22

55

99

1144

44

88

1133

77

1122 1111

n = 0

Radial

order

-4 -3 -2 -1 0 +1 +2 +3 +4

n = 1

n = 2

n = 3

n = 4

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compared to more peripheral rays. It is the 12th one as shown in figure 2. Spherical aberration could be positive or negative. When the peripheral rays are refracted more than the paraxial rays, then the eye suffers from positive spherical aberration (figure 3). If the peripheral rays are refracted less than the paraxial rays, then the eye suffers from negative spherical aberration (figure 4).

Figure 3 . Schematic drawing of positive spherical aberration

Figure 4 . Schematic drawing of negative spherical aberration

7

OCULAR ABERRATIONS AND MYOPIA

Several studies have investigated the relationship between ocular aberrations and refractive error. Pi [1925] and Stine [1930] studied ocular spherical aberration using peripheral retinoscopy and found that it was not related to refractive error. Further studies have also shown similar results. Porter et al. [2001] studied monochromatic aberrations in 109 subjects across a 5.7 mm pupil using the Hartmann-Shack aberrometer and found no relationship with myopia, emmetropia or hyperopia. However they found large inter subject variability among their population. Carkeet et al. [2002] studied higher-order aberrations in 273 cyclopleged Singaporean school children using a Bausch and Lomb Zywave aberrometer, which is based on Hartmann-Shack principle [Liang et al. 1994]. They found no significant difference in the root mean square (RMS) value (the square root of the sum of the squares of a set of numbers) of higher-order aberrations between myopes, emmetropes and hyperopes. However the results may not be valid since the aberration measurements were taken without considering centration of the pupil. In aberrometry, if pupil centration is not controlled then results will be less accurate and will vary more from one reading to another [Applegate et al. 2000]. One interesting finding from this study is that they found that within the myopic group low myopes had significantly less positive spherical aberration than high myopes. This suggests that high myopes are likely to have a higher magnitude of spherical aberration indicating that aberrations may be related to the degree of refractive error. Since a relationship between aberrations and refractive error was not established Cheng et al. [2003] also conducted a study in 100 subjects. They studied the relationship between refractive error and aberrations with a refractive error range from +5.00 to –10.00 D using a Hartmann-Shack aberrometer across the central 6 mm pupil of cyclopleged eyes. They also found no correlation between RMS value of higher-order aberrations, or spherical aberration, with refractive error, but they concluded that this was

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because of the presence of large amounts of individual variability in the magnitude of higher-order aberrations. The reason for this individual variability was attributed to error in calculation of aberrations due to variations in axial length of the eye. Llorente et al. [2003] found a relationship between refractive error and aberrations, but they found that the total and corneal spherical aberration in hyperopes was higher than in myopes. They also found that RMS value for third-order aberrations was significantly higher in hyperopes. The results are weakened by the small sample size used and the fact that the aberration data obtained was measured only once for each subject. A longitudinal study would have permitted the aberration data to be correlated with any change in refractive error. Several other studies described below have found that myopes have higher amounts of ocular aberrations than emmetropes. Applegate [1991] studied monochromatic aberrations using a subjective single-pass aberroscope and found that some of the myopic eyes in his study had greater amounts of coma and spherical aberration. He also found that myopes had a mean increase in aberrations. Since this technique uses lower sampling rates across the pupil compared to the new instruments, the results could be underestimated. Collins, Wildsoet, & Atchison [1995] studied monochromatic aberrations in 21 young myopic subjects and 16 young emmetropes using an objective aberroscope technique described by Atchison et al. [1995]. They found that the fourth-order aberrations (spherical aberration) in myopes were significantly lower than emmetropes. They suggested that their results in myopes might be underestimated since they excluded a large proportion of the aberroscope grids photographed in myopes as they were highly distorted to permit analysis. But this also shows that myopes might have had higher aberrations which would have distorted the aberroscope grid. He et al. [2002] studied wavefront aberrations in 316 emmetropic and myopic school children and young adults using a psychophysical ray-tracing technique. They found that the myopes (both children and young adults) had greater mean RMS value of wavefront aberrations than emmetropes. Marcos, Barbero, & Llorente [2002] wanted to know whether this greater RMS in myopes depends on their degree of myopia. They studied wavefront aberrations in 49 young eyes with spherical error ranging from -0.25 to -15 D using Laser Ray Tracing. They found that the total RMS (for third-order and higher aberrations) increased significantly with amount of myopia. Paquin, Hamam, & Simonet [2002] also found similar result. They studied

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monochromatic aberrations of the human eye as a function of the degree of myopia using a modified Hartmann-Shack method in 27 myopes and 7 emmetropes. They calculated the RMS and found that RMS value is directly proportional to the spherical equivalent error for pupil diameters of 5 and 9 mm. This shows that high myopes will have higher aberrations and this will decrease the optical quality. Earlier studies done by our research team also found an indirect evidence for higher levels of spherical aberration in myopes. Radhakrishnan et al. [2004] found that myopes showed a significantly greater loss in contrast sensitivity with positive defocus compared to emmetropes. With negative defocus, myopes showed a smaller loss in sensitivity than was found in emmetropes. This was attributed to higher levels of spherical aberration in myopic eyes, which would be expected to lead to spatial-frequency-dependent asymmetries in through-focus modulation transfer [Charman 2005;Charman, Jennings, & Whitefoot 1978;Green & Campbell 1965;Jansonius & Kooijman 1998]. These results are further confirmed by a study by Kirwan, O'Keefe, & Soeldner [2006]. They investigated total monochromatic aberrations within the central 6 mm optical zone in 82 children aged between 4-14 years using a Hartmann-Shack wavefront aberrometer. They found that myopes had statistically significant greater levels of total (0.462 ± 0.10μm) and fourth-order (0.216 ± 0.088μm) aberrations (which include spherical aberration) compared with hyperopes (total = 0.357 ± 0.131μm and fourth-order = 0.151 ± 0.107μm). From the above studies (which differ in the subject groups, techniques and analysis) it is not clear whether myopes have higher amounts of ocular aberration compared to emmetropes and hyperopes. But in this study we still wanted to correct part of higher-order aberrations (spherical aberration) along with the refractive error because it is not yet established whether myopia is developed due to visual blur. It is possible that both myopes and emmetropes have the same (or similar) visual experience, but myopes are more sensitive to the blur, in terms of axial growth.

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ABERRATIONS AND ACCOMMODATION

Studies have shown that the higher-order aberrations nearing the accommodated eye are different from aberrations with accommodation relaxed. At near, aberrations tend to change due to changes in the shape, position and refractive index gradient of the crystalline lens [Garner & Smith 1997;Garner & Yap 1997;Koretz, Cook, & Kaufman 2002], which occur during accommodation of the eye. As early as 1949, Koomen, Tousey, & Scolnik [1949] measured longitudinal spherical aberration and found that the spherical aberration reduced with accommodation and also in one case became negative with accommodation. In 1956, Ivanoff [1956] also measured longitudinal spherical aberration along the horizontal meridian using a vernier acuity method. He found that seven out of ten eyes showed a change in spherical aberration from positive to negative when accommodation stimuli was changed from 0 to 3 D. Jenkins [Jenkins 1963a;Jenkins 1963b] repeated Ivanoff`s study by measuring the spherical aberration along both horizontal and vertical meridians. He also found a similar result, though there was a large inter-subject variability. A detailed study was conducted by Atchison et al. [1995] in 15 subjects. They also found the shift to negative spherical aberration with increase in accommodation, but only in half of their subjects. The important finding they found was that the third-order (coma-like) aberrations dominated at all accommodations levels (0, 1.5 and 3 D). He, Burns, & Marcos [2000] measured changes in monochromatic wavefront aberrations with accommodation (0 to -6 D stimuli) in 8 subjects using a spatially resolved refractometer. They found that aberrations tend to increase with increasing levels of accommodation and the optical quality of the eye is best at the resting point of accommodation. Among higher-order aberrations

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the average spherical aberration changed from positive to negative with increasing level of accommodation. They also found that the change in the aberrations with accommodation varied from one subject to another. Ninomiya et al. [2002] also studied the effect of accommodation on ocular aberrations. They measured ocular aberrations in 33 eyes with a Hartmann-Shack wavefront aberrometer. They compared the aberrations in the unaccommodated eye with aberrations when the subjects were focusing on a

were analysed in both conditions for both the central 4mm and 6 mm zones of the pupil. They found no significant difference in the RMS value of the total higher-order aberrations between the unaccommodated eye and the accommodated eye, however there was a significant increase in the spherical aberration between the unaccommodated eye and the accommodated eye. Their results also suggested a significant negative shift in spherical aberration with accommodation. Since the previous studies were done on small sample size Cheng et al. [2004] measured changes in aberration with accommodation (0, 3 and 6 D) in 76 young adults using a Hartmann-Shack wave-front sensor. They found that among all the higher-order aberrations the spherical aberration showed the largest change with accommodation and the direction of change was always negative. They also found that the magnitude of change in aberrations with accommodation even with a 6 D stimulus was less than the magnitude of the uncorrected aberrations at distance. They suggested that if the aberrations at distance were corrected then the eye would benefit for near as well. Although these studies agree that aberrations change with accommodation, they did not look at the role of refractive error in these aberration changes. He et al. [2003] examined whether this change in aberrations with accommodation is related to refractive error. They measured aberrations using a psychophysical wavefront sensor in 12 young subjects (7 emmetropes and 5 myopes). They found that in myopes the aberrations either increased or did not change with accommodation compared to emmetropes whose ocular aberrations decreased with accommodation. This suggests that at near (due to accommodation) myopes will experience higher amounts of ocular aberrations, especially spherical aberration, than emmetropes. This increase in aberrations could cause more retinal image degradation leading to progression of myopia.

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built-in target that required an accommodation of 3.00 D. The aberrations

MYOPIA AND ACCOMMODATION

Several studies have looked at the relationship between myopia and accommodation. Gwiazda et al. [1993] studied accommodative responses in newly myopic and emmetropic (5 to 17 years old) children. They found that the mean slope of the accommodative response function (for objects placed at different distances from the eye) was significantly lower in myopic children (0.78) than in emmetropic children (0.88). For negative lens induced accommodation, the mean slope for myopes (0.20) was much shallower than for emmetropes (0.61). However the effect of positive lenses on accommodation showed no significant difference between the myopic children (0.64) and emmetropic children (0.69). They concluded that myopic children accommodate insufficiently to blur induced by negative lenses causing hyperopic defocus and hence myopia progression. The high amount of lag reported in this study suggests that the children would not have seen the targets clearly, casting some doubt on the results [Allen 2004]. Later, Gwiazda et al. [1995] investigated whether the reduced accommodative response function is associated with progression of myopia. They measured accommodative response functions in 23 myopic and 40 emmetropic children (age 6-18 years) and correlated this data with their refractive error over periods of 6-12 months. They found significant differences in the mean slope of the accommodative response function between myopes (0.50) and emmetropes (0.70). In myopic children they found a strong correlation (r=0.77) between the change in refractive error over a one year period and accommodative lag. They suggested that during the progression of myopia, the accommodation response is reduced in young children. Abbott, Schmid, & Strang [1998] replicated the previous study in adults. They investigated the differences in accommodative stimulus response curves between adult myopes and emmetropes. They confirmed that the response gradients to negative lenses in progressing adult myopes were shallower (0.70) than in emmetropes (0.85) and in stable myopes (0.85). Since the refractive error data was taken from previous clinical records, it is not clear whether

13

myopes were still progressing at the time of accommodative measurements. However a recent study has clarified this. Allen & O'Leary [2006] studied a range of accommodative functions in young adults (30 myopes and 34 non-myopes) and correlated them with progression of myopia over a 12-month period. They found a significant correlation between myopia progression and both lag of accommodation and reduced facility of accommodation. Based on the hypothesis that hyperopic defocus during near work causes myopia, Gwiazda et al. [2004] investigated whether reducing this hyperopic defocus by prescribing Progressive Addition Lenses would reduce the progression of myopia. They prescribed Progressive Lenses with +2.00D addition and studied several risk factors (such as accommodative lag, phoria, reading distance, amount of near work and level of myopia) for progression of myopia for a period of 3 years. The results of the study lent some support to their theory, although children wearing progressive lenses still showed myopia progression. They found that in children (age: 6-11 years) with larger accommodative lags (>0.43 D) the myopia progression was reduced by the progressive addition lenses. One possible cause for an increased lag in myopes is the presence of higher amounts of ocular aberration, as shown in the some of the studies referred to in the previous section. Charman [1999] suggested that presence of more ocular aberrations increases the depth of focus which in turn decreases the sensitivity to defocus and hence reducing the accuracy of the accommodative response. Radhakrishnan et al. [2004] argued a different explanation for the increased lag. They suggested that in the presence of higher amounts of ocular aberrations there is a difference in the axial position of high and medium spatial frequency peaks in myopes. They postulated that the high spatial frequency peak is located posterior to the medium spatial frequency peak. During near work since the accommodative system is driven by medium spatial frequencies, the medium spatial frequency peak will be positioned on the retina and the high spatial frequency peak will located behind the retina and this introduces accommodative lag. Further evidence for an association between the lag of accommodation and ocular aberration was given by He et al. [2005]. They studied accommodative lags and wavefront aberrations in myopes and emmetropes. They calculated the strehl ratio (the ratio of modulation transfer function of a real eye to modulation transfer function of a diffraction limited theoretical eye) using measured wavefront aberrations and found that myopes had a smaller ratio than emmetropes. Smaller the ratio poorer the retinal image quality. They found a correlation between the accommodative lag and the reciprocal of the

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strehl ratio. This suggests that myopes have poorer image quality than emmetropes, causing retinal blur that may be responsible for their larger lag of accommodation. A similar study was conducted in progressing myopes by Collins, Buehren, & Iskander [2006]. They studied the effect of higher-order aberrations on the retinal image quality in progressing myopes (20 subjects) and emmetropes (20 subjects). They found that the lead and lag of accommodation are influenced by the higher-order aberrations of the eye. They suggested that the interaction between lower- and higher-order aberrations play an important role in reducing the retinal image quality of myopic eyes compared with emmetropes. From the previous studies it is clear that myopes may have either higher-order aberrations or poor accommodative function. According to a study by Buehren, Collins, & Carney [2005] it is better to have both of them than either of them alone. They investigated the effect of accommodation stimulus-response function on retinal image quality in ten subjects using a modified wavefront sensor. They calculated the retinal image quality in the presence of higher-order aberrations alone, accommodation errors alone and a combination of higher-order aberrations and accommodation errors. They found that the combination of higher-order aberrations and accommodation errors improved the retinal image quality compared with higher-order aberrations or accommodation errors alone. This suggests that myopes with both higher-order aberrations and poor accommodative function might have better retinal image quality, than myopes with either higher-order aberrations or poor accommodative function alone, although the underlying mechanism for this combined effect is not yet established.

15

OPTICAL INTERVENTIONS IN MYOPIA

Over the past 50 years, many studies have investigated the use of different interventions or techniques to slow the progression of myopia or to reduce the existing amount of myopia. However although many promising leads have been produced, the initial excitement has almost invariably been lost after careful scrutiny in controlled clinical trials. Nonetheless, these studies are valuable in trying to construct new approaches to the treatment of myopia progression.

Rigid and Rigid Gas-Permeable (RGP) contact lenses

Morrison [1956] was the first to report an effect of rigid (hard) contact lenses on myopia progression. He prescribed polymethyl methacrylate (PMMA) contact lenses for 1021 myopes aged between 7 and 19 years. He retrospectively analysed the data from his clinical practice and did not have any control group. He found that after 2 years of PMMA lens wear, there was no increase in myopia. Similar results were reported by Dickinson [1957], Bier [1958] and Silbert [1962]. However all these studies failed to use cycloplegia either to establish the initial refraction, the contact lens correction or the follow-up refraction.

Kelly, Chatfield, & Tustin [1975] and Stone [1976] also prescribed rigid

contact lenses in myopes and compared the progression rate between the contact lens wearers group and spectacle lens wearers group. Both the studies found a decrease in myopia progression in the group wearing rigid lenses. Stone [1976] was the first to suggest that the rigid lenses not only flattens the cornea and hence reduces the amount of myopia, but also might reduce the axial elongation of the eye, though the mechanism behind this is not yet

16

understood. She found the progression of myopia over a 5 year period to be -0.50 D in the contact lens group and -1.75 D in the spectacle lens group. Changes in the corneal shape, as measured by keratometry, between the 2 groups accounted for about 0.50D of the difference, and Stone speculated that the rest may be due to a reduction in the rate of axial elongation in the contact lens wearers.

Grosvenor et al. [1989] and Perrigin et al. [1990] studied the effect of

RGP lenses on myopia progression in 56 myopic children aged between 8 and 13 years. They prescribed silicone-acrylate contact lenses to the treatment group and used a control group of 20 single-vision spectacle wearers from a previous study [Grosvenor et al. 1987]. They found that the contact lens group (-0.16 D per year) progressed less than the spectacle lens group (-0.51 D per year) over a 3 year period, and half of the treatment effect was due to the flattening of the cornea by contact lenses, as determined by keratometry.. However there was no significant difference in the rate of axial elongation between the 2 groups, and the authors speculated that the central corneal curvature was flattening by a greater amount that was indicated by the K readings.

Khoo, Chong, & Rajan [1999] conducted a 3 year study in 100 myopic

children to see whether RGP contact lenses could control the progression of myopia in Singaporean children since the progression rate in these children was more than the Caucasian children. They found a decrease in the progression of myopia in the contact lens group (-0.42 D) compared to the spectacle group (-0.78 D) after the first 2 years. This decrease was not mainly due to corneal change and even after discontinuing the lenses for 2 months the refraction was still the same. They also measured the axial length in their myopes and found a statistically significant difference in the mean axial length increase between their treatment (0.22 mm) and control (0.31 mm) groups. But the main drawback of this study is that the allocation of the subjects to treatment and control groups were not randomised and also by the end of the study the contact lens group had a high dropout rate of 47%. A later study by the same group showing the results over 3 year period failed to show a significant difference between the two groups.

Since the previous studies had drawbacks, Katz et al. [2003] used a larger

sample and also randomised the subjects between treatment and control group. The subjects were 298 myopic children aged 6-12 years. The children were randomly allocated to a spectacle group or to a RGP lens group and were followed up for 24 months. They found no significant difference in the progression of myopia between the spectacle and RGP lens group. They also did not find any significant difference in the increase in axial length over 2 years between the spectacle (0.79 mm) and RGP lens (0.84) groups. Their

17

results suggest that prescribing RGP lenses for myopia progression is not an effective treatment.

At the same time in USA, another study by Walline et al. [2004] also

looked at the effect of RGPs on myopia progression in 116 myopic children. Instead of having a spectacle lens as a control group they used soft contact lens. The subjects were randomly prescribed either a RGP contact lens or a soft contact lens and were followed up for 3 years. They found that the

wearing RGP lenses. But they did not find any difference in the axial growth of the eyes in both the groups. The treatment effect was found only in the first year of the study.

Soft contact lenses In contrast to RGP lenses soft lenses have been found to either increase or

no effect on myopia progression. Grosvenor [1975] analysed his private practise data and found an increase

in myopia in some of his subjects during first few months of soft lens wear along with corneal steepening. Andreo [1990] reported myopic changes in 14 to 19 year old patients. All the subjects were examined 11 to 13 months after the baseline examination, and there was not a significant difference in the

progression of myopia between contact lens and spectacle wearers. Horner et al. [1999] conducted a randomised controlled clinical trial to

compare the progression of myopia in soft contact lens wearers and spectacle lens wearers over 3 years. They found no significant difference in the myopia progression between the groups and concluded that soft contact lenses do not reduce myopia progression.

Walline et al. [2008] conducted a randomized clinical trial in children also

looking at effect of soft contact lenses on myopia progression. There was no significant difference in the change in the axial length between the soft contact lens group and the spectacle lens group after three years. They concluded that soft contact lens wear by children does not cause a clinically relevant increase in axial length, corneal curvature, or myopia relative to spectacle lens wear.

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children wearing soft contact lens progressed 0.63D more than the children

Bifocal Spectacle Lenses The rationale for using bifocal lenses was originally to reduce the amount

of accommodation exerted, because it was hypothesised that accommodative effort led mechanically to axial elongation, either through traction on the sclera, or indirectly through elevating the Intra-ocular pressure. More recently, in the light of Gwiazda et al. [2004] findings, the rationale has changed to reducing the accommodative lag during near work.

Grosvenor et al. [1987] conducted a clinical trial to test the efficacy of

bifocals in decreasing the progression of myopia in 207 children aged between 6 and 15 years. The children were divided into three groups and prescribed either single vision spectacles, +1.00 D add bifocals or +2.00 D add bifocals for three years. They found no significant difference in myopia progression in the three groups. However, the study had a large number of dropouts and only 124 subjects completed the three-year period. Parssinen, Hemminki, & Klemetti [1989] also divided their subjects (240 myopic children) into three groups but used two groups of single vision spectacle wearers and one group of bifocal wearers. One group wearing single vision lenses for full-time, a second group wearing single vision lenses for distance vision only and a third group wearing bifocals with a +1.75 D add. They analysed the mean progression rate for three years and found no statistically significant difference between the three groups. Similar results were found in another two year clinical trial conducted on 145 Danish children by Jensen [1991]. Fulk & Cyert [1996] reduced the bifocal add to +1.25 D in their study and studied the progression rate in 32 children with near-point esophoria for 18-month period. They also did not find any significant difference in progression rate over an 18-month period. One interesting finding from this study was when they reanalysed their data for every 6 month interval they found that the progression rate for the single vision group (0.80 D/year) was higher than the bifocal group (0.37 D/year) during the 12-18 month period.

Goss & Grosvenor [1990] reanalysed the results of 3 previous studies and

found that bifocals compared to single vision lenses are more effective in reducing the progression of myopia in subjects with esophoria.

These studies have shown that the bifocals do not reduce the progression

of myopia and is not a suitable intervention for myopia control, with the possible exception of children with esophoria. This does not necessarily mean that the hypothesis that accommodative lag causes myopia can safely be rejected, for 2 reasons: (a) the children might not be always using the near

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segment for near work and (b) since the bifocals has only two segments (one for distance and one for near) there might be retinal defocus at intermediate distances which might cause eye growth. Hence later studies concentrated on reducing the retinal defocus at all distances with the use of progressive addition multifocal lenses.

Progressive addition lenses Progressive addition lenses have an advantage over bifocals as they are

more cosmetically acceptable and they also potentially reduce accommodative demand at all distances, reducing retinal blur.

Leung & Brown [1999] conducted a 2-year longitudinal study in 68

myopic children aged between 9 and 12 years. The subjects were divided in to three groups. 32 children were prescribed single vision lenses, 22 children were prescribed progressive addition lenses with a +1.50 D addition and 14 children with a +2.00 D addition. They found that both the progressive addition groups progressed less than the single vision group and the +2.00 D addition group progressed less than +1.50 D group. Though they found a significant difference in the treatment groups, the study was not randomised, and the refractive error measurements were unmasked, and not made under cycloplegia.

Edwards et al. [2002] also studied the effect of progressive addition lenses

on myopia progression in 254 children aged between 7 and 10.5 years for 2 years but with +1.50 D addition. They found no significant difference in progression of myopia between the single vision group and progressive addition group. The results of this study compared to the previous study are more reliable since the study was masked, subjects were randomised and also the refractive error assessment was done under cycloplegia. These results were further supported by another randomised clinical trial by [Shih et al. 2001] in 227 myopic children aged 6-12 years. They also found no significant decrease in progression with progressive addition lenses.

Gwiazda et al. [2004] conducted a randomised clinical trial in 469 children

to study the effect of progressive addition lenses (+2.00 D addition) on myopia progression for 3 years. They found a significant difference in progression between the treatment groups. But the magnitude of this difference was 0.20 ± 0.08 D which the authors did not consider to be clinically significant. This difference was found only in the first year of the 3-year trial. [Hasebe et al. 2008], also found a small but significant difference in the myopia progression between their Progressive addition group and single vision group. The

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children wearing progressive lenses progressed less by 0.17 D over an 18 month period.

Undercorrection of myopia The rationale for undercorrection of distance vision is that it will lead to

myopic defocus (when the retinal image is formed in front of the retina) for distance vision and also a decrease in the hyperopic defocus (when the retinal image is formed behind the retina) at near. Studies done on animals [Schmid & Wildsoet 1996;Shaikh, Siegwart, Jr., & Norton 1999;Smith III & Hung 1999;Whatham & Judge 2001] have shown that myopic defocus decreases the ocular elongation and hence reduces the myopia progression.

Tokoro & Kabe [1965] studied myopia progression in 11 fully corrected

and 5 undercorrected myopes. They found that the mean annual rate of progression in undercorrected group (0.47±0.09 D) was less than the full-time fully corrected group (0.83±0.18 D). Though the difference was statistically significant, [Goss 1994], the study was not randomised, had a very small sample size, and the two groups were not matched for their age. Chung, Mohidin, & O'Leary [2002] conducted a two year randomised controlled clinical trial to study the effects of undercorrection on myopia progression in 94 myopes aged 9-14 years. The experimental group were under corrected by 0.75 D and the control group were fully corrected. They found that the experimental group (mean progression = -1.00 D) had progressed significantly more than the fully corrected control group (mean progression = -0.77 D) in 2 years. Their results support the hypothesis that myopes have an abnormal mechanism in detecting the direction of optical defocus of the retinal image.

Phillips [2005] investigated the effect of monocular undercorrection on

myopia progression in 13 myopic children aged 10-13 years. Spectacle lenses were prescribed for both the eyes. The dominant eye was prescribed with a full myopic prescription and the non-dominant eye received an undercorrection of up to +2.00 D. They found an increase in progression of myopia in both the eyes. The rate of myopia progression in the non-dominant undercorrected eye (-0.32 D/year) was less than the dominant fully corrected eye (-0.72 D/year).

A study conducted by Adler & Millodot [2006] also looked at the effects

of undercorrection on myopia progression in 48 myopic children. They also found a greater increase in myopia over an 18-month period in the undercorrected group than in the fully corrected group, but the difference was not statistically significant.

21

From these studies it is clear that undercorrection is not an effective

therapy to reduce myopia progression.

Overcorrection of myopia Goss [1984] studied the effect of distance overcorrection on progression of

myopia in 72 subjects aged 7-16 years. The subjects were divided into two equal groups, an experimental group wearing spectacles with overcorrected prescription by 0.75D and a control group wearing spectacles with full prescription. He did not find any significant difference in the progression of myopia between the experimental and control group; both groups progressed by half a dioptre.

Orthokeratology Orthokeratology (OK) was defined by the International Orthokeratology

Section of the National Eye Research Foundation as ‘the reduction, modification or elimination of refractive anomalies by the programmed application of contact lenses’ [Swarbrick 2006]. As early as in 1960s PMMA lenses and later on RGP lenses have been used either to reduce or to eliminate myopia.

Polse et al. [1983] studied the effect of orthokeratology on reduction of

myopia in 59 subjects for 1.5 years. The subjects were divided in to two groups, one treatment group wearing OK contact lenses and a control group wearing conventional hard contact lenses. They found a significant decrease in myopia in the treatment group compared to the conventional lens group. But this decrease in myopia was not maintained after discontinuing the treatment lenses indicating that it is not a permanent solution in reduction of myopia.

Cho, Cheung, & Edwards [2005] conducted a 2-year study in 43 children

aged between 7 and 12 years to test whether OK can decrease myopia progression. They used a data of 35 children wearing single-vision spectacles from a previous study by Edwards et al. [2002] for control group. They monitored growth in axial length and vitreous chamber depth for 2 year period in the treatment group and compared them with previous data in the control group. After 2 year period the mean changes in axial length in the treatment group was about half the changes observed in the control group. They also

22

found similar results for vitreous chamber depth. But when we look at the individual subjects there was a large variation in the degree of growth of axial length, making it difficult to predict the amount of slowing of myopia progression.

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PERIPHERAL ABERRATIONS AND MYOPIA

The human eye not only suffers from on-axis aberrations, but it also has

peripheral off-axis aberrations. Studies have shown that aberrations increase from centre to periphery of the visual field and are dominated by defocus and astigmatism. [Atchison 2006;Atchison & Scott 2002;Guirao & Artal 1999;Millodot 1981;Navarro, Moreno, & Dorronsoro 1998;Rempt, Hoogerheide, & Hoogenboom 1971]. Higher-order aberrations have also been studied using different techniques in the peripheral visual field. The studies have shown a quadratic increase in the higher-order RMS in the periphery [Atchison & Scott 2002;Lundstrom, Gustafsson, & Unsbo 2009;Mathur, Atchison, & Scott 2008;Navarro, Moreno, & Dorronsoro 1998].

In the last few years studies have looked at the role of peripheral vision in

the emmetropization process. From the studies of Earl Smith [Smith, III et al. 2007;Smith, III et al. 2005] two findings could be concluded. First was that in infant rhesus monkeys peripheral form deprivation can induce axial myopia, even in the presence of unrestricted central vision. Secondly, the peripheral retina, in isolation, can regulate emmetropizing responses.

It has been suggested that the hyperopic defocus in the peripheral retina

may act as a signal to axial elongation of the eye in myopes [Smith, III et al. 2005;Stone & Flitcroft 2004;Wallman & Winawer 2004]. Recently studies have been initiated to develop new spectacle designs to reduce the hyperopic defocus. Tabernero et al. [2009] investigated a newly designed radial refractive gradient lens to modify the peripheral defocus. These lenses induced relative peripheral myopia. The effect of these lenses on myopia progression is not yet investigated.

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If the peripheral retina plays a major role in the myopia development then it is essential to correct not only the on-axis aberrations, but also the peripheral aberrations. In order to correct aberrations, it is important to measure them accurately using an aberrometer. The recent introduction of the COAS-HD VR, makes it possible to measure off-axis aberrations in a larger area in the visual field. Hence the repeatability of this instrument is evaluated in experiment V.

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AIM

The purpose of this thesis was to investigate the effect of manipulation of spherical aberration of the eye on accommodative response and visual acuity in myopes using custom designed soft contact lenses. In addition, repeatability and distribution of peripheral aberrations in young emmetropes were also investigated using a new open field aberrometer.

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MATERIAL AND METHODS

This thesis consists of five experiments. The first four experiments were conducted in Cambridge in United Kingdom and the fifth study was conducted in Kalmar in Sweden. The first four experiments forms part of a large clinical trial called Cambridge Anti-myopia Study. Experiments I and II were pilot studies which helped in developing the clinical trial. Experiments III and IV were some of the results from the clinical trial. In the clinical trial two treatment modalities were used. One of the modalities was custom-designed soft contact lenses to alter the spherical aberration of the eye and hence improve the accommodative response in myopes and a second treatment modality was a vision training program to improve the accommodative dynamics. The author of this thesis was not involved in the vision training program since it formed part of another PhD thesis. Hence in this section the material and methods related to the spherical aberration treatment is presented. Experiment V was conducted to gain more knowledge in the field of peripheral optics.

Subjects

Experiment I Ten subjects were included in this study. They were recruited from the student population at Anglia Ruskin University, Cambridge in United Kingdom. The mean age ± S.D. in this study was 23.7 ± 3.7 years.

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Experiment II Subjects were recruited from the student and staff population at Anglia Ruskin University. Five myopic subjects with a mean age of 25.2 (range 20-34) participated in this study.

Experiment III The subjects in this study were recruited by putting appropriate notices in the schools, universities and city council notice boards in and around Cambridge, United Kingdom. Also publicity came from articles published in the Times, Guardian and Daily Mail newspapers and national news programmes in BBC, ITV, Channel 5 and Sky TV. 500 volunteers were interested in participating in the trial. Letters were sent to them providing information about the trial and the treatment and control group. 280 subjects were excluded after they read the letter and also after speaking to them on phone and based on their recent prescription (high astigmatism, inclusion criteria, unable to travel). 220 attended the baseline assessment visit and 38 were excluded due to unsuitable refractive error, amblyopia, corneal disease, or unwillingness to proceed. During the contact lens fitting five more subjects were excluded since they could not handle the lenses and leaving a total of 177 subjects. The whole recruitment process took place from April 2005 to December 2005. The results presented in this paper were from 93 subjects who all had positive baseline spherical aberration and also who came after three month use of lenses. The mean age ± S.D. was 16.8 ± 2.1 years.

Experiment IV The subjects in this study were also recruited in the same way as described in experiment III. The results of 98 subjects were presented in this paper who had been wearing the lenses for a minimum of 12 months at the time of the vision assessment. The mean age ± S.D. was 17.8 ± 2.0 years.

Experiment V The subjects were recruited from the student population in Linnaeus University at Kalmar, Sweden. Eighteen subjects were included in this study. The mean age ± S.D. was 23.9 ± 3.1 years.

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Ethics In all the experiments informed consent was obtained from every participant after verbal and written explanation of the nature and possible consequences of the study. The tenets of the Declaration of Helsinki were followed. The first four experiments were approved by Anglia Ruskin University Ethics Committee, and the fifth was approved by the local ethics committee, etikprövningskommitten Sydost, in Växjö.

Instrumentation and experimental procedure

Aberrometry The Wavefront aberrations were measured in experiments I-IV using the Complete Ophthalmic Analysis System Model G200 (COAS) (figure 5) (Wavefront Sciences, Albuquerque, New Mexico) which uses the Hartmann-Shack principle and a proprietary computation technique. This system was used since each measurement takes only a few seconds (usually depends on the slider, a mechanical translation stage inside the aberrometer) and also it displays a real-time image of the pupil with which the pupil centre can be determined accurately. The method uses several light flashes from a Super Luminescence Diode (SLD) and the measurement light is in the near infrared region of the spectrum (840nm). The exposure time of this light is about 250 ms at less than 50 μWatt which is well below the Maximum Permissible Exposure (10 minutes). Since the system uses the near infrared light, a chromatic aberration correction option was used in the system configuration to correct the values from 840 nm to 555 nm.

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Monitor showing output image

of aberrations COAS Head

Computer

Figure 5 . Complete Ophthalmic Analysis System

The COAS has been found to produce results similar to laser ray-tracing and psychophysical ray-tracing techniques [Moreno-Barriuso et al. 2001]. The accuracy and repeatability of the COAS has also been assessed for the measurement of higher-order aberrations [Cheng et al. 2003b]. It has been shown to be very accurate in measuring primary spherical aberration (average absolute error = 0.007μm). Three successive aberration readings were taken each time in experiments I-IV and the mean was calculated. All the subjects were asked to blink once before each reading. The analysis pupil diameter was 5 mm in all the experiments. Pupil diameter was measured using the COAS in experiment IV. The measurement was done with ambient room illumination. The COAS was set up in the “multibuffer” mode which captures up to eight readings continuously. The subjects were asked to look at the internal target so that the accommodation is relaxed and five readings were obtained for each eye. In experiment V, monochromatic aberrations were measured with a Complete Ophthalmic Analysis System Model 2800 High Definition aberrometer (COAS-HD VR) . The COAS-HD VR (figure 6) integrates a COAS-HD

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aberrometer with VR (Vision Research open view optical relay). COAS-HD VR measures the aberrations by Hartmann-Shack principle. The light source is a superluminescent diode that emits 840 nm near infrared radiation. The wavefront sensor uses an 83×62 array of lenslets each being 108 μm in diameter. The pupil magnification factor is 0.68 and this samples the exiting wavefront in steps of 158 μm in the pupil plane. There are 766 sample points for a 5 mm diameter pupil. This instrument has an open field of view and VR consists of a large 4×8 inch hot mirror, which transmits 95% of visible light but reflects 95% infrared light from the superluminescent diode, which allows us to present any stimuli at any distance and gaze angle. The stimulus can also be presented simultaneously to both eyes. Any changes in aberrations with accommodation can also be measured for both central and peripheral vision.

Figure 6 . Complete Ophthalmic Analysis System-High Definition with the Vision Research Tool

The target used for peripheral aberration measurements was a non-accommodative red light emitting diodes (LED) with a wavelength of 635 nm. The LED was 3 mm in diameter and was placed 3 meters from the subject’s eye. The target construction consisted of 11 LED’s placed in a radial geometry subtending a ± 40o horizontally and +20o superiorly. The measurements were performed at 11 different retinal locations: fovea (on-axis), out to ±40o horizontally and +20o superiorly, in steps of 10o (figure 7). Subjects were asked to blink once and hold their eyes wide open before each measurement. They turned their eyes to view the off-axis fixation target, during the measurement. Five readings were taken at each angle. Each such measurement took approximately five seconds to perform. It took about thirty seconds to perform a set of five repeated measurements.

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Figure 7 . A schematic drawing showing the position of fixation targets relative to the measuring

direction for off-axis measurements

Accommodation measurement Accommodative response was measurement using a Shin-Nippon SRW-5000 autorefractor (SRW-5000) (Grafton Optical, Herts, UK). The SRW-5000 (figure 8) uses a ring target of infrared light which is reflected off the retina to measure the refractive error. A lens is rapidly moved on a motorized tract to place this ring target in focus. The reflected image is then digitally analysed in multiple meridians to calculate the toroidal refractive prescription. The advantage of using this auto refractor over others is that it allows the binocular view of the targets. The accuracy and reliability of this instrument has been demonstrated in both adult [Mallen et al. 2001] and paediatric [Chat & Edwards 2001] populations.

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Open field of view

Display for eye

alignment

Figure 8. Shin-Nippon SRW-5000 autorefractor

In all the experiments whenever the accommodative response was measured, the measured eye was occluded with a Kodak Wratten 88A filter. This was done so that the measurements were not affected by the aberrations in the contact lenses. This filter transmits infrared radiation but not visible radiation (effective cut-off at 700nm) and so acts as an occluder whilst allowing the auto refractor to obtain a reading.

Accommodative response was measured in two ways in this thesis. In one

procedure an accommodative target was brought closer in free space from 6 m to closer distances (e.g. 33 cm, 25 cm) and the accommodative response measured. Always the targets were presented in the order of decreasing distance. This procedure was called distance series. In the second procedure negative lenses were placed in front of the eyes to induce accommodation while the subject looks at a distant accommodative target. The lenses were placed in the order of increasing negative power (for e.g. -1 D, -2 D, -3 D). This procedure was called negative lens series. In both the procedures the targets were presented on the axis of the measured eye to prevent any measurement errors. Participants were instructed to keep the letters clear at all times and to inform the examiner if this was not possible.

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In both the procedures the target letters were presented to one eye (non-

dominant eye in experiment I and right eye in experiments II, III and IV) and the accommodative response measurements were measured in the contralateral eye which was occluded with the filter. The contralateral eye measurements reflect the accommodation in the fixating eye, as accommodation is equal in the two eyes [Campbell 1960].

Visual acuity and contrast sensitivity assessment In experiment I visual acuity was measured using the computer generated Test Chart 2000 PRO LogMAR (logarithm of the minimum angle of resolution) visual acuity chart (Thomson Software Solutions, Herts, U.K.). The advantage of using this chart is that the letters can be randomised for each presentation, which reduces learning effects. This was required since in experiment I several repeated measures of visual acuity were done on the same subjects with different contact lenses. The 21” computer CRT monitor was placed next to the patient and a mirror was used to achieve a viewing distance of 5.9 m from the eye. From the Setup screen “mirror optotypes” option was selected to reverse the letters. The test chart was calibrated before starting the visual acuity assessment. The calibration screen was shown automatically when the program was run for the first time. This had three calibration boxes, a) Letter size calibration, b) Screen size calibration, c) Window size and position, along with a letter E. The measurements were done using a measurement scale and documented below: a) Height of E (mm): 109 Chart viewing distance (cm): 590 b) Width of blue rectangle (mm): 347 Height of blue rectangle (mm): 233 c) Since we used a single monitor the test window was sized and positioned automatically. In experiment IV the contrast sensitivity was measured using Pelli Robson contrast sensitivity chart. This chart consists of eight lines of letters with different contrast. Each line has six letters of which the first three letters (a triplet) on the left have more contrast than the next three letters on the right. The contrast also decreases from 0.00 log units (100%) as you go down the chart from top line to a minimum of 2.25 log units (0.6%). The letter size corresponds approximately to the peak of the contrast sensitivity function. Subjects were asked to read the lowest contrast triplet that could be seen, then encouraged to attempt the next triplet, stopping when all the letters in a triplet were either not visible or were read incorrectly. The letter ‘C’ read as the letter

34

‘O’ and vice versa was taken as a correct answer. Each correctly read letter was scored as 0.05 log units as recommended by Arditi [2005] and Elliott, Bullimore, & Bailey [1991]. Low contrast visual acuity were also measured in this experiment using a 10% contrast Bailey Lovie logMAR chart at 4 m. Subjects were asked to read the lowest line that they could. If some letters were correctly read on a line, they were asked to attempt the next line, until all the letters on a line were either not visible or were read incorrectly [Carkeet 2001].

Contact lenses All the contact lenses were manufactured by UltraVision CLPL (Leighton Buzzard, UK). The lenses used in experiment I had different amounts of positive and negative spherical aberration and had no refractive error correction whereas lenses used in experiments II, III and IV had either refractive error correction with altered spherical aberration (treatment group) or refractive error correction with zero spherical aberration in air (control group). Corneal Topography was measured using the Humphrey ATLASTM Corneal Topography System with MaterVueTM software (ATLAS). This system projects a series of light rays onto the cornea and captures the reflected images using a video camera. The MaterVueTM software converts these images into a corneal power map and calculates the corneal curvature. This system has been found to be highly accurate and repeatable [Jeandervin & Barr 1998]. One measurement was taken for each eye which was used to decide the required BOZR for the contact lenses in experiments I, II and III. Optical design (experiments II, III and IV) Soft contact lenses were designed to alter ocular spherical aberration in addition to correcting the spherical equivalent axial refractive error. The front surface curvature was calculated using paraxial optics to correct the axial refractive error. The spherical aberration of the lens was manipulated by altering the eccentricity value of the front surface of the lens. The contact lenses were designed to alter the existing fourth-order spherical aberration of the patient to -0.1μm (referenced to a 5-mm diameter pupil) while maintaining the appropriate paraxial correction. Spherical aberration of -0.1 microns for a 5mm pupil diameter will equate to 0.137D/mm2 and therefore approximately 0.34D at the edge of a 4mm pupil. In equivalent dioptric terms the spherical defocus required to produce the same wavefront variance as -0.1 microns spherical aberration equates to -

35

0.17D. A ray tracing program (Zemax) was used to calculate the required surface parameters of the contact lenses. The spherical aberration of the control group lenses was designed to have zero spherical aberration in the contact lenses regardless of the measured spherical aberration level of the eye. All lenses were made of 58% HEMA based material. The back optic zone radius (BOZR) and total diameter (TD) of each lens were specified depending on the participant’s palpebral aperture, corneal radius and horizontal visible iris diameter. The contact lenses were fitted such that the movement on blink was approximately 0.25mm. Because this small movement of the lens during blink is likely to induce transient coma like aberration, the aberrations with these contact lenses were measured only after the lens settled in the centred position. The aberrations in the contact lenses were assessed by measuring the total aberrations of the eye after fitting the contact lens to the patient. Replacement of lenses and follow up In case of subjects loosing or damaging the lenses, new lens/pair were ordered and sent by post with in 2 weeks. The lenses were sent in bottle containers indicating right and left lens. The right lens had a small line drawn on the edge to help the subjects. After sending the lenses the subjects were contacted by phone or email to check whether they received the lenses and also whether they were comfortable with the new lens/pair. Before each visit the subjects were contacted either by telephone or email or by a letter sent to their address to provide information about their next visit. If they were unable to reach before the appointment, they were sent another reminder in the form of a letter suggesting them to contact us as soon as possible. All the subjects were seen from Monday to Friday 08:30 to 18:00. Some aftercares were done on the weekends. The research team of the trial were reached by an office phone and also a one of the clinical team member had an emergency mobile phone to reach us anytime for advice. There was also an email address to reach the team. The author of this thesis had a major contribution in several aspects of this clinical trial like recruiting the subjects, designing the lenses, ordering the lenses from the manufacturer and data collection up to 18 months of treatment period.

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EXPERIMENTS

The significant results of all the five experiments are presented in this section. All the results are published except experiment two. Experiment two is presented as a paper rather than only results section since it forms a link between experiment one and three.

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Experiment I The effect of altering spherical aberration on the static accommodative

The purpose of this study was to investigate the effects of added positive and negative spherical aberration on accommodative response accuracy. The results suggest that accommodative response can be altered by modulating the spherical aberration of the eye with soft contact lenses. There was an improvement in the accommodative response gradient and a decrease in the lag of accommodation with the negative spherical aberration lenses compared to positive spherical aberration lenses for both distance and lens series. Even though the higher-order RMS increased with both positive and negative spherical aberration lenses, this did not affect the accommodative response in this sample. The total spherical aberration and higher-order RMS of the eye plus contact lens and the lag of accommodation for a 3D stimulus is shown in the figure 9. The improvement in response is maintained even after one hour of adaptation. So we conducted the next study to investigate whether this improvement in the response could be applied to myopes, who tend to have poor accommodative response so that there is an improvement in their accommodative response and hence decrease the myopia progression.

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

-0.2 -0.1 0 0.1 0.2

Lens nominal SA

Mic

rons

/ Dio

ptre

s

MEAN SAPupil size = 5 mm MEAN RMS HO

MEAN LAG

Figure 9 . Accommodative lag for a 3 dioptre stimulus (black bars), measured spherical aberration

(SA) of the eye plus contact lens (μm) (open bars) and measured higher-order (HO) RMS

berrations of the eye plus contact lens (μm) (diagonal stripes) are shown with each added spherical

aberration contact lens. Each bar is the mean of the results for 10 participants.

38

response (Paper 1)

Experiment II Phase 1 Trial: Altered spherical aberration and acceptability of the treatment lenses

Introduction The results from the previous experiment have shown that by changing the spherical aberration of the eye to a slightly negative amount using soft contact lenses, the accuracy of accommodation could be improved, at least in the short term. Allen & O'Leary [2006] demonstrated that lag of accommodation was significantly correlated with myopia progression. We therefore suggested that inducing a small amount of negative spherical aberration in a contact lens correction could be used to reduce the lag of accommodation in myopes in an attempt to reduce the rate of myopia progression. As far as we are aware there have been no studies of the visual discomfort associated with changed aberrations, although we are aware that post-surgical refractive surgical patients tolerate high amounts of positive spherical aberrations [Bailey et al. 2004;Marcos 2001]. This section presents the results of a phase 1 study of a contact lens correction with negative spherical aberration as a preliminary to a full-scale clinical trial. Following normal protocols for phase 1 trials, a small number of participants were used, and additionally accommodation responses were measured to see if there were any notable changes in the trial period since previous studies have shown only short term treatment effect. Gwiazda et al. [2004] conducted a randomised clinical trial in 469 children to study the effect of progressive addition lenses (+2.00 D addition) on myopia progression for 3 years. They found a statistically significant difference in progression between the treatment groups. But this difference was found only in the first year of the 3-year trial. The purpose of this study was to investigate whether the contact lens correction was tolerated visually in terms of wearability and comfort.

Materials and methods Participants were recruited from the student and staff population at Anglia Ruskin University. Five myopic subjects with a mean age of 25.2 (range 20-34) participated in this study. All were screened for any ocular pathology. None had any ocular disease and the best corrected visual acuity in both eyes was 6/6 (LogMAR 0.0) or better. Mean spherical equivalent refractive error ±

39

SD in the right and the left eye were -4.12 ± 2.48 D and -3.70 ± 2.05 D respectively. For all the participants, astigmatism was less than 1.25 D in either eye. The lenses were designed to correct the ocular refraction of the participants and to induce the required negative spherical aberration. Non-cycloplegic subjective refraction was determined in both eyes to an endpoint accuracy of ±0.12D. The end point of refraction was maximum plus for maximum visual acuity, which was crosschecked with a +1.00DS blur test. The refraction values were used to calculate the front surface curvature using paraxial optics. The spherical aberration of the lens was manipulated by altering the p value of the front surface of the lens to produce the required amount of spherical aberration in air for a 5mm pupil size. Spherical aberration of the treatment lens = [(-Spherical aberration of the eye) + (-0.11 microns of spherical aberration)] A ray tracing program was used to calculate the required surface characteristics so that when the lenses are worn on the eye, they corrected the ocular refraction and also altered the spherical aberration of the eye to -0.11 μm at 5 mm aperture. The monochromatic wavefront aberration function of the eyes was measured using the Complete Ophthalmic Analysis System (COAS). The spherical aberration was analyzed for a 5mm aperture.

Wavefront aberration function was assessed for both eyes for all 5 participants. The spherical aberration of the eye was calculated as the mean of three successive readings taken at approximately 30 s intervals. Visual acuity was measured using customised LogMAR (logarithm of the minimum angle of resolution) visual acuity chart calibrated at 3 m distance. The chart was externally illuminated with illuminance of 160 lux and had 14 rows of letters starting with 1.0 LogMAR unit (6/60). Further rows had letters with size reduced by 0.1 LogMAR unit and the last row being -0.3 LogMAR unit. Each row had 5 letters and each letter had a LogMAR unit of 0.02. The end point of assessment was when the subjects read all the letters in a line incorrectly [Carkeet 2001]. Visual acuity was measured for right and left eye. A questionnaire was given to the participants on the first and the last day of the trial period to assess the subjective contact lens comfort, distant and near vision with contact lenses compared to their glasses and the stability of vision

40

with contact lenses. The participants rated the questions on a 10-point scale from 1 to 10. Accommodative response amplitudes were measured with a Shin Nippon SRW 5000 auto-refractor. For all measurements the back vertex distance of the instrument was set to 0mm to measure accommodation responses at the corneal plane. The measurement interval of the SRW5000 was set to 0.12 D. Accommodation responses were measured through an infra-red transmitting filter (Wratten 88a gelatin filter) which will occlude the view of the target whilst still allowing a measurement to be made. Accommodation responses were measured for targets presented in free space (distance series) and to negative lens induced blur (negative lens series). The accommodative demands for the altering distance series were -0.17 D, -1.00 D, -2.00 D, -2.50 D and -3.00 D. For the negative lenses series demands were generated using a target at -0.17 D and adding lenses of powers -1.00 D to -4.00 D in -1 D steps. The target for the negative lenses series was a row of 6/12 letters at 6 m. For the distance series the same row of letters was scaled so that the angular subtense of the target remained constant irrespective of distance [Atchison, Capper, & McCabe 1994]. The target letters were presented to the right eye. The participants were asked to fixate the letters and keep them clear at all times. The accommodative response was measured in the left eye, which was occluded with the filter for both distance series and negative lens series. Ten consecutive readings were taken for each stimulus condition and the mean of the spherical equivalent calculated. The accommodative response measurements were taken twice on each participant for both negative lens and distance series to determine any change in the response with time. The initial series of measurements were taken on the first day after the lenses had been allowed to settle for a period of 30 minutes. Participants were asked to wear the contact lenses for 10 hours per day for 7 days. A second series of measurements were taken on the 8th day. Informed consent was obtained from every participant after verbal and written explanation of the nature and possible consequences of the study. The Tenets of the Declaration of Helsinki were followed and the study was approved by Anglia Ruskin University’s Research Ethics Committee.

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Results A paired-samples t-test was conducted to compare the spherical aberration of the eye with and without contact lenses. The test showed that the spherical aberration of the eye was significantly different with and without contact lenses (p < 0.001). The mean spherical aberration of the right eye with and without contact lenses is shown in figure 10.

With lens

Without lens

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15

0.2

SA of the eye

aber

ratio

n (m

icro

ns)

Figure 10 . Spherical aberration (SA) of the eye with and without contact lenses. Error bars

represent±1 standard deviation

A paired-samples t-test was conducted to compare the logMAR visual acuity of spectacles with contact lenses. There was no statistically significant difference in the visual acuity with spectacles and contact lenses (p = 0.056). The logMAR visual acuity values for right eye with spectacles and with contact lenses are shown in figure 11.

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-0.2-0.18-0.16-0.14-0.12-0.1

-0.08-0.06-0.04-0.02

0

logM

AR v

isua

l acu

ity

1 2 3 4 5

WITH SPECTACLES

WITH CONTACT LENSES

Figure 11 . Visual acuity with spectacles and contact lenses.

The mean contact lens comfort on the first day was 8.6 on a scale of 10 (1=unwearable of the lens, 10=unaware of the lens) and with seven day wearing period the comfort either remained the same (in two) or improved slightly. A paired samples t-test showed no significant difference in comfort scores between day one and day eight (p>0.05). The individual comfort scores of each participant are shown in figure 12.

123456789

10

1 2 3 4 5

Participants

Com

fort

sco

re

DAY ONEMEAN=8.6

DAY EIGHTMEAN=9.2

Figure 12 .The individual comfort scores of each participant.

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The distance and near vision with contact lenses was rated at least as good as or better than their glasses on both the first and last day of the trial period. The stability of vision with lenses was rated very good on both initial and final day of the study. The mean scores for distant, near and stability of vision is shown in figure 13.

12345

6789

10

Distancevision

Near vision Stability ofvision

Day OneDay Eight

Figure 13 .The mean scores for distance, near and stability of vision

A paired-samples t-test was conducted to compare the accommodative response slopes with contact lenses on the first and the last day of the treatment period. There was no significant difference in the slopes for both distance series (p=0.94) and negative lens series (p=0.91). The mean accommodative response slopes with contact lenses on first and the last day are shown figure 14.

44

y = 0.9295x - 0.398R2 = 0.9931

y = 0.9389x - 0.2129R2 = 0.9992

-0.5

0

0.5

1

1.5

2

2.5

3

0 0.5 1 1.5 2 2.5 3 3.5Accommodative Demand (D)

Acc

omm

odat

ive

resp

onse

(D)

INTIAL VISIT WITHCL

FINAL VISIT WITHCL

Linear (INTIAL VISITWITH CL)

Linear (FINAL VISITWITH CL)

Figure 14. The mean accommodative response slopes with contact lenses on first and the last day

Discussion The results have shown that all the participants were satisfied with the contact lens comfort, distant and near vision and the stability of the vision with the treatment lenses. All the participants found their vision with the lenses to be acceptable. The calculated and the measured spherical aberration of the eye were well correlated. This is in agreement with a previous study where it was shown that the spherical aberration of a soft contact lens on-eye is very similar to the spherical aberration in air [Dietze & Cox 2003]. An earlier study done by Cox & Holden [1990] altered the longitudinal spherical aberration of the eye using soft contact lenses and measured the change in the visual performance. They used five different levels of spherical aberration +2.00, +1.00, 0.00, -1.00, -2.00 D measured at 3 mm ray height from the optical axis of the lens. Among their findings the main result related to this study is that they found the spherical aberration measured on the eye is less than the spherical aberration calculated in air. The high contrast visual acuity was not affected by inducing negative spherical aberration with the treatment lenses. The human visual system can tolerate low levels of spherical aberration. Recently Li et al. [2009] have shown that

45

spherical aberration up to ± 0.1 microns has no effect on high contrast visual acuity. The results also show that the accommodative response was stable throughout the period of the trial. This is in agreement with results from our previous experiment where we showed that the response was stable with one hour wearing period. We conclude that the strategy of using negative spherical aberration would be tolerated well by participants, and so went ahead with the main trial.

46

Experiment III Aberration Control and Vision Training as an Effective Means of Improving

The purpose of this study was to test the efficacy of a novel dual treatment for improving the accommodative accuracy and dynamics in myopes. The spherical aberration of the eye was altered to improve the accommodative accuracy and vision training was provided to improve the accommodative dynamics. The author was involved in the spherical aberration treatment and not in the vision training treatment; hence the results presented here are related to spherical aberration treatment. The spherical aberration of the eye was effectively altered to negative in the treatment group as calculated. In the control group as expected there was no significant change in the spherical aberration of the eye with and without contact lenses. Higher-order RMS increased in both treatment and control groups with the contact lenses compared to baseline (without any lenses), but there was no significant difference between the groups at 3 months. The treatment lenses decreased the lag of accommodation (figure 15) and increased the accommodative response gradient at 3 months.

Figure 15. Change in lag of accommodation for the contact lens treatment (▲) and contact lens

control (■) groups between the baseline and 3-month visits. Error bar indicate 0.95 CI.

47

Accommodation in Individuals with Myopia (Paper 2)

Experiment IV Increasing negative spherical aberration with soft contact lenses improves

This study investigated the effect of a customised spherical aberration lenses on the high and low contrast visual acuity in myopes. The high and low contrast logMAR acuities were significantly better in the treatment group than the control group at one year visit. Even though the treatment group had -0.104 μm spherical aberration, this did not affect the high and low contrast acuities. There was no significant difference in the Pelli Robson contrast sensitivity between the treatment and control group. The mean values for both the groups are presented in table 1. The author was involved in designing both treatment and control lenses and in the data collection in this experiment.

Group HC logMAR ± SD LC logMAR ± SD

PR CS ± SD

Treatment (n = 106)

-0.09 ± 0.09 0.47 ± 0.11 1.57 ± 0.07

Control

(n = 90)

-0.06 ± 0.08 0.51 ± 0.14 1.57 ± 0.09

Table 1. Mean visual acuity for each contact lens group. HC logMAR-high contrast logMAR acuity; LC logMAR-low contrast logMAR acuity; PR CS-Pelli Robson contrast sensitivity; SD-standard deviation.

48

high and low contrast visual acuity in young adults (Paper 3)

Experiment V

The purpose of this study was to evaluate the intrasession repeatability of

peripheral aberrations using COAS-HD VR and also to report distribution of higher-order aberrations in a group of young emmetropes. There was no significant difference in the variance of total higher-order RMS between on- and off-axis measurements. The repeatability of third- and fourth-order aberrations was better than the fifth- and sixth-order aberrations. There was a significant difference in the horizontal coma, spherical aberration and higher-order RMS with off-axis angle along the horizontal visual field. The horizontal coma changed significantly at each off-axis angle whereas spherical aberration and higher-order RMS changed only at ± 30° and ± 40° eccentricity (figure 16). The author was involved in the experimental design and analysis and presentation of statistical results.

Figure 16. Aberration data plotted across the horizontal visual field for horizontal coma (C1

3),

spherical aberration (C04) and higher-order RMS (HO RMS)

49

Repeatability of Peripheral Aberrations in Young Emmetropes (Paper 4)

DISCUSSION AND CONCLUSION

We found that spherical aberration of the eye could be successfully altered

using soft contact lenses. In all the experiments the calculated and measured spherical aberration was similar and even after one year wearing period the treatment group had -0.104 μm. Artal et al. [2004] showed that human eyes adapt to ocular aberrations produced by adaptive optics techniques. But we did not find any adaptation to induced spherical aberrations after one year. It will be interesting to see whether there will be any adaptation effect after a two year wearing period.

We have shown that altering the spherical aberration of the eye with

refractive error correction could improve the accommodative response and this improvement was maintained even after a three month treatment period. After one year there was also a statistically significant improvement in the high and low contrast distance visual acuities with negative spherical aberration lenses even though it was not clinically significant. If lag of accommodation is a stimulus to axial elongation of the eye, and if the improvement in the accommodation response is maintained even after two year treatment period, then the treatment group could show less progression of myopia.

Contact lens manufacturers like Bausch & Lomb have also recently

introduced lenses with fixed amounts of negative spherical aberration. Their PureVision monthly disposable silicone hydrogel lenses have -0.15 μm spherical aberration for 6 mm pupil. Lindskoog et al. [2008] showed that these lenses made the spherical aberration of the eye to change from 0.056 to -0.03 μm for a 5 mm pupil, which is less than our clinical trial.

It is established that the spherical aberration of the eye becomes more

negative at near with increase in accommodation. In the treatment group the spherical aberration of the eye was altered to negative for distance vision. When these subjects are performing near work, this negative spherical aberration could become more negative and hence affect the image quality.

50

But simultaneously there is also decrease in the pupil size at near which could counter affect this increase, which could be the reason that we found in all the experiments an improvement in the accommodative response. Unfortunately it was not possible to measure the accommodative response and the actual amount of change in aberrations at near simultaneously with the COAS we used in the first four experiments. In the future it will be possible to measure this with the new COAS-HD VR which we used in the fifth experiment. With this instrument we could also investigate the change in peripheral aberrations with accommodation.

In the last few years, great interests have been shown in the correction of

not only the central vision but also the peripheral vision. Sankaridurg et al. [2010] recently investigated the effect of three different spectacle designs intended to reduce the peripheral hyperopic defocus. The lenses had various amounts of relative positive power in the periphery. The results after one year treatment period showed no significant difference in the myopia progression between any of the lens design and the control group. However they found a significant decrease in the myopia progression with one of the lens types compared to the control group in a subgroup of younger children with parental history of myopia. Further studies are needed to investigate the long term effects of both on- and off-axis aberration correction in myopes on myopia progression.

51

ACKNOWLEDGEMENTS

I would like to thank Prof. Daniel O’Leary for providing me the opportunity to do research under his guidance. I thank you for all your advices, ideas, encouragement and patience.

I would like to thank Richard Calver for supervising me during third and

fourth year of my PhD, for your guidance and for teaching me good scientific writing in English.

I would like to thank my co-supervisors in the first four experiments in this

thesis, Hema Radhakrishnan and Peter Allen for their ideas and input during these experiments.

I would like to thank my team members in Cambridge Anti-myopia Study

and my dear friends, Sheila Rae and Holly Price for all the help during this project.

I would like to thank my co-authors in the first three papers Paul Nelson,

Ebi Osuobeni and Ananth Sailoganathan. In Sweden, I would like to thank my supervisor Jörgen Gustafsson for all

your feedback, advice, editing this thesis, your continuous encouragement and your instant replies for my questions. Thank you for everything.

I would like to thank my co-supervisors, Peter Unsbo and Staffan Carius

for your corrections and input in the kappa. I would like to thank Sven Tågerud for your advice and support from the

beginning of the registration process to the end of this thesis.

52

I would like to thank Ian Nicholls for initiating the process of this PhD in Kalmar and Michael Lindberg for explaining to me about the Swedish system of PhD process.

I would like to thank Karthikeyan Baskaran, first author in the fourth

paper for his technical support and help with references. I would like to thank Oskar Johansson for designing the front cover picture

in this thesis. I would like to thank Peter Lewis for his help in finding some of the

clarifying my doubts in optics all the time. I would like to thank all the publishers of the four papers for granting

permission to reprint the papers and to reuse the figures. I would like to thank Anna Engberg for her advice on this thesis template

and kappa. I would like to thank Vision CRC, Anglia Ruskin University, FNT at

Linneaus University and Berit och Carl Johan Wettergrens Stiffelse for providing research and travel grants during this thesis work.

I would like to thank all my colleagues in Kalmar, Johanna, Jenny, Carina

and Peter Gierow and all the staff and post graduate students at both universities in Cambridge (especially John Siderov and John Ross) and Kalmar for your moral support.

I would like to thank all my friends especially Carmen for being my very

good friend and all the dinners you cooked for me, Ahalya, Abhi, Lee, Monika, Raju, Ananth Napa, Oskar and Jessica, Rupal and Stephen.

I would like to thank all my subjects who volunteered for their time and

patience.

53

references and also his family for their hospitality.

I would like to thank Robert Rosén and Linda Lundström at KTH for

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