Myopia progression control lens reverses induced myopia in chicks

Abstract

Purpose

To determine whether lens induced myopia in chicks can be reversed or reduced by wearing myopia progression control lenses of the same nominal (central) power but different peripheral designs.

Methods

Newly hatched chicks wore −10D Conventional lenses unilaterally for 7 days. The myopic chicks were then randomly divided into three groups: one fitted with Type 1 myopia progression control lenses, the second with Type 2 myopia progression control lenses and the third continued to wear Conventional lenses for seven more days. All lenses had −10D central power, but Type 1 and Type 2 lenses had differing peripheral designs; +2.75D and +1.32D power rise at pupil edge, respectively. Axial length and refractive error were measured on Days 0, 7 and 14. Analyses were performed on the mean differences between treated and untreated eyes.

Results

Refractive error and axial length differences between treated and untreated eyes were insignificant on Day 0. On Day 7 treated eyes were longer (T1; 0.44 ± 0.07 mm, T2; 0.27 ± 0.06 mm, C; 0.40 ± 0.06 mm) and more myopic (T1; −9.61 ± 0.52D, T2; −9.57 ± 0.61D, C; −9.50 ± 0.58D) than untreated eyes with no significant differences between treatment groups. On Day 14 myopia was reversed (+2.91 ± 1.08D), reduced (−3.83 ± 0.94D) or insignificantly increased (−11.89 ± 0.79D) in treated eyes of Type 1, Type 2 and Conventional treated chicks respectively. Relative changes in axial lengths (T1; −0.13 ± 0.09 mm, T2; 0.36 ± 0.09 mm, C; 0.56 ± 0.05 mm) were consistent with changes in refraction. Refractive error differences were significant for all group comparisons (p < 0.001). Type 1 length differences were significantly different from Conventional and Type 2 groups (p < 0.001).

Conclusions

Myopia progression control lens designs can reverse lens-induced myopia in chicks. The effect is primarily due to axial length changes. Different lens designs produce different effects indicating that lens design is important in modifying refractive error.

Introduction

The prevalence of myopia has been shown in a number of studies to be increasing over time1 and has reached particularly high proportions in certain Asian populations.6 This has generated considerable interest in developing strategies to control myopia. To date these strategies have involved control of progression or prevention of onset (see Chassine et al., Cooper et al., Walline, or Sivak for reviews).10 Animal models can provide insight into the mechanisms controlling eye growth,14 and as such, they are valuable tools for developing new strategies for myopia control and possibly even reversal of existing myopia.

In chicks, minus lenses induce myopia approximately equal to the inducing lens power.15 This myopia comes about mostly via an increase in axial length15 although, a role for the optical components has also been shown.18 These studies clearly demonstrate the ability of the visual environment to influence ocular growth and refractive error. Similar findings in other species21 including monkeys24 led to the search for myopia control strategies in humans.

Some success has been achieved in slowing myopic progression with lens designs that reduce relative peripheral hyperopia.25 It has not been shown definitively that it is the reduction in peripheral hyperopia that is specifically responsible for the success and there is evidence that peripheral refraction is unrelated to myopia progression in children.36 Most of the results attributed to relative peripheral hyperopia can be explained by alternative mechanisms.36 In general, the animal studies, in chicks, marmosets and guinea pigs, using dual focus Fresnel40 or two zone lenses42 that claim to support the peripheral hyperopia hypothesis give results that are consistent with a response close to the average or weighted average power across the pupil. As such, none of these studies have findings that completely inhibit lens-induced myopia. Two studies have reported results that do not correspond to the average power of the lens across the pupil. In one, monkeys subjected to dual focus lenses emmetropise to the relatively myopic focus.45 In the other, we (Woods et al.46) showed that lens induced myopia can be completely inhibited in chicks when the minus power is combined with Visioneering Technologies Inc. (http://www.vtivision.com) myopia progression control extended depth of focus lens designs (US patents 6,474,814/7,178,918). These lenses have a relatively positive powered peripheral lens design.

There are at least two possible explanations for the Woods et al.46 results. The first is that a reduction in relative peripheral hyperopia does play an active role in reducing the development of myopia. Alternatively, a second explanation is that the increased depth of focus of the lenses reduces the emmetropization signal and the chicks simply fail to emmetropise to the inducing lens power. Should the second explanation hold, then if one were to induce myopia and subsequently apply the myopia progression control lenses, the expectation would be that the chicks would remain myopic (i.e., there is no need for the refractive error to change and no signal for change). If however, the chicks were to decrease in myopia, then there would be strong evidence that the eyes were in fact responding to the periphery of the lens. Therefore, the specific aim of this study was to determine whether myopia induced with conventional minus lenses worn for a period of 7 days could be reversed or reduced by wearing these myopia progression control lenses of the same nominal power but different peripheral designs (Type 1 and Type 2), over the next 7 days.

Methods

The study received ethical approval from the University of Waterloo's Animal Care Committee, complied with the Canadian Council on Animal Care use and treatment of research animals, and adhered to the ARVO guidelines for the use of animals in ophthalmic and vision research. The animals used in the study were Ross-Ross strain chickens (Gallus gallus domesticus). They were raised on a 14 h light/10 h dark cycle in stainless steel brooders at 32°C and given food and water ad libitum. Chicks were monitored twice daily, once by the animal care technicians for health, and once by the researcher to assess the lenses.

All lenses were supplied by Visioneering Technologies Inc. and had a measured power of −10.00D, verified using a lensometer (focimeter) with a 5 mm aperture. Conventional and Test lenses were identical in every respect, with the exception that the peripheral power profiles of the Test lenses had a continuous relative positive power gradient without any distinct optical zones or discontinuities. For specific details regarding the power profile the reader is referred to Figure 3 and the formula in Claim 1 of US patent #6474814. Type 1 decreased in minus from −10.00D at the centre to −7.25D (i.e., 2.75D less minus) at the pupil edge based on a 2.5 mm pupil diameter and were designed for and fitted at a vertex distance of 5 mm. Root mean square higher order aberrations provided by Visioneering Technologies, Inc. for a −10.00D lens power at a 2.5 mm aperture were 0.041 microns, as measured by the NIMO Model TR1504 (Lambda-X, http://www.lambda-x.com) using a phase-shifting Schlieren measurement technique. Type 2 lenses were similar but with a less steep power gradient which decreased from a central power of −10.00D to −8.68D (i.e., 1.32D less minus). Aberration data were not available for the Type 2 lenses but would be expected to be less than that of the Type 1 lenses. The overall diameter of the lenses was 20 mm including a flat flange to which Velcro™ was glued that was used to attach the lens to the bird. The optical portion of the lens was 15 mm in diameter and the lens was transparent throughout. The lens designs, which are highly aspheric and gradually change power creating a smooth, continuous power curve of increasing relative plus, were originally created based on human physiology and the predicted amount of lens power required to create the unique extended depth of focus. Those power profiles were then scaled to the anatomy (i.e., the pupil) of the chick to be equivalent to what the relative power profile would be in a human. Two different lens designs were chosen to be quite distinct from each other, so that the possibility of a dose-response relationship could be examined between the two different lens designs.

Figure 3.

Correlation between axial length difference between the two eyes and refractive error difference between the two eyes for Day 14 birds (r = −0.64, p < 0.05).

Fifty-two newly hatched chicks were fitted unilaterally with Conventional design −10.00D lenses (spherical design), which they wore for 7 days to induce myopia. The lenses were attached to the right eye (RE) of all birds using Velcro™ rings held on by cyanoacrylic glue to the feathers around the eye. This allowed the lenses to be removed for cleaning. Two birds lost lenses prior to Day 7 and were eliminated from the study. On Day 7, the remaining 50 myopic chicks were randomly divided into three groups. Sixteen chicks were fitted with Type 1 lenses, 19 chicks were fitted with Type 2 lenses, and 15 remained with Conventional design lenses. Thus, all right eyes are considered treated; initially all had Conventional designs and then right eyes were subsequently treated with either Conventional, Type 1 or Type 2 designs. The left eyes were untreated and served as control eyes.

Refractive error and axial length (anterior cornea to retina) were measured on alert birds using retinoscopy (precision of 0.50 dioptres)5 and ultrasonography (Accutome A-Scan Plus Ultrasound, http://www.accutome.com, precision of 0.02 mm)48 respectively on Days 0 (prior to lens application), 7 and 14 on all birds. The experimenter making the refractive error and axial length measurements was blind as to which of the three groups the chicks belonged. Lenses were only removed for measurement and cleaning when necessary. Birds that lost their lenses were removed from the study (N = 9; 2 prior to day 7, 1 Conventional, 2 Type 1, 4 Type 2). For birds with astigmatic refractive error, the mean ocular refractions (spherical equivalent) were used in the analysis. Results were analysed with respect to the mean differences (Mean [right eye (RE) – left eye (LE)] ± S.E.) between treated and untreated eyes in order to control for the small eye artefact.49 Comparisons were made between treatment assessment day (within group—Day 0, Day 7, Day 14) and lens design (between groups—Conventional, Type 1, Type 2) using a mixed design ANOVA and Bonferonni corrected post-hoc tests (Statistica 8 software, http://www.statsoft.com).

Results

On Day 0 there were no statistically significant differences (p < 0.05) in refractive error or axial length between treated (RE) and untreated (LE) eyes for any of the groups and therefore no interocular differences between groups (see Table 1, Figure 1). On Day 7 treated eyes were longer and more myopic (~10D ≥95% compensation) than untreated eyes for all groups and there were no statistically significant differences (p < 0.05) between the groups (Table 1, Figure 1).

Table 1.

Mean (S.E.) for treated eyes (RE), untreated eyes (LE), and differences (RE-LE) in refractive error (Rx) in Dioptres (D) and axial length for Days 0, 7 and 14 for Conventional, Type 1 and Type 2 Treated Birds that still had their lenses at Day 14

Day	Rx RE D (S.E.)	Rx LE D (S.E.)	Rx RE-LE D (S.E.)	Length RE mm (S.E.)	Length LE mm (S.E.)	Length RE-LE mm (S.E.)
Conventional lens (n = 14)
0	3.93 (0.63)	3.93 (0.64)	0.00 (0.14)	7.90 (0.06)	7.84 (0.06)	0.05 (0.05)
7	−6.07 (0.62)	3.43 (0.25)	−9.50 (0.58)	9.04 (0.04)	8.64 (0.07)	0.40 (0.06)
14	−9.36 (0.71)	2.54 (0.19)	−11.89 (0.79)	10.31 (0.06)	9.75 (0.08)	0.56 (0.05)
Type 1 lens (n = 14)
0	3.86 (0.77)	3.86 (0.70)	0.00 (0.16)	7.80 (0.07)	7.81 (0.04)	−0.01 (0.05)
7	−5.96 (0.55)	3.64 (0.25)	−9.61 (0.52)	8.97 (0.10)	8.53 (0.07)	0.44 (0.07)
14	5.27 (1.12)	2.36 (0.18)	2.91 (1.08)	9.47 (0.11)	9.60 (0.08)	−0.13 (0.09)
Type 2 lens (n = 15)
0	4.37 (0.68)	4.37 (0.67)	0.00 (0.05)	7.72 (0.05)	7.77 (0.04)	−0.05 (0.06)
7	−5.57 (0.58)	4.00 (0.24)	−9.57 (0.61)	8.88 (0.05)	8.61 (0.06)	0.27 (0.06)
14	−1.47 (0.88)	2.37 (0.12)	−3.83 (0.94)	10.02 (0.09)	9.66 (0.05)	0.36 (0.09)

Figure 1.

Mean (S.E.) change in refractive error and axial length for three treatment days, for Conventional, Type 1, and Type 2 lens designs. Panels (a, d) treated eye, (b, e) untreated eye, (c, f) difference between treated (RE) and untreated (LE) eyes (*p < 0.001).

At Day 14, 14 Conventional treated birds, 14 Type 1 treated birds and 15 Type 2 treated birds still had lenses. As shown in Table 1 and Figure 1, treated eyes of chicks wearing Conventional design lenses were still longer (Mean RE-LE = 0.56 mm ± 0.05) and more myopic (Mean RE-LE = −11.89 D ± 0.79) than untreated eyes. Myopia progression control Type 1 treated eyes became more hyperopic (Mean RE-LE = 2.91 D ± 1.08) and were shorter (Mean RE-LE = −0.13 mm ± 0.09) than untreated eyes. Figure 1d,e indicates that treated eyes were longer than untreated eyes at Day 7. Treated eyes wearing myopia progression control Type 1 lenses that were longer than their untreated counter parts on Day 7 (8.97 treated vs 8.53 untreated) did become shorter than their untreated counterparts at Day 14 (9.47 treated vs 9.60 untreated), but did not shrink (9.47 Day 14 vs 8.97 Day 7). Rather, they continued to grow over the 7-day period, albeit at a slower rate than previously (0.07 mm/day week 2 treatment vs 0.17 mm/day week 1 treatment). In Type 1 treated birds the treated eyes also grew slower during week 2 of treatment (0.07 mm/day) than the untreated eyes (0.15 mm/day). Refractive error, on the other hand, did reverse direction in absolute (Figure 1a) as well as relative (Figure 1c) terms with the Type 1 lenses. Myopia progression control Type 2 treated eyes were more myopic (Mean RE-LE = −3.83 D ± 0.94) and longer (Mean RE-LE = 0.36 mm ± 0.09) than untreated eyes but less myopic than Conventional treated eyes. Some but not all treated eyes developed astigmatism by day 14 (Table 2). No birds had astigmatism >1D on Day 0 or 7. The prevalence of astigmatism >1D on Day 14 for Conventional, Type 1 and Type 2 treated eyes was 14%, 43% and 53% respectively. Using Fisher's exact test, this prevalence was not significantly different between Conventional and Type 1 (p = 0.21) or Conventional and Type 2 (p = 0.0502) treated eyes.

Table 2.

Astigmatism (Dioptres, D) in treated eyes (RE) for Conventional, Type 1 and Type 2 Treated Birds that still had their lenses at Day 14

	Percentage with astigmatism	Mean (S.E.) D
Conventional lens (n = 14)	14%	−1.357 (0.923)
Type 1 lens (n = 14)	43%	−2.679 (0.913)
Type 2 lens (n = 15)	53%	−3.133 (0.844)

A mixed design analysis of variance indicated a significant effect of lens design for both refractive error difference (F_2,40 = 33.7; p < 0.001) and axial length difference (F_2,40 = 7.1; p = 0.002). There was also a significant main effect of day for both refractive error difference (F_2,80 = 193.6; p < 0.001) and axial length difference (F_2,80 = 30.6; p < 0.001) as well as a significant interaction between lens type and day for refractive error difference (F_2,80 = 50.8; p < 0.001) and axial length difference (F_2,80 = 12.6; p < 0.001). Post hoc tests showed that the refractive error differences for all of the groups on Day 14 were significantly different from each other (p < 0.001). On Day 14 Type 1 length differences were significantly different from both the Conventional group and the Type 2 group (p < 0.001). Type 2 length differences were not significantly different from the Conventional group (p > 0.05).

Figure 2 shows the individual variability of refractive error difference between the two eyes and axial length difference between the two eyes for the treatment days assessed and the three lens designs. Figure 3 shows the correlation between refractive error and axial length differences between the two eyes on Day 14 (Pearson's correlation coefficient, r = −0.64, p < 0.05).

Figure 2.

Variability of axial length difference and refractive error difference between the two eyes for individual birds on the three treatment days, for three lens designs (a) Conventional, (b) Type 1 and (c) Type 2.

Discussion and conclusions

Although unexpected, it is clear from these results that these myopia progression control lens designs can reverse lens-induced myopia in 7–14 day old chickens and that the effect is largely the result of axial length changes (Figure 3). The results also suggest that peripheral lens design can affect refractive error. If in the Woods et al.46 study the large depth of focus produced by these lenses simply overwhelmed the normal emmetropization mechanism such that the eyes did not respond to the central minus power, then the expectation in this experiment would be that the birds would again not respond and remain myopic once myopia had been induced by the Conventional lenses. Since the birds did not maintain the same degree of myopia (and in the case of the Type 1 design, had a complete refractive reversal) that hypothesis is not supported. The two different myopia progression control lens designs behaved differently, indicating that the lens design itself is an important factor.

There appear to be some outliers in the data. For example, three birds (one from each group) did not become as myopic on Day 7 with the Conventional lenses as one would expect (Figure 2). It is not clear why this occurred as there were no obvious differences between these birds and those that did respond as expected. There were also some birds (four on Day 7 and one on Day 14) whose refractive errors were not consistent with their axial lengths. Again, the reason for this is unclear. Axial length measurement error, inherent in measuring very small eyes, may account for some of the differences, however other physiological factors, such as cornea and crystalline lens powers, may contribute.

While every effort was made to keep the lenses clean and centred on the pupil, the effects of any inadvertent decentration are unknown. Chickens, like most birds, have limited eye movement.50 They also do not have a fovea, although they do have an area centralis. Any effects of eye movement and/or looking through the periphery of the lens with ‘central’ vision as a result of eye movement could not be controlled for and are unknown. That being said, no behavioural differences between birds with regard to head or eye posture were observed and birds with Test lenses could not be distinguished from those with conventional lenses on this basis. It is highly unlikely that any birds viewed only through the peripheral portion and not the central portion of the lens.

It is well known that experimental myopia reverses quite rapidly in chicks (≤4 days) when either form deprivation52 or an inducing lens17 is removed. Induced myopia also reverses when negative lenses are replaced with positive lenses,15 although in chicks this can induce significant astigmatism.15 The question addressed by the current experiment is whether or not myopia can be reversed while maintaining the same minus power in the central portion of the lens and altering the peripheral power. To our knowledge, the results from the Type 1 lens are the first in which myopia is completely reversed while maintaining the same central minus power and no positive power within the lens.

Schaeffel and Howland55 did have a portion of their birds recover from myopia despite continuing to wear minus lenses. Unlike their findings, none of our birds that were treated continuously with the conventional lenses showed recovery. McFadden et al.40 have shown partial reversal of previously induced myopia in guinea pigs using −5D/+5D Fresnel lenses. Their lens design had both positive and negative power presented within the pupil. The refractive result for replacement of the initial myopia inducing minus lens with Fresnel lenses (−5D/+5D) was intermediate, between that of continued single vision minus lens wear and replacement of the initial myopia inducing lens with a single vision positive lens. Liu and Wildsoet43 induced myopia in 12 day old chicks by having them wear single vision −10D lenses for 5 days. They then replaced the −10D inducing lenses with 2 zone lenses (−5C/−10P or −10C/−5P). There was some regression of the previously induced myopia as would be expected from averaging of the power of the 2 zones but all chicks still remained somewhat myopic. Tse et al.41 did get complete recovery when −10D was replaced with a lens design incorporating both + and − 10D. This also is the response that would be expected if the eye were responding to the average of the two powers within the lens, which in the Tse et al. study would have averaged to plano.

Although the Visioneering Technologies Inc. myopia progression control lenses have a gradient rise in relative plus power, the actual power throughout the lens is still negative. This negative lens power was verified by the use of a lensometer with a 5 mm lens stop aperture. Unlike the McFadden et al.40 experiment, our chicks cannot be responding directly to plus power as there is no actual plus power within the lens design. However, this does not prevent the peripheral image from lying in front of the retina. If the central power corrects the myopia induced by the Conventional lenses and the eye shape is flatter than the image surface created by the nominal central lens power, which in the chick it will be, any reduced minus power in the periphery will put the image in front of the retina presumably sending a stop signal to axial eye growth. This of course will change as the eye changes shape and the exact image position will depend where the peripheral focus was to start with, the shape of the eye and the manner in which the eye shape changes.

Similar to our study, the Liu and Wildsoet43 experiment does have negative power throughout the lens (their −10C/−5P lens would be most similar to ours), but unlike our study, they did not observe complete reversal of previously induced myopia. This finding would suggest that the gradient nature of the design of the Visioneering Technologies Inc. myopia progression control lenses is of some significance, with a potential dose-response type relationship being shown with these data between the Type 1 and Type 2 myopia progression control lens designs.

A significant difference between our study and previous ones is that we used a lens design with continuous power change rather than one with discrete zones. It has been shown that the size of the central zone has an effect on whether or not central refractive status is affected.54 It may be that the absolute power values are not as important as the relative difference between the centre and the periphery or possibly the change in power from centre to periphery. These data do suggest that perhaps the exact mechanism is more complicated than simply responding to absolute image position; there could be integration of information such that the eye is detecting the defocus gradient itself and using this to control eye growth.

Another possibility is that the lenses are creating a ‘virtual aperture effect’ with the Type 1 lenses creating a smaller ‘aperture’ and therefore greater effect than the Type 2 lenses. Peripheral annular blur is visible through Type 1 but not Type 2 lenses. We have seen in other animal studies with real apertures that once the aperture size decreases below a critical level, usually about 4 mm the normal response to imposed defocus is altered.44 This has been interpreted as the periphery having more influence than the centre as the aperture decreases. Irving et al.54 found decreased compensation to both plus and minus lenses with apertures ≤5 mm. Interestingly in these experiments, despite the periphery being a translucent goggle, the default did not appear to be form deprivation myopia as would be expected if the periphery was simply having more influence. There may be some similarities to the ‘set point’ of McLean and Wallman59 or the ‘eye size effect’ of Siegwart and Norton.61 McLean and Wallman, creating large amounts of blur with high powered cylindrical lenses, observed that the eye returned to some ‘set point’. Siegwart and Norton found that pre-treatment with plus lenses resulted in increased response to subsequent treatment and gave this as evidence for the operation of an ‘eye size’ mechanism. It is possible that the peripheral optics of these lenses are preventing the centre from controlling eye growth without providing any usable peripheral signal and the eye is reverting to some inherent refractive state or ‘set point’ via some ‘eye size’ mechanism. Further study is necessary to understand the underlying mechanisms of refractive control in general and the current lens design in particular. These results provide incentive to explore new possibilities.

A limitation of the study is that peripheral refractions and ocular component data other than axial length were not obtained. Axial length measures were to the retina so, although we do not know what choroidal effects there may have been, any choroidal effects on axial length would have been accounted for in the length measures. Peripheral refractions and ocular component measures would be necessary for future research in optical modelling of image surfaces in relation to three dimensional continuous growth, but getting accurate, reliable peripheral refraction data will be a challenge because of the small eyes and inability to control fixation in chickens. Any induced astigmatism should also be considered.

Apart from furthering our knowledge of how these myopia progression control lenses might work, the results of this study raise the issue of whether or not myopia, once it exists, can be reversed as the eye grows. Up until now efforts have been directed at reducing progression, or at best, preventing its occurrence. If in fact active myopia reversal turns out to be achievable, the practical application would be of considerable consequence to the human condition.

Disclosure

The authors have no proprietary interest in any of the materials mentioned in this article. Visioneering Technologies, Inc. partially funded the study and paid consulting fees indirectly related to the study to E. Irving.