294 N.A. McBrien

will enable more refined treatments to be devised than currently available to reduce the impact of the biomechanical weakening of the sclera in high myopia on visual function.

Scleral Changes in Myopia are Reversible

To date we have concentrated on the role of the sclera in the development of myopia and the pathological complications consequent to the axial elongation of the eye. However, although it is has not yet been explicitly discussed, there is substantive evidence to demonstrate the vital role that visual information plays in the control of this scleral remodelling. Indeed, there is strong evidence to show that scleral thinning and loss of tissue in myopia are reversible in paradigms resulting in recovery from axial myopia, and as such, provide insight into potential treatment approaches.

Eye growth regulation during recovery from induced myopia

Recovery from induced myopia in experimental models of refractive error can be considered a manifestation of the innate emmetropization process. In essence, once myopia is induced, either through monocular deprivation or using a negative lens, removal of the inductive device results in the eye altering its growth pattern to eliminate the induced refractive error. It is assumed that this process occurs through the recognition of myopic blur by the retina, on removal of the occluder or negative lens, and subsequent modification of the ocular growth rate to compensate. This essentially can be considered an emmetropization response as the eye alters its growth rate to reduce the defocus. In the avian model of myopia, recovery occurs initially through thickening of the choroid. This moves the retina physically forward and reduces the amount of defocus by bringing the plane of the photoreceptors closer to the image plane. This is followed by a reduction in the growth rate of the sclera until the axial eye length is again coordinated with the optical power of the eye at which time the choroid returns to its normal thickness as does the scleral growth rate.61 In the mammalian and primate models of myopia, however, recovery involves only a minor contribution from changes in choroidal thickness.43,62 Such findings indicate that scleral changes are the principal factor in the recovery process in mammalian species.

295 Changes to the Sclera in Myopia

As discussed earlier, scleral glycosaminoglycan synthesis is reduced during myopia development, however, on removal of the occluder/lens there is a rapid rise in glycosaminoglycan synthesis, such that, within 24 hours of recovery, glycosaminoglycan synthesis levels have returned to control eye levels (Fig. 12A).43 At this stage there is no significant change in the degree of myopia or in the length of the eye, however, after three days of recovery, the eye has started to shorten and reduce its refractive error. By this time there is found to be a significant increase in scleral glycosaminoglycan synthesis relative to the control eye. Between days 3 and 5 of recovery, the most marked reduction in refractive error occurs, primarily through a reduction in the axial length of the eye. Importantly, the period of peak glycosaminoglycan synthesis precedes the most rapid period of eye size change, suggesting that the scleral remodelling may lead to the changes in eye size. Thereafter, the magnitude of increase in glycosaminoglycan synthesis begins to diminish, and by the time the relative refractive error is eliminated (around seven to nine days), glycosaminoglycan synthesis is returning to control eye levels (Fig. 12A). There is also a replacement of the tissue that is lost during the development of myopia and this tissue mass briefly exceeds that of the control eye when recovery is achieved.43 Other studies have shown that DNA synthesis is also upregulated during the recovery process in the tree shrew (Fig. 12B) and there is also a relative reduction in the levels of MMP-2 and TIMP-2 mRNA and protein production (see Fig. 6). This results in an overall reduction in active levels of MMP-2 in the sclera, which is consistent with the increase in scleral dry weight observed.26,29 Such findings are important in demonstrating that the direction of eye growth is specifically dependent on the direction of regulation of scleral remodelling.

Biochemical studies show that the major replacement of scleral tissue during recovery occurs at the posterior pole of the eye, and that the major increase in glycosaminoglycan synthesis also occurs in this region. Although this might be expected, as this is the location where most of the scleral tissue is lost during myopia development, there is evidence of some remodelling of the equatorial regions of the sclera during recovery from axial myopia.43 The significance of changes in the equatorial region of the sclera during recovery has not been fully elucidated, however, it is possible that it plays a role in the shortening of the eye that occurs in recovery.

Recent studies have confirmed the importance of visual information in the control of scleral remodelling in myopia. Studies have established that accurate correction of induced myopia, simulating correction of myopia

297 Changes to the Sclera in Myopia

Figure 13. Correction of induced myopia with eyeglass lenses results in the prevention of recovery from induced myopia in tree shrews. Corrective lenses also prevent the scleral changes in glycosaminoglycan synthesis that are characteristic of the recovery from induced myopia. A. Interocular difference in refractive error between treated and control eyes of animals following five days of myopia progression or five days of myopia progression followed by five days of recovery from induced myopia, either with or without corrective lenses. Normal eyes were age-matched to the five-day myopia animals. B. Interocular difference in vitreous chamber depth between treated and control eyes of animals following five days of myopia progression or five days of myopia progression followed by five days of recovery from induced myopia, either with or without corrective lenses. Normal eyes were age-matched to the fiveday myopia animals. C. Interocular difference in scleral glycosaminoglycan synthesis between treated and control eyes of animals following five days of myopia progression or five days of myopia progression followed by five days of recovery from induced myopia, either with or without corrective lenses. Normal eyes were age-matched to the five-day myopia animals. n = 5 animals per group. Error bars are 1 SEM. **p < 0.01, *p < 0.05. (Reproduced with permission from McBrien et al., 1999 © American Academy of Optometry.)