1 I. Introduction 1.1 Myopia Myopia has reached epidemic proportions in Singapore (Rajan et al 1994, Saw et al 1996). Myopia is 1.5 to 2.5 times more prevalent in adult Chinese residing in Singapore than similarly aged European-derived populations in the United States and Australia where the sociodemographic associations are similar (Wong et al 2000). In the United States 25% of children become myopic and it affects 15-20% of the adult population (Sperduto et al 1983, Hirsch and Weymouth 1990). Optically, myopia is defined as a mismatch between the refractive optics and the length of the eye that causes an image to be focused in front of the retina leading to an out of focus image. High myopia is an important cause of visual disability (Klein et al 1995). It has been noted as the cause of blindness due to the many associated complications, such as retinal break, retinal detachment and myopic retinopathy. Myopia also places a burden on society and on the individual. The cost of glasses, contact lenses and refractive surgery has been estimated to be $13 billion annually (Sheedy 1996). Quality of life issues associated with myopia are also considerable. Myopia limits career choices, social interaction and in underdeveloped countries, myopes may not have corrective choices. Despite the high prevalence and associated social and economic costs of correcting myopia, we know little about the etiology of myopia. 1.1.1 Refractive development Human studies have found that myopia results from axial elongation of the sclera that is not corrected by a concommitant change in corneal curvature. At birth, the cornea and lens are sharply curved so the focal plane is short. As the eye matures, the axial length increases, rapidly at first during the “infant” high growth period and then slowly during the “juvenile” slow elongation period (Sorsby et al 1961). Growth moves the retina away from the cornea and toward the focal plane so that eventually the axial length matches the focal plane, producing an emmetropic eye that focuses distant objects without accommodation. In some cases, the axial length becomes longer than the focal plane, so the image of distant object is focused in front of the retina causing blurring. The eye is approximately 17mm long at birth. From birth to age 6, the eye grows by approximately mm. During this period there will be a loss of 4D of corneal power, and 20D of lens power. Through the process of emmetropisation, the distribution of refractive error becomes narrow and the prevalence of myopia is only 2% at age 6. During the next years, the average eye will grow approximately a millimeter. The prevalence of myopia during this time will increase more than seven fold, to 15% by 15 years of age (Mutti et al 1996). Gross and Wickman (1995) concluded that both emmetropisation and juvenile onset myopia are best explained by a retinal image-mediated biochemical mechanism that modulates eye growth. However, the nature of this growth mechanism has not been elucidated. The emmetropisation mechanism in chickens and tree shrews appear to require visual signals to guide the elongation of the eye. If the focal length is artificially lengthened by wearing a minus-power lens, the eye will elongate until the axial length approximately matches the amount of increase in imposed focal length (Irving et al 1991, Siegwart et al 1993). When the eyes are deprived of form vision with a translucent diffuser, there is no visual image to indicate that the appropriate axial length has been reached. In this situation, elongation continues unchecked, moving the retina past the focal plane (PickettSeltner et al 1988, Wallman et al 1987). If humans have an emmetropisation mechanism similar to that demonstrated in animals, juvenile-onset myopia may occur if a child inherits a dysfunctional emmetropisation mechanism. It is not clear if dysfunction occurs in photoreceptors, in the communication of an unknown signal to the sclera, or in some intrinsic control of sclera growth. This suggests that there may be an emmetropisation feedback loop, and this becomes disrupted in myopia. Several studies have found pharmacological treatments that reduce axial elongation in animal models (Stone et al 1989, McBrien et al 1993, Rohrer et al 1993, Seltner et al 1993), and there are current clinical trials testing some of these in children. 1.1.2 Genetic influences Several lines of evidence point to a role of genetics in the development of myopia. Monozygotic twins tend to resemble each other more closely in refractive error than dizygotic twins. 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Vision Res. 1995;35:1283-1288 [...]... deprivation in chick and in rhesus monkey (Stone et al 19 89 ,19 91, Iuvone 19 91) In chicks, normalisation of retinal dopamine correlated with recovery from myopia (Pendrak et al 19 97) Use of atropine Historically atropine was used because it is a cycloplegic agent in human antagonising the mAChRs of the cilliary muscle It also reduces axial elongation in deprivation models of myopia (McBrien et al 19 93, Stone.. .11 19 56, Kalina 19 69, Fledelius 19 76, Shapiro et al 19 80, Kushner 19 82, Koole et al 19 90, Gallo et al 19 91, Fledelius 19 93) Johnson and colleagues (19 82) have described axial myopia in one eye in one sibling of a pair of identical twins, which had a posterior subcapsular cataract Von Noorden and Lewis (19 87) examined 10 young patients who had unilateral cataracts and in seven out of ten cases the involved... monkey and dopamine was decreased in both chick and monkey (Iuvone et al 19 89, Stone et al 19 88 ,19 89) A recent study found that glucagon-containing amacrine cells respond differentially to the sign of defocus and may mediate lens-induced changes in ocular growth refraction (Fischer et al, 19 99) Local application of the dopamine agonist, apomorphin blocked the axial elongation that ordinarily follows... (VIP) in the control of eye growth (Schaeffel et al 19 95, Stone et al 19 88) 13 1. 1.9 Pharmacology of myopia Several studies have reported the modulation of the effect of pharmacological agents on experimental myopia Raviola and Wiesel (19 85) found that atropine had no effect in the rhesus macaque, but prevented axial elongation in the stump-tailed macaque Wildsoet and Pettigrew (19 88) have shown that intravitreal... (TNF-α) (Moses 19 97, Wojtowicz-Praga et al 19 97) 18 1. 2.2 Sclera fibroblast control Sclera cells are the final effectors in a complex signal cascade leading to axial elongation Several studies have established the effectiveness of atropine in decreasing the progression of axial length in humans and in experimental myopia, however the mechanism is still elusive Atropine may act directly on sclera fibroblasts... range between 51 kd and 66 kd (Kerlavage et al 19 87, Ashkenazi et al 19 88) 1. 2 Sclera Alteration in visual experiences can increase scleral growth, leading to axial elongation and myopia (Hodos et al 19 84, March-Tootle et al 19 89, Sherman et al 19 77, Tigges et al 19 90, Wallman et al 19 78, Wiesel et al 19 77, Yinon et al 19 80) It has been reported that the cartilaginous part of the sclera of form deprived... elongation (Wallman et al 19 78, Norton et al 19 90) Active sclera growth is a primary event in the axial elongation therefore control of the sclera fibroblast may lead to a possible therapy for myopia prevention or decreasing the development of myopia 17 1. 2 .1 Matrix Metalloproteinases (MMPs) Evidence has been obtained that the sclera extracellular matrix (ECM) remodelling of the sclera is part of. .. al 19 91) In the case of chicks, the ciliary muscle is striated and therefore is innervated via nicotinic rather than muscarinic cholinergic receptors (McBrien et al 19 93) Therefore the effect of 14 atropine must have been exerted on the retina or directly on the sclera Indeed, there is evidence that atropine inhibits cellular proliferation of sclera chondrocytes and extra cellular matrix production... pirenzepine, may slow axial elongation in both experimental and clinical myopia (Cottrial et al 19 96) Pharmacological treatment of myopia and its potential widespread application raise a number of questions Experimental myopia leads to an increase in ECM production and accumulation of proteoglycans within the cartilaginous sclera while fibrous sclera was opposite as similarly observed in monkey and tree... response of sclera fibroblasts to atropine A culture system for sclera fibroblasts will be developed and used to test the effect of atropine on proliferation, receptor activity and intracellular signal transduction pathways To test the overall hypothesis, the following specific phenomena will be studied 1 The presence of muscarinic receptors in sclera fibroblasts (SF) 2 The response of SF to muscarinic agents . apomorphin blocked the axial elongation that ordinarily follows visual deprivation in chick and in rhesus monkey (Stone et al 19 89 ,19 91, Iuvone 19 91) . In chicks, normalisation of retinal dopamine. myopia, specifically VIP was increased in monkey and dopamine was decreased in both chick and monkey (Iuvone et al 19 89, Stone et al 19 88 ,19 89). A recent study found that glucagon-containing. explained as the effect of a reduction in pattern vision. Raviola and Wiesel (19 85) went on to examine the effects of optic nerve section on lid suture myopia. In one stump tailed macaque myopia