Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

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I. INTRODUCTION

Myopia (or nearsightedness) is a major public health problem. Its prevalence is increasing in many parts of the world, and it predisposes to serious ocular disease. Myopia is assumed to develop from both

genetic and environmental influences, but its etiology is poorly understood at best. While many approaches can correct the defocused image, validated and acceptable therapies to correct the developmental problem are not available for clinical use. Several laboratory approaches have been

developed that predictably alter refraction and eye growth in experimental animals, and these are beginning to reveal biological mechanisms that regulate refractive development. Each approach modifies some aspect of the visual environment: image degradation, image defocus or altered photoperiod. While mechanistically different from common clinical myopia, these approaches can produce anatomical features in animal eyes that resemble those seen in human refractive disorders. These investigations have established that a visual feedback mechanism modulates refractive development, and that this mechanism localizes largely to the retina. From the application of neurobiology and pharmacology methods, several receptor systems have now been identified in experimental animals that may participate in the signaling cascade that links visual input to eye growth control. So far, however, the diverse available data do not permit a detailed description of the signaling pathway at either the anatomical or molecular level. Recent clinical extensions underscore the potential of laboratory pharmacology to impact favorably on future mechanistic studies and ultimately to produce much needed clinical therapies to arrest myopia in children.

Ocular refraction depends primarily on matching of the optical properties of the cornea and lens with the length of the eye, chiefly the length of the vitreous chamber. The normal condition of emmetropia occurs when, with relaxed accommodation, distant images focus at the retinal photoreceptors. During childhood, an active process termed emmetropization coordinates the expanding eye length with the powers of the cornea and lens, tending to result in emmetropia. Regulatory failure, that is the failure of emmetropization, causes refractive errors. In myopia (nearsightedness), the eye is relatively long for the optical power of the cornea and lens, and distant images focus in front of the photoreceptor plane. In hyperopia (farsightedness), the eye is relatively short, and distant images focus behind

it. Myopia is the most common refractive error, usually from excessive axial length (Curtin, 1985; Zadnik and Mutti, 1998).

There currently are no approved and clinically acceptable therapies that have been shown to reduce meaningfully either myopia incidence or myopia progression in children (Saw et al., 1996, 2002b). This chapter summarizes some key clinical features of myopia as a justification for the recent initiatives into pharmacology and outlines some major conventional theories on myopia pathogenesis. It emphasizes laboratory pharmacology as an approach to develop much-needed new ideas to understand the mechanisms governing refractive development, with the ultimate hope of identifying leads to ameliorate myopia in children.

II. CLINICAL MYOPIA

The prevalence of myopia varies considerably between countries. Its prevalence generally is highest in more economically developed regions and frequently increases as a society’s economy moves from agriculture to industrial and service-related activities. The overall prevalence of myopia is increasing, particularly in developed regions of Asia where it affects some 80% of young adults (Lin et al., 1999; Rose et al., 2001; Saw et al., 1996; Wu et al., 2001). While it is less clear if myopia prevalence is also increasing in Western societies (Mutti and Zadnik, 2000; Park and Congdon, 2004), recent myopia prevalences of 57% of 23–34- year-olds in the United States Framingham Study (Framingham Offspring Eye Study Group, 1996), 35% of 20–25-year-old Norwegians (Midelfart et al., 2002) and 39% of Swedish 12–13-year-olds (Villarreal et al., 2000) illustrate a formidable public health problem of international scope.

A. Associations of Myopia with Eye

Disease

Besides the obvious need for optical correction, myopia predisposes to serious eye

diseases, presumably because of the distorted anatomy of the enlarged myopic eye. Long recognized to develop with higher degrees of myopia, these diseases include various pathologies in the posterior fundus, peripheral retinal degenerations with associated retinal detachments, glaucoma and cataract (Curtin, 1985; Rose et al., 2001).

Contemporary population-based epidemiology not only confirms these well-known disease risks of high myopia, but also demonstrates a less pronounced but still noteworthy association of low myopia with ocular disease in later life. Retinal detachment and myopic retinopathy, the most widely recognized complications of high myopia, also have been linked at reduced rates with lower levels of myopia (Eye Disease Case-Control Study Group, 1993; Ogawa and Tanaka, 1988; Vongphanit et al., 2002). Myopia of any degree is a risk factor both for open-angle and normal tension glaucoma (Grødum et al., 2001; Leske et al., 2001; Mitchell et al., 1999; Ponte et al., 1994; Seddon et al., 1983; Wilson et al., 1987; Wong et al., 2003). Cataract has long been associated with higher degrees of myopia (Curtin, 1985), but lower degrees of myopia also have now been linked to cataract, particularly posterior subcapsular cataract and perhaps nuclear sclerosis (Harding et al., 1989; Leske et al., 1998, 2002; Lim et al., 1999; McCarty et al., 1999; Wong et al., 2001; Younan et al., 2002).

Recent surveys testify to the significant burden of blindness from myopia (Xu et al., 2006). As two examples, retinal complications of myopia account for 14% and 12.5% of adult blindness in Scandinavia (Buch et al., 2004) and Taiwan (Hsu et al., 2004) respectively. As presently understood, the diseases associated with myopia are neither prevented nor lessened by any optical or surgical approaches to correct the image defocus.

B. An Unmet Therapeutic Need

Many methods are available to correct the defocused images of myopic eyes. Especially considering the association of

ocular disease with myopia, the unmet therapeutic need is normalizing eye development to prevent or lessen myopia and its burden of associated eye disease. The evidence for enhanced risk, particularly for retinal complications (Ogawa and Tanaka, 1988; Vongphanit et al., 2002), with relatively small increments in refractive error emphasizes the potential public health benefit even from partial arrest of myopia progression during childhood. Because most of the risks for future disease seem related to the degree of myopia, strategies to reduce myopia progression in the young, even if only partial, could save vision in later life.

III. WHY MYOPIA?

The biological etiology of refractive errors and the reason for the apparent increases in myopia prevalence are unknown. Clinical studies typically survey parameters long hypothesized to relate to myopia, such as family history, nearwork, education, intelligence, socioeconomic status, diet, personality, stress, etc. (Angi et al., 1993; Angle and Wissmann, 1980; Cordain et al., 2002; Curtin, 1985; Saw et al., 1996). These studies, however, have neither unambiguously identified mechanisms responsible for myopia, nor have they yet introduced validated and effective clinical therapies to normalize eye growth. Perhaps, as implied in many reports, improved methods to measure these conventional risk factors are needed. Alternatively, as suggested by the evolving pharmacology of refractive development, novel approaches to study myopia pathogenesis are needed to formulate more informative and clinically useful hypotheses.

Contemporaryepidemiologicandgenetic research supports the notion that myopia represents a “complex” disorder involving both genetic and environmental influences (Farbrother et al., 2004a; Klein et al., 2005; Morgan and Rose, 2005; Zadnik, 1997), but the relative importance of genes or environment remains controversial

(Lyhne et al., 2001; Morgan and Rose, 2005; Rose et al., 2002). The relative contribution of genetics or environment is pertinent in addressing myopia pharmacology because the laboratory approaches so far have depended mainly on studying developmental responses to various visual (i.e. environmental) manipulations.

A. Genes in Myopia Pathogenesis?

Evidence for a genetic contribution to myopia includes the clustering of myopia among children in individual families, increased prevalence of myopia in children of myopic parents, and a greater correlation of refraction and its anatomical components among monozygotic twins compared with either dizygotic twins or non-twin siblings (Klein et al., 2005; Lyhne et al., 2001; Morgan and Rose, 2005; Rose et al., 2002; Zadnik, 1997). Linkage analysis has identified several gene loci for myopia (Hammond et al., 2004; Stambolian et al., 2004), including high myopia (Farbrother et al., 2004b; Paluru et al., 2005), but highly penetrant myopia genes would seem to account only for a minority of cases (Farbrother et al., 2004a). In many analyses, it has been difficult to distinguish shared genes from shared environment and/ or common behavior within families (Morgan and Rose, 2005; Rose et al., 2002). For instance, the between-sibling strength of the association for myopia diminishes with increasing age differences between siblings, suggesting a significant environmental component even within families (Framingham Offspring Eye Study Group, 1996). While racial and/or ethnic differences in myopia prevalence are well documented, these differences may be lessening (Morgan and Rose, 2005; Rose et al., 2002).

B. Environmental Influences in Myopia

Pathogenesis?

Rapidly rising myopia prevalence with increasing education, urbanization and

other socioeconomic changes strongly implicates environmental influences on refractive development (Morgan and Rose, 2005; Rose et al., 2002; Zadnik, 1997). Biological interpretations of the extensive literature on conventional myopia risk factors, though, have proved difficult.

As just one example of a conventional risk factor, nearwork (i.e. visual activity at close distances, such as reading) is repeatedly hypothesized as a major cause of myopia (Angle and Wissmann, 1980; Dunphy, 1970; Mutti et al., 2002; Saw et al., 2002a, 1996) and illustrates well the difficulty interpreting the clinical literature on myopia mechanisms. Arguments that visual nearwork contribute to the etiology of myopia include the high proportion of children who develop myopia during the years of schooling, the high proportion of young adults who develop myopia during their training in certain professions that require intensive reading (e.g. law or engineering), and the myopic refractive shifts of members of certain professions, such as microscopists or submariners. The low myopia prevalence in societies with less emphasis on education, and the increasing myopia prevalence in societies after the introduction of intensive schooling, also suggest an association. On the other hand, nearwork is difficult to distinguish from other broad differences between societies, such as diet, economic status and level of technology, and education involves more than reading. Covariates in regression models or frankly negative epidemiologic findings, frequently never published, make it difficult to decide whether nearwork per se is an independent myopia risk factor or whether it reflects other features of education, socioeconomic status or other possible risk factors (Rosenfield and Gilmartin, 1998). Perhaps the quantitative approaches used by clinical investigators to model nearwork activity have been inappropriate (Wallman and Winawer, 2004). Despite a massive literature, it remains indeterminate whether visual near work is causative for myopia or a

confounding association that correlates with other primary environmental or personal qualities (Rosenfield and Gilmartin, 1998).

Why visual activity at near might actually cause myopia also is unclear. Classically, hypotheses linking nearwork to myopia involve mechanical mechanisms (Greene, 1980) – most commonly, the muscular effects of accommodation (van Alphen, 1986), changes in intraocular pressure (IOP) (Pruett, 1988) or stresses from extraocular muscle contraction (Greene, 1981). Little, if any, experimental evidence, however, supports these mechanical mechanisms as the basis for myopia. As examples, removal of the ciliary ganglion which controls ciliary muscle contraction and hence accommodation fails to prevent experimental myopia in monkey (Raviola and Wiesel, 1985) or chick (Lin et al., 1996). While IOP seems slightly higher in both juvenile and adult myopia (David et al., 1985; Grødum et al., 2001; Quinn et al., 1995; Shiose et al., 1991; Wong et al., 2003), lowering IOP with drugs fails to inhibit myopia in children (Jensen, 1991); and available prospective clinical data suggest that higher IOP is a consequence rather than a cause of myopia (Edwards and Brown, 1996; Goss and Caffey, 1999). By analogy with recent results in animal models of refractive development, it has been suggested that visual defocus or blur might occur during reading and precipitate myopia (He et al., 2002; Thorn et al., 2000); but unambiguous clinical evidence to support the latter hypotheses is still needed.

IV. BASIC RESEARCH

APPROACHES TO STUDYING

MYOPIA PATHOGENESIS

A. Laboratory Models for Understanding Refractive Development

Studying refractive development in laboratory animals offers the possibility of developing hypotheses under more controlled

conditions than clinical surveys, if the laboratory findings can be shown to be clinically relevant. Laboratory research to understand myopia mechanisms was long hampered by the difficulties of identifying suitable animal models with reproducible and sufficiently robust effects, and of establishing their relevance to human myopia. The observation that lid fusion in neonatal monkeys induces significant myopia with axial and vitreous chamber enlargement, mimicking the anatomical changes of common human myopias (Wiesel and Raviola, 1977), opened the modern era of refractive research. This finding, and subsequent research, has led to the now widely accepted concept that vision-dependent feedback mechanisms regulate eye growth (Stone, 1997; Wallman, 1993; Wallman and Winawer, 2004). At present, three major approaches are used to modify eye development in laboratory animals and study myopia mechanisms, including pharmacologic mechanisms. Each approach alters visual experience in some manner.

1. Form deprivation myopia

Interfering with the quality of visual images by lid fusion or image diffusing goggles produces marked ipsilateral myopia in species as varied as chick (Wallman et al., 1978), cat (Kirby et al., 1982), squirrel (McBrien et al., 1993), guinea pig (McFadden et al., 2004), tree shrew (McBrien and Norton, 1992) and many primates (Raviola and Wiesel, 1985; Thorn et al., 1981/1982; Tokoro et al., 1984; Troilo and Judge, 1993; Wiesel and Raviola, 1977). As in common myopias in humans, the major anatomical alteration of so-called “form deprivation myopia” is enlargement of the vitreous chamber (Figure 9.1). Stimulated by the laboratory findings, clinical investigators subsequently found that form deprivation myopia also occurs in young children since ipsilateral myopia follows a variety of conditions that degrade the visual image, such as ptosis, vitreous hemorrhage, corneal

FIGURE 9.1 The eye in myopia. The profile of a myopic eye is superimposed over that of a non-myopic eye in (a) a classic illustration for human myopia (reprinted from Heine, 1899) and (b) a schematic representation of form deprivation myopia in the monkey (reprinted from Raviola and Wiesel, 1985, with permission. Copyright © 1985 Massachusetts Medical Society). The similar vitreous cavity expansion in the two illustrations is evident

abnormalities, etc. (Gee and Tabbara, 1988; Hoyt et al., 1981; Miller-Meeks et al., 1990; Nathan et al., 1985; O’Leary and Millodot, 1979; Robb, 1977; von Noorden and Lewis, 1987). Following restoration of non-restricted visual input, young chicks, tree shrews, monkeys, but evidently not marmosets, also can “recover” from form deprivation myopia by slowing their eye growth so that emmetropia results (QiaoGrider et al., 2004; Siegwart and Norton, 1998; Troilo and Judge, 1993; Wallman and Adams, 1987). While form deprivation typically induces a very robust eye growth and myopic response in young animals, it also develops in chicks, tree shrews and primates at developmental stages comparable to human adolescence, although at a considerably reduced rate and more in line with what might be expected for a clinically relevant model (Papastergiou et al., 1998a; Siegwart and Norton, 1998; Smith et al., 1999; Troilo et al., 2000b). It recently has been suggested that the absence of high spatial frequencies in the visual image, rather than degradation of all aspects of the image, may account for form deprivation myopia (Hess et al., 2006; Schaeffel, 2006); but a dependency on only high spatial frequency images seems unlikely to account fully for the visual regulation

of eye growth (Schaeffel, 2006). The anatomical changes, myopia development in children with degraded visual images and the susceptibility of adolescent animals are features supporting some degree of clinical relevance for this model, but the pronounced degradation of the visual image as caused by lid suture or goggles does not precede most human myopia.

2. Modifying eye growth by spectacle lens wear

The eyes of young chicks and mammals, including tree shrews, guinea pigs and monkeys, alter their growth to compensate for image shifts induced by spectacle lenses (Graham and Judge, 1999; Hung et al., 1995; McFadden et al., 2004; Schaeffel et al., 1988; Shaikh et al., 1999). Concave (minus powered) spectacle lenses and convex (plus powered) spectacle lenses shift the visual image posteriorly or anteriorly, respectively, and eye growth is correspondingly accelerated or slowed to maintain the photoreceptor position conjugate with the focal position of distant images (Figure 9.2). With lens removal, myopia is evident following minus lens wear; and hyperopia, following plus lens wear. Despite their superficial anatomical similarities, lens-induced myopia and form deprivation myopia are not identical mechanistically. They differ in the electroretinogram (Fujikado et al., 1997b), in the time course, in the response to altered lighting (Kee et al., 2001) and, of course, in the nature of the visual perturbation. Recently reviewed (Wallman and Winawer, 2004), the developmental responses to spectacle lenses provide further compelling evidence for the visual control of eye growth and have proved useful in addressing emmetropization mechanisms.

The responses of animal eyes to defocusing spectacle lenses are difficult to reconcile with the clinical development of myopia, however, though many have tried (Schmid and Wildsoet, 2004; Wallman and

(a) Sclera

Choroid

Retina

(b)

FIGURE 9.2 The effect of lens induced defocus on eye development (Wallman and Winawer, 2004).

(a)In an emmetropic eye, a convex lens (positive lens in blue) shifts the distance image anterior to the retina; and a concave lens (negative lens in orange) shifts the distance image behind the retina. Without a lens, distance images focus at the position of the retina.

(b)The eyes of young animals adjust to defocus distance images by changing choroidal thickness and altering the ocular growth rate to reposition the retina at the location of distance images. With images in front of the retina (e.g. from a convex lens in blue), the choroid thickens and ocular growth slows to permit this adjustment. With images behind the retina (e.g. from a concave lens in orange), the choroid thins and ocular growth accelerates to permit this adjustment. With no superimposed defocus, the choroidal thickness and axial size of an emmetropic eye lies between the other two conditions. With removal of the convex or concave lens and the restoration of non-restricted visual input, the eye initially will manifest a hyperopic or myopic refractive error, respectively, from which it can recover at sufficiently young ages. Reprinted from Wallman and Winawer, 2004. Copyright © 2004, with permission from Elsevier

Winawer, 2004). The accuracy with which animal eyes correct eye growth for defocus suggests that refractive errors ought not to develop, if human eyes behave similarly. In addition, the effect of positive lenses predominates if negative and positive lens wear is alternated in individual

animals. That is, the growth inhibiting actions of images focused anterior to the retina are more potent than the growth enhancing effects of images focused behind it (Wallman and Winawer, 2004; Winawer and Wallman, 2002; Zhu et al., 2003). This non-linearity in the temporal weighting of anteriorly and posteriorly defocused images would seemingly also bias against myopia. Similarly, relatively brief periods of unobstructed vision in chicks or monkeys (Napper et al., 1995, 1997; Smith et al., 2002) counteract the myopic effects of form deprivation and largely permit emmetropization. Further questioning the role of simple defocus in myopia pathogenesis are the disappointing results of optical interventions in slowing myopia progression in children (Chung et al., 2002; Edwards et al., 2002; Goss, 1994; Katz et al., 2003; Saw et al., 2002b; Walline et al., 2004). Some studies suggest that bifocal wear may be an exception, but the few positive observations have refractive effects too small to the clinically meaningful (Fulk et al., 2000; Gwiazda et al., 2003). Perhaps subgroups of myopic children might be benefited by specific optical interventions, such as children with near esophoria and high accommodative lag (Goss and Grosvenor, 1990; Gwiazda et al., 2004), or perhaps novel and innovative optical strategies might yet prove effective at slowing myopia progression (Phillips, 2005). Adequately powered clinical studies with favorable outcomes in children would still seem needed, though, to decide if and how the responses of animal eyes to defocusing lenses relate mechanistically to clinical ametropias, as distinct from emmetropia, and whether results from these laboratory experiments can provide guidance for designing clinically effective, optically based anti-myopia therapies.

3. Altered photoperiod

The growth of chick eyes has long been known to be markedly perturbed by disrupting the daily light:dark cycle,