Epidemiology

Myopia is more common among Asian populations, especially in East Asian countries, than among white, black, or Hispanic people. The prevalence of myopia (spherical equivalent (SE) < –0.5 or –1.0 D) is reported to range from 17% to 43% among Asian populations.^9–17 Among white populations in Europe, the USA, and Australia, it is reported to be between 13% and 27%.^18–21 In Hispanic and black populations, it is reported to be 17% and 21%, respectively.^{19, 22} The prevalence of high myopia (SE < –5.0 or –6.0 D) is also greater in Asian populations, ranging from 1.7% to 9.1%, than that in white, Hispanic, and black populations (2.0%, 2.4%, and 1.0%, respectively) (Table 68.1).^9–22

Table 68.1 Comparison of prevalence of myopia in population-based studies

Pathologic myopia is one of the major causes of visual impairment and blindness worldwide. For example, myopic macular degeneration is the leading cause of blindness in Japan, the second most common cause in Denmark⁴ and in China,²³ and the third cause of blindness in Latinos 40 years and older in USA.^3, Myopic macular degeneration was the leading cause of impaired vision for persons aged between 55 and 75 years in the Netherlands.^3,23,24 In Italy and Taiwan, it is the second most common cause of low vision.^25,26 The impact of myopic retinopathy on visual impairment is of great concern because it is often bilateral and irreversible, and it frequently affects individuals during their most productive years.^7,27

To date, three population-based studies have estimated the prevalence of myopic retinopathy. The Blue Mountains Eye Study in Australia, which focused on a white population, reported that the prevalence of myopic retinopathy was 1.2%.²⁷ In the Beijing Eye Study in China and the Hisayama Study in Japan, the prevalence was 3.1% and 1.7%, respectively.^28a Study participants’ characteristics, methodology, and study design (for example, the definition of myopic retinopathy) were different between those studies, therefore the precise racial difference in myopic retinopathy prevalence is unknown. But it may be higher in East Asian populations than in white populations and the prevalence of high myopia is probably higher as well (Table 68.2).

Table 68.2 Comparison of prevalence of myopic retinopathy in population-based studies

The prevalence of myopic retinopathy is increased with advancing age in those population-based studies. Histological studies have shown a decreased density of photoreceptors, ganglion cells, retinal pigment epithelium (RPE), and optic nerve fibers with age.^29,30 Several studies using OCT have examined subjects with healthy eyes with neither high myopia nor hyperopia and reported a negative relationship between retinal thickness and age.^31,32 In addition to the axial elongation of the eyeball in highly myopic eyes, increasing age may contribute to the pathogenesis of myopic retinopathy by causing retinal thinning.

Although it is reported that men have longer axial length than women,^33,34 many hospital-based studies showed higher prevalence of myopic retinopathy in women than in men.^35–37 For example, Hayashi et al. showed that, of 429 consecutive patients with pathologic myopia, 147 were men and 282 were women, which is about twice as many cases in women as in men.⁷ Comparable findings were also observed in population-based studies. In the Blue Mountains Eye Study, the prevalence of myopic retinopathy in men was 0.06% and that in women was 0.4%. In the Hisayama Study, the prevalence of myopic retinopathy in men and in women was 1.2% and 2.2%, respectively. The Beijing Eye Study did not report the prevalence of myopic retinopathy by sex, but the numbers of female/male subjects with and without myopic retinopathy were 75/57 and 570/489, respectively. It suggests that not only greater axial length but other risk factors such as genetic factors and lifestyle risk factors may contribute to the pathogenesis of myopic retinopathy.

Pathogenesis

Hereditary or genetic factors play important roles in the development of pathologic myopia. There is a large international linkage study on familial high myopia, in which linkage analyses were performed on 1201 samples from Asian, African American, and Caucasian families, finding that the MYP1, MYP3, MYP6, MYP11, MYP12, and MYP14 loci were replicated.³⁸ Recent genomewide studies identified susceptibility loci at 15q14 and 15q25 for myopia.^39,40 However, the genetic influence on the development of myopic macular degeneration is not clear. The genetic risk factors of age-related macular degeneration related to rs11200638 of HTRA1, and rs1061170 (Y402H) of complement factor H did not appear to contribute significantly to the development of CNV in a highly myopic elderly Japanese population.⁴¹ It was reported that the responsiveness of myopic CNV to PDT had a correlation with common coagulation balance gene polymorphisms.⁴²

Various factors, such as aging, and biomechanical factors in addition to hereditary factors, have been considered to contribute to the development of myopic macular degeneration in highly myopic eyes.^43–45 Excessive axial elongation and posterior staphyloma (defined below) formation are critical features of pathologic myopia and these are considered important for the development and progression of myopic macular degeneration.⁴⁴ Large-scale studies show that a peripapillary crescent, chorioretinal atrophy, and posterior staphyloma are significantly related to increased axial length.^28,44 Above all, the incidence, size, and type of peripapillary crescent have the strongest correlation with the axial length;^6,44 more than 95% of eyes with an axial length of 26.5 mm or more have a peripapillary crescent, while 0% of eyes with an axial length of 21.4 mm or less have a peripapillary crescent.⁴⁴ Chorioretinal atrophy has also been related directly to increased axial length.

In addition to the influence of biomechanical factors, aging is an important factor for the development of posterior staphyloma and subsequent myopic macular degeneration. A posterior staphyloma is rarely found in highly myopic patients younger than 40 years of age.⁴⁶ The posterior staphyloma develops as patients age, and this accelerates the further mechanical extension of the posterior fundus and causes the development of myopic macular degeneration. The incidence of myopic chorioretinal atrophy increases with age, and these changes are rarely seen in persons less than 20 years old.^6,44 Childhood high myopes do not develop myopic macular degeneration or posterior staphyloma.⁴⁷

The development of myopic CNV and lacquer cracks is not directly correlated with axial length. The incidence of myopic CNV peaks in the fourth decade. There may be biological mechanisms of neovascular membrane formation other than axial elongation or aging.⁶ Steidl and Pruett⁴⁸ reported that eyes with a shallow staphyloma had the high frequency of CNV. They suggested that it is possible that eyes with a shallow staphyloma may be healthier and more metabolically active with well-perfused chorioretinal tissue and good capacity to respond to injury by neovascular ingrowth. It appears that the influence of aging and mechanical factors is rather complicated and different lesions may have different pathogenetic influences.

Histopathology

Animal models

Rhesus monkeys, chickens, fish, tree shrews, marmosets, and guinea pigs have long been used as animal models of experimental myopia by inducing form deprivation myopia by lid suture or by wearing plastic goggles (Figs 68.1 and 68.2).^50–52 Chicks have long been the main animal model for experimental myopia because myopia accompanying a dramatic increase of the axial length can be induced easily by wearing plastic goggles in about 2 weeks.⁵³ Therefore, many studies were performed using chick models of experimental myopia; these studies identified responsible factors which cause excessive eye growth. However the sclera of chickens differs from that of humans. The chicken has the classic vertebrate sclera, consisting of a layer of cartilage surrounded by layers of fibrous connective tissue, whereas in most mammals, including primates and rodents, the cartilage has been lost.

Fig. 68.1 Monkey model of experimental myopia. Form deprivation myopia is induced by lid fusion in neonate monkeys.

(Courtesy of Prof. Takashi Tokoro.)

Fig. 68.2 Chick models of experimental myopia. One eye is covered by plastic goggle to induce blurred image on the retina.

(Courtesy of Prof. Takashi Tokoro.)

Based on the benefit of having similar scleral components, mice have commonly been used as examples of experimental myopia (Fig. 68.3),^54,55 although there is some drawback that the induced myopia is not as severe as in chickens because mice are not “visual animals.” Mouse model advantages also include the availability of numerous knockout mutants, more advanced gene microarrays for screening the transcriptome, and a completely sequenced genome.

Fig. 68.3 Mouse models of experimental myopia. One eye is covered by plastic goggle to induce blurred image on the retina.

The transcriptome of neurosensory retina without RPE was analyzed with Affymetrix GeneChip mouse genome 430 2.0 arrays after unilateral retinal image degradation by use of frosted goggles in mice,⁵⁶ and some genes were identified as being altered, including a downregulation of the early growth response 1 (Egr-1) gene. The refractions of homozygous Egr-1 knockout mice were some 4–5 D less hyperopic relative to the wild type.⁵⁸ Zebrafish have also been considered as a model of experimental myopia. Downregulation of zebrafish lumican gene expression manifested ocular enlargement resembling axial myopia due to disruption of the collagen fibril arrangement in the sclera and resulted in scleral thinning.⁵⁸ The lumican gene, which encodes one of the major keratan sulfate proteoglycans in the vertebrate cornea and sclera, has been linked to axial myopia in humans. Veth and colleagues⁵⁹ have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma, including adult-onset severe myopia, elevated intraocular pressure, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a noncomplementing allele indicated that nonsense mutations in low-density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype.