Chapter 68 Myopic Macular Degeneration
Pathologic myopia is a major cause of legal blindness and low vision worldwide,1–5 and its prevalence is increasing in modern society, presumably due to an increase of near activities. In patients with pathologic myopia, various kinds of myopic macular degeneration develop in the posterior fundus, and these are the cause of visual impairment.6,7 There are new ideas concerning the pathogenesis of pathologic myopia and novel treatments for myopic macular degeneration. Although myopic macular degeneration had been an incurable degenerative disorder, the recent application of photodynamic therapy (PDT) with verteporfin and anti-vascular endothelial growth factor (VEGF) therapy has enabled treatment of myopic choroidal neovascularization (CNV). With these advances, myopic macular degeneration is now a curable disorder in some patients to some extent. Importantly, a novel pathology called “myopic macular retinoschisis” has been described using optical coherence tomography (OCT).8 The OCT examinations showed that retinoschisis was present in some eyes with pathologic myopia before the development of myopic macular holes. With the description of myopic macular retinoschisis, vitrectomy has been actively performed to reduce the chance of progression to more serious conditions like macular holes or macular retinal detachment.
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
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).
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.
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.
Scleral thinning and localized ectasia of the posterior sclera are characteristic changes of the eyes with pathologic myopia. Microscopically, the normal sclera consists of interwoven bands or bundles of collagen fibers.43 These are usually well integrated and in longitudinal section present a relatively homogeneous appearance throughout their extent. The architectural changes in the longitudinal fibers in pathologic myopia consist of thinning of the collagen bundles, a reduction in refringence of the bundle edges, and the loss of longitudinal fiber striations. The cross-sectional fibers demonstrate dissociation such that the individual fibers separate from one another. There is also a reduction in the size of the individual dissociated fibers. The more advanced examples of architectural disorganization are found in and about the regions of the posterior pole and peripapillary sclera. It has also been reported that the elastic fibers within the sclera showed a definite decrease in the number of fibers.
Electron microscopic analyses showed that a predominance of collagen fibrils of small diameter, usually averaging below 60–70 nm, was found.43 Fibrils of a very fine diameter were also observed. Also, the cross-sectioned fibrils showed a marked increase in the prevalence of fissured or “star-shaped” forms. Most of the ultramicroscopic alterations seen in the myopic sclera indicate a derangement of the growth and organization of the fibrils. These may be products of defective fibrillogenesis. These aspects of development are thought to be under the control of the acidic glycosaminoglycan composition of the interfibrillar substance. It is also conceivable that this picture corresponds to abnormal fibril growth in the presence of an accentuated breakdown or catabolism of the sclera.
The degenerative changes found in pathologic myopia initially appear to involve the choriocapillaris – Bruch’s membrane – RPE complex. The changes subsequently affecting the choroid were essentially degenerative and atrophic. Thinning of the choroid and loss of the choriocapillaris were reported. Choroidal vascular occlusions are a prominent feature of the disease, and this process appears to affect the smaller-diameter vessels initially. The choroidal vessels appear to be fewer and to have thinner walls than seen normally. There is a generalized loss of the normal connective tissue framework of the choroid with some degree of compaction of the vessels. Although the large-sized choroidal vessels tend to be most resistant, these, too, may undergo occlusion in the late stages of the disease. Recent studies using enhanced-depth imaging of OCT or high-penetrance OCT also showed significant thinning of the choroid in highly myopic eyes.49
The RPE cells are seen to be flatter and larger than usual, a possible consequence of passive expansion. Hyperpigmentation, hypopigmentation, and multilayered clumping of the RPE cells may also be seen. Bruch’s membrane may show a variety of changes, including thinning, splitting, and rupture. These ruptures of Bruch’s membrane can be seen clinically as “lacquer cracks.”
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.
(Courtesy of Prof. Takashi Tokoro.)
(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.
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.