Myopia and Other Refractive Error and Their Relationships to Glaucoma Screening.

PRCIS: A large disk, a large parapapillary delta zone and a long axial length may be used as screening criteria to detect glaucomatous optic neuropathy in highly myopic eyes. PURPOSE: To describe aspects for screening of glaucomatous optic neuropathy in dependence of refractive error, under special consideration of high myopia. METHODS/RESULTS: Studies on the anatomy of the myopic optic nerve head and results of investigations on the relationship between glaucomatous optic neuropathy and axial myopia were included. CONCLUSIONS: In the range from hyperopia to moderate myopia, refractive error is not a strong glaucoma risk factor and may not be included in glaucoma screening strategies. Care should be taken, that in moderate myopia, a shift of Bruch´s membrane opening usually into the temporal direction leads to parapapillary gamma zone and a corresponding shortening of the horizontal disk diameter. In these moderately myopic eyes, a secondarily small optic disk with a correspondingly small optic cup should not lead to an overlooking of intrapapillary glaucomatous changes. Prevalence of glaucomatous or glaucoma-like optic nerve atrophy (GOA) steeply increases with longer axial length in highly myopic eyes (cutoff approximately -8 diopters/axial length 26.5 mm), with prevalences higher than 50% in extremely high myopia. Besides longer axial length, morphological parameters associated with GOA in highly myopic eyes are a secondarily enlarged disk and large parapapillary delta zone. Both parameters, together with long axial length, may be used as screening criteria in high myopia for GOA. The latter is characterized by an abnormal neuroretinal rim shape, that is, vessel kinking close to the intrapapillary disk border. Factors associated with nonglaucomatous optic neuropathy are larger gamma zone and longer axial length, potentially due to an axial elongation-related retinal nerve fiber stretching.

Myopic Macular Atrophy in the Two-Continent Population-Based Study.

Purpose: To examine the prevalence of Bruch's membrane defects (BMDs) and subretinal proliferations (SRPs) in highly myopic eyes with myopic macular atrophy (myopic macular degeneration [MMD] stage 4) and myopic patchy atrophies (MMD stage 3) in three ethnically different cohorts recruited in a population-based manner. Methods: The Ural Eye and Medical Study (UEMS) and Beijing Eye Study (BES) included individuals aged 40+ years, and the Ural Very Old Study (UVOS) examined individuals aged 85+ years. Main outcome measures were the prevalence of BMDs and SRPs. Results: Among 5794 UEMS participants, 19 eyes had MMD stage 4, with 17 (89%) eyes showing a foveal BMD; two eyes could not fully be explored. All 19 eyes showed localized SRPs. Among 21 eyes with MMD stage 3, BMD and SRP prevalence was 9 of 21 (44%) and 7 of 21 (33%), respectively. Among 930 UVOS participants, 17 eyes had MMD stage 4, with 16 (94%) eyes showing foveal BMDs and SRPs; one eye could not be assessed. Among 18 eyes with MMD stage 3, BMD and SRP prevalence was 3 of 18 (17%) and 2 of 18 (11%), respectively. Among 3468 BES participants, 8 eyes had MMD stage 4, with all eyes showing foveal BMDs and SRPs. Among 14 eyes with MMD stage 3, BMD and SRP prevalence was 10 of 14 (71%) and 7 of 21 (33%), respectively. Conclusions: All eyes with assessable myopic macular atrophy showed foveal BMDs associated with SRPs, while patchy atrophies could be differentiated into those with BMDs and SRPs and those without BMDs and without SRPs. Independent of the MMD stage, the prevalences of BMDs and SRPs were highly significantly associated with each other.

Drusen in the macula and parapapillary region.

PURPOSE: To examine histological characteristics and differences between drusen beneath the retinal pigment epithelium (small hard drusen) located in the macula and located in the parapapillary region. METHODS: We histomorphometrically examined human eyes enucleated due to uveal melanomas or secondary angle-closure glaucoma. RESULTS: The study included 106 eyes (age, 62.6 ± 15.2 years) with macular drusen (n = 7 globes) or parapapillary drusen (n = 29 eyes) and 70 eyes without drusen. In all drusen, periodic-acid-Schiff-positive material was located between the RPE basal membrane and the inner collagenous layer of Bruch's membrane (BM). Macular drusen as compared with parapapillary drusen had lower height (15.2 ± 10.1 µm versus 34.3 ± 19.8 µm; P = 0.003), while both groups did not differ significantly in basal drusen width (74.0 ± 36.3 µm versus 108.7 ± 101.0 µm; P = 0.95). Eyes with macular drusen and eyes without drusen did not differ significantly in BM thickness (2.74 ± 0.44 µm versus 2.55 ± 0.88 µm; P = 0.57) or in RPE cell density (35.4 ± 10.4 cells/480 µm versus 32.8 ± 7.5 cells/480 µm; P = 0.53), neither in the drusen region nor in the drusen vicinity, while BM thickness (4.60 ± 1.490 µm; P < 0.001) and RPE cell density (56.9 ± 26.8 cells/480 µm; P = 0.005) were higher at the parapapillary drusen. Eyes with macular drusen, eyes with parapapillary drusen, and eyes without drusen did not differ significantly in choriocapillaris density (all P > 0.10) and thickness (all P > 0.35). Limitations of the study, among others, were a small number and size of drusen examined, diseases leading to enucleation, lack of serial sections, limited resolution of light microscopy, and enucleation-related and histological preparation-associated artefacts. CONCLUSIONS: The findings of this study, also taking into account its methodological limitations, suggest that macular drusen and parapapillary drusen shared the morphological feature of periodic-acid-Schiff-positive material between the RPE basal membrane and BM and that they did not vary significantly in choriocapillaris thickness and density. RPE cell density and BM thickness were higher in parapapillary drusen than in macular drusen.

Bruch's membrane and Brücke's muscle in the pars plana region.

PURPOSE: To examine Bruch's membrane (BM) in association with the longitudinal part of the ciliary muscle (LPCM) in the pars plana region. METHODS: Using light microscopy, we histomorphometrically assessed BM and the LPCM in the pars plana region. RESULTS: The histomorphometric study included 51 eyes (51 patients; mean age: 60.8 ± 15.0 years; axial length: 26.0 ± 3.3 mm; range: 21.0-36.0 mm). The LPCM (total length: 4.60 ± 1.10 mm) ended 1.15 ± 0.56 mm anterior to the ora serrata. Within the pars plana region, the LPCM (length: 2.58 ± 0.98 mm) had direct contact with BM for 1.95 ± 0.99 mm (71.1 ± 18.4% of the BM undersurface), while a capillary layer was interposed between the BM and the LPCM for 0.70 ± 0.40 mm (29.0 ± 18.4%). In the pars plana region free of LPCM close to the ora serrata, the percentage of BM covered by the capillary layer was higher than in the pars plana region containing the LPCM (63.0 ± 42.1% vs. 29.0 ± 18.4%; p < 0.001). At the LPCM end, BM was in direct contact with a collagenous tissue from the LPCM and was focally thickened as compared to BM with an underlying capillary layer (9.5 ± 5.3 µm vs. 4.3 ± 1.2 µm; p < 0.001). CONCLUSIONS: The direct contact of BM with the LPCM in the pars plana in association with focal BM thickening at the LPCM end suggests an insertion of LPCM on the BM. Taking into account the biomechanical strength of BM, it may imply a functional unit of the LPCM with BM in the process of accommodation with a secondary movement of the posterior BM and tertiary thickening of the subfoveal choroidal space.

Prevalence and Cause of Loss of Visual Acuity and Visual Field in Highly Myopic Eyes: The Beijing Eye Study.

PURPOSE: To explore the prevalence and causes of loss of visual acuity and visual field in highly myopic eyes. DESIGN: Population-based study. PARTICIPANTS: 4439 subjects of the Beijing Eye Study underwent ophthalmological and systemic examinations including frequency doubling technology perimetry. METHODS: High myopia was defined by a refractive error of ≤-6 diopters (D) or axial length >26.0 mm. MAIN OUTCOME MEASURES: Prevalence of vision impairment causes. RESULTS: 212 highly myopic eyes from 154 participants were included with a mean age of 56.2 ± 9.6 years, a mean refractive error of -9.87 ± 3.70 D and a mean axial length of 27.2 ± 1.3 mm. We observed moderate/severe vision impairment (MSVI) in 40 eyes (18.9%; 95% confidence interval [CI], 13.6-24.2) and blindness in 10 eyes (4.7%; 95% CI, 1.8-7.6). Primary causes for MSVI and blindness were myopic macular degeneration (MMD) (29/50; 58%), age-related macular degeneration (1/50; 2%), and branch macular retinal vein occlusion (1/50; 2%). Secondary causes were MMD (4/50; 8%) and optic nerve atrophy (14/50, 28%), further differentiated into non-glaucomatous optic atrophy (NGOA) (9/50; 18%) and glaucomatous optic atrophy (GOA) (5/50; 10%). Prevalence of MMD as vision impairment cause increased significantly from 1/61 (1.6%) in the refractive error group of -6.00 to ≥-7.00 D, to 16/25 (64%) in the group of <-15.0 D. Higher MMD prevalence correlated with higher myopic refractive error (P < 0.001) and increased likelihood of concomitant optic neuropathy (P < 0.001). Similarly, prevalence of optic neuropathy as vision impairment cause increased from 0/61 (0%) in the refractive error group of -6.00 D to ≥-7.00 D, to 9/25 (36%) in the group of <-15.0 D. Higher optic neuropathy prevalence correlated with more myopic refraction (P < 0.001) and older age (P = 0.02). CONCLUSIONS: In this population-based recruited cohort of highly myopic patients, optic neuropathy accounted for vision impairment in 9.0% eyes, which was lower than the prevalence of MMD as vision impairment cause (18.9%). Notably, optic neuropathy became a significant contributor to vision impairment in more advanced high myopia, reaching 36% in the group with refractive error of <-15.0 D. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Parapapillary drusen of the retinal pigment epithelium.

PURPOSE: To describe the occurrence, morphology and associations of parapapillary drusen of the retinal pigment epithelium (RPE-drusen). METHODS: Using light microscopy, we histomorphometrically examined enucleated human eyes. RESULTS: The study included 83 eyes (axial length: 25.9 ± 3.2 mm; range: 20.0-35.0 mm). Eyes with parapapillary RPE-drusen (n = 29 (35%) eyes) as compared to those without drusen had a significantly shorter axial length (24.0 ± 1.8 mm vs 27.0 ± 3.3 mm; p < 0.001), higher prevalence (27/29 vs 12/54; p < 0.001) and longer width (213 ± 125 µm vs 96 ± 282 µm; p < 0.0001) of parapapillary alpha zone, and thicker BM in parapapillary beta zone (8.4 ± 2.7 µm vs 3.9 ± 2.0 µm; p < 0.001) and alpha zone (6.6 ± 3.9 µm vs 4.4 ± 1.5 µm; p = 0.02). Prevalence of parapapillary RPE-drusen was 27 (69%) out of 39 eyes with alpha zone. Beneath the RPE-drusen and in total alpha zone, choriocapillaris was open, while it was closed in the central part of parapapillary beta zone. BM thickness was thicker (p = 0.001) in alpha zone than beta zone, where it was thicker (p < 0.001) than in the region outside of alpha/beta zone. BM thickness outside of alpha/beta zone was not correlated with prevalence of parapapillary RPE-drusen (p = 0.47) or axial length (p = 0.31). RPE cell density was higher in alpha zone than in the region adjacent to alpha zone (22.7 ± 7.3 cells/240 µm vs 18.3 ± 4.1 cells/240 µm; p < 0.001). In the parapapillary RPE-drusen, RPE cells were connected with a PAS-positive basal membrane. CONCLUSIONS: Parapapillary RPE-drusen as fibrous pseudo-metaplasia of the RPE were associated with shorter axial length, higher prevalence and larger size of alpha zone, and thicker BM in alpha zone and beta zone. The RPE-drusen may be helpful to differentiate glaucomatous parapapillary beta zone from myopic beta zone.

Prevalence and Associations of Peripheral Arterial Disease in China: The Beijing Eye Study.

PURPOSE: To explore the prevalence and associations of peripheral arterial disease (PAD) in China. DESIGN: Population-based incidence estimate and cross-sectional study. METHODS: The participants (n=3468) of the Beijing Eye Study underwent a detailed ophthalmologic and systemic examination including assessment of the ankle-brachial index (ABI). PAD was defined by an ABI of less than 0.9. RESULTS: Blood pressure measurements of both arms and ankles were available for 1078 (31.1%) individuals. An ABI (mean: 1.09±0.11; median: 1.10; range: 0.25, 1.36) of <0.9 and <0.95 was found in 32 of 1078 participants (3.0%, 95% CI 2.0, 4.0) and 70 of 1078 individuals (6.5%, 95% CI 5.0, 8.0), respectively. Higher PAD prevalence (multivariable analysis) was associated with older age (odds ratio [OR] 1.08, 95% CI 1.02, 1.15; P = .009), lower level of education (OR 0.62, 95% CI 0.43, 0.90; P = .01), lower quality of life (OR 0.67, 95% CI 1.11, 2.32), higher glucose serum concentration (OR 1.36, 95% CI 1.09, 1.58; P = .006), lower estimated glomerular filtration rate (OR 0.98, 95% CI 0.96, 0.99; P = .04), and higher prevalence of retinal vein occlusions (OR 7.30, 95% CI 1.63, 32.6; P = .009). PAD prevalence was not associated with the prevalence of glaucoma (P = .53) (open-angle glaucoma: P = .42; angle-closure glaucoma: P = .57) and age-related macular degeneration (any AMD: P = .39; early AMD: P = .31; intermediate AMD: P = .92; late AMD: P = .99), prevalence (P = .26) and stage (P = .07) of diabetic retinopathy, prevalence (P = .38) and degree (P = .68) of nuclear cataract, prevalence (P = .39) and degree (P = .72) of cortical cataract, prevalence of subcapsular cataract (P = .86), prevalence of pseudoexfoliation (P = .65), intraocular pressure (P = .50), axial length (P = .56), and peripapillary retinal nerve fiber layer thickness (P = .68). CONCLUSIONS: The PAD prevalence (3.0%, 95% CI 2.0%, 4.0%) was relatively low in this cohort from rural and urban Beijing, with older age, lower educational level, lower quality of life, higher glucose serum concentration, lower estimated glomerular filtration rate, and higher prevalence of retinal vein occlusions as main associated factors.

Ciliary body size in chronic angle-closure glaucoma.

To examine the size of the ciliary body stroma (CBS) in dependence of the morphology of the anterior chamber angle in enucleated human eyes, we histomorphometrically examined human enucleated eyes. The study included 107 eyes (with a mean axial length of 25.1 ± 2.8 mm (range 21.0-36.0 mm). The anterior chamber angle was open in 68 eyes and it was closed and endothelialized in 39 eyes. The maximal CBS width (541 ± 210 µm versus 59 ± 179 µm; P < 0.001) and the minimal CBS width (214 ± 107 µm versus 17 ± 55 µm; P < 0.001) and maximal ciliary muscle height (593 ± 557 µm versus 293 ± 111 µm; P = 0.001) were significantly smaller in the angle-closure group than in the open-angle group. Maximal CBS width increased with presence of an open anterior chamber angle (beta: 0.82; B: 517; 95% CI 435, 599; P < 0.001) and longer axial length (beta: 0.17; B: 18.2; 95% CI 4.2, 32.2; P = 0.01). Minimal CBS width increased with the presence of an open anterior chamber angle (beta: 0.48; B: 131; 95% CI 80.4, 181; P < 0.001) and a larger maximal ciliary muscle height (beta: 0.33; B: 0.28; 95% CI 0.12, 0.44; P = 0.001). Maximal ciliary muscle height correlated with the maximal CBS height (beta: 0.35; B: 0.53; 95% CI 0.25, 0.81; P < 0.001). The findings suggest that the CBS size is markedly smaller in eyes with a chronically closed endothelialized anterior chamber angle than in eyes with open angles. The tightening of the angle in eyes with angle-closure may prevent the access of aqueous humor not only to the trabecular meshwork but also to the ciliary body and may reduce the uveoscleral or uveovortex outflow pathway.

Choriocapillaris, Photoreceptors, and Inner Retinal Layer in Spatial Relationship to Parapapillary Alpha, Beta, Gamma, and Delta Zones.

Purpose: To examine the spatial relationships between the retinal inner nuclear layer (INL), outer nuclear layer (ONL), retinal pigment epithelium (RPE) layer, Bruch's membrane (BM), and choriocapillaris in the parapapillary region. Methods: Human eyes enucleated due to uveal melanomas or secondary angle-closure glaucoma were histomorphometrically examined. We compared the tissue dimensions between four groups of eyes categorized based on the presence/absence of high myopia and glaucoma. Results: The investigation consisted of 100 globes (axial length: 25.6 ± 3.1 mm; range: 20.0-35.0 mm). In non-highly myopic nonglaucomatous eyes, the INL, ONL, RPE, BM, and choriocapillaris ended approximately at the end of the RPE layer, with no significant (all P ≥ 0.10) difference between the layers in their distance to the RPE-layer end. From non-highly myopic nonglaucomatous eyes to non-highly myopic glaucomatous eyes, highly myopic nonglaucomatous eyes, and eventually highly myopic glaucomatous eyes, the choriocapillaris, INL, and ONL increasingly extended into the beta zone, most marked for the choriocapillaris and least marked for the ONL. A larger extension of the choriocapillaris into the parapapillary beta zone correlated with longer axial length (standardized regression coefficient ß, 0.24; B, 23.0; 95% confidence interval [CI], 1.6-44.5; P = 0.04) and wider parapapillary beta zone (ß, 0.59; B, 0.32; 95% CI, 0.22-0.41; P < 0.001); a larger extension of the INL correlated with longer axial length (ß, 0.34; B, 43.7; 95% CI, 11.6-75.7; P = 0.009), longer gamma zone (ß, 0.52; B, 0.28; 95% CI, 0.15-0.41; P < 0.001), and diagnosis of non-highly myopic glaucoma (ß, 0.28; B, 267; 95% CI, 80.8-454; P = 0.006); and a larger extension of the ONL into parapapillary beta zone correlated with longer axial length (ß, 0.50; B, 32.2; 95% CI, 21.6-42.8; P < 0.001) and wider parapapillary beta zone (ß, 0.28; B, 0.10; 95% CI, 0.04-0.16; P < 0.001). Conclusions: Nonglaucomatous non-highly myopic eyes differ from highly myopic eyes and glaucomatous eyes in the spatial relationship of the parapapillary tissue layers.

Myopic Versus Glaucomatous Parapapillary Beta Zone in Myopic Eyes Versus Eyes With Secondary Angle-Closure Glaucoma.

Purpose: To search for histologic differences in the beta zone between myopic eyes versus eyes with secondary angle-closure glaucoma. Methods: The histomorphometric study consisted of human eyes enucleated due to uveal melanomas or secondary angle-closure glaucoma. Results: The study included 100 eyes (age: 62.1 ± 15.1 years; axial length: 25.6 ± 3.1 mm; range: 20.0-35.0 mm). In non-highly myopic glaucomatous eyes compared with non-highly myopic nonglaucomatous eyes, the parapapillary alpha zone was longer (223 ± 168 µm vs. 125 ± 128 µm; P = 0.03), beta zone prevalence (15/20 vs. 6/41; P < 0.001) and length (277 ± 245 µm vs. 44 ± 150 µm; P = 0.001) were higher, and RPE cell density in the alpha zone and alpha zone border was lower (all P < 0.05). In highly myopic nonglaucomatous eyes compared with non-highly myopic glaucomatous eyes, parapapillary RPE drusen prevalence (2/19 vs. 10/10; P = 0.01) and alpha zone prevalence (2/19 vs. 16/20; P < 0.001) and length (23 ± 68 µm vs. 223 ± 168 µm; P < 0.001) were lower. In non-highly myopic glaucomatous eyes, Bruch's membrane (BM) thickness decreased (P < 0.001) from the beta zone (6.0 ± 3.1 µm) to the alpha zone (5.1 ± 4.3 µm) and peripheral to it (3.0 ± 0.9 µm). In highly myopic nonglaucomatous eyes, BM thickness did not differ (P > 0.10) between all three regions. In the total study population, RPE cell density in the alpha zone (24.5 ± 9.3 cells/240 µm) was higher than at the alpha zone border (19.2 ± 4.8 cells/240 µm; P < 0.001) or peripheral to it (19.0 ± 3.6 cells/240 µm; P < 0.001). Conclusions: The glaucomatous beta zone in eyes with chronic angle-closure glaucoma (with the alpha zone, parapapillary RPE drusen, thickened BM, and higher RPE cell count in the adjacent alpha zone) differs histologically from the myopic beta zone (characterized by the absence of the alpha zone and parapapillary RPE drusen, unremarkable BM thickness, and unremarkable parapapillary RPE). The differences suggest different etiologies of the glaucomatous versus myopic beta zone.

Anatomic Peculiarities Associated with Axial Elongation of the Myopic Eye.

PURPOSE: To describe anatomical peculiarities associated with axial elongation in the human myopic eye. METHODS: Reviewing the results of previous histomorphometrical investigations of enucleated human globes, as well as reviewing findings obtained in population-based studies and hospital-based clinical investigations of myopic patients and non-myopic individuals. RESULTS: Myopic axial elongation is associated with a change from a mostly spherical eye shape to a prolate ellipsoid form. It is combined with choroidal and scleral thinning, most pronounced at the posterior pole and less pronounced in the fundus midperiphery. In the fundus midperiphery, the retina and density of the retinal pigment epithelium (RPE) and photoreceptors decrease with a longer axial length, while in the macular region, retinal thickness, RPE cell density, and choriocapillaris thickness are not related to axial length. With axial elongation, a parapapillary gamma zone develops, leading to an enlargement of the optic disc-fovea distance and a decrease in angle kappa. Axial elongation is also correlated with an increase in the surface and volume of Bruch's membrane (BM), while BM thickness remains unchanged. Axial elongation causes moderately myopic eyes to show a shift of BM opening to the foveal direction so that the horizontal disc diameter becomes shorter (with a consequent vertical ovalization of the optic disc shape), a temporal gamma zone develops, and the optic nerve exit takes an oblique course. Features of high myopia are an enlargement of the RPE opening (myopic parapapillary beta zone) and BM opening (secondary macrodisc), elongation and thinning of the lamina cribrosa, peripapillary scleral flange (parapapillary delta zone) and peripapillary choroidal border tissue, secondary BM defects in the macular region, myopic maculoschisis, macular neovascularization, and cobblestones in the fundus periphery. CONCLUSIONS: These features combined may be explained by a growth in BM in the fundus midperiphery leading to axial elongation.

Myopic macular Bruch's membrane defects.

Purpose: To examine histologic characteristics of macular Bruchs membrane defects (BMD) in axially elongated eyes. Design: Histomorphometric study. Methods: Using light microscopy, we examined enucleated human globes for BMDs. Results: In 247 eyes, BMDs were detected in 15 (6.1%) eyes (axial length:27.0-36.0 mm), in 10 of them in the macular region. Prevalence and size of BMDs (mean:1.93 ± 1.62 mm; range:0.22mm-6.24 mm) correlated with longer axial length (OR:1.52; 95%CI:1.19,1.94; P = 0.001) and higher prevalence of scleral staphylomas (OR:16.3; 95%CI:2.67,99.3; P < 0.001). The BMDs were smaller than corresponding gaps in the retinal pigment epithelium (RPE) (1.93 ± 1.62 mm versus 2.61 mm ± 1.73 mm; P = 0.003), and larger than corresponding gaps in the inner nuclear layer (0.43 ± 0.76 mm; P = 0.008) and inner limiting membrane bridges (0.13 ± 0.33 mm; P = 0.001). Choriocapillaris thickness, BM thickness and RPE cell density did not vary (all P > 0.05) between the BDM border and adjacent areas. In the BMD, choriocapillaris and RPE were absent. The sclera was thinner in the BDM area than in adjacent areas (0.28 ± 0.19 mm versus 0.36 ± 0.13 mm; P = 0.006). Conclusions: BMDs as hallmarks of myopic macular degeneration are characterized by longer gaps in the RPE and smaller gaps in the outer nuclear layer and inner nuclear layer, by localized scleral thinning, and by a spatial association with scleral staphylomas. Thickness of the choriocapillaris and density of the RPE cell layer, both absent within the BDMs, do not vary between the BMD border and adjacent regions. The results suggest an association between BDMs and absolute scotomas, stretching of the adjacent retinal nerve fiver layer, and an axial elongation-associated stretching effect on BM as etiology of the BDMs.

Change in the ophthalmoscopical optic disc size and shape in a 10-year follow-up: the Beijing Eye Study 2001-2011.

BACKGROUND: To assess prevalence and associated factors of changes in the ophthalmoscopic optic disc size and shape. METHODS: The case-control study included all highly myopic eyes (myopic refractive error ≤-6.0 diopters) and a randomly selected group of non-highly myopic eyes, examined in the population-based Beijing Eye Study 2001 and 2011. RESULTS: The study included 89 highly myopic eyes (age:65.0±9.8 years) and 86 non-highly myopic eyes. Reduction in ophthalmoscopic disc size (prevalence, high myopia: 30 (33.7%) eyes; non-high myopia: 7 (8.1%) eyes) was associated with non-circular gamma zone enlargement (OR: 19.4; 95% CI: 6.7 to 56.6; p<0.001) and disc-fovea line elongation (OR: 2.80;95% CI: 1.12 to 6.98; p=0.03). Disc size reduction was correlated with a disc diameter shortening in direction of the widest gamma zone enlargement (correlation coefficient r=34; p=0.01). The perpendicular disc diameter remained mostly unchanged, resulting in an ovalisation of the ophthalmoscopic disc shape. Enlargement of the ophthalmoscopic disc size (prevalence, high myopia: 22 (24.7%) eyes; non-high myopia: 4 (4.7%) eyes) was associated with circular gamma zone enlargement (4.99; 95% CI: 1.95 to 12.8; p=0.001) and high myopia (OR: 4.29; 95% CI: 1.34 to 13.8; p=0.01). CONCLUSIONS: Myopic axial elongation may lead first to a Bruch's membrane (BM) opening (BMO) shift into the foveal direction leading to BM overhanging into the nasal intrapapillary compartment, development and enlargement of gamma zone at the temporal disc side, reduction in the ophthalmoscopically visible disc area and ovalisation of the ophthalmoscopic disc shape. In a second step, an axial elongation-associated BMO enlargement may lead to a circular gamma zone increase and, due to the retraction of BM at the nasal disc border, to an enlargement of the ophthalmoscopically visible optic disc.

Parapapillary gamma zone enlargement in a 10-year follow-up: the Beijing Eye Study 2001-2011.

PURPOSE: To assess prevalence and associated factors of parapapillary gamma zone enlargement (GZE). METHODS: Using fundus photographs and optical coherence tomographic images of participants of the population-based Beijing Eye Study, we examined gamma zone changes in a 10-year follow-up. RESULTS: The study included 89 highly myopic eyes (61 participants; age: 65.0 ± 9.8 years) and 86 randomly selected non-highly myopic eyes. GZE prevalence was significantly higher in highly myopic eyes than non-highly myopic eyes (75/89; 84%; 95% CI: 77, 92 versus 18/86; 21%; 95% CI:12, 30; p < 0.001). None of the eyes showed a reduction in gamma zone size. Higher prevalence of segmental GZE without enlargement of Bruch's membrane opening (BMO) (mean: 26/175; 14.9%; 95% CI: 9.5, 20.2) was associated with optic disc size reduction (OR: 43.3; 95% CI: 10.9, 172; p < 0.001), disc-fovea distance elongation (OR: 15.4; 95% CI: 3.12, 76.4; p = 0.001) and lower prevalence of high axial myopia (OR: 0.08; 95% CI: 0.01, 0.44; p = 0.001). Higher prevalence of circular GZE (mean: 38/175; 21.7%; 95% CI: 16, 28) was correlated with optic disc enlargement (OR: 4.30; 95% CI: 1.58, 11.7; p = 0.004), and higher prevalence of myopic maculopathy progression (OR: 4.04; 95% CI: 1.60, 10.2; p = 0.003), or alternatively, higher prevalence of high myopia (OR: 4.44; 95% CI: 1.76, 11.2; p = 0.002). Circular GZE or BMO enlargement was associated with lower prevalence of macular BM defect enlargement (p = 0.035). GZE occurred perpendicular to the orientation of myopic lacquer cracks in 12 out of 17 (71%; 95% CI: 46, 95) eyes with lacquer cracks. Segmental GZE occurred in 49 (89%) out of 55 eyes in the same direction as shortening of the disc diameter developed. CONCLUSIONS: The observations support the possibility of a posterior myopic axial elongation-associated BMO shift, leading to a segmental GZE in non-highly myopic eyes, followed by a circular GZE in highly myopic eyes. Large gamma zone might be protective against macular Bruch's membrane defects.

Myopia: Histology, clinical features, and potential implications for the etiology of axial elongation.

Myopic axial elongation is associated with various non-pathological changes. These include a decrease in photoreceptor cell and retinal pigment epithelium (RPE) cell density and retinal layer thickness, mainly in the retro-equatorial to equatorial regions; choroidal and scleral thinning pronounced at the posterior pole and least marked at the ora serrata; and a shift in Bruch's membrane opening (BMO) occurring in moderately myopic eyes and typically in the temporal/inferior direction. The BMO shift leads to an overhang of Bruch's membrane (BM) into the nasal intrapapillary compartment and BM absence in the temporal region (i.e., parapapillary gamma zone), optic disc ovalization due to shortening of the ophthalmoscopically visible horizontal disc diameter, fovea-optic disc distance elongation, reduction in angle kappa, and straightening/stretching of the papillomacular retinal blood vessels and retinal nerve fibers. Highly myopic eyes additionally show an enlargement of all layers of the optic nerve canal, elongation and thinning of the lamina cribrosa, peripapillary scleral flange (i.e., parapapillary delta zone) and peripapillary choroidal border tissue, and development of circular parapapillary beta, gamma, and delta zone. Pathological features of high myopia include development of macular linear RPE defects (lacquer cracks), which widen to round RPE defects (patchy atrophies) with central BM defects, macular neovascularization, myopic macular retinoschisis, and glaucomatous/glaucoma-like and non-glaucomatous optic neuropathy. BM thickness is unrelated to axial length. Including the change in eye shape from a sphere in emmetropia to a prolate (rotational) ellipsoid in myopia, the features may be explained by a primary BM enlargement in the retro-equatorial/equatorial region leading to axial elongation.

Photoreceptor density in relation to axial length and retinal location in human eyes.

The purpose of the study was to examine the density of retinal photoreceptors and retinal pigment epithelium (RPE) cells in relation to myopic axial elongation in human eyes. Using light microscopy, we assessed the density of photoreceptors and RPE cells at the ora serrata, equator, and midperiphery (equator/posterior pole midpoint), and the RPE cell density additionally at the posterior pole, in enucleated human globes. The study included 78 eyes (mean age: 59.2 ± 15.6 years; range: 32-85 years) with a mean axial length of 27.3 ± 3.6 mm (range: 21.5-37.0 mm). Close to the ora serrata, at the equator and midperiphery, photoreceptor and RPE cell density was 246 ± 183, 605 ± 299 and 1089 ± 441 photoreceptors/mm and 56.1 ± 13.7, 45.2 ± 15.1, and 48.8 ± 15.6 RPE cells/mm, respectively. Densities of both cell types in all three regions were positively correlated with each other (all P < 0.001) and decreased with longer axial length (all P < 0.001) and longer distance between the ora serrata and the posterior pole (all P < 0.001), most marked at the midperiphery and least marked close to the ora serrata. The PRE cell density at the posterior pole was not significantly (P = 0.35) related to axial length. The photoreceptor density at the ora serrata (beta:- 0.33) and equator (beta: - 0.27) and RPE cell density at the ora serrata (beta: - 0.27) decreased additionally with the presence of glaucoma. The findings suggest that the axial elongation-related decrease in photoreceptor and RPE cell density is most marked at the midperiphery, followed by the equator and finally the ora serrata region. It suggests that the axial elongation-related enlargement of the eye wall predominantly takes place in the retro-equatorial region, followed by the equatorial region.

Inner limiting membrane bridges within Bruch's membrane defects in pathological myopia.

The purpose of the study was to examine peculiarities of the inner limiting membrane (ILM) in axially elongated eyes. The histomorphometric study included human globes enucleated due to reasons such as painful secondary angle-closure glaucoma or malignant uveal melanomas. Using light microscopy, we searched for regions with ILM-specific features in association with a marked axial elongation. Out of 279 eyes (279 patients) (mean age: 61.8 ± 13.9 years; axial length: 25.5 ± 3.1 mm (range: 20.0-37.0 mm)), two eyes (axial length: 30 mm and 34 mm, respectively) showed one region and two regions, respectively, characterized by ILM presence and absence of all other retinal layers, retinal pigment epithelium, Bruch´s membrane (BM) and choroid. The length of these regions, called ILM-bridges, was 1.06 mm, 0.73 mm, and 0.62 mm, respectively. All ILM-bridges were spatially associated with a larger, underlying BM defect and with localized scleral thinning without a staphylomatous scleral configuration. The distance between the ILM-bridges and the optic disc ranged between 1.92 mm and 4.21 mm. In univariable analysis, ILM-bridge number increased with longer axial length (beta: 0.19; P = 0.002) and higher BM defect prevalence (beta: 0.21; P = 0.001), while in multivariable analysis, the ILM-bridges number remained to be significantly correlated only with a higher prevalence of BM defect (beta: 0.15; P = 0.048). ILM-bridges occur in eyes with pathologic myopia in spatial association with underlying, larger BM defects. They may be due to an axial elongation-associated local stretching and rupture of all other retinal layers, caused by the BM defect-related enlargement of the retinal undersurface. Future studies may explore whether these histologic observations support the notion of the ILM having a relatively high biomechanical strength against myopic stretching-associated forces.

Elongation of the Retina and Ciliary Body in Dependence of the Sagittal Eye Diameter.

Purpose: To examine the elongation of the retina and ciliary body in relation to myopic axial elongation. Methods: Using light microscopy, we histomorphometrically measured in enucleated human globes the length of the retina from the ora serrata to the optic disc borders. The total retinal length was the mean of the retinal length measurements obtained on both sides of the optic disc. We additionally determined the length of the ciliary body between the ora serrata and the scleral spur. Results: The study included 174 eyes (mean age, 61.7 ± 14.8 years; range, 24-89 years) with a mean sagittal eye diameter of 25.9 ± 3.2 mm (range, 21.0-37.0 mm). Retinal length (beta, 0.81; nonstandardized regression coefficient B, 0.73; 95% confidence interval (CI), 0.65-0.81; P < 0.001) and ciliary body length elongated (beta, 0.49; nonstandardized regression coefficient B, 0.16; 95% CI, 0.12-0.20; P < 0.001) with a longer sagittal eye diameter. Retinal length and ciliary body length were associated with each other (beta, 0.34; nonstandardized regression coefficient B, 0.12; 95% CI, 0.07-0.17). Conclusions: The retina elongates by 0.73 mm (95% CI, 0.65-0.81) and the ciliary body by 0.16 mm (95% CI, 0.12-0.20) for each millimeter of axial elongation. With the inner limiting membrane and retinal nerve fibers forming the only structures connecting the deeper retinal layers with the optic disc, retinal elongation may be associated with a stretching of the retinal nerve fibers, potentially leading to optic nerve damage in highly myopic eyes, and with an increased strain within the inner limiting membrane, potentially leading to an intraretinal elevation at the posterior pole with the sequel of a myopic maculoschisis.

Progression and associated factors of lacquer cracks/patchy atrophies in high myopia: the Beijing Eye Study 2001-2011.

PURPOSE: To assess the development and progression of lacquer cracks/patchy atrophies (LCs/PAs) in high myopia. METHODS: The case control study included highly myopic eyes (refractive error ≤ - 6.0 diopters), examined in the population-based Beijing Eye Study 2001/2011. Using fundus photographs taken in 2001 and 2011 and optical coherence tomographic images obtained in 2011, we assessed the incidence and enlargement of pre-existing LC/PAs. RESULTS: The study included 89 highly myopic eyes (age: 65.0 ± 9.4 years). Newly developed or enlarged LC/PAs were detected in 17 (19.1%; 95% confidence interval (CI): 11.0, 27.0) eyes, with a new LC development without previous LCs, enlargement of a pre-existing LC, LC enlargement to a PA, development of a new PA without any previous LCs, and enlargement of a pre-existing PA detected in 3, 3, 5, 3, and 3 eyes, respectively. In 14 (82.4%; 95%CI: 62.3, 100) of the 17 eyes with LC/PA development or enlargement, the LC/PAs elongated perpendicularly to, and widened in, the direction of gamma zone enlargement. Higher prevalence of LC/PA enlargement was associated (multivariable analysis) with higher myopic maculopathy stage in 2001 (odds ratio (OR): 7.83; 95%CI: 2.65, 23.2; P < 0.001) and higher frequency of parapapillary delta zone enlargement (OR: 32.0; 95%CI: 3.07, 334; P < 0.001). Prevalence of LC/PA enlargement was lower than the prevalence of changes in other myopic maculopathy features (disc-fovea distance elongation: 71%; choroidal vessel shift: 55%; reduction in ophthalmoscopical disc size: 34%; ophthalmoscopic disc size enlargement: 25%). All eyes with LC/PA enlargement showed a pre-existing and enlarging gamma zone. CONCLUSIONS: Development and enlargement of LC/PAs were associated with enlargement of parapapillary delta zone and often occurred in association with the direction of gamma zone enlargement.

Retinal nerve fibre layer thickness in association with gamma zone width and disc-fovea distance.

PURPOSE: Previous studies have shown that the retinal nerve fibre layer (RNFL) thickness as surrogate of the optic nerve decreases with longer axial length. We explored which explanatory parameters might explain that association. METHODS: Participants of the population-based Beijing Eye Study 2011 without any retinal or optic nerve disease were selected based on a refractive error-based stratified randomization. RESULTS: The study included of 632 participants (age: 59.1 ± 7.3 years; axial length: 23.5 ± 1.2 mm; range: 20.88-28.68 mm). Thicker RNFL (mean: 101.0 ± 10.0 µm) was associated (multivariable analysis) with smaller parapapillary gamma zone (defined as Bruch's membrane-free parapapillary region) (standardized regression coefficient beta: -0.13; non-stadardized regression coefficient B: -0.008; 95% confidence interval (CI): -0.014, -0.003; p = 0.005) and shorter disc-fovea distance (beta: -0.15; B: -3.91; 95% CI: -6.60; -1.22; p = 0.004), after adjusting for age (beta: -0.22; B: -030; 95% CI: -0.41, -0.19; p < 0.001), gender (beta: 0.12; B: 2.37; 95% CI 0.77, 3.97; p = 0.004) and larger optic disc area (beta: 0.12; B: 0.12; 95% CI: 2.14; 95% CI: 0.54, 3.73; p = 0.009). RNFL thickness decreased by 8 µm (95% CI: 3, 14) for each mm increase in gamma zone width, and by 3.91 µm (95% CI: 1.22, 6.60) for each mm elongation of the disc-fovea distance. If disc-fovea distance and gamma zone width were replaced by axial length, the latter was correlated with RNFL thickness (beta: -0.37; B: -3.12; 95% CI: -3.88, -2.35; p < 0.001). Longer disc-fovea distance was directly associated with larger gamma zone (beta: 0.50; B: p < 0.001). CONCLUSIONS: The RNFL thickness decrease with longer axial length is associated with a longer optic disc-fovea distance and larger parapapillary gamma zone. Longer disc-fovea distance and larger gamma zone lead to an elongation and stretching of the retinal nerve fibres, potentially causing a thinning or loss of the nerve fibres. It may explain the occurrence of visual field defects in some non-glaucomatous highly myopic eyes without macular correlates of the perimetric defects.