Beta Zone Parapapillary Atrophy in Elderly Chinese

doi:10.21203/rs.3.rs-1434904/v1

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Beta Zone Parapapillary Atrophy in Elderly Chinese

https://doi.org/10.21203/rs.3.rs-1434904/v1

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Purpose: Assess the beta zone parapapillary atrophy in elderly Chinese.

Patients and methods: The Beijing Eye Study 2011 is a population-based cross-sectional study，which includes 3468 patients with the average age of 64.5±9.8 years. The beta zone of parapapillary atrophy was captured and analyzed morphometrically by using colour optic disc photographs.

Results: The beta zone was found in 1358 (39.9%) eyes, measuring 0.37± 0.84mm² in size, 203.5±81.8° in circumferential angle, 0.36±0.27mm in the maximum radial extent, the most often and longest in the temporal peripapillary region, followed by the temporal inferior region and the temporal superior region, the nasal region at least. Beta zone has statistically significant association with male gender (P=0.001), myopic refractive error (P=0.003), thinner retinal nerve fiber layer thickness (P＜0.001), thinner subfoveal choroidal thickness (P＜0.001), bigger size of optic disc size (P＜0.001). The size of beta zone has statistically significant association with longer axial length (P=0.004)，increasing age (P＜0.001), urban (P=0.025), cardiovascular disease history (P=0.025), without age related macular degeneration (P=0.038), myopic ametropia (P＜0.001), thinner retinal nerve fiber layer thickness (P=0.001), thinner subfoveal choroidal thickness (P＜0.001), bigger size of optic disc size (P=0.001).

Conclusion: The population prevalence of beta zone was 39.9% in elderly Chinese. The area of the beta zone has statistically significant association with age, urban, the thickness of retinal nerve fiber layer, age related macular degeneration, cardiovascular disease history, axial length, myopic refractive error, size of optic disc size, the thickness of subfoveal choroidal.

Beta Zone

The Beijing Eye Study 2011

colour optic disc photographs

morphometrically analyze

Elschnig found that the patients with glaucoma often had chorioretinal atrophy area around optic disc in the early twentieth century, and called the parapapillary atrophy (PPA) “Holo Glaucomatosus”. ¹ With the development of modern imaging technologies and ophthalmology, some scholars divided PPA into two parts: alpha zone and beta zone, the definition of alpha zone is irregular hypopigmentation and hyperpigmentation of the retinal pigment epithelium(RPE), beta zone lies in the area next to the disc and appears as exposed sclera and choroidal macrovascular with complete RPE atrophy.^2,3 Due to the large variation and low specificity, the clinical significance of alpha zone has been limited. The presence, size and enlargement of beta zone has important clinical value in glaucoma and predicting subsequent visual field progression.^4–6 In recent investigation, the beta zone has been found not just in glaucoma patients, but can be seen in the normal population, and is related to age and refractive error.^7.8

Ethics Statement

The data are from The Beijing Eye Study 2011. The Beijing Eye Study was a population-based prospective cohort study in Northern China. The protocol was approved by the Medical Ethics Committee of the Beijing Tongren Hospital, all investigations conformed to the tenets of the Declaration of Helsinki, and all participants gave informed written consent. The study was applied in 5 communities in the urban area and 3 communities in rural area of Beijing in 2001 and followed in 2006 and 2011, respectively. People over the age of 50 were included into the Beijing Eye Study 2011. Some literatures reported this study in detail.^9–11

Study design and patients

The current study was part of the cross-sectional Beijing Eye Study 2011. An interview with standardized questions and systemic examinations is implemented in all participants. The questions were about demographic variables, socioeconomic background, and known major systemic diseases; the systemic examinations included a fasting blood test of blood lipids, glucose and glycosylated hemoglobin HbA1c, blood pressure, body height and weight and the circumference of the waist and hip. All participants underwent comprehensive ophthalmic examination by the trained ophthalmologists, such as visual acuity assessment, intraocular pressure (CT-60 computed tonometer, Topcon Ltd., Tokyo, Japan), slit-lamp examination of the external eye and anterior segment, and photography of the lens (Neitz CT-R camera, Neitz Instruments Co., Tokyo, Japan) and macula and optic disc (fundus camera Type CR6-45NM, Canon Inc. U.S.A.). The visual field examinations were performed by frequency- doubling perimetry using the screening program C-20-1 (Zeiss- Humphrey, Dublin, California, USA). The spectral domain optical coherence tomography (SD-OCT; Spectralis®, Wavelength: 870nm; Heidelberg Engineering Co., Heidelberg, Germany) with enhanced depth imaging (EDI) was first performed on the participants in this time.

In our study, assessment and measuring of the beta zone was based on the color photography of the fundus with centered on optic disc. Available optic papilla photographs of the right eyes were included in the study. After qualitative assessment, we recognized the beta zone and then measured it on the computer screen. The definition of beta zone is the area absence or marked atrophy of the retinal pigment epithelium (RPE), showed exposed sclera and visible choroidal macrovascular, located around to the optic papilla border.¹² After a training period, all of the selected photos were checked to distinguish the beta zone by one examiner (LXZ). If there had any queries, a panel (YXW and JBJ) would reassess the photographs. For those still with difficulties in regcognition, the images of OCT was referenced. The microstructure of optic nerve and peripapillary connective tissues can be comprehensively displayed by the enhanced depth imaging (EDI) spectral-domain OCT (SD-OCT). Using the Image J software (version 1.49v; National Institutes of Health, USA; http://imagej. nih.gov/ij), the topographic parameters of the beta zone were measured respectively, including area, the circumferential angle, maximum radial extent (location), the distance between point of maximum radial extent and optic disc border (Fig. 1). Four sectors constitute the area of optic disc in clinical setting: the inferior temporal and superior temporal sectors were right-angled and their middle lines were tilted 13° temporal to the vertical optic disc axis. Sector temporal and sector nasal covered the remaining area (64° and 116°) (Fig. 2).

Statistical analysis

We used SPSS (SPSS for Windows, version 22.0, IBM-SPSS Inc. Chicago, IL, USA), a commercially available statistical software package, for statistical analysis. Only the right eye was statistically analyzed. First of all, we calculated the frequency of the beta zone, determined position of the beta zone through which sector the maximum radial extent was located, then the data of area and the circumferential angle were given as mean ± standard deviation. In the next step, a univariate logistic regression analysis was performed, with the beta zone as dependent parameter and ocular and general parameters as independent parameters. A multivariate logistic regression analysis was performed in the last step, with the beta zone as dependent parameter and all those parameters as independent parameters which were significantly associated with the beta zone in univariate analysis. We used the correlation coefficient r or r² for reporting the statistical strength of correlations. All P-values were bilateral and statistical significance existed only when the P-values were lower than 0.05.

Our study is the third time follow-up of the Beijing Eye Study, out of the 4403 subjects included at baseline, 3468 (1963 (56.6%) women) said they would take part in the examination, therefore, the response rate is 78.8%. The average age of all subjects was 64.6 ± 9.8 years (median age: 64 years; range from 50 to 93 years). Out of the 3468 participants, the optic disc photographs of right eyes reaching the standard of reading were available for 3406 (98.2%) eyes (1921 (56.4%) women). The mean age was 64.5 ± 9.8 years (median: 63 years; range: 50 to 93 years), the mean refractive error (spherical equivalent) was − 0.20 ± 2.03 diopters (median: 0.25 diopters; range: -22.0 to + 7.0 diopters). For 62 (1.8%) eyes, the optic disc photographs could not be measured either because photographs were not taken or because available photographs could not be assessed owing to keratoleukoma, lens opacities or vitreous clouding, et al.

The beta zone was found in 1358 (39.9%±1.6%) eyes. Mean age of all subjects with the beta zone was 67.3 ± 9.8 years (median: 68, range, 50–93years), mean refractive error was − 0.66 ± 2.59 diopters (median: 0.0 diopter, range, -20.0 to + 6.0 diopter). Area of the beta zone measured 0.37 ± 0.84mm², (median: 0.0, range, 0.0 to 14.98 mm²). The circumferential angle (width) of the beta zone was 203.5 ± 81.8° (median: 174.35°, range, 50.1 to 360.0°). The maximum radial extent was 0.36 ± 0.27mm (median: 0.36mm, range, 0.12 to 2.47mm), was significantly longest in the temporal peripapillary region (883/1358 or 65.0%), followed by the temporal inferior region (297/1358 or 21.9%), the temporal superior region (119/1358 or 8.8%), and finally the nasal region (59/1358 or 4.3%).

In univariate analysis, the beta zone significantly related or unrelated to the systemic parameters and ocular parameters were shown in the Table 1; the size of the beta zone significantly related or unrelated to the systemic parameters and ocular parameters were shown in the Table 2.

Table 1

Factors Associated with the 𝛃-zone in the Beijing Eye Study (Univariate Analysis).
Parameter	P-Value	Odds Ratio	95% Confidence Interval
Age (Years)	༜0.001	1.051	1.043	1.059
Gender (men / Women)	༜0.001	0.602	0.524	0.692
Rural / Urban Region of Habitation	༜0.001	1.185	1.142	1.231
Body Mass Index (kg/m²)	༜0.001	0.954	0.937	0.972
Level of Education (1–5)	༜0.001	1.139	1.063	1.220
Self-Reported Income	༜0.001	1.119	1.084	1.156
Cognitive Score	0.186	0.987	0.967	1.007
Alcohol Consumption Frequency	0.765	0.994	0.955	1.034
Smoking Never / Ever	0.549	1.048	0.899	1.222
Smoking Package Years	0.941	1.001	0.964	1.040
Hours Spent With Vigorously Intensive Physical Activities Per Week	0.824	0.991	0.913	1.075
Hours Spent With Moderate Physical Activities Per week	༜0.001	0.915	0.890	0.941
Number of Hours Spent With Walking Per Week	0.109	1.026	0.994	1.058
Number of Hours Spent With Sitting Per Week	0.202	1.018	0.990	1.047
Hypertension history	0.436	1.060	0.916	1.225
Cardiovascular disease history	0.009	1.281	1.063	1.542
Diabetes history	0.705	0.959	0.770	1.194
Systolic Blood Pressure (mmHg)	0.798	1.000	0.996	1.003
Diastolic Blood Pressure (mmHg)	༜0.001	0.988	0.983	0.994
Mean Blood Pressure (mmHg)	0.180	0.987	0.967	1.006
Glucose (mmol/L)	0.020	0.932	0.878	0.989
Cholesterol (mmol/L)	0.080	0.926	0.849	1.009
Creatinine	༜0.001	1.011	1.005	1.017
High-Density Lipoproteins (mmol/L)	0.219	1.142	0.924	1.411
Low-Density Lipoproteins (mmol/L)	0.022	0.894	0.812	0.984
Triglycerides (mmol/L)	0.044	0.926	0.859	0.998
Use of Aspirin Yes / No	0.255	1.093	0.938	1.275
Depression Score	0.674	0.998	0.987	1.009
Ophthalmological Parameters
Visual Acuity	༜0.001	0.341	0.273	0.427
BCVA(LogMAR)	༜0.001	2.291	1.543	3.400
Axial Length (mm)	༜0.001	1.650	1.532	1.778
refractive errors	༜0.001	0.825	0.793	0.858
Anterior Corneal Curvature Radius (mm)	༜0.001	2.387	1.792	3.180
Central Corneal Thickness (µm)	0.007	1.003	1.001	1.005
Anterior Chamber Depth (mm)	༜0.001	1.466	1.265	1.698
Lens Thickness (mm)	༜0.001	1.579	1.264	1.973
Intraocular Pressure mmHg)	0.908	0.998	0.973	1.024
Retinal Nerve Fiber Layer Thickness (µm)	༜0.001	0.964	0.958	0.970
Subfoveal Choroidal Thickness (µm)	༜0.001	0.993	0.992	0.993
Fundus Tessellation	0.666	1.151	0.608	2.182
Macular Retinal Thickness (µm)	0.277	0.998	0.996	1.001
Optic Disc Size (mm²)	༜0.001	1.756	1.491	2.068
Nuclear Cataract	༜0.001	1.201	1.121	1.288
Cortical Cataract	0.240	1.369	0.811	2.310
Subcapsular Posterior Cataract	0.104	0.113	0.008	1.563
Glaucoma history	0.012	1.727	1.126	2.648
Glaucoma prevalence	༜0.001	2.538	1.882	3.424
Age-Related Macular Degeneration, Prevalence, Total	0.006	0.819	0.710	0.944
Age-Related Macular Degeneration, Early Stage	0.428	0.902	0.699	1.164
Age-Related Macular Degeneration, Intermediate Stage	0.010	0.783	0.650	0.943
Age-Related Macular Degeneration, Late Stage	0.145	1.740	0.825	3.669
Diabetic Retinopathy, Prevalence	0.787	1.093	0.572	2.091
Retinal Vein Occlusion, Total	0.052	1.500	0.997	2.256
Polypoidal Choroidal Vasculopathy	0.120	2.158	0.819	5.683

Table 2

Factors Associated with area of the 𝛃-zone in the Beijing Eye Study (Univariate Analysis).
Parameter	P-Value	Standardized Coefficient Beta	Regression Coefficient B	95% Confidence Interval
Age (Years)	༜0.001	0.236	0.020	0.017, 0.023
Gender (men / Women)	0.006	-0.047	-0.079	-0.136, -0.022
Rural / Urban Region of Habitation	༜0.001	0.149	0.067	0.052, 0.082
Body Mass Index (kg/m2)	༜0.001	-0.097	-0.021	-0.028, -0.013
Level of Education (1–5)	0.037	0.037	0.029	0.002, 0.056
Self-Reported Income	༜0.001	0.113	0.042	0.029, 0.055
Cognitive Score	༜0.001	-0.064	-0.014	-0.021, -0.006
Alcohol Consumption Frequency	0.010	-0.045	-0.021	-0.037, -0.005
Smoking Never / Ever	0.049	-0.035	-0.063	-0.125, 0
Smoking Package Years	0.069	-0.032	-0.014	-0.029, 0.001
Hours Spent With Vigorously Intensive Physical Activities Per Week	0.417	0.015	0.014	-0.019, 0.046
Hours Spent With Moderate Physical Activities Per week	༜0.001	-0.108	-0.030	-0.040, -0.021
Hours Spent With Walking Per Week	0.020	0.042	0.015	0.002, 0.027
Hours Spent With Sitting Per Week	0.873	0.003	0.001	-0.010, 0.012
Hypertension history	0.013	0.045	0.076	0.016, 0.135
Cardiovascular disease history	༜0.001	0.088	0.188	0.112, 0.264
Diabetes history	0.434	0.015	0.035	-0.053, 0.123
Systolic Blood Pressure (mmHg)	0.347	0.016	0.001	-0.001, 0.002
Diastolic Blood Pressure (mmHg)	༜0.001	-0.077	-0.005	-0.007, -0.003
Mean Blood Pressure (mmHg)	0.699	-0.023	-0.001	-0.005, 0.003
Glucose (mmol/L)	0.050	-0.040	-0.019	-0.037, 0
Cholesterol (mmol/L)	0.380	-0.018	-0.013	-0.042, 0.016
Creatinine	0.005	0.071	0.002	0.001, 0.003
High-Density Lipoproteins (mmol/L)	0.341	0.019	0.035	-0.037, 0.107
Low-Density Lipoproteins (mmol/L)	0.229	-0.025	-0.020	-0.052, 0.013
Triglycerides (mmol/L)	0.104	-0.033	-0.020	-0.044, 0.004
Use of Aspirin Yes / No	0.011	0.045	0.080	0.018, 0.142
Depression Score	0.256	0.020	0.003	-0.002, 0.007
Ophthalmological Parameters
Visual Acuity	༜0.001	-0.247	-0.647	-0.732, -0.562
BCVA(LogMAR)	༜0.001	0.168	0.748	0.600, 0.896
Axial Length (mm)	༜0.001	0.385	0.261	0.239, 0.283
refractive errors	༜0.001	-0.387	-0.155	-0.168, -0.142
Anterior Corneal Curvature Radius (mm)	༜0.001	0.087	0.263	0.157, 0.369
Central Corneal Thickness (µm)	0.012	0.045	0.001	0, 0.002
Anterior Chamber Depth (mm)	༜0.001	0.081	0.124	0.070, 0.178
Lens Thickness (mm)	༜0.001	0.090	0.198	0.120, 0.277
Intraocular Pressure mmHg)	0.371	-0.016	-0.005	-0.015, 0.006
Retinal Nerve Fiber Layer Thickness (µm)	༜0.001	-0.256	-0.017	-0.019, -0.014
Subfoveal Choroidal Thickness (µm)	༜0.001	-0.367	-0.003	-0.003, -0.002
Fundus Tessellation	0.149	-0.025	-0.190	-0.447, 0.068
Macular Retinal Thickness (µm)	0.878	0.003	0.0000747	-0.001, 0.001
Optic Disc Size (mm2)	༜0.001	0.097	0.152	0.091, 0.213
Nuclear Cataract	༜0.001	0.117	0.075	0.051, 0.099
Cortical Cataract	༜0.001	0.106	0.515	0.333, 0.698
Subcapsular Posterior Cataract	0.851	0.004	0.065	-0.616, 0.746
Glaucoma history	༜0.001	0.078	0.372	0.198, 0.547
Glaucoma prevalence	༜0.001	0.148	0.535	0.415, 0.655
Age-Related Macular Degeneration, Prevalence, Total	0.004	-0.050	-0.085	-0.142, 0.028
Age-Related Macular Degeneration, Early Stage	0.950	-0.001	-0.003	-0.107, -0.100
Age-Related Macular Degeneration, Intermediate Stage	0.002	-0.054	-0.118	-0.193, 0.044
Age-Related Macular Degeneration, Late Stage	0.218	0.021	0.195	-0.116, 0.506
Diabetic Retinopathy, Prevalence	0.017	0.044	0.304	0.053, 0.555
Retinal Vein Occlusion, Total	0.215	0.021	0.104	-0.060, 0.268
Polypoidal Choroidal Vasculopathy	0.022	0.039	0.455	0.065, 0.846

In the multivariate analysis, all factors with statistical significance in the univariate associations (Table 1 and Table 2) were considered as the starting points of our model construction. From this full model, we used a step-wise manner to remove non-significant terms, beginning with the parameters that have the highest P-values. Finally, the beta zone has statistically significant association with male gender (P = 0.001), myopic ametropia (P = 0.003), thinner retinal nerve fiber layer thickness (P༜0.001), thinner subfoveal choroidal thickness (P༜0.001), bigger size of optic disc size (P༜0.001) (Table 3). The size of beta zone has statistically significant association with increasing age (P༜0.001), urban (P = 0.025), cardiovascular disease history (P = 0.025), longer axial length (P = 0.004), myopic refractive error (P༜0.001), thinner retinal nerve fiber layer thickness (P = 0.001), thinner subfoveal choroidal thickness (P༜0.001), bigger size of optic disc size (P = 0.001), no age related macular degeneration (P = 0.038) (Table 4).

Table 3

Factors Associated with the beta-zone in the Beijing Eye Study (Multivariate Analysis)
Parameter	P-Value	Odds Ratio	95% Confidence Interval
Gender (men / Women)	0.001	0.548	0.384	0.782
Refractive errors	0.003	0.856	0.774	0.948
Retinal Nerve Fiber Layer Thickness (µm)	༜0.001	0.969	0.952	0.986
Subfoveal Choroidal Thickness (µm)	༜0.001	0.992	0.990	0.994
Optic Disc Size (mm²)	༜0.001	2.628	1.787	3.865

Table 4

Factors Associated with area of the beta-zone in the Beijing Eye Study (Multivariate Analysis)
Parameter	P-Value	Standardized Coefficient Beta	Regression Coefficient B	95% Confidence Interval
Age (Years)	༜0.001	0.242	0.018	0.012, 0.024
Rural / Urban Region of Habitation	0.025	-0.089	-0.043	-0.080, -0.005
Cardiovascular disease history	0.025	-0.085	-0.141	-0.265, -0.018
Axial Length (mm)	0.004	0.141	0.084	0.026, 0.142
refractive errors	༜0.001	-0.245	-0.087	-0.121, -0.053
Retinal Nerve Fiber Layer Thickness (µm)	0.001	-0.125	-0.007	-0.012, -0.003
Subfoveal Choroidal Thickness (µm)	༜0.001	-0.154	-0.001	-0.002, 0
Optic Disc Size (mm²)	0.001	0.125	0.168	0.072, 0.263
Age-Related Macular Degeneration, Prevalence, Total	0.038	-0.074	-0.099	-0.192, 0.006

Peripapillary atrophy has always been considered as a possible risk factors related to glaucoma progression since found in the 20th century. Histological and radiographic evidences demonstrate that significant disappearance of photoreceptor cells and retinal pigment epithelial cells as well as occlusion of choroid capillary is the the main causes of formation of the beta zone.¹³ Studies have confirmed that the peripapillary atrophy zone has correspondence in space with the most obvious visual field damage. Jonas pointed out that in primary open-angle glaucoma, α zone is related to the relative scotoma of vision while the β zone is related to the absolute scotoma of vision.³ The area of the beta zone will change with the development of optic nerve damage in glaucoma, such as loss of disc edge, decrease of the diameter of retinal vessels, retinal nerve fiber layer defect, fundus hemorrhage and degree of visual field defect.^5.14 The probability of future optic nerve damage and visual field defect of the suffering eyes with the beta zone at the very beginning was almost 3 times that of the eyes without the beta zone, and glaucoma of the patients with the beta zone progressed faster.⁴ Therefore, existence and development of the beta zone is an important parameter to identify glaucoma or the development of nervous lesion in glaucoma, and study of the beta zone may contribute to detection and diagnosis of early glaucoma and prediction of glaucoma development^2.3. The reproducibility of the discrimination of alpha zone was poor, and the specificity and sensitivity of using alpha zone to identify the normal and glaucoma patients was low, so only the beta zone was selected as the research target in this study. At present, direct ophthalmoscope, indirect ophthalmoscope, slit lamp with pre-set lens and fundus stereoscopic photography are commonly used to observe the beta zone. These detection methods are convenient and fast, but with poor reliability and accuracy. In recent years, along with the enhancement of computer image processing technology, researchers can take advantage of the computer image processing softwares, such as photoshop and Image J to outline the boundary of optic disc and peripapillary atrophy zone as well as the angle and line o that need to be measured. Then, quantitative measurement of these parameters can be more accurate to study the morphology of peripapillary atrophy zone and the results are more credible.^15.16 The population prevalence of the beta zone was 15–20% according to a report.¹⁷ It was easy to appear in the temporal region with the largest atrophy area, followed by the temporal inferior region and temporal superior region, and at least the nasal region with the minimal atrophy area. The population prevalence of the beta zone was 20.95% according to the Beijing Eye Study 2001,¹² and the position and size of peripapillary atrophy zone, related to age, refractive error, optic disc area and best corrected visual acuity, was basically consistent with the research results from other population-based studies. Five years later, Beijing Eye Study evaluated beta zone again in 2006 and found that the progress rate of beta zone was 8.2 ± 0.5%, and age, hypertension, high myopia, corneal thickness and glaucoma were the related factors. ⁸

In this study, we found that the population prevalence of beta zone was 39.9%, which was a significant increase compared to the past prevalence study and the Beijing Eye Study in 2001. This may be due to the following reasons. First, the age of Beijing Eye Study population was older as a whole (over 50 in 2011), and this number increased significantly because the occurrence and development of the beta zone have obvious relationship with age. Second, the previous studies have determined beta zone only by the subjective judgment of an ophthalmologist, so it was hard to ascertain the beta zone when it was small, atypical, or the refractive media was not clear. In this study, SD-OCT with enhanced depth imaging was used to evaluate the fundus for the first time. Clinical and scientific research workers can observe the fault structures of peripapillary retina and choroid better, so they can have a more clear judgment and positioning of beta zone to make the results more reliable and credible. In this study, the beta zone of all the images was further evaluated by comparing with SD-OCT images when the digital photos cannot be determined by human or questioned. It can be speculated that former researchers were likely to ignore or mistaken part of the beta zone for alpha zone, resulting in the previous lower population prevalence of the beta zone.

The distribution of the beta zone both in the present and previous research was consistent, namely easy to appear in the temporal region with the largest atrophy area, followed by the temporal inferior region and temporal superior region, and at least the nasal region with the minimal atrophy area. Jonas pointed out that the beta zone corresponds to the absolute scotoma of vision in primary open-angle glaucoma. ³ Subclinical process of very early glaucoma is about 14 to 20 years, and it may be difficult to find an early and slight optic cup enlargement and mild and diffuse nerve fiber layer defect. But the progressive changes of peripapillary atrophy zone may occur before the clinical visible change of the optic disc or vision damage, and its sensitivity was 49% and specificity was 90% according to a study.¹⁸ Sullivan-Mee found that in POAG patients with the β zone, peripapillary choroid volume was reduced, and the beta zone may be a biological sign of POAG and it seems to be associated with vascular injury of glaucoma. ¹⁴ Tezel considered that high intraocular pressure and peripapillary atrophy zone increase the susceptibility of glaucomatic optic nerve damage for the following reasons:¹⁹ (1) Inadequate blood flow perfusion of this area can lead to an increased sensitivity of the optic nerve and peripapillary choroidal and retinal tissues to local damages. (2) Because the outer blood-retinal barrier was damaged in the peripapillary atrophy zone, the optic nerve fibers may be damaged due to their exposure to blood vessels, immunity, or other substances in the circulatory system when they pass through that area or they are in the extension section of peripapillary areas. This hypothesis explains the relationship between the peripapillary atrophy zone and glaucoma. The morphology of beta zone in different types of glaucoma is also different. If POAG patients had high myopia or is in the early stage, the area of beta zone will be larger, while the size of beta zone is relatively small in the normal-tension glaucoma and adolescent patients with POAG. It is relatively rare in patients with secondary glaucoma when compared with the patients with POAG.²⁰ Therefore, it can be considered that the existence and development of the beta zone is an important parameter to diagnose and predict the progress of glaucoma or glaucomatic optic nerve damage. With the development of OCT technology, some scholars further use EDI-OCT to call the area which is closer to the optic papilla and lack of Bruch’s membrane as gamma zone, and this area was considered to be related with absence of glaucoma, age, and refractive status. ²¹ The combination of gamma zone can enhance the performance of the diagnosis and prediction of glaucoma with the beta zone. However, gamma zone is very difficult to distinguish without OCT.

In this study, the size of the beta zone has statistically significant association with increasing age, urban, cardiovascular disease history, axial length, myopic refractive error, retinal nerve fiber layer thickness, subfoveal choroidal thickness, optic disc size, age related macular degeneration. In Beijing Eye Study in 2001, the average age of the study population was 55. We found that age and the size of the beta zone were significantly related, and the area enlarged about 0.21 mm² every 10 years. ¹² In 2006, the population follow-up found that the progress rate of the size of the beta zone was 8.2 ± 0.5%. In 2011, the population was at an average age of 64 years, and the population prevalence of the beta zone was quite different from the previous study, so the data was not compared with that of 2001 and 2006. However, the population prevalence of the beta zone in this study was much higher than that of other population-based studies,^{17, 22} and age was probably one of the important influencing factors. Changes in histological structure may lead to decreased blood supply of the atrophy zone or blood-optic disc barrier dysfunction. Cardiovascular disease may cause eye ischemia and hypoxia which can lead to degenerate of RPE, at the same time RPE has the function of adjusting local blood circulation. So the larger atrophy area with less blood supply may cause enlargement of the atrophy zone easily. ²³ Prior studies have in-depth research on beta zone in high myopia. They found that peripapillary scleral ring broadened and the beta zone enlarged obviously in patients with high myopia compared to those without high myopia. The optic disc area increased by 1.6%, the disc edge area increased by 1.4% and the beta zone area increased by 1.3% when myopia increased a diopter¹⁷. In our study, the beta zone area is related to axial length, myopic ametropia and optic pallia size, which is consistent with previous studies. Imamura believed that the continuous growth of axial length causes the mechanical stretching and thinning of choroid and RPE, which is one of the main causes of the atrophy of choroid and retinal pigment epithelium. ²⁴ Therefore, the association of the existence of beta zone with myopia should be considered when the beta zone is used as the diagnosis indicator of glaucoma. However, the beta zone in presbyopia is relatively rare, so the beta zone found in presbyopia may predict an increased possibility of glaucoma. The histological character of the beta zone and age-related macular degeneration (AMD) is similar, both presenting retinal pigment epithelium layer degeneration and choroid capillary occlusion to cause the loss of retinal pigment epithelial cells. The results of Beijing Eye Study in 2001 demonstrated that the beta zone correlated with AMD in univariate analysis, but their correlation was not obvious in multivariate analysis. However, this study found that the beta zone was significantly related with no macular degeneration, and whether the existence of the beta zone would increase the risk of AMD is a meaningful research direction in the future. By the adjuvant of SD-OCT, SFCT was measured in this study for the first time, and we found that the beta zone and the SFCT could be relevant. The variation of the choroid thickness is very important for the accurate assessment of many diseases. The thickness of the choroid depends on choroidal blood perfusion, and the important factor of the occurrence of the beta zone is peripapillary poor choroidal perfusion. However, the change sequence of the beta zone and SFCT is not certain now, and research on their relationship has not been carried out yet. The causal relationship between them also needs long time follow-up and shorter follow-up interval to prove.

At present, most researches on the beta zone are around glaucoma. Certainly, the prevalence and the size of the beta zone of the patients with glaucomatic optic nerve injury are significantly greater than that of the normal eyes, and larger size of the beta-zone at baseline is the risk factor of the bata-zone expansion. ⁴ Changes in histological structure may lead to decreased blood supply of the atrophy zone or blood-optic disc barrier dysfunction. Larger atrophy area with less blood supply may cause enlargement of the atrophy zone easily. In the initial diagnosis of glaucoma, the disease progression was faster if there are beta zone in patients’ fundus, therefore, with the beta zone and its development is the important parameter of glaucoma. In our study, the presence and the area of the beta zone has statistically significant association with the glaucoma in univariate analysis, but the significant association does not exist in mulitiate analysis. The reason might be that the subjects were different, and most of previous studies were hospital-based studies. In the normal people, the glaucoma might not be the main cause of the beta zone changes.

There are still some insufficiencies of this study. The Beijing Eye Study 2011 is the third time follow up in the population, non-participation is the major concern. The response rate was 78.8%, which is reasonable, however, a selection bias may be caused by the differences between participants and nonparticipants. Participants cannot be taken an available fundus photographs for opacity of refracting media, which is also a limiting factor of this study. The measurement figures for peripapillary atrophy may be artificially underestimated because of it. Moreover, findings from our study cannot allow to directly drawing conclusions on cause-relationships. Strengths of our study are that SD-OCT with enhanced depth imaging was used for the first time in a population-based prevalence study, and maked the results more reliable and credible.

In conclusion, the population prevalence of beta zone was 39.9% in elderly Chinese. The beta zone most often appeared in the temporal peripapillary region, followed by the temporal inferior region, the temporal superior region, and finally the nasal region, and the size of beta zone was associated with age, urban, cardiovascular disease history, axial length, myopic refractive error, retinal nerve fiber layer thickness, subfoveal choroidal thickness, optic disc size, age related macular degeneration.

Ethics approval and consent to participate

The protocol was approved by the Medical Ethics Committee of the Beijing Tongren Hospital, all investigations conformed to the tenets of the Declaration of Helsinki, and all participants gave informed written consent.

Consent for publication

Not applicable

Availability of data and materials

The datasets generated and analysed during the current study are not publicly available due to some of the data are pending patent application, but are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding

This study was supported in part by grants from the Key Project of Science and Technology of Shaanxi Province (No.2022SF-339), National Natural Science Foundation of China (Nr. 82000916). The priming scientific research foundation for the junior researcher in Beijing Tongren Hospital, Capital Medical University(2016-YJJ-ZLL-009); Beijing Hospitals Authority Youth Programme, code:QML20180204;The priming scientific research foundation for the junior researcher in Beijing Tongren Hospital,Capital Medical University(No.2018-YJJ-ZZL-045). Dongcheng District Outstanding Talent Nurturing Program(2020-dchrcpyzz-42).

Author Contributions

Ling Xiao Zhou, Lei Shao, Wen Da Zhou and Rong Li wrote the main manuscript text and prepared figures and analyzed experimental result; Wen Bin Wei and Liang Xu designed experiments. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

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No competing interests reported.

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Beta Zone Parapapillary Atrophy in Elderly Chinese

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