Enlarged Blind Spot Linked to Gamma Zone and Peripapillary Hyperreflective Ovoid Mass-Like Structures in Non-Pathological Highly Myopic Eyes

Abstract

Purpose

To investigate the prevalence and risk factors of enlarged blind spots in non-pathological highly myopic eyes.

Methods

Visual field conditions of 313 eyes in 172 individuals with high myopia were evaluated. Clinical characteristics of 116 eyes with enlarged blind spots and 116 eyes with normal visual fields were compared. Generalized-estimating equation (GEE) regression model were used to assess the factors associated with enlarged blind spots.

Results

The frequency of enlarged blind spots in non-pathological highly myopic eyes was 37.06% in this sample. Eyes with enlarged blind spots had larger gamma zone (P = 0.038), larger PHOMS area (P < 0.001), increased peripapillary retinal nerve fiber layer thickness (P = 0.006), and decreased macular ganglion cell-inner plexiform layer thickness (P = 0.016) compared with eyes with normal visual fields. In multivariate regression analysis, an expanded gamma zone (OR = 2.004; P = 0.022) and a larger PHOMS area (OR = 4.414; P = 0.009) were associated with an enlarged blind spot.

Conclusions

An expanded gamma zone and a larger PHOMS area are associated with an enlarged blind spot, indicating that these two parameters may suggest a possibility of functional damage in early nonpathological, highly myopic eyes. This pattern of impairment might provide clues for the differential diagnosis between high myopia and glaucoma.

The global prevalence of high myopia is increasing and presents considerable clinical and public health challenges.^1,2 Individuals with high myopia exhibit an elevated risk of visual impairment.^3,4 Central vision impairment is commonly observed in pathological eyes with myopic maculopathy. Visual field defects may be present in non-pathological myopic eyes with myopic optic neuropathy. Although high myopia is a known risk factor for developing glaucoma,^5,6 distinguishing between myopic optic neuropathy and glaucomatous optic neuropathy remains challenging.

High myopia shows a distinct pattern of visual field (VF) defects, deviating from the classical defects observed in glaucoma.^7,8 Enlarged blind spot is the most frequently observed type of myopia-related defects in current classification frameworks.⁷ The optic nerve head (ONH) undergoes substantial alterations in highly myopic eyes, including optic disc shift and enlargement, and development of the alpha, beta, and gamma zones.^3,9,10 Abnormalities in optic disc morphology¹¹ and alterations in peripapillary tissue layers and microvasculature have been documented in high myopia.^12,13 Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are commonly seen in myopic eyes.^11,14 Moreover, peripapillary atrophy and optic disc tilt are highly prevalent in eyes with enlarged blind spots⁷; however, factors associated with enlarged blind spots remain unclear.

Technological advancements in optical coherence tomography (OCT) have enabled precise observations of optic nerve head structures.¹⁵ In this study, we quantified the parameters of peripapillary structures. The study aimed to identify factors associated with enlarged blind spots in highly myopic eyes. The findings provide novel insights into the mechanisms of visual function impairment in highly myopic eyes and aid in the differential diagnosis of glaucoma.

Methods

Study Participants

Participants were enrolled from a longitudinal, observational cohort study focused on high myopia, the Wuhan High Myopia Study (ClinicalTrials.gov; identifier: NCT06162234). The study involved three institutions: Renmin Hospital of Wuhan University, Zhongnan Hospital of Wuhan University and Wuhan University. All patients provided informed consent. The study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Renmin Hospital of Wuhan University (WDRY2023-K074). Inclusion criteria included individuals aged 18-65 years, with best-corrected visual acuity of ≥6/12, and a diagnosis of high myopia based on a spherical equivalent of ≤−6D or an axial length AL ≥26.5 mm. Exclusion criteria included a history of other vitreoretinal diseases or intraocular surgery, glaucoma, presence of opaque media, myopic maculopathy, or severe systemic diseases such as hypertension, diabetes, and heart disease.

Ophthalmic Evaluations, OCT, and OCTA

All participants underwent comprehensive ophthalmic evaluations, including slit-lamp examination, best-corrected visual acuity (BCVA) assessment with an autorefractor (AR-1; Nidek, Hiroishi, Japan), intraocular pressure (IOP) measurement using Goldmann applanation tonometry, AL and keratometry assessment using an optical biometer (IOL Master 700; Carl Zeiss Med, Jena, Germany) and central corneal thickness measurement using OCT (VG200S; SVision Imaging, Henan, China), along with fundus photography (VISUCAM 200; Zeiss) and fundoscopy.

The SS-OCT/OCTA system (VG200S; SVision Imaging) used for imaging assessment had a swept-source laser with a central wavelength of approximately 1050 nm and a scan rate of 200,000 A scans/s. Images that maintained a signal-strength index value of ≥6 were selected for subsequent analysis. Eighteen radial line OCT scans, 12 mm each, were centered on the fovea and ONH for structural imaging. Macular and ONH angiography were performed using 6 × 6 mm scans. The average peripapillary retinal nerve fiber layer (p-RNFL) thickness, macular ganglion cell-inner plexiform layer (m-GCIPL) thickness, peripapillary choroidal thickness, superficial vessel density (SVD), deep vessel density (DVD), and area of the optic disc were measured using built-in software. The margins of the peripapillary atrophy areas and PHOMS were accurately traced onto the en-face OCT images using a mouse-driven cursor with delineation guided by B-scans. Alpha zone is characterized by the presence of Bruch's membrane and retinal pigment epithelium (RPE), with the latter being irregularly structured. The beta zone is defined by the absence of the RPE but preservation of Bruch's membrane. The gamma zone is identified by the absence of both RPE and Bruch's membrane.¹⁰ The PHOMS area is defined as hyperreflective, ovoid, mass-like structures around the optic disc recommended by the Optic Disc Drusen (ODD) Studies Consortium.¹⁶ The ONH tilt angle was defined as the angle between the line connecting both Bruch's membrane openings (BMOs) and the line connecting the temporal oblique border tissue and the nasal BMO side (Fig. 1), the angle was measured using ImageJ, measurements were conducted thrice, the mean value of measurements was used.¹⁷ Corrections for macular and ONH centralization, segmentation errors, and image magnification were performed on all images.

Figure 1.

Peripapillary structure and ONH title angle measurements. (A, B) Alpha (irregular RPE, blue area), beta (RPE absent, green area), and gamma (Bruch's membrane absent, orange area) zones and PHOMS (pink area). (C) ONH tile angle. The angle between the BMO plane and the line connecting the temporal oblique border tissue and nasal BMO.

Visual Field Testing and Enlarged Blind Spot

Visual field examinations were conducted with a SITA standard 24-2 test pattern and Goldmann size III stimulus using a Humphrey field analyzer (HFA II; Carl Zeiss) in a dark room. Before the examination, comprehensive details of the perimetry process were provided to each participant. Participants with normal VF were tested only once, whereas those with abnormal visual fields required at least two and no more than three reliable examinations. To ensure the reliability of the results, VF measurements were deemed valid if they exhibited <15% false-positive results and <20% fixation losses. If the criteria were not met, VF examinations were repeated up to five additional times, either consecutively on the same day, after a rest period of at least 30 mins, or during a subsequent appointment within one month. Normal VF was defined as pattern standard deviation within normal limits and no VF defects. An enlarged blind spot was defined by having at least two abnormal test points with P < 0.05 contiguous with the blind spot and at least one test point with P < 0.01 in the pattern deviation plot.⁷ Eyes with enlarged blind spots and other high myopia-related defects (vertical step, partial peripheral rim, nonspecific defect)⁷ were included. Eyes with enlarged blind spots and glaucoma-like defects (paracentral defect, nasal step, partial arcuate defect, arcuate defect)⁷ were excluded.

Statistical Analysis

The comparisons of parameters between eyes with normal visual fields and eyes with enlarged blind spots were performed using a generalized-estimating-equation (GEE) regression model with normal distribution and identity-link function. The association between enlarged blind spots and various factors was explored using a GEE regression model with binomial distribution and logit-link function. In these models, an unstructured correlation matrix was used to account for clustering of eyes within a patient. Factors with P values <0.2 in the univariate regression were included in the multivariable regression. Statistical analyses were performed using IBM SPSS version 26. All tests were two-tailed, and P values <0.05 were considered to indicate statistical significance.

Results

Data were collected from 313 eyes of 172 participants with high myopia who fulfilled the inclusion criteria. Among the 24-2 VFs tested, normal VFs, enlarged blind spots, and abnormalities with other defects accounted for 41.53%, 37.06%, and 21.41%, respectively. The most common enlarged blind spots were temporal (46.55%) and temporal-inferior (25.00%). In total, 116 eyes with enlarged blind spots and 116 random selected eyes with normal VFs were enrolled for further analysis. Excellent agreement was observed between the two graders in the variable measurements. The intraclass correlation coefficients for the measurements were as follows: alpha, beta, gamma zones, PHOMS area, and ONH tilt angle were 0.987 (95% confidence interval [CI], 0.951–0.997), 0.990 (95% CI, 0.961–0.997), 0.996 (95% CI, 0.983–0.999), 0.968 (95% CI, 0.877–0.992), and 0.918 (95% CI, 0.722–0.979), respectively.

The demographics and clinical characteristics of the normal VF and enlarged blind spots in highly myopic eyes are presented in Table 1. No differences were observed in age, sex, IOP, SE, AL, peripapillary choroidal thickness, SVD, DVD, ONH tilt angle, alpha zone area, beta zone area between the two groups (P > 0.05). Eyes with enlarged blind spots had larger gamma zone (P = 0.038), larger PHOMS area (P < 0.001), increased p-RNFL thickness (P = 0.006), and decreased m-GCIPL thickness (P = 0.016) than eyes with normal VFs.

Table 1.

Comparison of the Demographics and Clinical Characteristics Between Highly Myopic Eyes With Normal Visual Fields and Enlarged Blind Spots

Parameter	Eyes With Normal Visual Fields (N = 116)	Eyes With Enlarged Blind Spots (N = 116)	P *
Age (y)	22.59 ± 2.41	22.92 ± 2.92	0.102
Sex			0.336†
Male	35	33
Female	81	83
Intraocular pressure (mm Hg)	18.15 ± 2.89	18.41 ± 3.15	0.17
Spherical equivalent (D)	−7.72 ± 1.43	−7.75 ± 1.68	0.839
Axial length (mm)	26.67 ± 0.85	26.60 ± 0.94	0.82
p-RNFL thickness (µm)	112.90 ± 10.83	113.43 ± 12.16	0.006‡
m-GCIPL thickness (µm)	61.06 ± 4.13	60.49 ± 4.32	0.016‡
Peripapillary choroidal thickness (µm)	157.47 ± 38.82	152.87 ± 38.34	0.152
SVD (%)	75.32 ± 4.41	74.61 ± 4.59	0.814
DVD (%)	19.05 ± 5.08	18.98 ± 5.19	0.628
ONH tilt angle (°)	14.45 ± 4.82	14.62 ± 5.53	0.397
Optic disc area (mm2)	2.29 ± 0.43	2.28 ± 0.61	0.883
Alpha zone area (mm2)	0.40 ± 0.23	0.46 ± 0.26	0.087
Beta zone area (mm2)	0.48 ± 0.43	0.59 ± 0.49	0.056
Gamma zone area (mm2)	0.54 ± 0.34	0.80 ± 0.76	0.038‡
PHOMS area (mm2)	0.21 ± 0.25	0.30 ± 0.31	<0.001‡
Visual field 24-2 MD (dB)	−3.94 ± 1.29	−4.22 ± 1.48	0.650

D, diopter; MD, mean deviation.

^* P values derived from GEE regression model with binomial distribution, logit-link function and unstructured correlation matrix, except for sex.

^† P values derived from GEE regression model with normal distribution, identity-link function and unstructured correlation matrix.

^‡Parameters with statistical significance.

GEE regression model was used to evaluate factors associated with enlarged blind spots in highly myopic eyes (Table 2). In univariate regression analysis, a larger PHOMS area (odds ratio [OR] = 4.597, P = 0.005) and a larger gamma zone (OR = 2.112, P = 0.015) and were associated with an enlarged blind spot. In multivariate regression analysis, a larger PHOMS area (OR = 4.414, P = 0.009), and a larger gamma zone (OR = 2.004, P = 0.022) were associated with an enlarged blind spot. The presence of PHOMS (OR = 1.961, P = 0.026) and a larger gamma zone (OR = 2.067, P = 0.019) were also associated with an enlarged blind spot (Supplemental Tables S1 and S2). Representative cases are shown in Figures 2 and 3.

Table 2.

Univariate and Multivariable Regression Analyses to Identify Factors Associated With Enlarged Blind Spots in Highly Myopic Eyes Using GEE^*

Parameter	OR (95% CI)	P	OR (95% CI)	P
Age (y)	1.040 (0.931–1.161)	0.490	—	—
Sex (Male/Female)	0.918 (0.481–1.753)	0.795	—	—
Intraocular pressure (mm Hg)	1.043 (0.949–1.145)	0.383	—	—
Spherical equivalent (D)	1.002 (0.840–1.196)	0.979	—	—
Axial length (mm)	0.914 (0.665–1.256)	0.578	—	—
p-RNFL thickness (µm)	1.010 (0.985–1.036)	0.436	—	—
m-GCIPL thickness (µm)	0.957 (0.893–1.026)	0.219	—	—
Peripapillary choroidal thickness (µm)	0.996 (0.989–1.004)	0.325	—	—
SVD (%)	0.975 (0.917–1.036)	0.416	—	—
DVD (%)	1.010 (0.960–1.063)	0.697	—	—
ONH tilt angle (°)	1.010 (0.957–1.067)	0.713	—	—
Optic disc area (mm2)	0.966 (0.570–1.639)	0.899	—	—
Alpha zone area (mm2)	2.404 (0.839–6.886)	0.102	2.564 (0.862–7.622)	0.090
Beta zone area (mm2)	1.759 (0.998–3.101)	0.051	1.269 (0.673–2.392)	0.462
Gamma zone area (mm2)	2.112 (1.155–3.860)	0.015†	2.004 (1.108–3.624)	0.022†
PHOMS area (mm2)	4.597 (1.601–13.195)	0.005†	4.414 (1.443–13.498)	0.009†

D, diopter; MD, mean deviation.

Factors with P < 0.2 in univariate analysis were included in multivariate analysis.

^*GEE regression model with binomial distribution, logit-link function and unstructured correlation matrix.

^†Parameters with statistical significance.

Figure 2.

Gamma zone area and enlarged blind spot. (A, C) The area of the gamma zone was measured as a crescent on en-face OCT, corresponding to the region lacking Bruch's membrane on the B-scan. (B) The gamma zone on the fundus photo (red arrow). (D) An enlarged blind spot on the visual field.

Figure 3.

PHOMS and an enlarged blind spot. (A, C) The PHOMS area was measured as a crescent (green line) on en-face OCT, corresponding to the area exhibiting PHOMS on Bruch's membrane on the B-scan (yellow line and blue line). (B) PHOMS on the fundus photo (red arrow). (D) An enlarged blind spot on the visual field.

Discussion

In this study, we assessed the prevalence and risk factors of enlarged blind spots in highly myopic eyes within a population-based cohort of Chinese individuals. Unlike the typical VF defects observed in glaucoma, an enlarged blind spot was the most common type of VF defects observed in non-pathological, highly myopic eyes^7,8 accounting for 37.06% in our study. Furthermore, temporal enlargement of blind spots was the most frequent, constituting 46.55% of cases, followed by the inferotemporal region at 25.00%. To the best of our knowledge, this is the first study demonstrating that the enlarged blind spots are associated with lager gamma zone and PHOMS areas in highly myopic eyes. These two characteristic changes may reveal a pattern of early highly myopic functional damage and provide clues for the differential diagnosis of glaucoma.

Highly myopic eyes exhibit a larger gamma zone than non-highly myopic eyes, owing to the shifting and enlargement of BMO.^18,19 We further observed that eyes with enlarged blind spots showed larger gamma zone areas than those with normal VFs in highly myopic eyes. The gamma zone is associated with longer axial length and is independent of glaucoma.¹⁰ Moreover, in our study, we observed a correlation between a larger gamma zone and an enlarged blind spot. We hypothesized that the shifting of the BMO toward the temporal direction stretches the nasal axons, contributing to the enlargement of the blind spot. Meanwhile, BMO expansion potentially leads to the loss of peripapillary photoreceptors, further exacerbating blind spot enlargement (Fig. 4).

Figure 4.

A schematic diagram illustrating the potential impact of PHOMS and the gamma zone on the RNFL. The yellow arrow indicates the lateral traction force resulting from the shift of the BMO, and the red arrow demonstrates the pushing or pressing force exerted by PHOMS.

The impact of PHOMS on visual function in early non-pathologic high myopia warrants attention. In contrast to ODD,¹⁶ PHOMS, characterized by hyperreflective ovoid mass-like structures around the optic disc sitting on top of Bruch's membrane,²⁰ is associated with nerve fiber herniations or axoplasmic stasis.²¹ PHOMS is commonly observed in myopia and can also be found in a broad spectrum of neurological disorders.^22,23 Our finding revealed that participants with enlarged blind spots had larger PHOMS areas than those with normal VFs. Larger PHOMS areas correlated significantly with enlarged blind spots. Enlarged blind spots may be associated with the blockage of axonal transport, mechanical stress on the RNFL, and vascular compromise in the PHOMS areas (Fig. 4).

Our findings also suggest that an expanded gamma zone and a larger PHOMS area are early features of myopic optic neuropathy. Shin et al.²⁴ proposed the concept of myopic optical neuropathy as eyes without glaucomatous damage but with decreased RNFL at the superonasal or nasal area, accompanied by corresponding VF defects. Similarly, Lin et al.⁷ defined blind spot enlargement, vertical steps, and partial peripheral rim defects as myopia-related VF defects. In this study, we identified an early pattern of structural and functional damage in nonpathological, highly myopic eyes. However, whether this pattern changes during myopia progression still needs to be observed longitudinally.

The optic disc showed no correlation with enlarged blind spots, although it is notable that when discussing the disc size and shape, only the visible part of the optic disc was considered, whereas the part covered by an overhanging Bruch's membrane often excluded.¹⁰ The absence of correlation between average p-RNFL thickness and enlarged blind spots could be attributed to significant regional variations of the p-RNFL,²⁵ which might be masked by averaging.

The study has several limitations. First, our cohort consisted primarily of young individuals with high myopia, which may not represent the entire spectrum of individuals with high myopia. Second, the quadrant-specific relationships among the gamma zone, PHOMS, and enlarged blind spot need more detailed exploration. Third, as our study was based on cross-sectional data, the sequence and progression of structural and functional abnormalities warrant further investigation through longitudinal studies. In conclusion, our results indicated that in highly myopic eyes, enlarged blind spots were associated with larger gammas zone and larger PHOMS areas, suggesting potential mechanisms of visual function impairment in high myopia and providing clues for the differential diagnosis of glaucoma.