Diagnostic ability of superficial vascular density measured by optical coherence tomography angiography to differentiate high myopic eyes from eyes with primary open angle glaucoma : Indian Journal of Ophthalmology

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Original Article, Special Focus – Glaucoma

Diagnostic ability of superficial vascular density measured by optical coherence tomography angiography to differentiate high myopic eyes from eyes with primary open angle glaucoma

Santhosh, Liz Mary; Elias, Anna; Anup, Manju1; Nair, Abhilash1; Anantharaman, Giridhar2; Prakash, Nimmi3

Author Information
Indian Journal of Ophthalmology 70(12):p 4138-4143, December 2022. | DOI: 10.4103/ijo.IJO_597_22
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Abstract

Glaucoma is one of the leading causes of blindness, characterized by progressive degeneration of the ganglion cells, resulting in cupping of the optic nerve head (ONH), field defects, and gradual, progressive, irreversible loss of vision.[12] Elevated intraocular pressure (IOP) and vascular insufficiency in the ONH play an important role in the progression of glaucoma.[3]

Myopia is a refractive error with increased axial length (AL) of the eye, reduction in retinal nerve fiber layer (RNFL) thickness, and increasing peripapillary atrophy.[4] Changes in ocular microcirculation are hypothesized to be a precursor for myopic degenerative fundus changes.[56789]

Myopic and glaucomatous optic discs may show similar morphology. As glaucoma is a blinding disease whose treatment is life-long and myopia requires only refractive correction, it is important to differentiate between the two. Visual fields in myopic eyes may fallaciously show a picture simulating glaucomatous field defects and hence may pose a diagnostic dilemma.[10]

Optical coherence tomography angiography (OCTA) is a novel noninvasive technique used to evaluate retinal vasculature and blood flow by providing high-resolution, three-dimensional images of retinal vasculature without the use of any intravenous dye.[111213] Using OCTA, morphological information about the retinal vasculature as well as quantitative measurement of vascular density can be obtained.[1415]

In this study, we used OCTA to compare the density of the superficial vascular complex of the disc and peripapillary area and macula in high myopic and glaucomatous eyes to determine the presence of any characteristic vascular density changes that would help us distinguish between them.

Methods

This prospective, observational, comparative, cross-sectional study was carried out between November 2017 and November 2018 in a tertiary care ophthalmic institute in South India and included patients between the age of 40 and 60 years who visited the OPD and were diagnosed as primary open-angle glaucoma (POAG), high myopia, and age-matched controls. POAG was defined as those individuals with open angles on gonioscopy, ONH changes characteristic of glaucoma such as thinning of the neuroretinal rim, notching, excavation, or RNFL defects detected on slit-lamp (S/L) biomicroscopy, with corresponding visual field defects on Humphrey SITA 24-2, with pattern standard deviation outside normal limits with P < 0.05 or glaucoma hemi-field test outside normal limits. For subset analysis, the subjects in the POAG group were classified as mild, moderate, and severe glaucoma based on mean deviation (MD). Mild was defined as MD of less than −6 dB, moderate as −6 to −12 dB, and severe as MD of more than −12 dB. High myopia was defined as those individuals having spherical equivalent (SE) more than or equal to −6.00 D. The control group consisted of age-matched patients with IOP <21 mm Hg, refractive error between −1.00 D and + 1.00 D, with no evidence of glaucomatous ONH changes.

Patients having concurrent POAG with high myopia, history of ocular trauma, history of intraocular surgery, pan-retinal photocoagulation, diabetic or hypertensive retinopathy, retinal detachment, retinal dystrophies, and conditions preventing clear visualization of fundus such as corneal opacities, cataract, or other ocular pathologies were excluded from the study.

The sample size was calculated using the following formula:

where

: standard deviation in the first group

: standard deviation in the second group

: mean difference between the samples

α: significance level

1-β: power

Z1-α/2 (1.96) is the value of the area under the normal curve at a considered level of significance.

Z1-β (0.842) is the value corresponding to the power of the study.

The sample size was calculated using nMaster 2.0 software.

The alpha error and power of the study considered were 5% and 80%, respectively.

The study was approved by the institutional review board and strictly adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all patients who satisfied the inclusion criteria, and they underwent detailed ophthalmologic evaluation including assessment of best-corrected visual acuity (BCVA), IOP measurement with Goldmann applanation tonometry, AL, and central corneal thickness measurement using Lenstar (LS-900, Haag-Streit Int, USA), Gonioscopy, dilated fundus examination using S/L and 90-D lens, indirect ophthalmoscopy using a 20-D lens, Humphrey SITA 24-2 visual field analysis (HFA3 model-860,720i, Carl Zeiss Meditech, Dublin, USA), and OCT glaucoma overview (Heidelberg Engg, GmbH, Germany). The patients were then categorized as high myopes, POAG, and controls as per the definitions. All the participants were then subjected to OCTA [Spectralis-OCT angiography module, Heidelberg Engineering GmbH, Germany]. Images were captured from a 3 mm × 3 mm peripapillary zone centered at the optic disc and a 3 mm × 3 mm zone at the macula centered at the fovea. The angiographic images of the superficial vascular complex in each zone were extracted and binarized, and the superficial vascular density (SVD) in each zone was calculated using ImageJ software (version 1.51j8), a public domain Java-based image processing system [National Institutes of Health, Bethesda, Maryland, USA]. Initially, binary images of the vascular networks were created using an inbuilt automated thresholding algorithm. The blood vessels were defined as pixels having values above the threshold level. Vascular density was defined as the percentage area occupied by the blood vessels. The vessel density was then calculated from the binarized image by the software automatically [Fig. 1].

F1
Figure 1:
Optical coherence tomography angiography image at the level of the superficial vascular complex of disc and peripapillary area and macular area of high myopic eye (a and b) and primary open-angle glaucoma (c and d), respectively, and the corresponding binarized image using ImageJ software (e–h)

The patient data were recorded and analyzed using Microsoft Excel. Descriptive analyses of the population’s characteristics were carried out. The differences between quantitative variables were analyzed using one-way ANOVA and nonparametric Kruskal–Wallis test. Values of P < 0.05 were considered statistically significant.

Results

In total, 128 eyes of 70 patients who satisfied the inclusion criteria were enrolled in the study, of which 48 eyes belonged to the control group, 46 to POAG, of which mild POAG included 20 eyes, moderate included 16 eyes, and severe included 10 eyes. Furthermore, 34 eyes belonged to the high myopia group. In the POAG group, eight were ≤50 years of age, 17 were >50 years of age (Male:Female = 16:9). In the high myopia group, 16 were ≤50 years and four were >50 years (Male:Female = 10:10). In the control group, 20 were ≤50 years and five were >50 years (Male:Female = 5:20).

Analysis showed a statistically significant difference in the mean Peripapillary Superficial Vascular Density (PSVD) between POAG, high myopia, and control groups (P < 0.001), with the mean vascular density decreasing from the controls (45.07 ± 3.44) to high myopia (40.36 ± 8.3) to the POAG group (31.80 ± 9.01) as shown in Table 1. The PSVD of both the POAG group and the high myopia group were less as compared to the controls, with the POAG group showing a substantial reduction. Post-hoc analysis of the above data confirmed a statistically significant difference between the PSVD of the POAG group and the high myopia group; the POAG group showed a significantly lower PSVD [Table 2].

T1
Table 1:
Determination of relation of peripapillary and macular superficial vascular density across different groups
T2
Table 2:
Post-hoc analysis of Table 1

Subset analysis of the PSVD of high myopia versus mild, moderate, and severe glaucoma is shown in Table 3. PSVD showed a significant difference across all four groups with P < 0.001. Post-hoc analysis of the above data showed that the mean difference in PSVD between high myopia and severe glaucoma was statistically significant (mean difference = 19.04, P < 0.001). The mean difference in PSVD between high myopia and moderate glaucoma was also statistically significant (mean difference = 7.14, P = 0.018), however, it was less significant when compared to severe glaucoma [Table 4].

T3
Table 3:
Subset analysis showing the relation of peripapillary and macular superficial vascular density between high myopia and mild, moderate, and severe subsets of POAG
T4
Table 4:
Post-hoc analysis of Table 3

There was a statistically significant difference in the mean macular superficial vascular density (MSVD) between the POAG, high myopia, and control groups (P < 0.001), with the MSVD decreasing from the controls (27.30 ± 3.44) to the high myopia group (22.33 ± 6.01) to the POAG group (21.21 ± 5.6) as shown in Table 1. The post-hoc analysis of the above data confirmed that there was no statistically significant difference in the MSVD between the POAG and high myopia groups [Table 2]. However, there was a statistically significant difference in the MSVD between the POAG and the controls as well as between the high myopia and the controls.

Subset analysis of the MSVD of the high myopia group versus mild, moderate, and severe glaucoma is shown in Table 3. MSVD showed a significant difference across all four groups with P = 0.010. Post-hoc analysis of the above data [Table 5] showed that there was a statistically significant difference in the MSVD between high myopia and severe glaucoma (mean difference: 5.6, P = 0.036), whereas the mean difference in the MSVD between high myopia and moderate glaucoma, high myopia, and mild glaucoma were not statistically significant (P = 1.00).

T5
Table 5:
Post-hoc analysis of Table 3

Further analysis showed that the PSVD reduced with an increase in AL in the three groups. However, there was no statistically significant correlation between the three groups. On comparing the AL to the MSVD of the three groups, there existed a statistically significant correlation between AL and MSVD in the high myopia group and control group, with MSVD reducing with increasing AL in the high myopia group [Table 6].

T6
Table 6:
Correlation between axial length, spherical equivalent, and peripapillary and macular superficial vascular density in POAG, high myopia, and control groups

The SE showed no significant correlation to the PSVD of POAG, high myopia, or control group, but there existed a statistically significant correlation between SE with the high myopia group, that is, the higher the myopia (more negative SE), the lower the MSVD and vice versa. However, no significant correlation was found between SE and MSVD of the POAG or the control group [Table 6].

Discussion

This study primarily compared the SVD of the peripapillary and macular regions of established POAG and high myopic eyes to determine if the two entities can be differentiated based on any specific characteristic patterns in the vascular densities in these two regions.

  1. Peripapillary SVD
    1. PSVD – POAG versus control group:
    2. Post-hoc analysis showed a statistically significant reduction in the mean PSVD of the POAG group compared to that of the control group, with the PSVD of the POAG group being lower than that of the control group [Table 2]. Similar findings were also put forth by Liu et al.,[16] who reported that PSVD and peripapillary flow index were much lower in glaucomatous eyes as against age-matched controls. Studies by Suwan et al.[17] and Chen et al.[18] further support this finding and showed significantly lower PSVD in eyes with POAG without myopia as against controls and significantly lower vessel density in the peripapillary region in glaucomatous eyes than in healthy eyes in whole image vessel density assessment respectively. Lower PSVD in POAG patients was also reported by Rao et al.[19]
    3. PSVD – High myopia versus control group:
    4. Post-hoc analysis also revealed a statistically significant difference in the mean PSVD of the high myopia group and the control group, with the PSVD of the high myopia group being lower than that of the control group [Table 2]. This is in accordance with the findings by Wang et al.[20] and Guo et al.,[21] who showed a lower peripapillary retinal flow index and lower peripapillary microvascular density in myopic eyes.
      In contrast to our study, Fan et al.[22] reported that the PSVD showed no significant difference between the controls and the high myopia group. This difference could be because in their study, Fan et al.[22] included subjects with SE between +3.00 D and −3.00 D in their control group, whereas in this study, the control group had patients with SE ranging from +1.00 D to −1.00 D.
    5. PSVD – POAG versus high myopia group:
    6. The most important finding put forth by this study was that there was a significant difference in the PSVD between the POAG group and the high myopia group, with the PSVD of the POAG group being lower than that of the high myopia group. The difference takes on significance when distinguishing between high myopia and moderate and severe glaucoma.
  2. Macular SVD
    1. MSVD – POAG versus control group:
    2. Post-hoc analysis showed a statistically significant difference between the mean MSVD of the POAG and control groups [Table 2], with the mean MSVD of the POAG group being lower than that of the control group. This was similar to the reports published by Shoji et al. and Chen et al., who also showed a statistically significant reduction in the MSVD of glaucomatous eyes in comparison to that of the controls.[2318] Shoji et al.[23] followed up the patients in control, glaucoma suspect, and glaucoma eyes for 13 months and quantitatively assessed the rate of change of vessel density over time and found that there was a significant difference in the rate of change in vessel density among the three groups, with the mean rate of change in MSVD being the fastest in glaucomatous eyes.
    3. MSVD – High myopia versus control group:
    4. Post-hoc analysis also showed that there was a statistically significant difference in the mean MSVD of the high myopia group and the control group [Table 2], with the mean MSVD of the high myopia group being lower than that of the control group. Similar findings were put forth by Fan et al.,[22] who compared the MSVD in high (SE > −6.00 D) and moderate myopia (SE ≥ −3.00 D and ≤ −6.00 D) with that of the controls (SE between + 3.00 D and − 3.00 D) and reported that there was a significant reduction in the MSVD in high and moderate myopes compared to that of the control group. However, a contrasting finding was reported by Wang et al.,[20] who concluded that there is no significant difference in the MSVD among patients with different degrees of myopia.
    5. MSVD – POAG versus high myopia group:
    6. Initial analysis showed no significant difference in the mean MSVD between the POAG group and the high myopia group. However, subset analysis revealed that though the MSVD may play a minor role in distinguishing high myopic eyes from mild or moderate glaucoma, it can aid in distinguishing high myopia from severe glaucoma.

Analysis of AL showed a significant negative correlation to the MSVD of high myopes, but it had no significant correlation to the PSVD in any of the three arms [Table 6]. Fan et al.[22] also showed a significant association of MSVD with AL and further stated that there was no association between AL and PSVD. Wang et al.[20] also reported that no significant correlation between AL and PSVD in myopic eyes. However, Sung et al.[24] assessed superficial and deep peri-papillary vascular density in healthy myopic eyes and found a significant negative correlation between AL and PSVD. This difference may be due to the different areas of measurement used in the studies. In their study, Sung et al.[24] measured the peripapillary microvascular density in a 0.75-mm-wide elliptical annulus extending from the optic disc boundary, whereas in this study, the entire 3 mm × 3 mm zone centered on the optic disc was measured. SE only showed a significant correlation to the MSVD in the high myopia group [Table 6]. There was no significant association with PSVD in any of the three study groups. This is comparable to the study conducted by Fan et al.,[22] where they demonstrated a significant association of MSVD with SE, with the MSVD reducing with increasing myopia.

Our study revealed a greater reduction in the PSVD in glaucomatous eyes compared to myopic eyes. The most probable explanation could be that in glaucoma, there is death of the ganglion cells (dendrite, nucleus, and axon), which form the three inner layers of the retina. The oxygen demand ceases and hence there is a significant reduction in vascular density. In high myopes, there is thinning and stretching of all layers of the eye due to the increase in AL, but there is no significant cell death or loss of tissue as in glaucoma. This may explain the significant difference in the SVD between glaucomatous eyes and myopic eyes.

Conclusion

In conclusion, OCTA can be a defining tool in distinguishing eyes with high myopia and glaucoma, overcoming the gray area of diagnostic dilemma posed by similar clinical findings. The measurement of PSVD has greater discriminatory ability than the measurement of MSVD to differentiate eyes with high myopia from glaucomatous eyes, especially with reference to moderate and severe glaucoma The main limitation of this study was that the study duration was too short to prospectively follow up the patients and assess any progression in the variables, which can further aid in confirming the diagnosis of glaucoma in a given myopic eye. The inclusion of patients with high myopia with coexistent glaucoma as a separate group could have thrown more light into this difficult-to-diagnose subset. This study was conducted with a small sample size; a larger study population may provide a better validation to the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

High myopia; OCTA; POAG; superficial vascular density

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