Microvascular alterations of peripapillary choriocapillaris in young adult high myopia detected by optical coherence tomography angiography

doi:10.21203/rs.3.rs-1982162/v1

Download PDF

Article

Microvascular alterations of peripapillary choriocapillaris in young adult high myopia detected by optical coherence tomography angiography

https://doi.org/10.21203/rs.3.rs-1982162/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objectives.

To characterize the microstructural alterations of peripapillary choriocapillaris in young adult high myopes using optical coherence tomography angiography (OCTA) and to explore factors involved in the alterations.

Methods.

This cross-sectional control study included 205 eyes (95 with high myopia and 110 with mild-moderate myopia). The choroidal vascular network was imaged using OCTA, and the images underwent manual adjustments to determine the peripapillary atrophy (PPA)-β zone and microvascular dropout (MvD). The area of MvD and PPA-β zone, spherical equivalent (SE), and axial length (AL) were collected and compared across groups.

Results.

The MvD was identified in 195 eyes (95.1%). Highly myopic eyes exhibited significantly greater area of PPA-β zone (1.221 ± 0.073 vs. 0.562 ± 0.383 mm², P = 0.001) and MvD (0.248 ± 0.191 vs. 0.089 ± 0.082 mm², P < 0.001) compared with mildly-moderately myopic eyes, and lower average density in the choriocapillaris. Linear regression analysis showed that MvD area correlated age, SE, AL, and PPA-β area (all P < 0.05).

Conclusions.

MvDs represent choroidal microvascular alterations in young adult high myopes, which were correlated with age, SE, AL, and PPA-β zone. In this disorder, OCTA matters for characterizing the underlying pathophysiological adaptations.

Biological sciences/Physiology/Circulation/Blood flow

Health sciences/Diseases/Eye diseases/Refractive errors

Choroidal microvascular dropout

high myopia

optical coherence tomography angiography

peripapillary atrophy

Myopia, the major cause of vision impairment and the second most common cause of blindness¹, affects nearly 2 billion people (28.3% of the global population), which includes 277 million people (4.0% of the global population) with high myopia². With the increase in refractive error and axial length (AL), the risk of adverse ocular tissue alterations increases dramatically, including posterior staphyloma, retinoschisis, retinal detachment, choroidal/scleral thinning, lacquer crack formation, myopic choroidal neovascularization, and glaucoma³, especially in populations with high levels of myopia. Accordingly, there has been a push to better control the onset and worsening of myopia and to place this public health problem high on the agenda. While improved strategies like the use of atropine, wearable optical devices, and surgical management have been employed to early intervene and limit myopia progression, the exact pathological mechanism of the myopia of the human eye remains elusive, hindering the development of successful treatment and reduction of disease burden⁴. Previous studies have suggested high myopia is associated with decreased blood supply^5,6. Li et al.⁵ found that the density of both superficial and deep microvascular plexuses dropped remarkably in highly myopic patients with normal visual ability before irreversible retinal damage. Sung et al.⁶ also described lower retinal vessel density and larger foveal avascular zone in high myopia. However, further evidence of vascular change in choroidal level is limited.

Not merely regarded as a densely vascularized structure lying between retina and sclera, the choroid possesses unexpectable elasticity in axial elongation⁷ and maybe the accommodation of intrinsic neurons⁸ and lymphatics⁹. The choriocapillaris, restricted to the innermost part of the choroid, is composed of a highly compacted capillaries separated by many tiny inter-capillary spaces that may grow with age and disease^10,11. Such inter-capillary spaces were strikingly captured by optical coherence tomography angiography (OCTA) and represented in the form of small dark regions, known as flow voids or microvascular dropouts (MvD)¹². Though there have studies that focused on central macular choroidal features in eyes with high myopia^13–15, less attention has been paid on the peripapillary choroidal alterations on OCTA.

OCTA provides non-invasive, rapid, and reproducible image acquisition of multiple layers of the posterior segment without the need for fluorescent dye injection by using phase or amplitude decorrelation to identify the motion contrast of blood flow^16–18. It shows detailed visualization of microvessels and analysis of blood signals in micrometer level so that MvDs, subtle sectoral capillary voids ignored by traditional imaging techniques, could be detected and shown in Choroid layer en-face images, usually appearing in the area of peripapillary atrophy (PPA) zone. PPA is the atrophy and thinning of local retina and choroid occurring in the juxtapapillary area adjoining the optic disc margin, mainly seen in elderly, glaucomatous, or highly myopic populations. It is classified into two categories based on histological characteristics: the α-zone features an irregular hypopigmentation and hyperpigmentation and intimated thinning of the chorioretinal tissue layer whereas the β-zone features the disappearance of the retinal pigment epithelium (RPE) and obvious atrophy of choriocapillaris with good visibility of the large choroidal vessels and the sclera¹⁹ (Fig. 1B&C). If both zones are present, the β-zone is always closer to the optic disc than the α-zone. Studies have confirmed that MvD was more frequently present in eyes with a β-zone than those without a β-zone in the PPA area in glaucoma^20,21.

In the present study, we employed OCTA to evaluate the relationship among PPA, MvD, and high myopia and investigate the underlying pathophysiological mechanism of the disorder which may facilitate the early management of high myopia.

The subjects were selected from populations at the First Affiliated Hospital of Nanjing Medical University (Nanjing, China) from April 2019 through January 2020. Written informed consent to participate was obtained from each of the enrolled subjects. The study protocol was registered at ClinicalTrial. gov (NCT04255524), and was approved by the Institutional Review Board of First Affiliated Hospital of Nanjing Medical University and followed the tenets of the Declaration of Helsinki.

Study Subjects

Subjects were divided into two groups based on the spherical equivalent (SE), which was calculated as the spherical dioptric power plus one-half of the cylindrical dioptric power. Subjects with a SE between − 10.0 diopters (D) and − 6.0D was allocated in high myopia group, while subjects with a SE between − 6.0D and − 0.5D was in mild-moderate myopia group.

Each subject underwent comprehensive ophthalmic examinations including slit-lamp biomicroscopy using Haag-Streit BM 900 slit-lamp microscope (Haag-Streit, Köniz, Switzerland), intraocular pressure using Canon TX-20 non-contact tonometer (Canon, Tokyo, Japan), best-corrected visual acuity, refraction test using autorefractometer RC-5000 (Tomey, Nagoya, Japan) and phoropter RT-5100 (Nidek, Tokyo, Japan), AL measurement using Nidek-AL Scan optical biometry (Nidek, Gamagori, Japan), fundus color photography and red-free fundus photography using Canon CR-2 Plus AF non-mydriatic retinal camera (Canon, Tokyo, Japan), and OCTA using Optovue Angio Vue™ System (Optovue, Fremont, California, USA). All the examinations were completed by one professionally trained ophthalmologist (J.L).

The main inclusion criteria were subjects (1) between 18–40 years old, (2) with a best-corrected visual acuity of ≥ 20/20 and a SE ranging from − 0.5 to -10.0 D, (3) with an intraocular pressure of < 21 mmHg and with < 5 mmHg difference between the two eyes, (4) with no history of elevated intraocular pressure, and no glaucomatous appearance. The absence of glaucomatous appearance was defined as follows: cup-disc ratio < 0.5 with ≤ 0.2 difference between the two eyes, an intact neuroretinal rim, no disc hemorrhages, notches or localized pallor, and normal retinal nerve fiber layer thickness without any defects. The exclusion criteria were (1) reluctance of signing informed consent or receiving consecutive following-up, (2) incapability of undergoing ocular examinations or producing good-quality images, (3) astigmatism beyond ± 4.0 D, (4) any history of intraocular or refractive surgery, (5) the presence of any retinal or neurological diseases (other than myopic degeneration), or opaque media, or glaucoma.

Octa And Determination Of The Presence Of a MvD

The optic nerve and peripapillary area were imaged using a commercially available spectral domain Optovue Angio Vue™ OCTA system (Optovue, USA) operating at a central wavelength of 840 nm, an acquisition speed of 70,000 A-scans per second, and axial and transverse resolutions of 5 and 15 µm in tissue, respectively. Scans were obtained from 4.5 × 4.5-mm cubes, with each cube consisting of 400 clusters of 2 repeated B-scans centered on the optic disc. Automatic layer segmentation in “Angio-disc” pattern performed by the built-in software controlling the OCT instrument generated scanning laser ophthalmoscope images of the disc and peripapillary region and en-face projections to visualize the vasculature and structure of Vitreous/Retina layer from vitreous body to outer plexiform layer (50 µm below internal limiting membrane), retinal posterior capillary layer from internal limiting membrane to nerve fiber layer, and Choroid layer below RPE.

All the OCTA images were exported in PNG format (Fig. 1A). The color fundus image, scanning laser ophthalmoscope image, and OCTA image of each participant were carefully evaluated by two ophthalmologists (J.L and Y.Y) to contour the PPA-α and PPA-β zone (Fig. 1B&C) under the supervision of two veteran ophthalmologists (Q.L and P.X). On the OCTA images, we manually defined “pixel” as the minimum unit of area measurement, that is, a pixel was equal to a cluster of a 4.5 × 4.5-mm cube (126.5625 µm²). When assessing MvD, the data set of OCTA images were then transferred to Nanjing University of Science and Technology (Nanjing, China). The appropriate threshold was identified as regions with a grey value less than 50 and an area exceeding 20 pixels (Fig. 1A). The area of MvD and PPA-β zone was calculated by PyCharm software counting the number of pixels that met this standard. Large vessels were removed from the OCTA image in advance, without whose influence the mean density of choroidal blood flow could be more accurately calculated as the area occupied by blood signals in the scanned region. All of the included OCT B-scan images had scan quality scores of ≥ 6/10. Any image with a double vessel pattern, motion artifacts, or segmentation errors extending more than three lines was excluded from the analysis.

Data Analysis

All data were expressed as the mean ± standard deviations and were analyzed statistically using SPSS software (version 25.0; SPSS, Chicago, Illinois, USA). Demographic, ocular, and systemic characteristics were compared between groups using the independent-samples t-test for numerical variables. We used analysis of variance to validate data accuracy if a measurement should be repeated for at least three times. Correlations between MvD area and age, SE, AL and the area of PPA-β zone were determined using the Spearman correlation test. The criterion for statistical significance was P < 0.05.

This study initially included 220 eyes from 110 subjects with myopia, from which 15 eyes were excluded due to poor OCTA image quality. 95 eyes were in high myopia group and 110 eyes were in the mild-moderate myopia group. An MvD was identified in 195 of the remaining 205 eyes (95.1%) in the PPA-β zone.

Demographics of the enrolled subjects are shown in Table 1. There was no significant difference in sex (P = 0.873) or age (P = 0.517) between the high myopia (n = 95) and mild-moderate myopia group (n = 110). The mean SE and AL in high myopia group were − 7.14 ± 0.927 D and 26.65 ± 0.88 mm in the high myopia group and − 2.51 ± 2.10 D and 24.36 ± 1.15 mm in the other, respectively. Both parameters were significantly different between the two groups (P < 0.05).

Table 1

Baseline characteristics of the included participants
Group	N (eyes)	Female	Age	SE	AL
High myopia group	95	32	36.21 ± 14.28	-7.14 ± 0.927	26.65 ± 0.88
Mild-moderate myopia group	110	31	32.30 ± 12.84	-2.51 ± 2.10	24.36 ± 1.15
P value	-	0.873	0.517	0.000	0.012
SE: spherical equivalent; AL: axial length.

In the high myopia group, the mean area of PPA-β zone was significantly greater than that of the mild-moderate myopes (1.221 ± 0.073 vs. 0.562 ± 0.383 mm², P < 0.05, Fig. 2A). A significantly larger area of MvD was also observed in highly myopic eyes (0.248 ± 0.191 vs. 0.089 ± 0.082 mm², P < 0.05, Fig. 2B). Meanwhile, the high myopia group exhibited a lower mean density of choroidal blood flow (157.60 ± 218.42 vs. 404.88 ± 432.47) in comparison to the mild-moderate myopia group, which marked a significant difference between the two groups (P < 0.05, Fig. 2C).

MvD was universally identified within the β-zone and additionally involved the α-zone in eyes with both β- and α-zones. As is shown in Table 2, 22.1% of subjects in the mild-moderate myopia group were found to have MvDs in the PPA-α area and 57.3% in the high myopia group. While the area of PPA-α is larger in the high myopia group, no significant difference was detected between groups in either the area of MvD in the PPA-α zone (P = 0.210) or PPA-α zone density (P = 0.159).

Table 2

Characteristics of participants having MvD in PPA-α zone
Group	N (total eyes)	n (eyes with MvD in PPA-α zone)	MvD area (mm2)	PPA-α area (mm2)	PPA-α density
High myopia group	95	21(22.1%)	0.068 ± 0.050	0.336 ± 0.188	428.89 ± 312.20
Mild-moderate myopia group	110	63(57.3%)	0.089 ± 0.082	0.235 ± 122	404.88 ± 432.47
P value	-	0.000	0.210	0.012	0.159
PPA: peripapillary atrophy; MvD: microvascular dropout

Linear regression analysis showed that age (P < 0.05), SE (r = -0.484, P < 0.05, Fig. 3A), AL (r = 0.477, P < 0.05, Fig. 3B), and the area of PPA-β zone (r = 0.894, P < 0.05, Fig. 3C) were all independent and significant factors that affected MvD area in myopia degeneration.

In this study, OCTA helped us to reveal microcirculatory alterations of juxtapapillary area at the choroid level in young adults with high myopia. The MvD was observed in 195 of 205 eyes (95.1%), more frequently detected in PPA-β zone and relevant to the PPA-β area, age, and AL. Choroidal capillary network provides oxygen and nourishment for the choroid and the outer retina of the eye²². PPA-α is defined as a peripheral area with misalignment of RPE while PPA-β is a more central area adjacent to the disc margin with the loss of RPE and atrophy of photoreceptors and choroid. Here, we found MvDs can be detected in almost all PPA-β zones, but also in some PPA-α zones, which indicated microcirculatory changes of choroid prior to RPE and choroidal dystrophy. In another word, the PPA originating from apoptosis of RPE cells may be caused by the insufficiency of life-sustaining materials due to choroidal ischemia.

There was also a distinguishable correlation of incremental MvD area with growth of SE and AL, suggesting that circulatory down-regulations were involved in the progression of high myopia.

Our results are in agreement with previous studies using pulse amplitude and other relevant parameters of ocular blood flow to evaluate choroidal perfusion^23,24. Decreased retinal nerve fiber layer and choroidal thickness accompanied by subsequent disc hemorrhage has been linked to myopia²⁵. A decline in choriocapillary perfusion may arise from reduced blood demands secondary to choroidal degeneration occurring in highly myopic eyes. Lack of blood supply from media- and large-sized choroidal layer may also contribute to lower choriocapillary perfusion as Jing Zhao et al.²⁶ found that axial elongation-associated choroidal thinning affected Haller's and Sattler's layers more markedly than the small-vessel layer. Besides, it is also speculated that the progression of optic disc tilt during global elongation may directly and mechanically deteriorate peripapillary microvasculature²⁷. Alternatively, hypoxia has been regarded as essential for scleral extracellular remodeling during myopia development²⁸. Visual perception may induce cell signaling pathway cascades that affect choroidal blood perfusion and scleral oxygenation, triggering a series of downstream events that diminish extracellular integrity and exacerbate scleral extension. This is a chicken-and-egg question in the light of which comes first, which warrants additional longitudinal studies to determine the sequence between structural and vascular alterations.

It also should be noted that the present study had several limitations. First, because of the cross-sectional property, this study was conducted at a specific time point instead of a period, which means we could not determine the cause and effect between MvD and PPA-β. Second, we did not represent choroidal vascular network during different stages of high myopia, due to our relatively unsatisfactory sample size and lack of pathologically myopic populations. Furthermore, our expectations for OCTA must be tempered given the challenges like failure to reflect patterns of ischemia, occlusion, and leakage in the periphery, unavoidable projection artifacts caused by moving shadows of blood cells, and lack of a standardized automated segmentation algorithm(16). Biases may also be produced by optical magnification for severe myopia due to the influence of axial length²⁹.

In conclusion, we characterized peripapillary alterations of the microcirculatory network at the choroid level in highly myopic eyes with the assistance of OCTA. MvD, more frequently appearing in high myopes than mild-moderate ones, correlated with age, AL, and SE, and the area of PPA-β zone, which may play an important role in early detection and diagnosis of myopia-associated retinopathies. Collectively, quantitive analysis from OCTA images of peripapillary microvasculature is extraordinarily conducive to digging out the underlying pathological mechanisms behind myopia. It is imperative to run further longitudinal investigations to elucidate if these mechanical and anatomical changes occur before or after the vascular changes.

Acknowledgements

The authors would like to thank all those patients with mild-moderate and high myopia who were willing to undergo the comprehensive optical examinations and consecutive follow-ups, and those who helped to perform the examination and are not listed as co-authors. Our study also received support from the Social Development Program of Jiangsu Province (BE2021744), Natural Science Foundation of Jiangsu Province (BK20191059), and General Project of the National Natural Science (Grant No. 81900875, 82070979).

Conflict of interest

The authors declare no conflict of interest.

Funding

This study was supported by the Social Development Program of Jiangsu Province (BE2021744), Natural Science Foundation of Jiangsu Province (BK20191059), and General Project of the National Natural Science (Grant No. 81900875, 82070979).

Bourne RR, Stevens GA, White RA, Smith JL, Flaxman SR, Price H, et al. Causes of vision loss worldwide, 1990–2010: a systematic analysis. Lancet Glob Health 1(6), e339-e349 (2013)
Holden BA, Fricke TR, Wilson DA, Jong M, Naidoo KS, Sankaridurg P, et al. Global Prevalence of Myopia and High Myopia and Temporal Trends from 2000 through 2050. Ophthalmology 123(5), 1036–1042 (2016)
Ikuno Y. OVERVIEW OF THE COMPLICATIONS OF HIGH MYOPIA. Retina 37(12), 2347–2351 (2017)
Pugazhendhi S, Ambati B, Hunter AA. Pathogenesis and Prevention of Worsening Axial Elongation in Pathological Myopia. Clin Ophthalmol 14, 853–873 (2020)
Li M, Yang Y, Jiang H, Gregori G, Roisman L, Zheng F, et al. Retinal Microvascular Network and Microcirculation Assessments in High Myopia. Am J Ophthalmol 174, 56–67 (2017)
Sung MS, Lee TH, Heo H, Park SW. Association Between Optic Nerve Head Deformation and Retinal Microvasculature in High Myopia. Am J Ophthalmol 188, 81–90 (2018)
van Alphen GW. Choroidal stress and emmetropization. Vision Res 26(5), 723–734 (1986)
Stübinger K, Brehmer A, Neuhuber WL, Reitsamer H, Nickla D, Schrödl F. Intrinsic choroidal neurons in the chicken eye: chemical coding and synaptic input. Histochem Cell Biol 134(2), 145–157 (2010)
Junghans BM, Crewther SG, Liang H, Crewther DP. A role for choroidal lymphatics during recovery from form deprivation myopia? Optom Vis Sci 76(11), 796–803 (1999)
Spaide RF. Choriocapillaris Flow Features Follow a Power Law Distribution: Implications for Characterization and Mechanisms of Disease Progression. Am J Ophthalmol 170, 58–67 (2016)
Al-Sheikh M, Phasukkijwatana N, Dolz-Marco R, Rahimi M, Iafe NA, Freund KB, et al. Quantitative OCT Angiography of the Retinal Microvasculature and the Choriocapillaris in Myopic Eyes. Invest Ophthalmol Vis Sci 58(4), 2063–2069 (2017)
Borrelli E, Sarraf D, Freund KB, Sadda SR. OCT angiography and evaluation of the choroid and choroidal vascular disorders. Prog Retin Eye Res 67, 30–55 (2018)
Sayanagi K, Ikuno Y, Uematsu S, Nishida K. Features of the choriocapillaris in myopic maculopathy identified by optical coherence tomography angiography. Br J Ophthalmol 101(11), 1524–1529 (2017)
Ye J, Wang M, Shen M, Huang S, Xue A, Lin J, et al. Deep Retinal Capillary Plexus Decreasing Correlated With the Outer Retinal Layer Alteration and Visual Acuity Impairment in Pathological Myopia. Invest Ophthalmol Vis Sci 61(4), 45 (2020)
Lee SSY, Lingham G, Alonso-Caneiro D, Chen FK, Yazar S, Hewitt AW, et al. Choroidal Thickness in Young Adults and its Association with Visual Acuity. Am J Ophthalmol 214, 40–51 (2020)
Nagiel A, Sadda SR, Sarraf D. A Promising Future for Optical Coherence Tomography Angiography. JAMA Ophthalmol 133(6), 629–630 (2015)
Spaide RF, Klancnik JM, Jr., Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol 133(1), 45–50 (2015)
Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G. Optical coherence tomography angiography. Prog Retin Eye Res 64, 1–55 (2018)
Jonas JB. Clinical implications of peripapillary atrophy in glaucoma. Curr Opin Ophthalmol 16(2), 84–88 (2005)
Lee EJ, Kim TW, Kim JA, Kim JA. Parapapillary Deep-Layer Microvasculature Dropout in Primary Open-Angle Glaucoma Eyes With a Parapapillary γ-Zone. Invest Ophthalmol Vis Sci 58(13), 5673–5680 (2017)
Lee SH, Lee EJ. Topographic correlation between juxtapapillary choroidal thickness and parapapillary deep-layer microvasculature dropout in primary open-angle glaucoma. Br J Ophthalmol 102(8), 1134–1140 (2018)
Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 29(2), 144–168 (2010)
Shih YF, Horng IH, Yang CH, Lin LL, Peng Y, Hung PT. Ocular pulse amplitude in myopia. J Ocul Pharmacol 7(1), 83–87 (1991)
Yang YS, Koh JW. Choroidal Blood Flow Change in Eyes with High Myopia. Korean J Ophthalmol 29(5), 309–314 (2015)
Kim CY, Lee EJ, Kim JA, Kim H, Kim TW. Progressive retinal nerve fibre layer thinning and choroidal microvasculature dropout at the location of disc haemorrhage in glaucoma. Br J Ophthalmol 105(5), 674–680 (2021)
Zhao J, Wang YX, Zhang Q, Wei WB, Xu L, Jonas JB. Macular Choroidal Small-Vessel Layer, Sattler's Layer and Haller's Layer Thicknesses: The Beijing Eye Study. Sci Rep 8(1), 4411 (2018)
He J, Chen Q, Yin Y, Zhou H, Fan Y, Zhu J, et al. Association between retinal microvasculature and optic disc alterations in high myopia. Eye (Lond) 33(9), 1494–1503 (2019)
Baird PN, Saw SM, Lanca C, Guggenheim JA, Smith Iii EL, Zhou X, et al. Myopia. Nat Rev Dis Primers 6(1), 99 (2020)
Lal B, Alonso-Caneiro D, Read SA, Carkeet A. Induced refractive error changes the optical coherence tomography angiography transverse magnification and vascular indices. Am J Ophthalmol 229, 230–241 (2021)

(Not answered)

Download PDF

Version 1

posted

You are reading this latest preprint version

Microvascular alterations of peripapillary choriocapillaris in young adult high myopia detected by optical coherence tomography angiography

Status:

Version 1

Abstract

Objectives.

Methods.

Results.

Conclusions.

Figures

Introduction

Methods

Study Subjects

Octa And Determination Of The Presence Of a MvD

Data Analysis

Results

Discussion

Declarations

References

Additional Declarations

Status:

Version 1