Comprehensive Visualization of Choroidal Alterations in Thyroid Eye Disease With Ultra-Widefield OCT Angiography

Abstract

Purpose: To evaluate choroidal and optic disc alterations in eyes with thyroid eye disease (TED) compared with healthy eyes by using TowardPi widefield optical coherence tomography angiography (OCTA).

Methods: This was a retrospective cross-sectional cohort study. A total of 112 participants (60 TED patients and 52 healthy controls) underwent TowardPi widefield OCTA, which provided detailed demographic and clinical data. Three-dimensional choroidal data, including thickness, vascular metrics, and optic disc measurements, were obtained from the built-in software.

Results: The study included 24 eyes with dysthyroid optic neuropathy (DON), 24 eyes with active non-DON TED, 71 eyes with inactive TED, and 104 healthy eyes. Choroidal thickness significantly decreased in the optic disc region during the DON phase (148.71 ± 78.98 µm) compared to normal eyes (182.35 ± 51.98 µm) and inactive TED eyes (191.34 ± 58.86 µm) (P = 0.030). In DON, choroidal stromal volume was reduced (34,183.81 ± 10,649.01 × 10⁶ µm³) compared to normal (46,339.53 ± 16,711.99 × 10⁶ µm³) (P = 0.002), whereas the choroidal vascular index increased (42.67% ± 3.41%) compared to normal (38.53% ± 6.35%) (P = 0.002). Optic disc area increased in DON (1.99 ± 1.24 mm²) compared to inactive TED (1.39 ± 0.38 mm²) (P < 0.001), along with reduced retinal nerve fiber layer blood-flow density in DON (45.09% ± 3.07%,) compared to normal (47.84% ± 1.41%) (P < 0.001).

Conclusions: This study highlights the critical role of choroidal and optic disc alterations in TED pathophysiology and underscore the utility of widefield OCTA in identifying these changes, particularly in DON-risk patients.

Thyroid eye disease (TED) is the most prevalent orbitopathy and the leading cause of proptosis in adults. This autoimmune disorder is characterized by inflammation and cellular infiltration into the orbital tissues, leading to an increase in orbital volume and a consequent rise in intraorbital pressure.^1,2 The majority of TED patients have mild symptoms, although approximately 3% to 5% experience more serious complications, such as severe inflammation, vision-threatening corneal ulcers, or dysthyroid optic neuropathy (DON).³ Clinically, disease activity and the necessity of treatment are most commonly assessed using the clinical activity score (CAS); vision, inflammation, strabismus, and appearance (VISA) score; or European Group of Graves’ Orbitopathy (EUGOGO) classifications.^4,5 Despite these measures, the optic disc and macular function in TED can deteriorate even when clinical disease activity appears absent. Therefore, advanced functional and structural assessments, such as visual field testing, visual evoked responses, contrast sensitivity measurements, and optical coherence tomography (OCT), are crucial for comprehensive evaluation. 

The choroidal vascular system, as the largest and most significant vascular system in the eyes, plays a critical role in supplying blood to both outer retina and sclera. It has been reported that choroid is related to a variety of ocular diseases, such as myopia and age-related macular degeneration.^6,7 Choroid impairment has also been associated with systemic disorders, including hypertension, cardiovascular diseases and Alzheimer's diseases,⁸ indicating that choroid is sensitive to inflammation and hemodynamic changes and could be a good biomedical indicator for the disease severity. 

Recent studies^9–13 have reported that TED choroidal thickness (CT) was markedly higher than in controls, particularly during the active phase of TED, suggesting choroid as a potential biomarker for disease activity and progression. However, such studies have only focused on CT in the macular region and have lacked comprehensive assessment of the whole choroid, as well as component analyses of blood and stroma, which would be of great value to assess the perfusion condition of choroid. This study aimed to explore the choroidal changes in patients with different severities of TED using widefield optical coherence tomography angiography (OCTA), providing insights into the pathogenesis of TED and offering clues for clinical management. 

Materials and Methods

Study Design and Participants

This was a single-center, retrospective, cross-sectional study that enrolled patients diagnosed with TED who were referred to the Department of Ophthalmology of Peking University from November 2023 to September 2024. All procedures were conducted in accordance with the tenets of the Declaration of Helsinki. 

Demographic information captured included age, gender, duration of TED symptoms, type of thyroid disease, medication being used, smoking history, hyperthyroidism treatment, and family history. All patients underwent standard ophthalmic examinations, which included best-corrected visual acuity (BCVA), refraction, intraocular pressure (IOP) measurement via non-contact tonopachymetry, and exophthalmometry using a Hertel exophthalmometer. Patients diagnosed with TED were included based on CAS and EUGOGO criteria. Individuals were excluded who reported any of the following: (1) had undergone bilateral orbital surgery; (2) had received glucocorticoid, monoclonal antibody therapy, or external radiation therapy for TED within the past 1 month, or (3) had any ambiguity with respect to presence of current/past retinal pathology or optic disc pathology. 

All participants were imaged using 400-kHz swept-source OCTA (TowardPi BMizar; TowardPi Medical Technology, Beijing, China), capable of performing 400,000 scans per second. This device employs a swept-source, vertical-cavity surface-emitting laser with a wavelength of 1060 nm, providing a transverse resolution of 10 µm and an optical resolution of 3.8 µm in tissue. Each OCTA scan covered a 24 × 20-mm rectangular area, corresponding to a 120° angular field of view centered on the fovea. 

Image Analysis

The extraction of three-dimensional (3D) choroidal data in this study utilized measurements obtained from the built-in software of the system. Following the methodology of previous research, the entire choroidal zone was divided into a 3 × 3 grid, consisting of nine rectangles: temporal-superior, superior, nasal-superior, temporal, macular, optic disc, temporal-inferior, inferior, and nasal-inferior.¹⁴ The software measured the choroidal parameters from 29 µm below Bruch's membrane to the choroid–sclera interface—choroidal vascular volume (CVV), choroidal stromal volume (CSV), and choroidal vascular index (CVI)—under both widefield OCTA and within each 3 × 3 grid (Fig. 1). CVI is defined as the ratio of choroidal vascular volume to the total volume within a given region. 

Figure 1.

 

The distribution trends of CT and choroidal blood flow images in patients with different stages of TED. The first row shows the distribution of CT in different stages of TED. The second row presents choroidal blood flow images corresponding to the different stages of TED. The third row shows B-scan images from the positions indicated by the arrows in the second row; the green arrow points to the B-scan around the optic disc, and the yellow arrow indicates the B-scan at the vortex vein outflow.

Additionally, the software was used to measure optic disc data under widefield OCTA, including optic disc area, cup volume, cup-to-disc area ratio, vertical cup-to-disc ratio, and horizontal cup-to-disc ratio. We also measured optic disc OCTA to obtain data on the average blood-flow density in the retinal nerve fiber layer (RNFL) (Fig. 2). 

Figure 2.

 

OCTA and B-scan images of the optic disc in patients with different stages of TED.

Statistical Analysis

Statistical analyses were conducted using SPSS Statistics 26.0 (IBM, Chicago, IL, USA). Categorical data are presented as frequency counts, and continuous variables are reported as mean ± SD. For samples larger than 50, the Kolmogorov–Smirnov test was used to assess normality; for samples smaller than 50, the Shapiro–Wilk test was applied to test for normality. Multifactorial analysis of variance (ANOVA) was used for data that met both normality and homogeneity of variance criteria (age, CT except for temporal-inferior CT, and CVV except for temporal-superior CVV, temporal-superior CSV, and CVI). Kruskal–Wallis one-way ANOVA was used for data that did not meet normality or homogeneity of variance criteria (spherical equivalent [SE], temporal-inferior CT, choriocapillaris density, temporal-superior CVV, CSV excluding temporal-superior CSV, and optic disc data). Post hoc comparisons were conducted using Tukey's multiple-comparisons test. To adjust for the effects of SE on the observed choroidal parameters, analysis of covariance (ANCOVA) was conducted, and the results are shown in the Supplementary Materials. P < 0.05 was considered statistically significant. 

Results

Clinical Characteristics of All Participants

In total, 60 TED patients and 52 healthy controls were enrolled in this study. The demographic characteristics of all participants are summarized in Table 1. The study involved a comparative analysis of four groups based on the activity status of TED: normal (104 eyes), inactive (36 eyes), active non-DON (24 eyes), and DON (24 eyes). Clinical characteristics are shown in Supplementary Table S1. 

Table 1.

 

Demographic Features of TED Subjects and Healthy Controls

 

Comparison of Choroidal Thickness in Different Phases of TED and Healthy Eye Groups

This study investigated variations in CT across the normal, inactive, active non-DON, and DON phases of TED. Measurements were taken across multiple ocular segments and expressed in micrometers. Table 2 showed that there was a significant difference in CT with specific regions. Notably, the optic disc region displayed a marked decrease in thickness during the DON phase (148.71 ± 78.98 µm) compared to the normal eyes (182.35 ± 51.98 µm) and inactive TED phase (191.34 ± 58.86 µm) (P = 0.030). Similarly, the temporal-inferior region exhibited a significant reduction in thickness in the DON phase (165.95 ± 42.80 µm) compared to the inactive phase (159.13 ± 52.76 µm) and normal eyes (138.40 ± 39.95 µm) (P = 0.005). Additionally, the inferior region demonstrated a significant reduction in CT in the DON phase (124.19 ± 51.85 µm) compared to the inactive phase (160.28 ± 49.72 µm) and normal eyes (142.64 ± 44.27 µm) (P = 0.010). Although other regions such as the wide-angle and subfovea showed trends of variation across TED phases, they did not reach statistical significance (P > 0.05). These findings may suggest that specific regions, particularly the optic disc and inferior regions, are more vulnerable to choroidal changes in TED, especially in patients with DON. 

Table 2.

 

Comparison of Choroidal Thickness in Different Phases of TED and Healthy Eye Groups

 

Comparison of Choroidal Three-Dimensional Vascular Metrics in Different Phases of TED and Healthy Eye Groups

Figures 3, 4, and 5 and Supplementary Table S3 compare choroidal 3D vascular metrics (CVV, CSV, and CVI) across different phases of TED. Significant differences were observed in wide-angle CSV (P = 0.001), with the DON phase showing a marked decrease (34,183.81 ± 10,649.01 × 10⁶ µm³) compared to the normal phase (46,339.53 ± 16,711.99 × 10⁶ µm³). Wide-angle CVI also demonstrated significant differences (P = 0.004), with the DON phase (42.67% ± 3.41%) being higher than the normal phase (38.53% ± 6.35%). 

Figure 3.

 

Characteristics of the CSV distribution in patients with different stages of TED and healthy eye group. I, inferior; M, macular; NI, nasal-inferior; NS, nasal-superior; OD, optic disc; S, superior; T, temporal; TI, temporal-inferior; TS, temporal-superior; WA, wide-angle. *P < 0.05, **P < 0.01, ***P < 0.001; ns, no significant difference.

Figure 4.

 

Characteristics of the CVV distribution in patients with different stages of TED. I, inferior; M, macular; NI, nasal-inferior; NS, nasal-superior, T, temporal; OD, optic disc; S, superior; TI, temporal-inferior; TS, temporal-superior; WA, wide-angle. *P < 0.05, **P < 0.01, ***P < 0.001; ns, no significant difference.

Figure 5.

 

Characteristics of the CVI distribution in patients with different stages of TED. I, inferior; M, macular; NI, nasal-inferior; NS, nasal-superior, T, temporal; OD, optic disc; S, superior; TI, temporal-inferior; TS, temporal-superior; WA, wide-angle. *P < 0.05, **P < 0.01, ***P < 0.001; ns, no significant difference.

Specific regions, such as the nasal-superior (P = 0.006), optic disc (P = 0.007), and nasal-inferior (P = 0.031) areas, showed significant differences in CVV across phases, particularly with decreased values in the DON phase. Furthermore, CSV by grid revealed significant reductions in the nasal-superior (P < 0.001), superior (P = 0.016), and optic disc (P < 0.001) regions in the DON phase, reflecting a decline in vascular parameters in the advanced stages of TED, especially in eyes with DON. CVI significantly differed across various regions and phases of TED, with all comparisons showing P < 0.001, indicating substantial changes in choroidal vascularity throughout disease progression. In addition, Supplementary Table S2 shows that there were no statistically significant differences in choriocapillaris density across the phases in either wide-angle or subfovea views. These findings highlight the impact of disease progression on vascular structures within the choroid in TED patients. 

Comparison of Optic Disc Metrics in Different Phases of TED and Healthy Eye Groups

Table 3 and Figure 6 present a comparison of optic disc metrics across the normal, inactive, active non-DON, and DON phases of TED. Significant differences were observed in optic disc area (P < 0.001), with the DON phase showing a notable increase (1.99 ± 1.24 mm²) compared to the inactive phase (1.39 ± 0.38 mm²). Cup volume also showed significant differences (P = 0.011), increasing in the active non-DON phase (0.14 ± 0.10 mm³) compared to the inactive phase (0.07 ± 0.09 mm³). Additionally, average RNFL blood-flow density was significantly reduced in the DON phase (45.09% ± 3.07%; P = 0.004), reflecting decreased blood flow as the disease progresses. The rim area and vertical cup-to-disc ratio did not show significant differences among phases (P = 0.728 and P = 0.077, respectively). These findings highlight the structural and vascular changes in the optic disc in TED, particularly in the advanced DON phase. 

Table 3.

 

Comparison of Optic Disc Metrics in Different Phases of TED and Healthy Eye Groups

 

Figure 6.

 

Characteristics of optic disc parameters in patients with different stages of TED and healthy eye group. *P < 0.05, **P < 0.01, ***P < 0.001; ns, no significant difference.

Discussion

TED is an autoimmune inflammatory disease characterized by extensive remodeling of orbital tissues, presenting a challenging ocular manifestation of Graves’ disease.¹⁵ This study provides a comprehensive analysis of CT, 3D vascular metrics, and optic disc metrics in various phases of TED. Our results demonstrate that TED induces significant changes in both structural and vascular parameters of the choroid and optic disc, particularly in patients with DON, which is considered the most severe form of the disease. We observed a significant reduction in CT, especially near the optic disc and in the inferior regions, during the DON phase compared to both normal and inactive TED eyes. Notably, there were marked decreases in the choroidal vascularity metrics CSV and CVV, further suggesting extensive vascular remodeling in this phase. Changes in optic disc metrics were also significant, including increased optic disc area and decreased RNFL blood-flow density, indicating potential optic nerve injury associated with TED progression. 

Although TED is associated with notable blood changes in outer tissues such as the conjunctiva and extraocular muscles, these alterations do not always reflect visual function changes, particularly in severe cases such as DON. In contrast, choroidal metrics appear to serve as promising biomarkers for the disease. Previous studies have linked increased CVI and thickness with TED activity, supporting the potential of OCT-measured choroidal parameters as clinical indicators. For example, Özkan et al.¹⁶ reported higher subfoveal choroidal thickness (SFCT) in TED patients compared to healthy controls, correlating with disease activity and visual evoked potential latency. Similarly, Çalışkan et al.¹³ confirmed elevated SFCT across active and inactive phases of TED associated with CAS, IOP, exophthalmos, and thyroid function. However, results have varied across studies, with some showing non-significant associations, particularly between CAS and SFCT. Chien et al.⁹ and Goel et al.¹⁷ noted thickening of the choroid in active TED, but Del Noce et al.¹⁸ reported conflicting results, potentially due to differences in patient demographics or measurement methodologies. Our findings align with previous research indicating that SFCT increases with TED severity, although this increase was not statistically significant, suggesting that SFCT may not be a sensitive biomarker for monitoring TED progression. Additionally, previous studies have primarily focused on the macular region and lack information on patients with DON, thus limiting insights into comprehensive structural changes throughout the choroid in the whole-stage progression of TED. 

The recent advancement of widefield OCTA offers significant improvements over traditional imaging techniques, enabling a broader view of retinal and choroidal blood flow while maintaining high resolution.¹⁹ Traditional OCTA devices typically have a limited scanning range (6 × 6 mm), often covering only the central macular region or a small peripheral area.²⁰ In contrast, the widefield OCTA used in our study offers ultra-widefield imaging (24 × 20 mm), providing a broader view of retinal and choroidal blood flow from the central retina to the peripheral choroid.^16,21 The automated measurement of 3D choroidal vascular metrics including CSV, CVV, and CVI obtained through ultra-widefield OCTA has been considered feasible in previous studies and is not influenced by differences in examination equipment.^22,23 This enables a more comprehensive evaluation of choroidal alterations in TED. 

Our results indicate notable reductions in CT, particularly near the optic disc and in the inferior regions during the DON phase. These reductions may be attributed to the compressive effects of inflammation and fibrosis within the orbit, which are more severe in DON cases. The observed thinning of the choroid in the inferior region during this phase may reflect increased pressure of the outlet and subsequent altered blood flow dynamics, potentially compromising vascular supply to the posterior segment of the eye. Additionally, our study revealed considerable variability in 3D choroidal vascular metrics, with greater intergroup variability in CSV than in CVV, alongside elevated CVI, suggesting that stromal atrophy is a prominent feature in TED development. Notably, the CVI in the optic disc region did not differ significantly among TED groups, indicating a parallel deterioration of both stromal and vascular components. It is noteworthy that both the CSV and CVV exhibit significant decreases with the increasing severity of myopia,^19,24 indicating that SE might be a significant confounding factor in choroidal parameters analyses. However, in our study, the SE values of the patients in the DON and active non-DON groups were significantly higher than those in the normal group (−1.21 ± −3.00 and −1.56 ± −2.12 vs. −3.21 ± −2.42), yet both the vascular and stromal layers of the choroid exhibited significant atrophy, indicating that changes of choroidal parameters could be attributed to the underlying pathophysiology of TED rather than myopia, which was further confirmed by the results of ANCOVA (Supplementary Tables S4, S5, S6). 

The structural changes of optic disc in TED were also important.^17,25 In our study, the optic disc area increased markedly in the DON phase compared to inactive phases, suggesting optic nerve involvement and swelling due to compressive effects within the orbit. Reduced average RNFL blood-flow density in the DON phase further supports the notion of compromised optic nerve perfusion, which is consistent with the vascular insufficiency hypothesis in TED, especially in patients with DON.²⁶ However, although there were overall significant difference in cup-to-disc ratios, the differences primarily existed between the normal and inactive TED groups, indicating that cup-to-disc ratios are of limited value in monitoring TED progression. These findings highlight the importance of early detection and monitoring of choroidal and optic disc changes in TED patients, particularly those at risk of or already exhibiting DON. The significant reductions in CT and vascular metrics could serve as early indicators of optic neuropathy, guiding clinicians to intervene earlier. Monitoring of optic disc metrics, especially optic disc area and RNFL blood flow, might offer valuable insights into the progression of TED and the risk of visual loss, particularly in advanced stages of the disease. 

Although this study presents robust evidence of structural and vascular changes in TED, there are limitations that should be addressed in future research. The cross-sectional nature of the study limits the ability to establish causality or to track the progression of changes longitudinally. Additionally, the sample sizes for certain TED phases, particularly DON, may be relatively small, limiting the generalizability of the results. Future studies with larger sample sizes and longitudinal designs could provide a clearer picture of how these changes evolve over time. 

In conclusion, this study highlights significant structural and vascular alterations in the choroid and optic disc associated with the progression of TED, particularly in the DON phase. CT showed significant reductions in specific regions such as the optic disc and inferior segments, whereas choroidal 3D vascular metrics, including CSV and CVI, were notably affected, with marked decreases in vascular volumes and densities in the DON phase. Additionally, optic disc metrics revealed increased optic disc area and reduced RNFL blood-flow density, reflecting advanced disease changes in TED patients with DON. These findings underscore the importance of monitoring both structural and vascular parameters to better understand and manage the progression of TED, especially in patients at risk for or who have DON. 

Further investigation into the underlying mechanisms driving choroidal and optic disc changes in TED, particularly in DON, is warranted. Understanding the role of inflammation, fibrosis, and vascular compromise in these alterations could lead to new approaches for therapeutic interventions. Additionally, exploring how these metrics respond to treatments such as corticosteroids or orbital decompression surgery could provide valuable insights into optimizing management strategies for TED. 

Acknowledgments

Supported by grants from the National Natural Science Foundation of China (82201180) and Beijing Natural Science Foundation (7244438). 

Disclosure: Y. Wang, None; T. Rao, None; J. Zhou, None; D. You, None; J. Yang, None; L. Suo, None