Thyroid eye disease (TED), also referred to as Graves’ ophthalmopathy (GO), is the most prevalent extrathyroidal condition related to Graves’ disease (GD). Approximately 20%–25% of GD patients experience clinically significant TED, with 3%–5% progressing to severe TED (1). TED is a pathologic autoimmune orbital disease characterized by diffuse lymphocytic infiltration of the extraocular muscles (EOMs) and periorbital connective tissues, leading to the enlargement of these structures (2). Treatment options are determined by disease severity and activity. Mild TED might improve spontaneously, whereas moderate to severe and active TED requires either medical or surgical treatment. High-dose intravenous administration of glucocorticoids is the first-line therapeutic regime for moderate to severe active TED; however, approximately 20%–40% of patients might not respond effectively (3, 4). Retro-orbital radiotherapy is recommended as one of the second-line treatment choices, especially for myopathic TED patients with diplopia and/or restricted eye movement. By suppressing lymphocyte infiltration and fibroblast proliferation, as well as glycosaminoglycan (GAG) secretion, radiotherapy provides non-specific anti-inflammatory effects to alleviate orbital pressure and local symptoms (5–7).

Previous studies have identified distinct alterations in corneal morphology and biomechanics in patients with TED (8–10). Notably, recent evidence suggests that TED patients exhibit characteristic corneal abnormalities resembling keratoconus, accompanied by elevated anterior corneal astigmatism along the oblique axis (8). Comparative analyses further demonstrated significantly reduced orbital compliance and impaired biomechanical parameters in active TED patients compared to healthy controls (11, 12). These findings highlight the potential utility of corneal parameters as diagnostic markers for early-stage TED detection. Furthermore, growing research suggests a potential association between TED and corneal ectatic disorders. A recent case report documented TED-induced progression of secondary keratoconus (13), while a cross-sectional study identified thyroid dysfunction as a possible risk factor for corneal ectasia (14). However, the relationship between TED and corneal morphology and biomechanics remains to be further explored.

Treatment of TED can alter corneal biomechanics. For moderate to severe active TED patients, intravenous glucocorticoids can improve orbital compliance as evidenced by improved whole eye movement obtained using a dynamic Scheimpflug analyzer (Corvis ST) (15). In stable TED, orbital decompression surgery leads to a decrease in ocular biomechanics, whereas corneal stiffness and orbital tissue compliance tend to increase following anterior blepharotomy (9, 10). In addition, strabismus surgery for TED may affect corneal topography by changing the tension of EOMs or altering intraocular pressure (IOP) (16). While radiotherapy has demonstrated efficacy in reducing EOM volume and improving ocular motility restrictions (17, 18), its potential effects on ocular biomechanics remain unexplored, with no reported data currently available. This study aims to evaluate the corneal morphological and biomechanical changes in patients with TED, as well as to assess radiotherapy-induced alterations in these parameters.

This prospective clinical study enrolled patients with myopathic TED who were recruited from Shenzhen Eye Hospital between August 2023 and July 2024. Healthy individuals, matched in terms of age, sex, and spherical equivalent (SE), were enrolled simultaneously. The diagnosis of TED was made according to the European Group on Graves’ Orbitopathy (EUGOGO) consensus statement (3). The inclusion criteria were as follows: ① Age between 30 and 70 years; ② SE of less than 6.0 diopters; ③ Diagnosis of active TED with diplopia or restricted eye movement, confirmed by CT or MRI showing EOM enlargement; and ④ No corticosteroid medications, biologic agents, or immunosuppressive therapies for at least 3 months before the study. The exclusion criteria included: ① Systemic diseases, including other autoimmune disorders, hypertension, or diabetes; ② History of ophthalmic conditions such as glaucoma, diabetic retinopathy, or uveitis; ③ Previous ocular surgeries or trauma; and ④ History of contact lens use. The disease activity of TED was assessed according to the EUGOGO guidelines (3).

At present, research on corneal morphology and biomechanics in TED remains limited. Only a few studies have reported the effects of surgical and medical interventions on corneal biomechanical properties in TED patients (9, 15, 22). There is a lack of data regarding changes in corneal morphology and biomechanical parameters following radiotherapy in patients with TED. In this study, patients with myopathic TED were found to have steeper corneas and more irregular corneal morphologies compared to NCs. After radiotherapy, improvements in irregular corneal morphology and changes in corneal curvature were observed. Additionally, radiotherapy can effectively improve corneal hysteresis and orbital compliance in TED patients. Furthermore, correlation analyses indicated that reductions in IOP and proptosis contribute to the improvements of corneal hysteresis and orbital compliance following radiotherapy in TED patients.

TED is classified into two subtypes. Approximately two-thirds of TED patients exhibit adipose tissue proliferation, which manifests as proptosis, upper eyelid retraction, and ocular exposure (24). The remaining one-third exhibit a myopathic phenotype, characterized by restricted ocular movement and diplopia (25, 26). In this study, individuals with myopathic TED demonstrate steeper corneas, a more uneven distribution of corneal thickness, and exhibit more irregular corneal morphology, which is generally consistent with previous research (16). These corneal changes likely result from biomechanical effects secondary to EOM enlargement and restriction in myopathic TED. The increased muscular tension induces characteristic topographic changes, including peripheral flattening with central steepening, which consequently elevates the TBI and potentially increases the risk of keratoconus development. Therefore, regular longitudinal evaluation of corneal morphology and biomechanics in myopathic TED patients is recommended, especially those with additional ectasia risk factors.

For the corneal biomechanical parameters, our study identified significant reduced corneal hysteresis and orbital compliance in patients with myopathic TED. The ocular biomechanical properties of patients with TED can vary depending on the activity and severity of the condition. Inflammatory cytokine-mediated activation of keratocytes during active disease stages stimulates the production of matrix metalloproteinases, leading to stromal degradation. Additionally, elevated tear film osmolarity plays a role in these changes. Collectively, these mechanisms contribute to viscoelastic alterations, resulting in alterations in corneal hysteresis (10, 27, 28). As the disease progresses, pathological changes may occur, including the enlargement of EOMs, proliferation of orbital adipose tissue, and fibrosis of orbital connective tissue. In addition, the deposition of GAG, including chondroitin sulfate and hyaluronan, can lead to orbital interstitial edema. These factors collectively increase intraorbital pressure, which in turn contribute to elevated WEML by reducing orbital compliance (11, 12, 29, 30). Moreover, the direct mechanical compression of the eye globe by the enlarged EOMs further exacerbates these biomechanical changes (16).

Currently, radiotherapy has been widely adopted as a standard second-line therapeutic approach for TED, particularly for the myopathic type. Radiotherapy can induce lymphocyte apoptosis, thereby disrupting the inflammatory cycle and subsequently decreasing inflammation (31). Additionally, radiotherapy can inhibit fibroblast differentiation and reduce GAG accumulation, which in turn decreases the volume of EOM. This reduction can alleviate muscular tension and improve restricted ocular motility (32, 33). A retrospective study revealed that radiotherapy may induce minor flattening of the central cornea and a slight improvement in the surface asymmetry index in TED patients, although these changes were not statistically significant (16). In this study, observed changes in corneal morphology and curvature were observed, and these changes are likely attributable to the reduction in EOM volume and muscle tension following radiotherapy. The cornea is a crucial component of vision, and radiotherapy-induced alterations in corneal curvature may have a potential impact on visual function. Despite no change was observed in visual acuity and refraction following radiotherapy, the treatment might still impact visual quality by affecting higher-order aberrations. Further research is needed to fully elucidate these effects. In addition, we performed the first comparison of ocular biomechanics in TED patients before and after radiotherapy, revealing significant improvements in orbital compliance after radiotherapy. These effects may be attributed to radiotherapy-induced inhibition of radiation-sensitive lymphocyte activation, suppression of fibroblast proliferation, and reduction in GAG secretion, collectively leading to decreased orbital pressure and improved orbital compliance.

Correlation analyses revealed that reductions in proptosis contribute to improvements in ocular biomechanics. In myopathic TED, the primary feature is EOM enlargement without significant adipose tissue expansion (25). we speculate that the improvement in EOM enlargement due to radiotherapy, leading to a reduction in orbital contents, alleviation of globe protrusion, and decreased retrobulbar resistance, which consequently results in improved corneal hysteresis and orbital compliance.

The elevation of IOP in TED patients is linked to several factors, including increased episcleral venous pressure resulting from elevated intraorbital pressure, compression by enlarged and fibrotic EOMs, and increased deposition of GAG in the trabecular meshwork, which obstructs aqueous humor outflow (34–36). Radiotherapy reduces orbital inflammatory infiltration by inducing lymphocyte apoptosis and decreases intraorbital pressure, which subsequently lowers IOP (31). Additionally, radiotherapy may directly affect the IOP regulation system, including the trabecular meshwork and ciliary body (37). Higher IOP corresponds with increased corneal resistance and decreased WEML, as measured by the Corvis ST (23). Our study revealed a positive correlation between a reduction in IOP following radiotherapy and improvements in corneal hysteresis and orbital compliance, which is consistent with the findings of previous studies (9, 23). Furthermore, our study revealed significant reductions in A1 time and SP-A1, accompanied by increases in A1 velocity, A2 time, HC deformation amplitude, and DA ratio after radiotherapy. However, these alterations became non-significant after bIOP adjustment, suggesting that IOP may be a primary factor influencing these corneal biomechanical changes.

This study has several limitations. First, this study included only TED patients of the myopathic type, limiting the applicability of these findings to adipose type TED cases. Second, the follow-up period of 6 months was relatively short, necessitating extended observation periods in future studies. Third, progressive fibrotic remodeling may significantly influence corneal morphology and biomechanics in TED. While radiotherapy effectively reduces orbital inflammation and EOM volume, its specific effects on fibrotic processes and their subsequent impact on corneal properties require further investigation. Fourth, TED-associated changes in tear film dynamics could potentially affect corneal parameters. The possible modulation of tear film stability by radiotherapy and its subsequent effects on corneal properties need additional study to fully understand the treatment’s comprehensive ocular effects.

In conclusion, our study revealed that patients with myopathic TED exhibited steeper and more irregular corneas. Biomechanically, these patients demonstrated higher TBI, reduced corneal hysteresis and orbital compliance. Our findings suggest that myopathic TED patients with additional pre-existing risk factors for corneal ectatic disorders, particularly keratoconus, should undergo longitudinal assessments of their corneal morphological and biomechanical properties. Following radiotherapy, improvements were observed in both corneal irregularity and curvature, along with significant enhancements in ocular biomechanics. Our analysis revealed significant correlations between proptosis, IOP, and corneal biomechanical parameters. These findings suggest that ocular biomechanical properties may serve as potential biomarkers for evaluating treatment efficacy in TED management.