Predictive demographic and clinical features for the development of dysthyroid optic neuropathy in a multi-ethnic TED population: A Retrospective Cohort Study

Predictive demographic and clinical features for the development of dysthyroid optic neuropathy in a multi-ethnic TED population: A Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Predictive demographic and clinical features for the development of dysthyroid optic neuropathy in a multi-ethnic TED population: A Retrospective Cohort Study Malik Moledina FRCOpth, Vickie Lee FRCOpth, Ahmed Alnahrawy FRCOpth, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6284756/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jul, 2025 Read the published version in Thyroid Research → Version 1 posted 11 You are reading this latest preprint version Abstract Background Dysthyroid Optic Neuropathy (DON) is a sight-threatening complication of Thyroid Eye Disease (TED). This study aims to identify the risk and predictive factors for DON in a multi-ethnic TED cohort. Methods: Retrospective, cohort study of consecutive TED patients attending a multidisciplinary service over an 11-year period. Consecutive patients aged over 18 years old with a minimum of 6 months follow-up post-diagnosis of TED were included. We compared those patients with DON and those without (no-DON) to determine which factors were more prevalent in patients with DON. Results: There were 26 and 516 consecutive patients with DON and no-DON. The DON prevalence in the cohort was 5.0%. The DON group had a Mean Age at TED Diagnosis (MATD) of 57.8 vs 46.1 years in the no-DON group. The mean presenting CAS, TRAb and GDS were significantly higher 3.73±1.80, 2.76±1.05 and 11.31±11.90 vs 0.54±0.80, 0.48±0.90 and 6.95±9.22 in the DON compared to the no-DON group respectively (p=0.00, p=0.00 and p=0.04). On multivariable regression, we found the following risk factors for developing DON (Odds Ratios): MATD ≥53 years (5.2 p=0.00), presenting GDS ≥3 (7.5 p=0.00), diabetes (5.7 p=0.00), and baseline TRAb ≥5.0 IU/L (2.9 p=0.04). Conclusion: Patients with diabetes, increased MATD, and high presenting CAS, GDS, and TRAb are at increased risk of developing DON in our cohort. Presenting TRAb titres may be predictive and useful for risk stratification. Clinicians should be especially vigilant of the risk of sight-threatening complications in TED patients with more than one of the above risk factors. Dysthyroid Optic Neuropathy Thyroid Eye Disease Graves Orbitopathy Risk Factors Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Thyroid Eye Disease (TED) is an autoimmune orbital inflammatory disease usually associated with Graves’ Hyperthyroidism (GH). Previous studies have found that 20–50% of GH patients develop TED. 1 One of the most consequential complications of TED is Dysthyroid Optic Neuropathy (DON), which can result in severe and irreversible visual impairment in 3–5% of patients. 2 3 4 The pathophysiology of DON is secondary to an autoimmune-mediated inflammation causing volume expansion of the orbital tissues within the confined orbital cavity. This can lead to secondary vascular and mechanical compromise of the optic nerve due to extraocular muscle (EOM) enlargement at the orbital apex. 3 Timely recognition and management of DON are critical to achieving a good visual outcome. 5 A well-recognized challenge is the lack of a gold-standard diagnostic algorithm. Controversy surrounds which diagnostic parameters should be given the greatest weight, particularly in early or atypical DON. 5 There are limited peer-reviewed large cohort studies evaluating the risk factors for developing DON. 678 Our study aims to provide an in-depth comparative analysis of the predictive factors and characteristics of DON patients uniquely in a multi-ethnic TED population from a large metropolitan tertiary centre. We aim to assess novel risk factors such as presenting TRAb levels and diplopia, as defined by Gorman Scores, that have not yet been evaluated in the context of DON. We also aim to understand how the application of GoQoL relates to DON patients. Methods This is an anonymised retrospective, comparative study of patients within a multidisciplinary TED (MDTED) service covering two large metropolitan NHS hospital clusters: London North West University Healthcare and Imperial College Healthcare NHS Trusts. We included consecutive TED patients diagnosed within an 11-year period between 01 January 2011 and 1 January 2022. All patients were managed jointly by TED-specialist oculoplastic consultants (VL, AA, RJ) and endocrinology consultants (KM, VB and CF) alongside technicians for imaging, visual field and ocular motility assessment. An immunosuppression specialist (RA) advised on non-steroidal immunosuppression treatment. The study was approved by the audit department and adhered to the Declaration of Helsinki and all laws in the United Kingdom. Data was extracted from a TED database populated contemporaneously following each clinic visit. Prospective data collection at each clinic visit included thyroid diagnosis (GH, hypothyroidism, Hashimotos or euthyroid) and thyroid status (euthyroid, hyper or hypothyroid). Treatment (medical management, radio-iodine (RAI), thyroidectomy or no treatment), TED severity (EUGOGO criteria: mild, moderate-severe or sight-threatening), Gorman diplopia score, 9 clinical activity score: CAS 10 , the quality of life Assessment: GoQoL 11 were also recorded. Previous and current treatments, including systemic immunosuppression, orbital radiotherapy and orbital decompression surgery, were also recorded. Active hyperthyroidism was defined as an elevated T3 or T4 level above the normal range. Further retrospective data collection included demographics ( age at TED diagnosis, ethnicity, gender, smoking status), clinical parameters (clinical history, diabetes mellitus (DM) status, visual acuity, RAPD status, colour vision, exophthalmometry, visual field assessment) and results of investigations (MRI radiological parameters and TRAb). The TRAb utilised is a human monoclonal autoantibody to the TSHR identifying blocking and stimulatory antibodies, labelled with biotin (M22-Biotin) where < 0.4 IU/Litre is considered negative). Inclusion criteria for the study: Age ≥ 18 years with a clinical diagnosis of TED with a minimum of 6 months follow-up following diagnosis. Exclusion criteria were: endocrinology input not based at either site and/or diagnosis of TED/DON in doubt, and/or significant co-existing ocular or general pathology, which could distort outcome measures and natural history, and/or insufficient data. (Fig. 2 ) DON was defined using modified criteria as per Khong et al. and Dayan et al. 712 DON was diagnosed by two of the following criteria: 1. decline of visual acuity of ≥ 1 line or ≥ 5 letters, 2. reduction in colour vision, 3 The presence of a Relative Afferent Pupillary Defect (RAPD), 4. optic disc swelling/abnormalities (without other ascribable causes), 5. MRI changes consistent with DON 13 , and 6. Visual field (VF) changes correlated with DON (utilizing Mean Deviation, common identifiable VF patterns found in DON 1415 without an alternative assignable cause and correlation to orbital imaging) AND without other attributable causes, e.g. cataract, ocular surface changes, retinal disease. Confounding variables were reviewed, and contributions were assessed to visual assessment. Where any doubt existed as to the contribution such confounders had on the decline in vision, these cases were excluded. 12 Baseline vision was determined from prior available notes or recent assessments from an ophthalmic professional, e.g., an optometrist visit. When diagnosing DON, the authors were cognisant of the formula developed by Callahan et al. and applied the tool where appropriate in conjunction with clinical judgement. 16 The standard of care for our TED patients is outlined in the EUGOGO (consensus) guidelines. 17 For DON patients, 1g intravenous methylprednisolone (IVMP) infusions administered over three days were performed with subsequent review. Treatment responders were moved onto the EUGOGO 12-week IVMP protocol in conjunction with an approved second-line agent. Usual second-line treatments included a 12–18 month course of mycophenolate mofetil (MMF) and/ or orbital radiotherapy. Non-responders or flares (defined as a deterioration of any of the DON diagnostic parameters) on immunosuppression underwent an endonasal medial wall orbital decompression and then were treated with the same regimen as above. Patients remain in the MDTED service until rehabilitative surgery, when they are transferred to the general oculoplastic surgical services, so the last follow-up visits recorded for this study are prior to any elective surgical intervention. The study approved by the institutional audit department was conducted by the tenets of the Declaration of Helsinki and all laws in the United Kingdom. Statistical analysis Patients were divided into two cohorts: those with DON and those without (no-DON). With continuous variables, normality was assessed using a histogram plot, Shapiro-Wilk and Kolmogorov-Smirnov Tests. Where normality existed (e.g age), an independent t-test was performed; otherwise, non-parametric equivalents were utilised, such as a Mann-Whitney U Test (e.g. TRAb and GoQoL). Categorical data (all other variables) were compared using Pearson’s Chi-Square/Fisher’s exact test. When a variable was < 5, Fisher’s Exact Test was performed. Univariable and multivariable binary logistic regression analyses were performed on all factors that were statistically significant and likely predictive of DON. Factors initially underwent univariable analysis (UVA), with those achieving significance proceeding to multivariable regression (MVA). Studies have shown CAS correlated to TRAb. 18 Therefore, CAS did not undergo multivariable regression due to multi-collinearity risk. Differences were considered statistically significant, where p < 0.05. Analyses were performed with SPSS V.24.0 (IBM SPSS Statistics for Macintosh). Results There were 26 and 516 consecutive patients with DON and no-DON. The mean follow-up at review for the DON group was 30.5 months compared to the Non-DON group, which was 25.2 months. The DON prevalence was 5.0%, with 84.6% (22/26) with bilateral DON in the cohort. 33.8% (157/464) of patients were Caucasian, 22% (110/500) were male, 25.8% (122/474) were active smokers, and 29.7% (159/535) were hyperthyroid at TED diagnosis. 15.3% (70/459) of patients had prior radioiodine treatment, and 9.5% (37/388) had concurrent diabetes mellitus (DM). In the DON group, 92.3% (24/26) of patients were started on steroid treatment, with only two patients where this was contraindicated. Mycophenolate mofetil was utilised in 65.4% (17/26), 30.8% (8/26) were treated with orbital radiotherapy and 7.7% (2/26) were treated with Ciclosporin; Urgent orbital decompression surgery was undertaken in 53.8% (14/26) of patients. The mean presenting CAS at TED diagnosis was 3.73 (± 1.80) in the DON group compared to 0.54 (± 0.80) in the no-DON group (p = 0.00). The mean CAS at DON diagnosis was 3.52 (± 1.72) in the DON group. The mean presenting diplopia score (Gorman) in the DON group at TED diagnosis was 2.76 ± 1.05 (SD) compared to 0.48 ± 0.90 in the no-DON group (p = 0.00). The mean GoQoL appearance score at the last follow-up visit in the DON group was 34.38 ± 33.66 compared to 64.49 ± 31.10 in the no-DON group (p = 0.00). The mean GoQoL visual function score at the last follow-up visit in the DON group was 41.80 ± 37.88 compared to 80.49 ± 25.38 in the no-DON group (p = 0.00). The mean TRAb at TED diagnosis for the DON cohort was 11.31 (± 11.90) compared to 6.95 (± 9.22) for the non-DON cohort (p = 0.04). The mean TRAb across all visits in the DON cohort was 9.19 (± 12.25) compared to 4.41 (± 7.22) in the no-DON group (p = 0.36). We identified the following risk factors for the development of DON on univariate analysis: MATD ≥ 53 years, presenting CAS ≥ 4, presenting diplopia score (Gorman) ≥ 3, DM, and baseline TRAb ≥ 5 IU/Litre. Risk factors identified on multivariate analysis: AATD ≥ 53 years, presenting diplopia score (Gorman) ≥ 3, DM, and baseline TRAb ≥ 5 IU/Litre. (Fig. 3 ) Discussion Our study provides a comparative analysis of the predictive and risk factors for developing DON in a multi-ethnic metropolitan TED cohort. Age at diagnosis of TED AATD We found a ten-year difference in MATD between DON and no-DON cohorts, with MATD ≥ 53 years having a 5.2 times increased odds of developing DON on multivariate regression. Our finding is relative to other studies with different ethnic make-ups. One study with a predominantly east asian cohort found a threefold increase in DON risk at an older age (≥ 55 years). 8 Another multicenter study, with a predominantly Caucasian cohort, found a 1.58 increased risk of DON with each decade rise in age of TED diagnosis. 7 Diabetes Mellitus (DM) There are conflicting reports in the literature regarding the role of diabetes in TED.. 6 19 20 21 . 22 In our study, 25% of DON patients had DM, similar to other studies that found DM prevalence at 25% and 19.23%. 623 We also found our TED DM patients had almost 6 times the risk of developing DON (p = 0.00). Other studies have observed patients with diabetes are at higher risk for recurrent DON and less responsive to conventional treatment. 819 20 Possible mechanisms may involve increased IGF-1 production in DM stimulating the co-located TSH-IGFR-1 receptor, leading to increased TED orbital inflammation. 24 DM-related micro-vasculopathy may also increase the risk of optic nerve hypoxia. 8 25 We recommend that all patients with DON have an HbA1c checked, and appropriate escalation in diabetes treatment for those found to have diabetes or pre-diabetes arranged with the introduction of glucocorticoid treatment. Clinical Activity Score (CAS) We found that a high CAS at TED diagnosis in our DON cohort (3.73 ± 1.80) increased the risk of developing DON by almost 7 times (p = 0.00). This trend was also observed in several other studies. 72226 Thyroid-Receptor Antibodies (TRAb) TRAb is the only biomarker for TED and is also widely used in predicting relapse of GH. Other published studies have found TRAb titres correlated with CAS so may be a possible predictor for future TED disease severity. However to our knowledge, presenting TRAb levels have not yet been investigated in relation to DON. 18272829 We found that our DON group had a higher baseline TRAb (p = 0.04) at presentation compared to the no DON group. On multivariate analysis, we found that TED patients presenting with a baseline TRAb ≥ 5 IU/Litre had an OR 2.939 of developing DON (p = 0.03). This may have clinical relevance in risk stratifying patients on presentation at risk of developing DON at a later stage. Gorman Diplopia Scoring GDS Studies have shown patients with DON have a greater propensity of having diplopia. Only one other study has evaluated strabismus as a predictive feature for developing DON. This study evaluated strabismus in terms of the Hirschberg test 26 7 . Our study has been the first to evaluate diplopia and its relationship to the development of DON utilising the Gorman score, a widely used, efficient and effective grading system for diplopia in the clinical setting. We found on multivariate analysis patients with constant diplopia (GDS 3) at TED diagnosis had an odds ratio of 7.5 of developing DON (p = 0.00). This can be correlated with the structural enlargement of the extraocular muscles, particularly the medial rectus and the superior muscle complex, which can lead to diplopia and increase DON risk due to the crowding at the orbital apex. 3015 Quality of Life Scores (Go-QoL) The Go-QoL is the only validated questionnaire for all levels of TED severity, but the literature is sparse when evaluating GoQoL in DON. 31 Our study found a significantly lower GoQoL (> 30 points ) at the last follow-up for both the visual function and appearance scores in the DON relative to the no-DON cohort. This is in the context of previously validated studies recommending a difference of 10 points should be considered clinically significant. 11 We identified 67% of post-DON patients in this study to have improved visual acuity and Ishihara colour vision back to ‘normal’ following treatment (Fig. 4 ). This discrepancy between our objective assessments and patient-reported subjective GoQoL measures are a novel finding in DON. The poor GoQoL visual function scores is likely to reflect the recognised discordance between objective clinical assessment and a patient’s lived experience of TED and may include subtle changes in colour vision particularly impacting tritan colours that Ishihara colour vision testing is not sensitive in detecting. 32 The persistence of diplopia in many patients may also be reflected in the low visual function scores. Moreover, it is well established that conventional immunosuppression does not improve proptosis 33 so continues to be reflected in the low GoQoL appearance scores before rehabilitation surgery. Our study did not identify gender or ethnicity as DON risk factors. Smoking is an established risk factor for developing TED, 34 and DON in some studies. 8 Our finding that smoking status did not appear to elevate DON risk correlates with a large Australian multicenter study with 1042 patients that found smoking status to be associated with increased odds of TED but not with DON. 7 Previous studies have shown that optimising thyroid status may reduce the chances of developing TED and also reduce severity, 35 whilst others have shown no association 3637 Our study did not find that a hyperthyroid status at TED diagnosis increased the risk of DON. The use of RAI in the treatment of GH is recognised as a risk factor for TED de-novo onset or exacerbation, 17 and in some studies increases the risk of DON, 2638 39 Our study did not show previous treatment with RAI increased the risk of DON and corroborates the findings from the Australian multi-centre study where TED risk following RAI was reduced from an odds ratio of 2.37 to 1.37 when other variables were controlled for in the multivariate analysis. 7 Nevertheless, it should be noted that our study, due to the relatively small number of DON patients despite the large overall cohort, has not been sufficiently powered to show such a difference. Limitations Our study is retrospective, non-blinded, with all inherent limitations that include missing data particularly inadequate visual field data. We have included all available data was included in the analysis. As far as we are aware, our study is the first to analyse the risk of presenting TRAb titres in a large multi-ethnic patient cohort. Conclusion We recommend increased vigilance for DON in TED patients with high presenting CAS and Gorman scores, higher TRAb titres, diabetes, and older age at TED diagnosis. Despite improved objective markers following DON treatment, many patients continue to have persistently low GoQoL scores. Declarations Ethics approval and consent to participate The study was approved by the institutional audit department and was conducted by the tenets of the Declaration of Helsinki and all laws in the United Kingdom. Consent for publication Not Applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request. Competing interests Miss Vickie Lee is the Principal Investigator for the Horizon, Viridian, Lassen and Sling Trials, BOPSS National Lead for Thyroid Eye Disease and has been a consultant for Horizon/Amgen and Viridian Pharmaceuticals. Mr Malik Moledina is: Sub Investigator for the Viridian, Horizon and Sling Trial. Miss Ourania Fydanaki, Miss Gabriella Guevara & Dr Nour Houbby are Sub Investigators for the Horizon Trial. Dr Claire Feeney is a Pfizer employee in an unrelated field since June 2018. This paper was recently presented at ESOPRS Rotterdam 2024, and formed part of the submission that went on to win the ESOPRS Richard Collins Prize 2024. Funding No funding was sought or obtained Authors' contributions All authors have made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND Drafting the work or revising it critically for important intellectual content; AND Final approval of the version to be published; Acknowledgements We would like to thank all members of the Thyroid Eye Disease Multi-Disciplinary team for their support. References Chin YH, Ng CH, Lee MH, Koh JWH, Kiew J, Yang SP, et al. Prevalence of thyroid eye disease in Graves’ disease: A meta‐analysis and systematic review. Clinical endocrinology (Oxford). 2020; 93 (4): 363–374. 10.1111/cen.14296. Garrity JA, Bahn RS. Pathogenesis of Graves Ophthalmopathy: Implications for Prediction, Prevention, and Treatment. American journal of ophthalmology. 2006; 142 (1): 147–153.e2. 10.1016/j.ajo.2006.02.047. Blandford AD, Zhang D, Chundury RV, Perry JD. Dysthyroid optic neuropathy: update on pathogenesis, diagnosis, and management. Expert review of ophthalmology. 2017; 12 (2): 111–121. 10.1080/17469899.2017.1276444. Wiersinga WM, Bartalena L. Epidemiology and Prevention of Graves' Ophthalmopathy. Thyroid. 2002; 12 (10): 855–860. 10.1089/105072502761016476. Wong Y, Dickinson J, Perros P, Dayan C, Veeramani P, Morris D, et al. A British Ophthalmological Surveillance Unit (BOSU) study into dysthyroid optic neuropathy in the United Kingdom. Eye (London). 2018; 32 (10): 1555–1562. 10.1038/s41433-018-0144-x. Poonam N, Alam M, Oberoi P, Mukherjee B. Dysthyroid optic neuropathy: Demographics, risk factors, investigations, and management outcomes. Indian journal of ophthalmology. 2022; 70 (12): 4419–4426. 10.4103/ijo.IJO_719_22. Khong JJ, Finch S, De Silva C, Rylander S, Craig JE, Selva D, et al. Risk Factors for Graves' Orbitopathy; the Australian Thyroid-Associated Orbitopathy Research (ATOR) Study. The journal of clinical endocrinology and metabolism. 2016; 101 (7): 2711–2720. 10.1210/jc.2015-4294. Kemchoknatee P, Thongsawangchai N, Srisombut T, Tangon D, Chantra S. Predictive factors of development of dysthyroid optic neuropathy among individuals with thyroid-eye disease. European journal of ophthalmology. 2023; 11206721231199868. 10.1177/11206721231199868. Bahn RS, Gorman CA. Choice of Therapy and Criteria for Assessing Treatment Outcome in Thyroid-associated Ophthalmopathy. Endocrinology and metabolism clinics of North America. 1987; 16 (2): 391–407. 10.1016/S0889-8529(18)30485-7. Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clinical endocrinology (Oxford). 1997; 47 (1): 9–14. 10.1046/j.1365-2265.1997.2331047.x. Terwee CB, Dekker FW, Mourits MP, Gerding MN, Baldeschi L, Kalmann R, et al. Interpretation and validity of changes in scores on the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clinical endocrinology (Oxford). 2001; 54 (3): 391–398. 10.1046/j.1365-2265.2001.01241.x. Dayan CM, Dayan MR. Dysthyroid optic neuropathy: a clinical diagnosis or a definable entity? British journal of ophthalmology. 2007; 91 (4): 409–410. 10.1136/bjo.2006.110932. Gonçalves ACP, Gebrim EMMS, Monteiro MLR. Imaging studies for diagnosing Graves’ orbitopathy and dysthyroid optic neuropathy. Clinics (São Paulo, Brazil). 2012; 67 (11): 1327–1334. 10.6061/clinics/2012(11)18. Choi CJ, Oropesa S, Callahan AB, Glass LR, Teo L, Cestari DM, et al. Patterns of visual field changes in thyroid eye disease. Orbit (Amsterdam). 2017; 36 (4): 201–207. 10.1080/01676830.2017.1314510. Starks VS, Reinshagen KL, Lee NG, Freitag SK. Visual field and orbital computed tomography correlation in dysthyroid optic neuropathy due to thyroid eye disease. Orbit. 2020; 39 (2): 77–83. 10.1080/01676830.2019.1600150. Callahan AB, Campbell AA, Oropesa S, Baraban A, Kazim M. The Columbia Thyroid Eye Disease-Compressive Optic Neuropathy Diagnostic Formula. Ophthalmic plastic and reconstructive surgery. 2018; 34 (4S Suppl 1): S68–S71. 10.1097/IOP.0000000000001128. Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, et al. The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. European journal of endocrinology. 2021; 185 (4): G43–G67. 10.1530/EJE-21-0479. Eckstein AK, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S, et al. Thyrotropin Receptor Autoantibodies Are Independent Risk Factors for Graves’ Ophthalmopathy and Help to Predict Severity and Outcome of the Disease. The journal of clinical endocrinology and metabolism. 2006; 91 (9): 3464–3470. 10.1210/jc.2005-2813. Rath S, Pattnaik M, Tripathy D, Mohapatra S, Panigrahy B, Ali MH. Sight-Threatening Thyroid Eye Disease: Role of Diabetes Mellitus and Interaction with Other Risk Factors. Ophthalmic plastic and reconstructive surgery. 2021; 37 (4): 352–360. 10.1097/IOP.0000000000001871. Ramamurthy L, Rangarajan V, Srirao N, Malini B, Bansal R, Yuvarajan K. Severity of thyroid eye disease and type-2 diabetes mellitus: Is there a correlation? Indian journal of ophthalmology. 2020; 68 (6): 1127–1131. 10.4103/ijo.IJO_1443_19. Gupta R, Thomas R, Almukhtar F, Kiran A. Visual morbidity in thyroid eye disease in Asian Indian patients. Indian journal of ophthalmology. 2020; 68 (8): 1622–1627. 10.4103/ijo.IJO_2284_19. Muralidhar A, Das S, Tiple S. Clinical profile of thyroid eye disease and factors predictive of disease severity. Indian journal of ophthalmology. 2020; 68 (8): 1629–1634. 10.4103/ijo.IJO_104_20. Jeon C, Shin JH, Woo KI, Kim Y. Clinical Profile and Visual Outcomes after Treatment in Patients with Dysthyroid Optic Neuropathy. Korean Journal of Ophthalmology : KJO. 2012; 26 (2): 73–79. 10.3341/kjo.2012.26.2.73. Le Moli R, Vella V, Tumino D, Piticchio T, Naselli A, Belfiore A, et al. Inflammasome activation as a link between obesity and thyroid disorders: Implications for an integrated clinical management. Frontiers in endocrinology (Lausanne). 2022; 13 959276. 10.3389/fendo.2022.959276. Kalmann R, Mourits MP. Diabetes mellitus: a risk factor in patients with Graves’ orbitopathy. British journal of ophthalmology. 1999; 83 (4): 463–465. 10.1136/bjo.83.4.463. McKeag D, Lane C, Lazarus JH, Baldeschi L, Boboridis K, Dickinson AJ, et al. Clinical features of dysthyroid optic neuropathy: a European Group on Graves’ Orbitopathy (EUGOGO) survey. British journal of ophthalmology. 2007; 91 (4): 455–458. 10.1136/bjo.2006.094607. Jeon H, Lee JY, Kim YJ, Lee MJ. Clinical relevance of thyroid-stimulating immunoglobulin as a biomarker of the activity of thyroid eye disease. Eye (London). 2023; 37 (3): 543–547. 10.1038/s41433-022-01981-z. Malik Moledina, Jonathan Roos, Rachna Murthy. Thyrotropin Receptor Autoantibody Assessment in Thyroid Eye Disease: Does the Assay Type Matter? Korean journal of ophthalmology. 2023; 37 (2): 147–156. https://scholar.kyobobook.co.kr/article/detail/4010047343547. . Ponto KA, Diana T, Binder H, Matheis N, Pitz S, Pfeiffer N, et al. Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy. Journal of endocrinological investigation. 2015; 38 (7): 769–777. 10.1007/s40618-015-0254-2. Feldon SE, Weiner JM. Clinical Significance of Extraocular Muscle Volumes in Graves' Ophthalmopathy: A Quantitative Computed Tomography Study. Archives of ophthalmology (1960). 1982; 100 (8): 1266–1269. 10.1001/archopht.1982.01030040244006. Uslar V, Becker C, Weyhe D, Tabriz N. Thyroid disease‐specific quality of life questionnaires ‐ A systematic review. Endocrinology, Diabetes & Metabolism. 2022; 5 (5): e357–n/a. 10.1002/edm2.357. Garip-Kuebler A, Halfter K, Reznicek L, Klingenstein A, Priglinger S, Hintschich CR. Subclinical dysthyroid optic neuropathy: tritan deficiency as an early sign of dysthyroid optic neuropathy. British journal of ophthalmology. 2021; 105 (7): 1019–1023. 10.1136/bjophthalmol-2020-316433. Douglas RS, Couch S, Wester ST, Fowler BT, Liu CY, Subramanian PS, et al. Efficacy and Safety of Teprotumumab in Patients With Thyroid Eye Disease of Long Duration and Low Disease Activity. The journal of clinical endocrinology and metabolism. 2023; 109 (1): 25–35. 10.1210/clinem/dgad637. Stan MN, Bahn RS. Risk Factors for Development or Deterioration of Graves' Ophthalmopathy. Thyroid (New York, N.Y.). 2010; 20 (7): 777–783. 10.1089/thy.2010.1634. Eckstein AK, Lösch C, Glowacka D, Schott M, Mann K, Esser J, et al. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy. British journal of ophthalmology. 2009; 93 (8): 1052–1056. 10.1136/bjo.2007.137265. Lee JH, Lee SY, Yoon JS. Risk Factors Associated with the Severity of Thyroid-Associated Orbitopathy in Korean Patients. Korean Journal of Ophthalmology : KJO. 2010; 24 (5): 267–273. 10.3341/kjo.2010.24.5.267. Hashizume K, Ichikawa K, Sakurai A, Suzuki S, Takeda T, Kobayashi M, et al. Administration of Thyroxine in Treated Graves' Disease. The New England journal of medicine. 1991; 324 (14): 947–953. 10.1056/NEJM199104043241403. Stein JD, Childers D, Gupta S, Talwar N, Nan B, Lee BJ, et al. Risk Factors for Developing Thyroid-Associated Ophthalmopathy Among Individuals With Graves Disease. JAMA ophthalmology. 2015; 133 (3): 290–296. 10.1001/jamaophthalmol.2014.5103. Sisson JC, Schipper MJ, Nelson CC, Freitas JE, Frueh BR. Radioiodine Therapy and Graves' Ophthalmopathy. Journal of Nuclear Medicine. 2008; 49 (6): 923–930. 10.2967/jnumed.107.049437. Additional Declarations Competing interest reported. Miss Vickie Lee is the Principal Investigator for the Horizon, Viridian, Lassen and Sling Trials, BOPSS National Lead for Thyroid Eye Disease and has been a consultant for Horizon/Amgen and Viridian Pharmaceuticals. Mr Malik Moledina is: Sub Investigator for the Viridian, Horizon and Sling Trial. Miss Ourania Fydanaki, Miss Gabriella Guevara & Dr Nour Houbby are Sub Investigators for the Horizon Trial. Dr Claire Feeney is a Pfizer employee in an unrelated field since June 2018. This paper was recently presented at ESOPRS Rotterdam 2024, and formed part of the submission that went on to win the ESOPRS Richard Collins Prize 2024. Cite Share Download PDF Status: Published Journal Publication published 22 Jul, 2025 Read the published version in Thyroid Research → Version 1 posted Editorial decision: Revision requested 01 Apr, 2025 Reviews received at journal 01 Apr, 2025 Reviewers agreed at journal 28 Mar, 2025 Reviews received at journal 26 Mar, 2025 Reviewers agreed at journal 26 Mar, 2025 Reviewers agreed at journal 26 Mar, 2025 Reviewers agreed at journal 26 Mar, 2025 Reviewers invited by journal 26 Mar, 2025 Editor assigned by journal 24 Mar, 2025 Submission checks completed at journal 24 Mar, 2025 First submitted to journal 22 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6284756","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":436749899,"identity":"bd6cde80-1621-4989-b5e1-e454f5cdba73","order_by":0,"name":"Malik Moledina FRCOpth","email":"","orcid":"","institution":"Western Eye Hospital, Imperial College NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Malik","middleName":"Moledina","lastName":"FRCOpth","suffix":""},{"id":436749900,"identity":"2f10fa7d-ad67-41b4-b2fb-04409f04ca53","order_by":1,"name":"Vickie Lee FRCOpth","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYDACZiBMYGCQAbIOMJOkhYeBgS0BooWNGE0MYC08BsRpMTjO/NjgQQUDDz97z7fHBX8Y8vjlGwhoOcxmnJBwhoFHsufsduOZbQzFkm0EbJFs5mE+kNgGdNWN3G3SvA0MiRuOEaXlHwOP/f03z6R5/jAk7iekhZ+ZhzkhsQFoiwQPmzQPG9AWQt7nZ2YzNkg4JsEjcSbNTJq3TSJxxrEE/FrY+A8/lvxRYyPH334Y5DCbxP7mAwSsgQAJDMYoGAWjYBSMAkoAAKqnNPPIZ0zcAAAAAElFTkSuQmCC","orcid":"","institution":"Western Eye Hospital, Imperial College NHS Foundation Trust","correspondingAuthor":true,"prefix":"","firstName":"Vickie","middleName":"Lee","lastName":"FRCOpth","suffix":""},{"id":436749901,"identity":"2b631fe6-3b66-43c9-9434-ec79eec8f832","order_by":2,"name":"Ahmed Alnahrawy FRCOpth","email":"","orcid":"","institution":"Western Eye Hospital, Imperial College NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"Alnahrawy","lastName":"FRCOpth","suffix":""},{"id":436749902,"identity":"b1307001-da05-41f3-90b8-d03549c8e007","order_by":3,"name":"Ourania Fydanaki FRCOpth","email":"","orcid":"","institution":"Western Eye Hospital, Imperial College NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Ourania","middleName":"Fydanaki","lastName":"FRCOpth","suffix":""},{"id":436749903,"identity":"667befb4-c282-4da5-bf79-02d11242b175","order_by":4,"name":"Nicole George","email":"","orcid":"","institution":"Western Eye Hospital, Imperial College NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Nicole","middleName":"","lastName":"George","suffix":""},{"id":436749904,"identity":"ab83be2e-5c98-48d1-9340-97509f5bb732","order_by":5,"name":"Nour Hubby","email":"","orcid":"","institution":"St Mary’s Hospital, Imperial College Healthcare NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Nour","middleName":"","lastName":"Hubby","suffix":""},{"id":436749905,"identity":"d5c4ea04-5e3b-493f-9be0-cccc8387ed93","order_by":6,"name":"Daisy Metcalf","email":"","orcid":"","institution":"St Mary’s Hospital, Imperial College Healthcare NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Daisy","middleName":"","lastName":"Metcalf","suffix":""},{"id":436749906,"identity":"5f6c80bb-69b0-4abd-92f4-654648a3bc93","order_by":7,"name":"Natalie Man","email":"","orcid":"","institution":"St Mary’s Hospital, Imperial College Healthcare NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Natalie","middleName":"","lastName":"Man","suffix":""},{"id":436749907,"identity":"270ff13d-4eba-4796-a4c9-8cc2ea9b8306","order_by":8,"name":"Gabriella Guevara","email":"","orcid":"","institution":"Western Eye Hospital, Imperial College NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Gabriella","middleName":"","lastName":"Guevara","suffix":""},{"id":436749908,"identity":"212471bc-2e5e-46cc-9361-dc06d22349b8","order_by":9,"name":"Claire Feeney","email":"","orcid":"","institution":"St Mary’s Hospital, Imperial College Healthcare NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Claire","middleName":"","lastName":"Feeney","suffix":""},{"id":436749909,"identity":"02e1363f-cd91-46d2-8c85-2ef6011532a1","order_by":10,"name":"Rashmi Akshikar","email":"","orcid":"","institution":"Western Eye Hospital, Imperial College NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Rashmi","middleName":"","lastName":"Akshikar","suffix":""},{"id":436749910,"identity":"e0be2ae5-f52a-4415-a957-1f67ad29070a","order_by":11,"name":"Rajni Jain FRCOpth","email":"","orcid":"","institution":"Western Eye Hospital, Imperial College NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Rajni","middleName":"Jain","lastName":"FRCOpth","suffix":""},{"id":436749911,"identity":"b987d909-64ca-4f66-9e91-3195d7d1dcee","order_by":12,"name":"Ahmad Aziz FRCOpth","email":"","orcid":"","institution":"Western Eye Hospital, Imperial College NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Ahmad","middleName":"Aziz","lastName":"FRCOpth","suffix":""},{"id":436749912,"identity":"c6ab7fa2-6c0a-4769-9738-3c97191d5aa5","order_by":13,"name":"Vassiliki Bravis FRCP","email":"","orcid":"","institution":"St Mary’s Hospital, Imperial College Healthcare NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Vassiliki","middleName":"Bravis","lastName":"FRCP","suffix":""},{"id":436749913,"identity":"8202ddad-b923-41b7-aea0-3da6a95f2bad","order_by":14,"name":"Karim Meeran","email":"","orcid":"","institution":"St Mary’s Hospital, Imperial College Healthcare NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Karim","middleName":"","lastName":"Meeran","suffix":""}],"badges":[],"createdAt":"2025-03-22 16:38:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6284756/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6284756/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13044-025-00249-4","type":"published","date":"2025-07-22T15:57:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80306870,"identity":"31142931-5eef-48b1-b71a-2bc854773a50","added_by":"auto","created_at":"2025-04-10 10:23:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":335758,"visible":true,"origin":"","legend":"\u003cp\u003eDemographic, clinical and baseline characteristics of DON and non-DON TED patients.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6284756/v1/51237a666170437e0c8a5abc.png"},{"id":80306120,"identity":"e1334d41-7013-461a-8bd2-c438bfc05626","added_by":"auto","created_at":"2025-04-10 10:15:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":163917,"visible":true,"origin":"","legend":"\u003cp\u003eStrobe diagram depicting excluded participants\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6284756/v1/be6bf3301183ee38fdee0fa5.png"},{"id":80306129,"identity":"5e5bd814-3e2b-4b92-b0f6-4f25fa2caab1","added_by":"auto","created_at":"2025-04-10 10:15:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":308700,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariable and multivariable binary regression analysis of DON risk factors.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6284756/v1/e6a49d9584226bddbc192156.png"},{"id":80306124,"identity":"73def93f-e7c7-4aaa-9787-80ad7dc42fa3","added_by":"auto","created_at":"2025-04-10 10:15:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":152266,"visible":true,"origin":"","legend":"\u003cp\u003eRight: Pie chart of presenting signs and symptoms during the diagnosis of DON, Left: Proportion of patients recovered following treatment of DON.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-6284756/v1/4e19f2eb4785c9f806266ff8.png"},{"id":87757506,"identity":"78995c17-a74f-4a21-ac15-28313667b3ca","added_by":"auto","created_at":"2025-07-28 16:10:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1596309,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6284756/v1/9828362f-af41-4a99-9b04-a16c194d30c8.pdf"}],"financialInterests":"Competing interest reported. Miss Vickie Lee is the Principal Investigator for the Horizon, Viridian, Lassen and Sling Trials, BOPSS National Lead for Thyroid Eye Disease and has been a consultant for Horizon/Amgen and Viridian Pharmaceuticals. Mr Malik Moledina is: Sub Investigator for the Viridian, Horizon and Sling Trial. Miss Ourania Fydanaki, Miss Gabriella Guevara \u0026 Dr Nour Houbby are Sub Investigators for the Horizon Trial. Dr Claire Feeney is a Pfizer employee in an unrelated field since June 2018. This paper was recently presented at ESOPRS Rotterdam 2024, and formed part of the submission that went on to win the ESOPRS Richard Collins Prize 2024.","formattedTitle":"Predictive demographic and clinical features for the development of dysthyroid optic neuropathy in a multi-ethnic TED population: A Retrospective Cohort Study","fulltext":[{"header":"Background","content":"\u003cp\u003eThyroid Eye Disease (TED) is an autoimmune orbital inflammatory disease usually associated with Graves\u0026rsquo; Hyperthyroidism (GH). Previous studies have found that 20\u0026ndash;50% of GH patients develop TED.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e One of the most consequential complications of TED is Dysthyroid Optic Neuropathy (DON), which can result in severe and irreversible visual impairment in 3\u0026ndash;5% of patients.\u003csup\u003e2 3 4\u003c/sup\u003e The pathophysiology of DON is secondary to an autoimmune-mediated inflammation causing volume expansion of the orbital tissues within the confined orbital cavity. This can lead to secondary vascular and mechanical compromise of the optic nerve due to extraocular muscle (EOM) enlargement at the orbital apex.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Timely recognition and management of DON are critical to achieving a good visual outcome.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e A well-recognized challenge is the lack of a gold-standard diagnostic algorithm. Controversy surrounds which diagnostic parameters should be given the greatest weight, particularly in early or atypical DON. \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere are limited peer-reviewed large cohort studies evaluating the risk factors for developing DON.\u003csup\u003e678\u003c/sup\u003e Our study aims to provide an in-depth comparative analysis of the predictive factors and characteristics of DON patients uniquely in a multi-ethnic TED population from a large metropolitan tertiary centre. We aim to assess novel risk factors such as presenting TRAb levels and diplopia, as defined by Gorman Scores, that have not yet been evaluated in the context of DON. We also aim to understand how the application of GoQoL relates to DON patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis is an anonymised retrospective, comparative study of patients within a multidisciplinary TED (MDTED) service covering two large metropolitan NHS hospital clusters: London North West University Healthcare and Imperial College Healthcare NHS Trusts. We included consecutive TED patients diagnosed within an 11-year period between 01 January 2011 and 1 January 2022. All patients were managed jointly by TED-specialist oculoplastic consultants (VL, AA, RJ) and endocrinology consultants (KM, VB and CF) alongside technicians for imaging, visual field and ocular motility assessment. An immunosuppression specialist (RA) advised on non-steroidal immunosuppression treatment. The study was approved by the audit department and adhered to the Declaration of Helsinki and all laws in the United Kingdom.\u003c/p\u003e \u003cp\u003eData was extracted from a TED database populated contemporaneously following each clinic visit. Prospective data collection at each clinic visit included thyroid diagnosis (GH, hypothyroidism, Hashimotos or euthyroid) and thyroid status (euthyroid, hyper or hypothyroid). Treatment (medical management, radio-iodine (RAI), thyroidectomy or no treatment), TED severity (EUGOGO criteria: mild, moderate-severe or sight-threatening), Gorman diplopia score, \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e clinical activity score: CAS \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, the quality of life Assessment: GoQoL\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e were also recorded. Previous and current treatments, including systemic immunosuppression, orbital radiotherapy and orbital decompression surgery, were also recorded. Active hyperthyroidism was defined as an elevated T3 or T4 level above the normal range. Further retrospective data collection included demographics ( age at TED diagnosis, ethnicity, gender, smoking status), clinical parameters (clinical history, diabetes mellitus (DM) status, visual acuity, RAPD status, colour vision, exophthalmometry, visual field assessment) and results of investigations (MRI radiological parameters and TRAb). The TRAb utilised is a human monoclonal autoantibody to the TSHR identifying blocking and stimulatory antibodies, labelled with biotin (M22-Biotin) where \u0026lt;\u0026thinsp;0.4 IU/Litre is considered negative).\u003c/p\u003e \u003cp\u003eInclusion criteria for the study: Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years with a clinical diagnosis of TED with a minimum of 6 months follow-up following diagnosis. Exclusion criteria were: endocrinology input not based at either site and/or diagnosis of TED/DON in doubt, and/or significant co-existing ocular or general pathology, which could distort outcome measures and natural history, and/or insufficient data. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDON was defined using modified criteria as per Khong et al. and Dayan et al.\u003csup\u003e712\u003c/sup\u003e DON was diagnosed by \u003cb\u003etwo\u003c/b\u003e of the following criteria: 1. decline of visual acuity of \u0026ge;\u0026thinsp;1 line or \u0026ge;\u0026thinsp;5 letters, 2. reduction in colour vision, 3 The presence of a Relative Afferent Pupillary Defect (RAPD), 4. optic disc swelling/abnormalities (without other ascribable causes), 5. MRI changes consistent with DON \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, and 6. Visual field (VF) changes correlated with DON (utilizing Mean Deviation, common identifiable VF patterns found in DON\u003csup\u003e1415\u003c/sup\u003e without an alternative assignable cause and correlation to orbital imaging) AND \u003cb\u003ewithout\u003c/b\u003e other attributable causes, e.g. cataract, ocular surface changes, retinal disease. Confounding variables were reviewed, and contributions were assessed to visual assessment. Where any doubt existed as to the contribution such confounders had on the decline in vision, these cases were excluded.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Baseline vision was determined from prior available notes or recent assessments from an ophthalmic professional, e.g., an optometrist visit. When diagnosing DON, the authors were cognisant of the formula developed by Callahan et al. and applied the tool where appropriate in conjunction with clinical judgement. \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe standard of care for our TED patients is outlined in the EUGOGO (consensus) guidelines.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e For DON patients, 1g intravenous methylprednisolone (IVMP) infusions administered over three days were performed with subsequent review. Treatment responders were moved onto the EUGOGO 12-week IVMP protocol in conjunction with an approved second-line agent. Usual second-line treatments included a 12\u0026ndash;18 month course of mycophenolate mofetil (MMF) and/ or orbital radiotherapy. Non-responders or flares (defined as a deterioration of any of the DON diagnostic parameters) on immunosuppression underwent an endonasal medial wall orbital decompression and then were treated with the same regimen as above. Patients remain in the MDTED service until rehabilitative surgery, when they are transferred to the general oculoplastic surgical services, so the last follow-up visits recorded for this study are prior to any elective surgical intervention.\u003c/p\u003e \u003cp\u003eThe study approved by the institutional audit department was conducted by the tenets of the Declaration of Helsinki and all laws in the United Kingdom.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePatients were divided into two cohorts: those with DON and those without (no-DON). With continuous variables, normality was assessed using a histogram plot, Shapiro-Wilk and Kolmogorov-Smirnov Tests. Where normality existed (e.g age), an independent t-test was performed; otherwise, non-parametric equivalents were utilised, such as a Mann-Whitney U Test (e.g. TRAb and GoQoL). Categorical data (all other variables) were compared using Pearson\u0026rsquo;s Chi-Square/Fisher\u0026rsquo;s exact test. When a variable was \u0026lt;\u0026thinsp;5, Fisher\u0026rsquo;s Exact Test was performed. Univariable and multivariable binary logistic regression analyses were performed on all factors that were statistically significant and likely predictive of DON. Factors initially underwent univariable analysis (UVA), with those achieving significance proceeding to multivariable regression (MVA). Studies have shown CAS correlated to TRAb.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Therefore, CAS did not undergo multivariable regression due to multi-collinearity risk. Differences were considered statistically significant, where p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Analyses were performed with SPSS V.24.0 (IBM SPSS Statistics for Macintosh).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThere were 26 and 516 consecutive patients with DON and no-DON. The mean follow-up at review for the DON group was 30.5 months compared to the Non-DON group, which was 25.2 months. The DON prevalence was 5.0%, with 84.6% (22/26) with bilateral DON in the cohort. 33.8% (157/464) of patients were Caucasian, 22% (110/500) were male, 25.8% (122/474) were active smokers, and 29.7% (159/535) were hyperthyroid at TED diagnosis. 15.3% (70/459) of patients had prior radioiodine treatment, and 9.5% (37/388) had concurrent diabetes mellitus (DM).\u003c/p\u003e \u003cp\u003eIn the DON group, 92.3% (24/26) of patients were started on steroid treatment, with only two patients where this was contraindicated. Mycophenolate mofetil was utilised in 65.4% (17/26), 30.8% (8/26) were treated with orbital radiotherapy and 7.7% (2/26) were treated with Ciclosporin; Urgent orbital decompression surgery was undertaken in 53.8% (14/26) of patients.\u003c/p\u003e \u003cp\u003eThe mean presenting CAS at TED diagnosis was 3.73 (\u0026plusmn;\u0026thinsp;1.80) in the DON group compared to 0.54 (\u0026plusmn;\u0026thinsp;0.80) in the no-DON group (p\u0026thinsp;=\u0026thinsp;0.00). The mean CAS at DON diagnosis was 3.52 (\u0026plusmn;\u0026thinsp;1.72) in the DON group. The mean presenting diplopia score (Gorman) in the DON group at TED diagnosis was 2.76\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05 (SD) compared to 0.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90 in the no-DON group (p\u0026thinsp;=\u0026thinsp;0.00). The mean GoQoL appearance score at the last follow-up visit in the DON group was 34.38\u0026thinsp;\u0026plusmn;\u0026thinsp;33.66 compared to 64.49\u0026thinsp;\u0026plusmn;\u0026thinsp;31.10 in the no-DON group (p\u0026thinsp;=\u0026thinsp;0.00). The mean GoQoL visual function score at the last follow-up visit in the DON group was 41.80\u0026thinsp;\u0026plusmn;\u0026thinsp;37.88 compared to 80.49\u0026thinsp;\u0026plusmn;\u0026thinsp;25.38 in the no-DON group (p\u0026thinsp;=\u0026thinsp;0.00).\u003c/p\u003e \u003cp\u003eThe mean TRAb at TED diagnosis for the DON cohort was 11.31 (\u0026plusmn;\u0026thinsp;11.90) compared to 6.95 (\u0026plusmn;\u0026thinsp;9.22) for the non-DON cohort (p\u0026thinsp;=\u0026thinsp;0.04). The mean TRAb across all visits in the DON cohort was 9.19 (\u0026plusmn;\u0026thinsp;12.25) compared to 4.41 (\u0026plusmn;\u0026thinsp;7.22) in the no-DON group (p\u0026thinsp;=\u0026thinsp;0.36).\u003c/p\u003e \u003cp\u003eWe identified the following risk factors for the development of DON on univariate analysis: MATD\u0026thinsp;\u0026ge;\u0026thinsp;53 years, presenting CAS\u0026thinsp;\u0026ge;\u0026thinsp;4, presenting diplopia score (Gorman)\u0026thinsp;\u0026ge;\u0026thinsp;3, DM, and baseline TRAb\u0026thinsp;\u0026ge;\u0026thinsp;5 IU/Litre. Risk factors identified on multivariate analysis: AATD\u0026thinsp;\u0026ge;\u0026thinsp;53 years, presenting diplopia score (Gorman)\u0026thinsp;\u0026ge;\u0026thinsp;3, DM, and baseline TRAb\u0026thinsp;\u0026ge;\u0026thinsp;5 IU/Litre. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study provides a comparative analysis of the predictive and risk factors for developing DON in a multi-ethnic metropolitan TED cohort.\u003c/p\u003e\n\u003ch3\u003eAge at diagnosis of TED AATD\u003c/h3\u003e\n\u003cp\u003eWe found a ten-year difference in MATD between DON and no-DON cohorts, with MATD\u0026thinsp;\u0026ge;\u0026thinsp;53 years having a 5.2 times increased odds of developing DON on multivariate regression. Our finding is relative to other studies with different ethnic make-ups. One study with a predominantly east asian cohort found a threefold increase in DON risk at an older age (\u0026ge;\u0026thinsp;55 years).\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Another multicenter study, with a predominantly Caucasian cohort, found a 1.58 increased risk of DON with each decade rise in age of TED diagnosis.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eDiabetes Mellitus (DM)\u003c/h3\u003e\n\u003cp\u003eThere are conflicting reports in the literature regarding the role of diabetes in TED..\u003csup\u003e6 19 20 21\u003c/sup\u003e .\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e In our study, 25% of DON patients had DM, similar to other studies that found DM prevalence at 25% and 19.23%.\u003csup\u003e623\u003c/sup\u003e We also found our TED DM patients had almost 6 times the risk of developing DON (p\u0026thinsp;=\u0026thinsp;0.00). Other studies have observed patients with diabetes are at higher risk for recurrent DON and less responsive to conventional treatment.\u003csup\u003e819 20\u003c/sup\u003e Possible mechanisms may involve increased IGF-1 production in DM stimulating the co-located TSH-IGFR-1 receptor, leading to increased TED orbital inflammation. \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e DM-related micro-vasculopathy may also increase the risk of optic nerve hypoxia.\u003csup\u003e8 25\u003c/sup\u003e We recommend that all patients with DON have an HbA1c checked, and appropriate escalation in diabetes treatment for those found to have diabetes or pre-diabetes arranged with the introduction of glucocorticoid treatment.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eClinical Activity Score (CAS)\u003c/h2\u003e \u003cp\u003eWe found that a high CAS at TED diagnosis in our DON cohort (3.73\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80) increased the risk of developing DON by almost 7 times (p\u0026thinsp;=\u0026thinsp;0.00). This trend was also observed in several other studies.\u003csup\u003e72226\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eThyroid-Receptor Antibodies (TRAb)\u003c/h3\u003e\n\u003cp\u003eTRAb is the only biomarker for TED and is also widely used in predicting relapse of GH. Other published studies have found TRAb titres correlated with CAS so may be a possible predictor for future TED disease severity. However to our knowledge, presenting TRAb levels have not yet been investigated in relation to DON.\u003csup\u003e18272829\u003c/sup\u003e We found that our DON group had a higher baseline TRAb (p\u0026thinsp;=\u0026thinsp;0.04) at presentation compared to the no DON group. On multivariate analysis, we found that TED patients presenting with a baseline TRAb\u0026thinsp;\u0026ge;\u0026thinsp;5 IU/Litre had an OR 2.939 of developing DON (p\u0026thinsp;=\u0026thinsp;0.03). This may have clinical relevance in risk stratifying patients on presentation at risk of developing DON at a later stage.\u003c/p\u003e\n\u003ch3\u003eGorman Diplopia Scoring GDS\u003c/h3\u003e\n\u003cp\u003eStudies have shown patients with DON have a greater propensity of having diplopia. Only one other study has evaluated strabismus as a predictive feature for developing DON. This study evaluated strabismus in terms of the Hirschberg test\u003csup\u003e26 7\u003c/sup\u003e. Our study has been the first to evaluate diplopia and its relationship to the development of DON utilising the Gorman score, a widely used, efficient and effective grading system for diplopia in the clinical setting. We found on multivariate analysis patients with constant diplopia (GDS 3) at TED diagnosis had an odds ratio of 7.5 of developing DON (p\u0026thinsp;=\u0026thinsp;0.00). This can be correlated with the structural enlargement of the extraocular muscles, particularly the medial rectus and the superior muscle complex, which can lead to diplopia and increase DON risk due to the crowding at the orbital apex.\u003csup\u003e3015\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eQuality of Life Scores (Go-QoL)\u003c/h2\u003e \u003cp\u003eThe Go-QoL is the only validated questionnaire for all levels of TED severity, but the literature is sparse when evaluating GoQoL in DON.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Our study found a significantly lower GoQoL (\u0026gt;\u0026thinsp;30 points ) at the last follow-up for both the visual function and appearance scores in the DON relative to the no-DON cohort. This is in the context of previously validated studies recommending a difference of 10 points should be considered clinically significant.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e We identified 67% of post-DON patients in this study to have improved visual acuity and Ishihara colour vision back to \u0026lsquo;normal\u0026rsquo; following treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This discrepancy between our objective assessments and patient-reported subjective GoQoL measures are a novel finding in DON. The poor GoQoL visual function scores is likely to reflect the recognised discordance between objective clinical assessment and a patient\u0026rsquo;s lived experience of TED and may include subtle changes in colour vision particularly impacting tritan colours that Ishihara colour vision testing is not sensitive in detecting.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e The persistence of diplopia in many patients may also be reflected in the low visual function scores. Moreover, it is well established that conventional immunosuppression does not improve proptosis\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e so continues to be reflected in the low GoQoL appearance scores before rehabilitation surgery.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOur study did not identify gender or ethnicity as DON risk factors. Smoking is an established risk factor for developing TED,\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e and DON in some studies.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Our finding that smoking status did not appear to elevate DON risk correlates with a large Australian multicenter study with 1042 patients that found smoking status to be associated with increased odds of TED but not with DON.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Previous studies have shown that optimising thyroid status may reduce the chances of developing TED and also reduce severity,\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e whilst others have shown no association\u003csup\u003e3637\u003c/sup\u003e Our study did not find that a hyperthyroid status at TED diagnosis increased the risk of DON. The use of RAI in the treatment of GH is recognised as a risk factor for TED de-novo onset or exacerbation, \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003eand in some studies increases the risk of DON,\u003csup\u003e2638 39\u003c/sup\u003eOur study did not show previous treatment with RAI increased the risk of DON and corroborates the findings from the Australian multi-centre study where TED risk following RAI was reduced from an odds ratio of 2.37 to 1.37 when other variables were controlled for in the multivariate analysis.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Nevertheless, it should be noted that our study, due to the relatively small number of DON patients despite the large overall cohort, has not been sufficiently powered to show such a difference.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eOur study is retrospective, non-blinded, with all inherent limitations that include missing data particularly inadequate visual field data. We have included all available data was included in the analysis. As far as we are aware, our study is the first to analyse the risk of presenting TRAb titres in a large multi-ethnic patient cohort.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe recommend increased vigilance for DON in TED patients with high presenting CAS and Gorman scores, higher TRAb titres, diabetes, and older age at TED diagnosis. Despite improved objective markers following DON treatment, many patients continue to have persistently low GoQoL scores.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\n\u003cp\u003eThe study was approved by the institutional audit department and was conducted by the tenets of the Declaration of Helsinki and all laws in the United Kingdom. \u003c/p\u003e\n\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot Applicable \u003c/p\u003e\n\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\n\n\u003ch4\u003eCompeting interests\u003c/h4\u003e\n\n\u003cp\u003eMiss Vickie Lee is the Principal Investigator for the Horizon, Viridian, Lassen and Sling Trials, BOPSS National Lead for Thyroid Eye Disease and has been a consultant for Horizon/Amgen and Viridian Pharmaceuticals. Mr Malik Moledina is: Sub Investigator for the Viridian, Horizon and Sling Trial. Miss Ourania Fydanaki, Miss Gabriella Guevara \u0026amp; Dr Nour Houbby are Sub Investigators for the Horizon Trial. Dr Claire Feeney is a Pfizer employee in an unrelated field since June 2018. This paper was recently presented at ESOPRS Rotterdam 2024, and formed part of the submission that went on to win the ESOPRS Richard Collins Prize 2024.\u003c/p\u003e\n\n\u003ch4\u003eFunding\u003c/h4\u003e\n\n\u003cp\u003eNo funding was sought or obtained\u003c/p\u003e\n\n\n\n\u003ch4\u003eAuthors\u0026apos; contributions\u003c/h4\u003e\n\n\u003cp\u003eAll authors have made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND \u003cbr\u003e Drafting the work or revising it critically for important intellectual content; AND \u003cbr\u003e Final approval of the version to be published;\u003c/p\u003e\n\n\n\n\u003ch4\u003eAcknowledgements\u003c/h4\u003e\n\n\u003cp\u003eWe would like to thank all members of the Thyroid Eye Disease Multi-Disciplinary team for their support. \u003c/p\u003e\n\n\n\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChin YH, Ng CH, Lee MH, Koh JWH, Kiew J, Yang SP, et al. Prevalence of thyroid eye disease in Graves\u0026rsquo; disease: A meta‐analysis and systematic review. \u003cem\u003eClinical endocrinology (Oxford). \u003c/em\u003e2020; 93 (4): 363\u0026ndash;374. 10.1111/cen.14296.\u003c/li\u003e\n\u003cli\u003eGarrity JA, Bahn RS. Pathogenesis of Graves Ophthalmopathy: Implications for Prediction, Prevention, and Treatment. \u003cem\u003eAmerican journal of ophthalmology. \u003c/em\u003e2006; 142 (1): 147\u0026ndash;153.e2. 10.1016/j.ajo.2006.02.047.\u003c/li\u003e\n\u003cli\u003eBlandford AD, Zhang D, Chundury RV, Perry JD. Dysthyroid optic neuropathy: update on pathogenesis, diagnosis, and management. \u003cem\u003eExpert review of ophthalmology. \u003c/em\u003e2017; 12 (2): 111\u0026ndash;121. 10.1080/17469899.2017.1276444.\u003c/li\u003e\n\u003cli\u003eWiersinga WM, Bartalena L. Epidemiology and Prevention of Graves\u0026apos; Ophthalmopathy. \u003cem\u003eThyroid. \u003c/em\u003e2002; 12 (10): 855\u0026ndash;860. 10.1089/105072502761016476.\u003c/li\u003e\n\u003cli\u003eWong Y, Dickinson J, Perros P, Dayan C, Veeramani P, Morris D, et al. A British Ophthalmological Surveillance Unit (BOSU) study into dysthyroid optic neuropathy in the United Kingdom. \u003cem\u003eEye (London). \u003c/em\u003e2018; 32 (10): 1555\u0026ndash;1562. 10.1038/s41433-018-0144-x.\u003c/li\u003e\n\u003cli\u003ePoonam N, Alam M, Oberoi P, Mukherjee B. Dysthyroid optic neuropathy: Demographics, risk factors, investigations, and management outcomes. \u003cem\u003eIndian journal of ophthalmology. \u003c/em\u003e2022; 70 (12): 4419\u0026ndash;4426. 10.4103/ijo.IJO_719_22.\u003c/li\u003e\n\u003cli\u003eKhong JJ, Finch S, De Silva C, Rylander S, Craig JE, Selva D, et al. Risk Factors for Graves\u0026apos; Orbitopathy; the Australian Thyroid-Associated Orbitopathy Research (ATOR) Study. \u003cem\u003eThe journal of clinical endocrinology and metabolism. \u003c/em\u003e2016; 101 (7): 2711\u0026ndash;2720. 10.1210/jc.2015-4294.\u003c/li\u003e\n\u003cli\u003eKemchoknatee P, Thongsawangchai N, Srisombut T, Tangon D, Chantra S. Predictive factors of development of dysthyroid optic neuropathy among individuals with thyroid-eye disease. \u003cem\u003eEuropean journal of ophthalmology. \u003c/em\u003e2023; 11206721231199868. 10.1177/11206721231199868.\u003c/li\u003e\n\u003cli\u003eBahn RS, Gorman CA. Choice of Therapy and Criteria for Assessing Treatment Outcome in Thyroid-associated Ophthalmopathy. \u003cem\u003eEndocrinology and metabolism clinics of North America. \u003c/em\u003e1987; 16 (2): 391\u0026ndash;407. 10.1016/S0889-8529(18)30485-7.\u003c/li\u003e\n\u003cli\u003eMourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves\u0026apos; ophthalmopathy. \u003cem\u003eClinical endocrinology (Oxford). \u003c/em\u003e1997; 47 (1): 9\u0026ndash;14. 10.1046/j.1365-2265.1997.2331047.x.\u003c/li\u003e\n\u003cli\u003eTerwee CB, Dekker FW, Mourits MP, Gerding MN, Baldeschi L, Kalmann R, et al. Interpretation and validity of changes in scores on the Graves\u0026apos; ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. \u003cem\u003eClinical endocrinology (Oxford). \u003c/em\u003e2001; 54 (3): 391\u0026ndash;398. 10.1046/j.1365-2265.2001.01241.x.\u003c/li\u003e\n\u003cli\u003eDayan CM, Dayan MR. Dysthyroid optic neuropathy: a clinical diagnosis or a definable entity? \u003cem\u003eBritish journal of ophthalmology. \u003c/em\u003e2007; 91 (4): 409\u0026ndash;410. 10.1136/bjo.2006.110932.\u003c/li\u003e\n\u003cli\u003eGon\u0026ccedil;alves ACP, Gebrim EMMS, Monteiro MLR. Imaging studies for diagnosing Graves\u0026rsquo; orbitopathy and dysthyroid optic neuropathy. \u003cem\u003eClinics (S\u0026atilde;o Paulo, Brazil). \u003c/em\u003e2012; 67 (11): 1327\u0026ndash;1334. 10.6061/clinics/2012(11)18.\u003c/li\u003e\n\u003cli\u003eChoi CJ, Oropesa S, Callahan AB, Glass LR, Teo L, Cestari DM, et al. Patterns of visual field changes in thyroid eye disease. \u003cem\u003eOrbit (Amsterdam). \u003c/em\u003e2017; 36 (4): 201\u0026ndash;207. 10.1080/01676830.2017.1314510.\u003c/li\u003e\n\u003cli\u003eStarks VS, Reinshagen KL, Lee NG, Freitag SK. Visual field and orbital computed tomography correlation in dysthyroid optic neuropathy due to thyroid eye disease. \u003cem\u003eOrbit. \u003c/em\u003e2020; 39 (2): 77\u0026ndash;83. 10.1080/01676830.2019.1600150.\u003c/li\u003e\n\u003cli\u003eCallahan AB, Campbell AA, Oropesa S, Baraban A, Kazim M. The Columbia Thyroid Eye Disease-Compressive Optic Neuropathy Diagnostic Formula. \u003cem\u003eOphthalmic plastic and reconstructive surgery. \u003c/em\u003e2018; 34 (4S Suppl 1): S68\u0026ndash;S71. 10.1097/IOP.0000000000001128.\u003c/li\u003e\n\u003cli\u003eBartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, et al. The 2021 European Group on Graves\u0026rsquo; orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves\u0026rsquo; orbitopathy. \u003cem\u003eEuropean journal of endocrinology. \u003c/em\u003e2021; 185 (4): G43\u0026ndash;G67. 10.1530/EJE-21-0479.\u003c/li\u003e\n\u003cli\u003eEckstein AK, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S, et al. Thyrotropin Receptor Autoantibodies Are Independent Risk Factors for Graves\u0026rsquo; Ophthalmopathy and Help to Predict Severity and Outcome of the Disease. \u003cem\u003eThe journal of clinical endocrinology and metabolism. \u003c/em\u003e2006; 91 (9): 3464\u0026ndash;3470. 10.1210/jc.2005-2813.\u003c/li\u003e\n\u003cli\u003eRath S, Pattnaik M, Tripathy D, Mohapatra S, Panigrahy B, Ali MH. Sight-Threatening Thyroid Eye Disease: Role of Diabetes Mellitus and Interaction with Other Risk Factors. \u003cem\u003eOphthalmic plastic and reconstructive surgery. \u003c/em\u003e2021; 37 (4): 352\u0026ndash;360. 10.1097/IOP.0000000000001871.\u003c/li\u003e\n\u003cli\u003eRamamurthy L, Rangarajan V, Srirao N, Malini B, Bansal R, Yuvarajan K. Severity of thyroid eye disease and type-2 diabetes mellitus: Is there a correlation? \u003cem\u003eIndian journal of ophthalmology. \u003c/em\u003e2020; 68 (6): 1127\u0026ndash;1131. 10.4103/ijo.IJO_1443_19.\u003c/li\u003e\n\u003cli\u003eGupta R, Thomas R, Almukhtar F, Kiran A. Visual morbidity in thyroid eye disease in Asian Indian patients. \u003cem\u003eIndian journal of ophthalmology. \u003c/em\u003e2020; 68 (8): 1622\u0026ndash;1627. 10.4103/ijo.IJO_2284_19.\u003c/li\u003e\n\u003cli\u003eMuralidhar A, Das S, Tiple S. Clinical profile of thyroid eye disease and factors predictive of disease severity. \u003cem\u003eIndian journal of ophthalmology. \u003c/em\u003e2020; 68 (8): 1629\u0026ndash;1634. 10.4103/ijo.IJO_104_20.\u003c/li\u003e\n\u003cli\u003eJeon C, Shin JH, Woo KI, Kim Y. Clinical Profile and Visual Outcomes after Treatment in Patients with Dysthyroid Optic Neuropathy. \u003cem\u003eKorean Journal of Ophthalmology : KJO. \u003c/em\u003e2012; 26 (2): 73\u0026ndash;79. 10.3341/kjo.2012.26.2.73.\u003c/li\u003e\n\u003cli\u003eLe Moli R, Vella V, Tumino D, Piticchio T, Naselli A, Belfiore A, et al. Inflammasome activation as a link between obesity and thyroid disorders: Implications for an integrated clinical management. \u003cem\u003eFrontiers in endocrinology (Lausanne). \u003c/em\u003e2022; 13 959276. 10.3389/fendo.2022.959276.\u003c/li\u003e\n\u003cli\u003eKalmann R, Mourits MP. Diabetes mellitus: a risk factor in patients with Graves\u0026rsquo; orbitopathy. \u003cem\u003eBritish journal of ophthalmology. \u003c/em\u003e1999; 83 (4): 463\u0026ndash;465. 10.1136/bjo.83.4.463.\u003c/li\u003e\n\u003cli\u003eMcKeag D, Lane C, Lazarus JH, Baldeschi L, Boboridis K, Dickinson AJ, et al. Clinical features of dysthyroid optic neuropathy: a European Group on Graves\u0026rsquo; Orbitopathy (EUGOGO) survey. \u003cem\u003eBritish journal of ophthalmology. \u003c/em\u003e2007; 91 (4): 455\u0026ndash;458. 10.1136/bjo.2006.094607.\u003c/li\u003e\n\u003cli\u003eJeon H, Lee JY, Kim YJ, Lee MJ. Clinical relevance of thyroid-stimulating immunoglobulin as a biomarker of the activity of thyroid eye disease. \u003cem\u003eEye (London). \u003c/em\u003e2023; 37 (3): 543\u0026ndash;547. 10.1038/s41433-022-01981-z.\u003c/li\u003e\n\u003cli\u003eMalik Moledina, Jonathan Roos, Rachna Murthy. Thyrotropin Receptor Autoantibody Assessment in Thyroid Eye Disease: Does the Assay Type Matter? \u003cem\u003eKorean journal of ophthalmology. \u003c/em\u003e2023; 37 (2): 147\u0026ndash;156. https://scholar.kyobobook.co.kr/article/detail/4010047343547. .\u003c/li\u003e\n\u003cli\u003ePonto KA, Diana T, Binder H, Matheis N, Pitz S, Pfeiffer N, et al. Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy. \u003cem\u003eJournal of endocrinological investigation. \u003c/em\u003e2015; 38 (7): 769\u0026ndash;777. 10.1007/s40618-015-0254-2.\u003c/li\u003e\n\u003cli\u003eFeldon SE, Weiner JM. Clinical Significance of Extraocular Muscle Volumes in Graves\u0026apos; Ophthalmopathy: A Quantitative Computed Tomography Study. \u003cem\u003eArchives of ophthalmology (1960). \u003c/em\u003e1982; 100 (8): 1266\u0026ndash;1269. 10.1001/archopht.1982.01030040244006.\u003c/li\u003e\n\u003cli\u003eUslar V, Becker C, Weyhe D, Tabriz N. Thyroid disease‐specific quality of life questionnaires ‐ A systematic review. \u003cem\u003eEndocrinology, Diabetes \u0026amp; Metabolism. \u003c/em\u003e2022; 5 (5): e357\u0026ndash;n/a. 10.1002/edm2.357.\u003c/li\u003e\n\u003cli\u003eGarip-Kuebler A, Halfter K, Reznicek L, Klingenstein A, Priglinger S, Hintschich CR. Subclinical dysthyroid optic neuropathy: tritan deficiency as an early sign of dysthyroid optic neuropathy. \u003cem\u003eBritish journal of ophthalmology. \u003c/em\u003e2021; 105 (7): 1019\u0026ndash;1023. 10.1136/bjophthalmol-2020-316433.\u003c/li\u003e\n\u003cli\u003eDouglas RS, Couch S, Wester ST, Fowler BT, Liu CY, Subramanian PS, et al. Efficacy and Safety of Teprotumumab in Patients With Thyroid Eye Disease of Long Duration and Low Disease Activity. \u003cem\u003eThe journal of clinical endocrinology and metabolism. \u003c/em\u003e2023; 109 (1): 25\u0026ndash;35. 10.1210/clinem/dgad637.\u003c/li\u003e\n\u003cli\u003eStan MN, Bahn RS. Risk Factors for Development or Deterioration of Graves\u0026apos; Ophthalmopathy. \u003cem\u003eThyroid (New York, N.Y.). \u003c/em\u003e2010; 20 (7): 777\u0026ndash;783. 10.1089/thy.2010.1634.\u003c/li\u003e\n\u003cli\u003eEckstein AK, L\u0026ouml;sch C, Glowacka D, Schott M, Mann K, Esser J, et al. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy. \u003cem\u003eBritish journal of ophthalmology. \u003c/em\u003e2009; 93 (8): 1052\u0026ndash;1056. 10.1136/bjo.2007.137265.\u003c/li\u003e\n\u003cli\u003eLee JH, Lee SY, Yoon JS. Risk Factors Associated with the Severity of Thyroid-Associated Orbitopathy in Korean Patients. \u003cem\u003eKorean Journal of Ophthalmology : KJO. \u003c/em\u003e2010; 24 (5): 267\u0026ndash;273. 10.3341/kjo.2010.24.5.267.\u003c/li\u003e\n\u003cli\u003eHashizume K, Ichikawa K, Sakurai A, Suzuki S, Takeda T, Kobayashi M, et al. Administration of Thyroxine in Treated Graves\u0026apos; Disease. \u003cem\u003eThe New England journal of medicine. \u003c/em\u003e1991; 324 (14): 947\u0026ndash;953. 10.1056/NEJM199104043241403.\u003c/li\u003e\n\u003cli\u003eStein JD, Childers D, Gupta S, Talwar N, Nan B, Lee BJ, et al. Risk Factors for Developing Thyroid-Associated Ophthalmopathy Among Individuals With Graves Disease. \u003cem\u003eJAMA ophthalmology. \u003c/em\u003e2015; 133 (3): 290\u0026ndash;296. 10.1001/jamaophthalmol.2014.5103.\u003c/li\u003e\n\u003cli\u003eSisson JC, Schipper MJ, Nelson CC, Freitas JE, Frueh BR. Radioiodine Therapy and Graves\u0026apos; Ophthalmopathy. \u003cem\u003eJournal of Nuclear Medicine. \u003c/em\u003e2008; 49 (6): 923\u0026ndash;930. 10.2967/jnumed.107.049437.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"thyroid-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thyr","sideBox":"Learn more about [Thyroid Research](http://thyroidresearchjournal.biomedcentral.com/)","snPcode":"13044","submissionUrl":"https://submission.nature.com/new-submission/13044/3","title":"Thyroid Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Dysthyroid Optic Neuropathy, Thyroid Eye Disease, Graves Orbitopathy, Risk Factors","lastPublishedDoi":"10.21203/rs.3.rs-6284756/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6284756/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDysthyroid Optic Neuropathy (DON) is a sight-threatening complication of Thyroid Eye Disease (TED). This study aims to identify the risk and predictive factors for DON in a multi-ethnic TED cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRetrospective, cohort study of consecutive TED patients attending a multidisciplinary service over an 11-year period. Consecutive patients aged over 18 years old with a minimum of 6 months follow-up post-diagnosis of TED were included. We compared those patients with DON and those without (no-DON) to determine which factors were more prevalent in patients with DON.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were 26 and 516 consecutive patients with DON and no-DON. The DON prevalence in the cohort was 5.0%.\u003c/p\u003e\n\u003cp\u003eThe DON group had a Mean Age at TED Diagnosis (MATD) of 57.8 vs 46.1 years in the no-DON group. The mean presenting CAS, TRAb and GDS were significantly higher 3.73±1.80, 2.76±1.05 and 11.31±11.90 vs 0.54±0.80, 0.48±0.90 and 6.95±9.22 in the DON compared to the no-DON group respectively (p=0.00, p=0.00 and p=0.04). On multivariable regression, we found the following risk factors for developing DON (Odds Ratios): MATD ≥53 years (5.2 p=0.00), presenting GDS ≥3 (7.5 p=0.00), diabetes (5.7 p=0.00), and baseline TRAb ≥5.0 IU/L (2.9 p=0.04).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with diabetes, increased MATD, and high presenting CAS, GDS, and TRAb are at increased risk of developing DON in our cohort. Presenting TRAb titres may be predictive and useful for risk stratification. Clinicians should be especially vigilant of the risk of sight-threatening complications in TED patients with more than one of the above risk factors.\u003c/p\u003e","manuscriptTitle":"Predictive demographic and clinical features for the development of dysthyroid optic neuropathy in a multi-ethnic TED population: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-10 10:15:48","doi":"10.21203/rs.3.rs-6284756/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-01T08:21:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-01T07:35:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178720551957798361715229646064979159149","date":"2025-03-28T11:07:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-26T17:27:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"153228126210885206609039666541434066891","date":"2025-03-26T16:08:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"243388936180328359826881476876110406201","date":"2025-03-26T14:08:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"316658900269854688934263287308835663646","date":"2025-03-26T14:07:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-26T10:10:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-24T07:50:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-24T07:49:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Thyroid Research","date":"2025-03-22T16:35:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"thyroid-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thyr","sideBox":"Learn more about [Thyroid Research](http://thyroidresearchjournal.biomedcentral.com/)","snPcode":"13044","submissionUrl":"https://submission.nature.com/new-submission/13044/3","title":"Thyroid Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3da43e65-1d64-43c0-b151-f44b081b1a8c","owner":[],"postedDate":"April 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T16:09:36+00:00","versionOfRecord":{"articleIdentity":"rs-6284756","link":"https://doi.org/10.1186/s13044-025-00249-4","journal":{"identity":"thyroid-research","isVorOnly":false,"title":"Thyroid Research"},"publishedOn":"2025-07-22 15:57:42","publishedOnDateReadable":"July 22nd, 2025"},"versionCreatedAt":"2025-04-10 10:15:48","video":"","vorDoi":"10.1186/s13044-025-00249-4","vorDoiUrl":"https://doi.org/10.1186/s13044-025-00249-4","workflowStages":[]},"version":"v1","identity":"rs-6284756","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6284756","identity":"rs-6284756","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}