Misdiagnosis of Thyroid-Associated Ophthalmopathy: a case report and literature review

Misdiagnosis of Thyroid-Associated Ophthalmopathy: a case report and literature review | 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 Case Report Misdiagnosis of Thyroid-Associated Ophthalmopathy: a case report and literature review Na Miao, Ping Qian, Weimin He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4571254/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The sudden onset of painful diplopia necessitates careful consideration and diagnosis due to the extensive range of potential differential diagnoses. Patients with thyroid-associated ophthalmopathy (TAO) typically exhibit proptosis, eyelid edema, eyelid retraction, and lid lag, herein we report a case of TAO patient whose initial symptom was diplopia accompanied by pain; however, the absence of obvious eyelid signs led to an easily misdiagnosed condition. Case presentation A 42-year-old male patient presented to our neurology department with a four-month history of diplopia and eye pain. The diagnosis of TAO was made after a four-month period from the onset of diplopia. Local orbital injection of triamcinolone acetonide and precision radiotherapy were administered to the patient. Following treatment, there was a significant improvement in subjective symptoms, including diplopia and pain; however, complete recovery of eye mobility was not achieved. Conclusion For patients presenting with diplopia as the initial symptom, even in the absence of evident TAO eyelid signs, it is crucial to obtain a comprehensive medical history and conduct thyroid function tests along with orbital enhanced MRI scans to minimize the risk of misdiagnosis. Accurate early-stage diagnosis enables targeted treatment interventions, thereby optimizing patient prognosis. diplopia thyroid-associated ophthalmopathy orbital enhanced MRI Figures Figure 1 Figure 2 Introduction Thyroid-associated ophthalmopathy (TAO) is a complex autoimmune condition that affects the orbital tissues and is characterized by a variety of ocular manifestations, including eyelid retraction, eyelid swelling, and proptosis. Despite the well-established clinical features of TAO, a subset of patients may exhibit minimal or no eyelid signs, posing significant diagnostic challenges and potentially delaying early detection and treatment. This subset of patients is often misdiagnosed, leading to exacerbation of the disease and even potential permanent vision loss. Case report A 42-year-old male, presented to the hospital in June 2023 with a complaint of persistent painful diplopia for four months. Initially, the patient sought medical attention at a local eye clinic due to diplopia and eye pain lasting over ten days. However, no external abnormalities such as eyelid swelling, upper lid retraction, or conjunctival congestion were observed during the examination. The ophthalmologist conducted a computed tomography (CT) scan of the orbital cavity in the patient, revealing no discernible abnormalities. Consequently, the patient was subsequently referred to the neurology department for further investigation into potential associated cerebral pathologies. Following a hospitalization in the neurology ward, the patient underwent a comprehensive evaluation that included head MRI, cerebrospinal fluid analysis, and thyroid hormone tests. However, no abnormalities were detected and he was subsequently discharged. Despite this initial assessment, two months later the patient continued to experience diplopia and pain symptoms while also noting an inability of his left eye to move upward. Therefore, we arranged for the patient to return to our Neurology Department for further evaluation. During this follow-up visit, the patient exhibited mild upper eyelid swelling in the left eye, and thyroid receptor antibody (TRAb) testing yielded positive results; however, all other thyroid hormones and antibodies remained within normal ranges. Despite these findings, TAO was not initially considered by the neurologist who proceeded with additional investigations including electromyography, assessment of autoantibodies against neuromuscular diseases (anti-AChR IgG, anti-MuSK IgG, anti-LRP4 IgG, anti-RyR IgG, anti-Titin IgG), as well as mitochondrial myopathy gene testing; unfortunately yielding no positive outcomes. Subsequently, at the patient's request and through extensive multidisciplinary discussions involving endocrinologists, ophthalmologists and neurologists alike - a collaborative approach was adopted leading us to consider a diagnosis of TAO. The presence of proptosis, upper eyelid lag and eyelid retraction was not observed in either eye (C, E, E, Fig. 1 ). However, the left eye demonstrated a slight edema of upper eyelid. (C, Fig. 1 ), and limited upward mobility was noted in the left eye (A, Fig. 1 ). The patient's clinical active score (CAS) was recorded as 1[ 1 ]. Thyroid function tests, including thyroid-stimulating hormone (TSH), T3, T4, fT3, and fT4, demonstrated normal results. Additionally, anti-thyroglobulin antibodies (TGAb) and anti-thyroid peroxidase (TPOAb) were found to be negative; however, TRAb was detected as positive.Orbital enhanced MRI revealed thickening, enhancement, and edema of the inferior rectus muscle in the left eye. (A, B, C, Fig. 2 ). The patient received local periorbital injection of dexamethasone and precise orbital radiotherapy. After treatment, a 6-month follow-up showed significant improvement in eye pain and eyelid swelling (D, Fig. 1 ); however, diplopia and impaired eye movement did not fully recover (B, Fig. 1 ). Discussion Diplopia is a common symptom in both ophthalmology and neurology; however, accurate diagnosis is crucial when encountering such conditions in clinical practice. Diplopia often results from nerve impairment responsible for eye movement, including the oculomotor, trochlear, or abducens nerves. Other systemic conditions associated with diplopia include thyroid disease and myasthenia gravis[ 2 ]. TAO is an autoimmune disorder commonly associated with Graves' disease. Despite its widespread recognition as an autoimmune disorder, the pathogenesis of TAO remains elusive. In approximately 90% of cases, TAO is typically linked to hyperthyroidism; however, about 10% of TAO patients present in a euthyroid or hypothyroid state[ 3 , 4 ]. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSH-R). Autoantibody mimicry of hormone action at the TSH-R and aberrant signaling of TSH-R by TRAB cause Graves' disease. TRAb, pathognomonic for TAO, are present in every patient with TAO, and their concentration positively correlates with the severity and the activity of the disease[ 5 , 6 ]. In this case report, the patient's thyroid function test (TRAb) was positive while others were normal. However, it did not receive much attention from the doctors during the early stages of diagnosis. Typically, TAO presents with discernible ocular manifestations including proptosis, eyelid edema, eyelid retraction, and ocular motility disorders. Clinicians can usually establish an accurate diagnosis and provide appropriate treatment for patients exhibiting evident ocular signs during the early stages of the disease. However, accurately diagnosing TAO in patients without obvious eyelid signs and normal thyroid function poses a challenge for healthcare professionals. The patient initially presented with symptoms of diplopia and ocular pain, without evidence of eyelid retraction or obvious eyelid edema. Despite the presence of abnormal TRAb antibodies, thyroid function tests and orbital CT scans yielded normal results. In clinical practice, such cases are prone to being overlooked in the diagnosis of TAO. Therefore, neurologists should consider potential causes for diplopia other than TAO, including eyelid muscle nerve injury, myasthenia gravis, mitochondrial myopathy, etc., and conduct relevant tests to evaluate these conditions. Consequently, this may result in a delay in accurately diagnosing and treating the patient. TAO is the most common cause of orbital tissues inflammation, accounting for 60% of all orbital inflammatory conditions in the population aged 21–60 years, and for 40% in the population aged > 60 years[ 7 ]. In clinical practice, thyroid-associated orbitopathy should not be ignored in the treatment of diplopia in ophthalmology or neurology. Orbital enhanced MRI is a non-invasive medical imaging technique that can aid in the accurate diagnosis of TAO. In TAO patients, typical muscle belly fusiform enlargement and normal tendon can be observed on high-resolution MRI scans. This radiation-free method has long been utilized for assessing and differentiating TAO, providing detailed visualization of soft tissue abnormalities[ 8 ]. Numerous pathological changes can be visualized using MRI, encompassing inflammation, steatosis, and fibrosis. The EOMs typically exhibit edema, with the inflamed region displaying hyperintense signals on T2-weighted images (T2WI), which have been employed for evaluating the activity of TAO[ 9 ]. The T2 relaxation time reflects the tissue's water content and serves as a means to evaluate the extent of inflammatory edema[ 10 ]. Currently, the CAS score is commonly utilized for assessing TAO activity; however, in this case report, the patient's CAS score was only 1. Therefore, relying solely on the CAS score to evaluate disease activity would be inaccurate. Notably, MRI imaging revealed increased signal intensity of the left inferior rectus (Fig. 2 , B), indicating active inflammation in the patient. Consequently, appropriate treatment targeting EOMs inflammation was administered and resulted in significant alleviation of eye pain symptoms and improvement of diplopia. Hence, routine orbital enhanced MRI is highly recommended for such patients. The patient underwent a 4-month period from symptom onset to diagnosis without receiving any effective treatment. Eventually, the patient was referred to the largest comprehensive hospital in southwest China for diagnostic purposes. Following diagnosis, the patient received periorbital injection of triamcinolone acetonide and localized radiation therapy around the orbital region. Previous studies conducted at this center have reported that intramuscular triamcinolone acetonide injection is an efficacious and cost-effective treatment with minimal adverse effects for patients with TAO[ 11 ]. According to a consensus statement published in 2022 by the American Thyroid Association and the European Thyroid Association, radiotherapy is an efficacious treatment modality for active moderate to severe TAO, particularly when progressive diplopia is the predominant symptom[ 12 ]. Multiple studies have demonstrated that radiotherapy can effectively improve symptoms of TAO, including alleviating orbital pain, reducing diplopia, and improving ocular motility[ 13 , 14 ]. To summarize, in patients presenting with diplopia as the initial symptom, even in the absence of evident TAO eyelid signs, it is crucial to obtain a comprehensive medical history and conduct thyroid function tests, orbital enhanced MRI scans, etc., to minimize the risk of misdiagnosis. Accurate early-stage diagnosis enables targeted treatment interventions aimed at optimizing patient prognosis. Declarations Ethics approval and consent to participate Not applicable (No human experimentation is involved). Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Competing interests The authors declare no competing interests. Funding information: This research was supported by the Sichuan Science and Technology Program (NO.22KJPX0238). Author Contribution N.M. conceived the study, conducted the research, analyzed the data, and wrote the main manuscript text. P.Q. prepared figures 1-2. W.H. contributed to the experimental design, revised the manuscript, and interpreted the results. All authors reviewed the manuscript. Availability of data and materials All the data supporting our finding is contained within the manuscript. References Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach. Br J Ophthalmol. 1989;73:639–44. 10.1136/bjo.73.8.639 . Jain S. Diplopia: Diagnosis and management. Clinical medicine. (London England). 2022;22:104–6. 10.7861/clinmed.2022-0045 . Suzuki N, Noh JY, Kameda T, Yoshihara A, Ohye H, Suzuki M, Matsumoto M, Kunii Y, Iwaku K, Watanabe N, Mukasa K, Kozaki A, Inoue T, Sugino K, Ito K. Clinical course of thyroid function and thyroid associated-ophthalmopathy in patients with euthyroid Graves' disease. Clin Ophthalmol (Auckland NZ). 2018;12:739–46. 10.2147/opth.S158967 . Yoshihara A, Yoshimura Noh J, Nakachi A, Ohye H, Sato S, Sekiya K, Kosuga Y, Suzuki M, Matsumoto M, Kunii Y, Watanabe N, Mukasa K, Inoue Y, Ito K, Ito K. Severe thyroid-associated orbitopathy in Hashimoto's thyroiditis. Report of 2 cases. Endocr J. 2011;58:343–8. 10.1507/endocrj.k11e-019 . Diana T, Ponto KA, Kahaly GJ. Correction to: Thyrotropin receptor antibodies and Graves' orbitopathy. J Endocrinol Invest. 2022;45:233. 10.1007/s40618-021-01632-2 . Wolf J, Alt S, Krämer I, Kahaly GJ. A Novel Monoclonal Antibody Degrades the Thyrotropin Receptor Autoantibodies in Graves' Disease. Endocr practice: official J Am Coll Endocrinol Am Association Clin Endocrinologists. 2023;29:553–9. 10.1016/j.eprac.2023.04.002 . Perros P, Hegedüs L, Bartalena L, Marcocci C, Kahaly GJ, Baldeschi L, Salvi M, Lazarus JH, Eckstein A, Pitz S, Boboridis K, Anagnostis P, Ayvaz G, Boschi A, Brix TH, Currò N, Konuk O, Marinò M, Mitchell AL, Stankovic B, Törüner FB, von Arx G, Zarković M, Wiersinga WM. Graves' orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement. Orphanet J Rare Dis. 2017;12:72. 10.1186/s13023-017-0625-1 . Gontarz-Nowak K, Szychlińska M, Matuszewski W, Stefanowicz-Rutkowska M, Bandurska-Stankiewicz E. Current Knowledge on Graves' Orbitopathy. J Clin Med. 2020;10. 10.3390/jcm10010016 . Song C, Luo Y, Yu G, Chen H, Shen J. Current insights of applying MRI in Graves' ophthalmopathy. Front Endocrinol (Lausanne). 2022;13:991588. 10.3389/fendo.2022.991588 . Marinelli NL, Haughton VM, Muñoz A, Anderson PA. T2 relaxation times of intervertebral disc tissue correlated with water content and proteoglycan content. Spine. 2009;34:520–4. 10.1097/BRS.0b013e318195dd44 . Wang Y, Du B, Yang M, Zhu Y, He W. Peribulbar injection of glucocorticoids for thyroid-associated ophthalmopathy and factors affecting therapeutic effectiveness: A retrospective cohort study of 386 cases. Exp Ther Med. 2020;20:2031–8. 10.3892/etm.2020.8896 . Burch HB, Perros P, Bednarczuk T, Cooper DS, Dolman PJ, Leung AM, Mombaerts I, Salvi M, Stan MN. Management of thyroid eye disease: a Consensus Statement by the American Thyroid Association and the European Thyroid Association. Eur thyroid J. 2022;11. 10.1530/etj-22-0189 . Choi JH, Lee JK. Efficacy of orbital radiotherapy in moderate-to-severe active graves' orbitopathy including long-lasting disease: a retrospective analysis. Radiation Oncol (London England). 2020;15:220. 10.1186/s13014-020-01663-8 . Grassi P, Strianese D, Piscopo R, Pacelli R, Bonavolontà G. Radiotherapy for the treatment of thyroid eye disease-a prospective comparison: Is orbital radiotherapy a suitable alternative to steroids? Ir J Med Sci. 2017;186:647–52. 10.1007/s11845-016-1542-3 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. 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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-4571254","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":314370586,"identity":"993d9867-1ea5-466f-8024-e52c300dc761","order_by":0,"name":"Na Miao","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Miao","suffix":""},{"id":314370587,"identity":"fa680518-7378-4a96-8ec5-e595c8e28f80","order_by":1,"name":"Ping Qian","email":"","orcid":"","institution":"Sichuan Armed Police Corps Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Qian","suffix":""},{"id":314370588,"identity":"4a3da513-a4e9-49e2-be15-24c2794ab0e6","order_by":2,"name":"Weimin He","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACAxDxocJGzgDCtSBOC+OMM2nGBgzMIK4EcVqYedsOJ24Aa2EgQos5e4/pRqAt6dvZ+49u+FEgwcDf3p2AV4tlzxmzG0C/5O7sOcx2swfoMIkzZzfgd9iN3G03gbbkbriRzHaDB6jFQCKXgJb7b7fdBvol3QCo5eYforTc4AVrSQBpuU2cLWfyv4EcZrjhzGGz2zIGEjyE/XL8WBrI+/IGxxuf3Xzzx0aOv70XvxYMwEOa8lEwCkbBKBgFWAEA0R1QIPtEfXoAAAAASUVORK5CYII=","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":true,"prefix":"","firstName":"Weimin","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2024-06-12 15:17:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4571254/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4571254/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60184986,"identity":"2c73a005-535a-47b7-a188-cae29b09d3ec","added_by":"auto","created_at":"2024-07-12 18:39:17","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":210473,"visible":true,"origin":"","legend":"\u003cp\u003eExternal eye images of the patient were captured before treatment (A, C, E) and after treatment (B, D, F), encompassing upward gaze (A, B), forward gaze (C, D), and downward gaze (E, F).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4571254/v1/b09ae159c6cefa31af2aa84c.jpeg"},{"id":60184988,"identity":"c7ba9d83-84ef-4a1f-b7cc-a6e2aa110c3c","added_by":"auto","created_at":"2024-07-12 18:39:18","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":283773,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of pre- and post-treatment orbital MRI scans in patients (Images A, B, and C represent the pre-treatment stage, while images D, E, and F depict the post-treatment stage). The T1 coronal fat-suppressed enhanced scan reveals thickening of the inferior rectus muscle in the left eye with reduced enhancement signal after treatment (A, D; red arrow). The sagittal plane T1 fat-suppressed enhanced scan exhibits diminished enhancement of the inferior rectus muscle along with a reduction in size of hypertrophied muscles in the left eye (B, E, red arrow). The tendon of the left inferior rectus muscle appears normal (B; yellow arrow). The T2 axial fat-suppressed image demonstrates a decrease in high signal intensity and thickening of the muscle belly of the inferior rectus muscle in the left eye following treatment (C, F; red arrow).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4571254/v1/724b8bb05224a98da9947e45.jpeg"},{"id":62322156,"identity":"d51fd676-ac9c-490d-9b1d-bc3348785b19","added_by":"auto","created_at":"2024-08-13 01:59:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":734699,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4571254/v1/14042a98-9b61-49b3-a3cc-9a79b11332a4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Misdiagnosis of Thyroid-Associated Ophthalmopathy: a case report and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThyroid-associated ophthalmopathy (TAO) is a complex autoimmune condition that affects the orbital tissues and is characterized by a variety of ocular manifestations, including eyelid retraction, eyelid swelling, and proptosis. Despite the well-established clinical features of TAO, a subset of patients may exhibit minimal or no eyelid signs, posing significant diagnostic challenges and potentially delaying early detection and treatment. This subset of patients is often misdiagnosed, leading to exacerbation of the disease and even potential permanent vision loss.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eA 42-year-old male, presented to the hospital in June 2023 with a complaint of persistent painful diplopia for four months. Initially, the patient sought medical attention at a local eye clinic due to diplopia and eye pain lasting over ten days. However, no external abnormalities such as eyelid swelling, upper lid retraction, or conjunctival congestion were observed during the examination. The ophthalmologist conducted a computed tomography (CT) scan of the orbital cavity in the patient, revealing no discernible abnormalities. Consequently, the patient was subsequently referred to the neurology department for further investigation into potential associated cerebral pathologies. Following a hospitalization in the neurology ward, the patient underwent a comprehensive evaluation that included head MRI, cerebrospinal fluid analysis, and thyroid hormone tests. However, no abnormalities were detected and he was subsequently discharged.\u003c/p\u003e \u003cp\u003eDespite this initial assessment, two months later the patient continued to experience diplopia and pain symptoms while also noting an inability of his left eye to move upward. Therefore, we arranged for the patient to return to our Neurology Department for further evaluation. During this follow-up visit, the patient exhibited mild upper eyelid swelling in the left eye, and thyroid receptor antibody (TRAb) testing yielded positive results; however, all other thyroid hormones and antibodies remained within normal ranges. Despite these findings, TAO was not initially considered by the neurologist who proceeded with additional investigations including electromyography, assessment of autoantibodies against neuromuscular diseases (anti-AChR IgG, anti-MuSK IgG, anti-LRP4 IgG, anti-RyR IgG, anti-Titin IgG), as well as mitochondrial myopathy gene testing; unfortunately yielding no positive outcomes. Subsequently, at the patient's request and through extensive multidisciplinary discussions involving endocrinologists, ophthalmologists and neurologists alike - a collaborative approach was adopted leading us to consider a diagnosis of TAO.\u003c/p\u003e \u003cp\u003eThe presence of proptosis, upper eyelid lag and eyelid retraction was not observed in either eye (C, E, E, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). However, the left eye demonstrated a slight edema of upper eyelid. (C, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), and limited upward mobility was noted in the left eye (A, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The patient's clinical active score (CAS) was recorded as 1[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThyroid function tests, including thyroid-stimulating hormone (TSH), T3, T4, fT3, and fT4, demonstrated normal results. Additionally, anti-thyroglobulin antibodies (TGAb) and anti-thyroid peroxidase (TPOAb) were found to be negative; however, TRAb was detected as positive.Orbital enhanced MRI revealed thickening, enhancement, and edema of the inferior rectus muscle in the left eye. (A, B, C, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient received local periorbital injection of dexamethasone and precise orbital radiotherapy. After treatment, a 6-month follow-up showed significant improvement in eye pain and eyelid swelling (D, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e); however, diplopia and impaired eye movement did not fully recover (B, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDiplopia is a common symptom in both ophthalmology and neurology; however, accurate diagnosis is crucial when encountering such conditions in clinical practice. Diplopia often results from nerve impairment responsible for eye movement, including the oculomotor, trochlear, or abducens nerves. Other systemic conditions associated with diplopia include thyroid disease and myasthenia gravis[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. TAO is an autoimmune disorder commonly associated with Graves' disease. Despite its widespread recognition as an autoimmune disorder, the pathogenesis of TAO remains elusive. In approximately 90% of cases, TAO is typically linked to hyperthyroidism; however, about 10% of TAO patients present in a euthyroid or hypothyroid state[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSH-R). Autoantibody mimicry of hormone action at the TSH-R and aberrant signaling of TSH-R by TRAB cause Graves' disease. TRAb, pathognomonic for TAO, are present in every patient with TAO, and their concentration positively correlates with the severity and the activity of the disease[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In this case report, the patient's thyroid function test (TRAb) was positive while others were normal. However, it did not receive much attention from the doctors during the early stages of diagnosis.\u003c/p\u003e \u003cp\u003eTypically, TAO presents with discernible ocular manifestations including proptosis, eyelid edema, eyelid retraction, and ocular motility disorders. Clinicians can usually establish an accurate diagnosis and provide appropriate treatment for patients exhibiting evident ocular signs during the early stages of the disease. However, accurately diagnosing TAO in patients without obvious eyelid signs and normal thyroid function poses a challenge for healthcare professionals.\u003c/p\u003e \u003cp\u003eThe patient initially presented with symptoms of diplopia and ocular pain, without evidence of eyelid retraction or obvious eyelid edema. Despite the presence of abnormal TRAb antibodies, thyroid function tests and orbital CT scans yielded normal results. In clinical practice, such cases are prone to being overlooked in the diagnosis of TAO. Therefore, neurologists should consider potential causes for diplopia other than TAO, including eyelid muscle nerve injury, myasthenia gravis, mitochondrial myopathy, etc., and conduct relevant tests to evaluate these conditions. Consequently, this may result in a delay in accurately diagnosing and treating the patient.\u003c/p\u003e \u003cp\u003eTAO is the most common cause of orbital tissues inflammation, accounting for 60% of all orbital inflammatory conditions in the population aged 21\u0026ndash;60 years, and\u003c/p\u003e \u003cp\u003efor 40% in the population aged\u0026thinsp;\u0026gt;\u0026thinsp;60 years[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In clinical practice, thyroid-associated orbitopathy should not be ignored in the treatment of diplopia in ophthalmology or neurology. Orbital enhanced MRI is a non-invasive medical imaging technique that can aid in the accurate diagnosis of TAO. In TAO patients, typical muscle belly fusiform enlargement and normal tendon can be observed on high-resolution MRI scans. This radiation-free method has long been utilized for assessing and differentiating TAO, providing detailed visualization of soft tissue abnormalities[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Numerous pathological changes can be visualized using MRI, encompassing inflammation, steatosis, and fibrosis. The EOMs typically exhibit edema, with the inflamed region displaying hyperintense signals on T2-weighted images (T2WI), which have been employed for evaluating the activity of TAO[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The T2 relaxation time reflects the tissue's water content and serves as a means to evaluate the extent of inflammatory edema[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Currently, the CAS score is commonly utilized for assessing TAO activity; however, in this case report, the patient's CAS score was only 1. Therefore, relying solely on the CAS score to evaluate disease activity would be inaccurate. Notably, MRI imaging revealed increased signal intensity of the left inferior rectus (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, B), indicating active inflammation in the patient. Consequently, appropriate treatment targeting EOMs inflammation was administered and resulted in significant alleviation of eye pain symptoms and improvement of diplopia. Hence, routine orbital enhanced MRI is highly recommended for such patients.\u003c/p\u003e \u003cp\u003eThe patient underwent a 4-month period from symptom onset to diagnosis without receiving any effective treatment. Eventually, the patient was referred to the largest comprehensive hospital in southwest China for diagnostic purposes. Following diagnosis, the patient received periorbital injection of triamcinolone acetonide and localized radiation therapy around the orbital region. Previous studies conducted at this center have reported that intramuscular triamcinolone acetonide injection is an efficacious and cost-effective treatment with minimal adverse effects for patients with TAO[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. According to a consensus statement published in 2022 by the American Thyroid Association and the European Thyroid Association, radiotherapy is an efficacious treatment modality for active moderate to severe TAO, particularly when progressive diplopia is the predominant symptom[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Multiple studies have demonstrated that radiotherapy can effectively improve symptoms of TAO, including alleviating orbital pain, reducing diplopia, and improving ocular motility[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo summarize, in patients presenting with diplopia as the initial symptom, even in the absence of evident TAO eyelid signs, it is crucial to obtain a comprehensive medical history and conduct thyroid function tests, orbital enhanced MRI scans, etc., to minimize the risk of misdiagnosis. Accurate early-stage diagnosis enables targeted treatment interventions aimed at optimizing patient prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eNot applicable (No human experimentation is involved).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests\u003c/strong\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding information:\u003c/h2\u003e \u003cp\u003eThis research was supported by the Sichuan Science and Technology Program (NO.22KJPX0238).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eN.M. conceived the study, conducted the research, analyzed the data, and wrote the main manuscript text. P.Q. prepared figures 1-2. W.H. contributed to the experimental design, revised the manuscript, and interpreted the results. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eAll the data supporting our finding is contained within the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach. Br J Ophthalmol. 1989;73:639\u0026ndash;44. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bjo.73.8.639\u003c/span\u003e\u003cspan address=\"10.1136/bjo.73.8.639\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJain S. Diplopia: Diagnosis and management. Clinical medicine. 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Ir J Med Sci. 2017;186:647\u0026ndash;52. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11845-016-1542-3\u003c/span\u003e\u003cspan address=\"10.1007/s11845-016-1542-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"diplopia, thyroid-associated ophthalmopathy, orbital enhanced MRI","lastPublishedDoi":"10.21203/rs.3.rs-4571254/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4571254/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe sudden onset of painful diplopia necessitates careful consideration and diagnosis due to the extensive range of potential differential diagnoses. Patients with thyroid-associated ophthalmopathy (TAO) typically exhibit proptosis, eyelid edema, eyelid retraction, and lid lag, herein we report a case of TAO patient whose initial symptom was diplopia accompanied by pain; however, the absence of obvious eyelid signs led to an easily misdiagnosed condition.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e \u003cp\u003eA 42-year-old male patient presented to our neurology department with a four-month history of diplopia and eye pain. The diagnosis of TAO was made after a four-month period from the onset of diplopia. Local orbital injection of triamcinolone acetonide and precision radiotherapy were administered to the patient. Following treatment, there was a significant improvement in subjective symptoms, including diplopia and pain; however, complete recovery of eye mobility was not achieved.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eFor patients presenting with diplopia as the initial symptom, even in the absence of evident TAO eyelid signs, it is crucial to obtain a comprehensive medical history and conduct thyroid function tests along with orbital enhanced MRI scans to minimize the risk of misdiagnosis. Accurate early-stage diagnosis enables targeted treatment interventions, thereby optimizing patient prognosis.\u003c/p\u003e","manuscriptTitle":"Misdiagnosis of Thyroid-Associated Ophthalmopathy: a case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-12 18:39:04","doi":"10.21203/rs.3.rs-4571254/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"06b752ff-6bf9-4ea8-9ccd-76b55b493064","owner":[],"postedDate":"July 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-13T01:51:14+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-12 18:39:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4571254","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4571254","identity":"rs-4571254","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}