Nour Houbby, Osama Munajjed
Thyroid eye disease (TED) is an autoimmune inflammatory disorder of the orbit related to autoimmune thyroid disease (1). It results in several disabling ocular sequelae, significant ocular morbidity and can be sight-threatening in severe cases. In over 90% of cases, TED is most often associated with Graves’ disease, with an overall prevalence of 40% in Graves’ disease patients (2). Risk factors for the development of TED include cigarette smoking, being female, increased age, thyroid dysregulation amongst others (3). TED is evaluated based on two main criteria; clinical activity most commonly categorised through the use of the Clinical Activity Score (4) and severity scoring through the use of the EUropean Group on Graves’ Orbitopathy (EUGOGO) guidelines (5). TED is a primarily clinical diagnosis, however imaging using CT or MRI modalities aid in clinical evaluation (6). Treatment approaches are disease-severity dependent and may include conservative management, medical management with intravenous steroids and biologics or surgical interventions (7). Overall, TED requires multidisciplinary management, with specialist input from endocrinology and ophthalmology specialities.
An Overview of Graves’ Disease
Graves’ disease is the most common cause of hyperthyroidism in the developed world. Graves’ disease is an autoimmune phenomenon most commonly affecting middle-aged women (8). The pathophysiology underlying Graves’ disease relates to autoantibodies to the thyroid-stimulating hormone receptor (TSHR) (9) which results in excessive release of thyroxine. TSHR and insulin-like growth factor 1 (IGF-1R) cross-react on the orbital fibroblasts and this is thought to be the mechanism underlying the development of TED (10). Common symptoms experienced by patients include fatigue, weight loss, anxiety, sleep disturbance, excessive swelling, some patients may additionally have a nodular goiter (11). Around 40% of patients with Graves’ disease will develop TED. Biochemistry evaluation demonstrates elevated T3 and T4 levels with suppressed TSH levels representing a dysregulation of the hypothalamic-pituitary axis. In addition, thyroid stimulating hormone receptor antibodies are typically positive. Management of Graves’ disease includes antithyroid medications, radioiodine or surgery (12).
The clinical manifestations of thyroid ophthalmopathy are well recognised and range from mild cases with minimal eyelid retraction, dry eyes to severe cases with exposure keratopathy and compressive optic neuropathy (13). TED may Eyelid retraction is the most common clinical sign of TED, arising in up to 90% of patients, and results in the characteristic wide-eyed appearance (14). This may become more severe over time and patients may develop severe keratopathy which increases risks of corneal scarring, perforation and endophthalmitis. Proptosis and lagophthalmos are found in around half of TED patients. Extraocular muscle dysfunction causes diplopia in some patients, while involvement of inferior and medial recti muscles leads to hypotropia and esotropia and restricted range of eye movements. Other symptoms commonly experienced by patients include excessive watering, photophobia, pressure-like pain behind the eyes amongst others. Sight-threatening orbitopathy (15) such as exposure keratopathy and compressive optic neuropathy are rare and affect up to 5% of patients. In particular, compressive optic neuropathy is an ocular emergency and requires urgent medical attention.
Key healthcare professionals involved in the clinical assessment of patients with TED are endocrinologists and ophthalmologists, where a multidisciplinary approach to care is essential to achieve holistic patient-centered care. Endocrinologists regularly care for patients with thyroid disease and therefore have an important role in the screening for TED and should refer patients with TED to ophthalmologists for further clinical evaluation, either for routine assessment or urgent evaluation depending on clinical severity (5).
Clinical assessment of TED is based on the consideration of two main factors: disease activity and severity. Disease activity is assessed commonly through the use of the Clinical Activity Score (CAS) (4). This is recorded across two visits. At the initial visit, patients are scored on a scale of 1-7 depending on the presence of symptoms/signs such as chemosis or gaze-evoked orbital pain. A CAS score of 3 or more indicates active disease. Patients are subsequently followed up in a second visit where the CAS score is scored out of 10, with a score of 4 or more indicating active disease. Disease severity is characterized in accordance with EUGOGO guidelines (5). The EUGOGO severity assessment classifies Graves’ orbitopathy into mild, moderate-severe and sight-threatening disease depending on signs and symptoms experienced by patients.
Ultimately, TED is a clinical diagnosis, however certain imaging modalities, particularly CT and MR imaging are valuable in evaluating orbital pathology (15). CT and MRI may additionally be helpful in monitoring disease progression and treatment response. CT is the preferred imaging modality for the evaluation of orbital bone structures, whereas MRI is the preferred method for the assessment of soft-tissue structures and often demonstrates enlargement of the extraocular muscles.
Management of thyroid eye disease is determined by disease severity and coordinated through the collaboration of endocrinologists and ophthalmologists, as per the EUGOGO 2016 guidelines (5).
For mild active disease, conservative management is the mainstay of treatment. This involves treatment to establish euthyroidism, smoking cessation advice, 6 month course of selenium supplementation and regular eye lubrication therapies.
Considering moderate-severe active thyroid disease, the main treatment options include corticosteroids, orbital radiation and emerging biologic therapies. Intravenous steroids are used in preference to oral steroids given their increased efficacy and improved side-effect profile (16). Limited data exists on long term efficacy of steroid treatment. Side effects associated with corticosteroid treatment include liver failure and mortality and therefore, safe dosing is considered to be below 6-8g cumulative dose, provided there are no contraindications to treatment (17). Orbital radiation, established in the 1970s for the treatment of TED, can improve eye symptoms when used in conjunction with steroids, although long-term randomized controlled trials and meta-analysis are lacking. Risks of orbital radiation mainly include retinopathy and a short-lived exacerbation in inflammatory symptoms (18). Mycophenolate (MMF) has been used alongside intravenous steroid therapy and has demonstrated improved ophthalmic outcomes compared to steroid therapy alone over a longer time period (19). Monoclonal antibody therapies such as rituximab, tocilizumab and teprotumumab are considered to be the more novel therapies for TED. Research and trials for treatment of TED are ongoing and the landscape for treatment is ever changing.
Thyroid eye disease is a complex autoimmune inflammatory disorder which requires prompt diagnosis, careful clinical evaluation and multidisciplinary team care from ophthalmology and endocrinology teams.
(1): Lazarus JH. Epidemiology of Graves’ orbitopathy (GO) and relationship with thyroid disease. Best Practice & Research Clinical Endocrinology & Metabolism. 2012 Jun;26(3):273–9.
(2): 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. 2020 Aug 10;93(4):363–74.
(3): 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 & Metabolism. 2016 Jul;101(7):2711–20.
(4): Mourits MPh, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clinical Endocrinology. 1997 Jul;47(1):9–14.
(5): Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, et al. The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. European Thyroid Journal [Internet]. 2016 [cited 2019 Jun 9];5(1):9–26. Available from: https://www.thyroid.org/wp-content/uploads/2012/04/EUGOGO_consensus.pdf
(6): Gonçalves A, Gebrim E, Monteiro M. Imaging studies for diagnosing Graves’ orbitopathy and dysthyroid optic neuropathy. Clinics. 2012 Nov 7;67(11):1327–34.
(7): Hoang TD, Stocker DJ, Chou EL, Burch HB. 2022 Update on Clinical Management of Graves Disease and Thyroid Eye Disease. Endocrinology and Metabolism Clinics of North America. 2022 Jun;51(2):287–304.
(8): Antonelli A, Ferrari SM, Ragusa F, Elia G, Paparo SR, Ruffilli I, et al. Graves’ disease: Epidemiology, genetic and environmental risk factors and viruses. Best Practice & Research Clinical Endocrinology & Metabolism [Internet]. 2020 Feb;34(1):101387.
(9): .Karoutsou E, Polymeris A. Pathogenesis of Graves’ disease focusing on Graves’ ophthalmopathy. Endocrine Regulations. 2011;45(04):209–20.
(10): Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, et al. Evidence for an Association between Thyroid-Stimulating Hormone and Insulin-Like Growth Factor 1 Receptors: A Tale of Two Antigens Implicated in Graves’ Disease. The Journal of Immunology. 2008 Sep 3;181(6):4397–405.
(11): Nagi D, Holems S, Jenkins R. Thyrotoxicosis resistant to treatment: Graves’ disease or Factitious thyrotoxicosis: A Puzzle. Endocrine Abstracts. 2016 Oct 14
(12): Emoto N. Practical diagnosis and treatment of graves’ disease. Journal of Nippon Medical School. 2000;67(1):35–7.
(13): Smith TJ, Hegedüs L. Graves’ Disease N Engl J Med. 2016;375(16):1552–1565
(14): BARTLEY GB, FATOURECHI V, KADRMAS EF, JACOBSEN SJ, ILSTRUP DM, GARRITY JA, et al. Clinical Features of Graves’ Ophthalmopathy in an Incidence Cohort. American Journal of Ophthalmology. 1996 Mar;121(3):284–90.
(15): Hutchings KR, Fritzhand SJ, Esmaeli B, Koka K, Zhao J, Ahmed S, Debnam JM. Graves’ Eye Disease: Clinical and Radiological Diagnosis. Biomedicines. 2023 Jan 22;11(2):312. doi: 10.3390/biomedicines11020312. PMID: 36830848; PMCID: PMC9953404.
(16): Zhao LQ. Intravenous glucocorticoids therapy in the treatment of Graves’ ophthalmopathy: a systematic review and Meta-analysis. International Journal of Ophthalmology. 2019 Jul 18;12(7):1177–86.
(17): Sari AP, Sidik M, Nusanti S. Outcome and Safety of Different Cumulative Doses and Protocols of Intravenous Methylprednisolone in Moderate to Severe and Active Graves’ Ophthalmopathy. Ophthalmologica Indonesiana. 2019 Jan 18;43(1):15.
(18): Wakelkamp IMMJ, Tan H, Saeed P, Schlingemann RO, Verbraak FD, Blank LECM, et al. Orbital irradiation for Graves’ ophthalmopathy. Ophthalmology. 2004 Aug;111(8):1557–62.
(19): Kahaly GJ, Riedl M, Jochem König, Pitz S, Ponto KA, Diana T, et al. Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): a randomised, observer-masked, multicentre trial. 2018 Apr 1;6(4):287–98.