Thyroid Eye Disease

From EyeWiki
(Redirected from Thyroid Ophthalmopathy)

All content on Eyewiki is protected by copyright law and the Terms of Service. This content may not be reproduced, copied, or put into any artificial intelligence program, including large language and generative AI models, without permission from the Academy.

Article initiated by:
Dr. Rashmin Gandhi FRCS (Edin.) FRCS (Glasg.), Vikram D. Durairaj, MD, Khyati Shah
All contributors:
Cat Nguyen Burkat, MD FACS, K. David Epley, M.D., Paul Phelps, MD, FACS, Rona Z Silkiss, MD FACS, Vikram D. Durairaj, MD, Audrey Yeung, Brad H. Feldman, M.D., Paul Phelps, MD, FACS, Guy V. Jirawuthiworavong, M.D., M.A., Dr. Rashmin Gandhi FRCS (Edin.) FRCS (Glasg.), Nagham Al-Zubidi, MD, Anne Barmettler, MD, Sudha Nallasamy, MD, Michael T Yen, MD, Sezen Karakus, MD, Harkaran S. Rana D.O., Preeti Thyparampil, MD, Bharat Gurnani MBBS,DNB,FCRS,FICO(UK), FAICO (Cornea, AIIMS, AIOS), FAICO (Refractive Surgery, AIIMS, AIOS), MRCS (Ed), MNAMS, Marcus M. Marcet, MD, Abdulrahman Alfarhan, MD, Alvaro Mejia-Vergara, MD
Assigned editor:
Rona Z Silkiss, MD FACS
Review:
Assigned status Up to Date
 by Paul Phelps, MD, FACS on April 14, 2026.


Thyroid Eye Disease
DiseasesDB
5419
ICD-10
[1]05.0
ICD-9
242.90
MedlinePlus
000358
MeSH
D049970
Before and after full course of Tepezza treatment in patient with active and moderate thyroid eye disease. Images courtesy of Dr. Paul Phelps, MD, FACS

Disease entity

  • ICD-10: E05.00

Disease

Thyroid eye disease (TED) is an autoimmune disease caused by the activation of orbital fibroblasts by autoantibodies directed against thyroid receptors. TED is a rare disease that had an incidence rate of approximately 19 in 100,000 people per year in 1 study.[1] The disorder is characterized by inflammation and swelling of the extraocular muscles, fatty tissue, and connective tissue within the orbit. Graves disease (GD) is an autoimmune disorder involving the thyroid gland. It is typically characterized by the presence of circulating autoantibodies that bind to and stimulate the thyroid hormone receptor (TSHR), resulting in hyperthyroidism and goiter. Organs other than the thyroid can also be affected, leading to the extrathyroidal (outside the thyroid gland itself) manifestations of GD. TED is observed in ~ 50% of patients, whereas Graves dermopathy and acropachy are quite rare.[2] TED was previously known as thyroid-associated ophthalmopathy (TAO), Graves orbitopathy (GO), and other variations.

Etiology

TED is most frequently associated with hyperthyroidism, constituting of approximately 90% of the cases. However, about 10% of patients with TED have either a normal-functioning (euthyroid) or under-functioning thyroid (hypothyroidism, eg, Hashimoto thyroiditis). Although strict control of thyroid function is crucial in patients with TED, the course and severity of ocular manifestation does not always correlate with thyroid hormone levels. Thus, treatment of thyroid dysfunction does not necessarily affect the course of Graves ophthalmopathy.

Risk factors

TED includes genetic, environmental, and immune risk factors. Among the environmental factors, smoking is the most consistently linked risk factor to the development or worsening of the disease.[3] The risk increases with the number of cigarettes smoked per day, and giving up smoking has been linked with reduced risk. Stress is another environmental factor that may contribute to the worsening of TED.[4] Patients treated with radioactive iodine may experience worsening of TED, especially if they are smokers.[2]

Epidemiology

TED has a higher prevalence in women than in men. Both men and women demonstrate a bimodal pattern of the age of diagnosis. The median age is 43 years for all patients, with a range from 8 to 88 years old. Women are affected 5 times more than men, and this has been linked to a higher incidence of Graves disease in women. Patients diagnosed after age 50 years have a worse prognosis overall.[1]

Pathophysiology

Although the underlying mechanisms of action of these processes are not completely understood, the presumed mechanism is activation of orbital fibroblasts by Graves disease-related autoantibodies, which lead to the release of T-cell chemoattractants, initiating an interaction that ultimately results in fibroblasts expressing extracellular matrix molecules, biologic materials proliferating and differentiating into myofibroblasts or lipofibroblasts, and deposition of glycosaminoglycans, which bind water that leads to swelling and congestion in addition to connective tissue remodeling. This results in extraocular muscle enlargement and orbital fat expansion.

Diagnosis

History/Symptoms

The patient complains of gritty sensations, photophobia, lacrimation, dry eye, discomfort, and forward protrusion of the eye. In more advanced cases, patients may have eye socket (orbital) pain, double vision, or blurred vision.

Signs

Exophthalmos noted in axial view of CT-scan. Patient with TED also demonstrates enlargement of extra ocular muscles (asterisk).
Eyelid retraction in patient with TED. Upper lid retraction measured with margin to reflex distance 1 (MRD1) and lower lid retraction measured with margin to reflex distance 2 (MRD2).
  1. Eyelid retraction (Dalrymple sign) is the most common presenting sign of TED, found in up to 90% of patients.[5]
  2. Lid lag of the upper eyelid on downward gaze (Von Graefe sign) and lid edema.[6]
  3. TED is the most common cause for both unilateral and bilateral axial proptosis (exophthalmos). There is increased resistance to retropulsion. The Hertel exophthalmometer is used for the measurement of proptosis.
  4. Bulbar conjunctiva may be injected (Goldzeiher sign). Exposure keratopathy ocular emergency can occur further due to lagophthalmos, which is a major cause for decrease in visual acuity and in blurred vision in TAO, apart from compressive optic neuropathy.
  5. Extraocular muscles are frequently involved in TAO. The most commonly affected muscle is the inferior rectus, followed by the medial, superior, levator, lateral rectus, and oblique (mnemonic: “I'M SLOw”). Extraocular muscles can affect results in ocular misalignment and diplopia. There can also be an inability to look up when the eye is adducted, which is termed double elevator palsy.
  6. Compressive optic neuropathy is an ocular emergency. It occurs in <5% of patients with typical TED and results in slowly progressive fulminant visual loss. It occurs due to compression from the oversized recti and orbital fat, causing compartment syndrome at the apex of orbit. It is characterized by decrease in vision, color vision, and contrast sensitivity, and development of relative afferent papillary defect. The characteristic visual fields commonly show central, cecocentral, paracentral, and nerve fiber layer bundle defects. Optic nerve head examination can be normal or show optic disc edema or pallor.
  7. Clinical course: TED typically has a progressive inflammatory phase, followed by a stable postinflammatory phase.
  8. The pattern of the disease follows the Rundle curve, which describes the plot of orbital disease severity against time.
    • Initial phase: inflammatory phase duration may last from 6 to 18 months, with orbital and periorbital signs including proptosis and retraction
    • Static phase: decrease in the inflammatory phase and minimal improvement
    • Quiescent phase: gradual improvement with improved motility and retraction of the muscles
  9. The upper lid signs in TED include:
    • Stellwag sign: incomplete and frequent blinking
    • Grove sign: resistance in pulling the retracted upper eyelid
    • Boston sign: jerky movements of eyelids in downgaze
    • Gifford sign: difficulty while everting the upper eyelid
    • Gellineck sign: abnormal pigmentation of the upper eyelid
  10. The lower lid signs in TED include:
    • Enroth sign: lower eyelid edema
    • Griffith sign: lid lag on upgaze
  11. The conjunctival signs include:
    • Goldzeiher sign: conjunctival injection
  12. The extraocular movements signs include:
    • Mobius sign: not able to converge eyes
    • Ballet sign: one or more extraocular muscle restriction
    • Suker sign: poor fixation in abduction
    • Jendrassik sign: paralysis of all EOM
  13. The pupillary signs-
    • Knies sign: uneven pupillary dilatation in dim light
    • Cowen sign: jerky contraction of the pupil to light
  14. Generalized signs
    • Vigouroux sign: eyelid fullness
    • Von Graefe sign: retarded descent of upper lid in downgaze
    • Jofforoy sign: absent crease of the forehead in superior gaze
    • Kocher sign: staring and frightened appearance of eyes

Diagnostic procedures

Laboratory test

The diagnosis can be done clinically with the characteristic clinical picture, restrictive nature of the disease, and associated systemic thyroid disease. Although not diagnostic, thyroid hormone levels, thyroid-stimulating immunoglobulins (TSI), and anti thyroid antibodies can be suggestive of diagnosis.

Ultrasonography: Both A-scan and B-scan transocular echograms can be used to visualize the orbital structures and to determine recti muscle enlargement. Advantage is its low cost, lack of ionizing radiation, and relatively short examination time.

Imaging

Computed tomography (CT) scan: This type of imaging without contrast may distinguish normal structures from abnormal structures of different tissue density. It demonstrates enlargement of the bellies and sparing of the tendons. It helps in assessing the relationship between the optic nerve and muscles at the apex, which helps in planning for the surgical intervention, if needed.

Magnetic resonance imaging (MRI): Fusiform rectus enlargement and orbital fat expansion may be identified. MRI may also aide in assessing water content in the muscles and other soft tissues. This may correlate with active inflammation.

Differential diagnosis

  • Orbital pseudotumor
  • Caroticocavernous fistula
  • Inflammatory orbitopathy, eg, granulomatosis with polyangiitis
  • Orbital myositis (OM)
  • Orbital tumors
  • IgG4 disease

Grading

Werner reported the NO SPECS (Nophysical signs or symptoms, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle signs, Corneal involvement, and Sight loss) Classification system in 1969 and a modified version was published in 1977. What is worth noting is that this system grades on disease severity and not the activity of the disease.

Clinical Activity Score

A shift in treatment began in 1989 when the clinical activity score (CAS) was created to help distinguish the active and stable phases of the disease. Its distinguishing feature is grading classic signs of acute inflammation. A CAS ≥3/7 is indicative of active disease. [7]

The most current grading systems of TED are the VISA (vision, inflammation, strabismus, and appearance) classification and the European Group of Graves Orbitopathy (EUGOGO) classification. [8] The utility of these grading systems is that both assess severity and activity.

In the VISA classification, the 4 severity parameters can be found in the name, and a maximum score of 20 is used to grade the severity of disease. Each of the 4 parameters has further divisions in order to better assess the activity of the disease; the form can be found at (http://www.thyroideyedisease.org).[9]

EUGOGO Classification of Thyroid Eye Disease (TED) disease severity

EUGOGO classification attempts to assess both disease activity and disease severity. Activity is based on 4 measures of inflammation, pain, redness, swelling, and impaired function, and function is graded with decreasing monocular motion and diminishing visual acuity. The classification system also has developed an image atlas that can be used to accurately grade the patient who is being examined. Additionally, the EUGOGO grading system does well in differentiating management categories.[10]

Management

Conservative: Both smoking cessation and euthyroid status help prevent further exacerbation and decrease the duration of active disease.[11] For corneal exposure, lubricants, taping, and protective shields can be tried, and if necessary, tarsorrhaphy can be done. For diplopia, Fresnel prisms or occlusion therapy may be considered. Others are lifestyle modifications, including sodium restriction to reduce water retention and tissue edema. Sleeping with the head of the bed elevated to decrease orbital edema is also useful. Oral nonsteroidal anti-inflammatory drugs (NSAIDs) may be used for periocular pain. Selenium has shown significant benefit in patients with mild, noninflammatory orbitopathy.[12]

Teprotumumab:  This biologic infusion therapy has been shown in clinical studies to reduce signs and symptoms of TED.[13][14] Teprotumumab binds to IGF-1R and blocks its activation and signaling. Tepezza (Teprotumumab-trbw) is the first and only FDA-approved prescription treatment for TED.

Systemic Glucocorticoids in Thyroid Eye Disease

Systemic glucocorticoids are a mainstay of treatment for active, moderate‑to‑severe thyroid eye disease (TED).[7][15][16] They are used to reduce orbital inflammation and soft tissue congestion, and may be administered as intravenous (IV) methylprednisolone pulse therapy or as high‑dose oral prednisone.[7][15][16]

IV vs. Oral: IV methylprednisolone is generally preferred over oral prednisone when available because it provides greater efficacy with fewer adverse effects than high‑dose oral therapy.[7][15][16][17] A common regimen is 500 mg IV methylprednisolone once weekly for 6 weeks, followed by 250 mg IV methylprednisolone once weekly for 6 weeks (a total cumulative dose of 4.5 g over 12 weeks).[7][15][16][17] A small trial using the same cumulative IV methylprednisolone dose (4.5 g over 12 weeks) found similar efficacy and safety when given either weekly or monthly.[17]

IV pulse therapy should be used within safe cumulative dose limits. Very high cumulative IV doses (>8 g) have been associated with liver failure and should be avoided.[7][15][16] Baseline labs and periodic monitoring, including liver function testing, are recommended during treatment.[7][15][16]

When IV therapy is unavailable or otherwise infeasible, high‑dose oral prednisone is an alternative, though dosing is not as standardized.[15][16][18] For severe active TED, oral prednisone may be given at 60‑100 mg/day initially.[15][16][18] In less severe disease, some clinicians begin with 30 mg/day and increase as needed according to response. If a good response is achieved, the daily dose is tapered to the lowest effective dose.[15][16][18]

Efficacy: Systematic reviews and meta‑analyses comparing IV pulse glucocorticoids with oral glucocorticoids in TED have shown higher overall response rates with IV therapy (approximately 82% vs 51% for oral regimens), with benefit most evident in patients with more severe disease.[7][15][16] A small randomized trial of 70 euthyroid patients with untreated, severe TED assigned to either weekly IV methylprednisolone (0.5 g then 0.25 g weekly for six weeks each) or high‑dose oral prednisone (100 mg/day tapered by 10 mg/week), the IV group demonstrated higher response rates at 3 months, greater improvements in visual acuity, chemosis, and quality of life, and fewer adverse events.[17]

Time Course and Monitoring: Clinical improvement with systemic glucocorticoids is usually seen by 4 weeks, and certainly by 6‑8 weeks.[15][16] If there is no meaningful improvement after 4–6 weeks, alternative approaches (e.g., biologic therapy, other immunosuppressants, radiation, or surgery) should be considered rather than continuing prolonged high‑dose prednisone.[15][16]

Side Effects: Patients on systemic glucocorticoids require monitoring for hyperglycemia, hypertension, weight gain, mood changes, and infection risk.[15][16][18] Although TED‑specific bone mineral density data for IV pulse regimens are limited, systemic glucocorticoid exposure in general is associated with increased fracture risk, and patients at elevated risk should be managed according to glucocorticoid‑induced osteoporosis guidelines.[19][20]

Orbital Radiation: This method can be used alone or in conjunction with corticosteroids The radiation therapy works on the similar mechanism of decreasing inflammation. A typical dose of 2000 cGy for each orbit 200 cGy / day is given over a period 10 days. It generally improves vertical motility. Radiation retinopathy may occur as a side effect.

Orbital Decompression: This surgical procedure enlarges the existing space of the orbit by partial removal of bony walls. Orbital decompression commonly involves the orbital floor, medial wall, and lateral wall. In rare cases, the roof of the orbit may also be decompressed surgically.

Strabismus surgery: In cases of significant strabismus, strabismus surgery may be required and should be done with adjustable sutures, since the muscles typically do not respond as normal muscles would to strabismus surgery. Strabismus surgery should be considered only after orbital decompression is complete and muscle alignment has stabilized.

Eyelid Retraction Repair and Tarsorrhaphy: These reconstructive surgical procedures may be preformed to address eyelid retraction or exposure keratitis.

Alternative Treatments: Rituximab is a monoclonal antibody that targets CD‐20 on B‐cells.[21][22]

Additional Resources

References

  1. ↑ 1.0 1.1 Bartley, G. B. (1994). The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Transactions of the American Ophthalmological Society, 92, 477.
  2. ↑ 2.0 2.1 Menconi, F., Marcocci, C., & Marinò, M. (2014). Diagnosis and classification of Graves' disease. Autoimmunity reviews, 13(4-5), 398-402.
  3. ↑ Thornton, J., Kelly, S. P., Harrison, R. A., & Edwards, R. (2007). Cigarette smoking and thyroid eye disease: a systematic review. Eye, 21(9), 1135-1145.
  4. ↑ Mizokami, T., Wu Li, A., El-Kaissi, S., & Wall, J. R. (2004). Stress and thyroid autoimmunity. Thyroid, 14(12), 1047-1055.
  5. ↑ Phelps PO, Williams K. Thyroid Eye Disease for the Primary Care  Practitioner. Dis.Mon 60(2014)292–298. [PMID  24906675]
  6. ↑ Albert and Jakobiec's Principles and Practice of Ophthalmology; Albert D M, Miller J W; 3rd edition- chapter 229- 230: page 2913-37.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 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. Eur J Endocrinol. 2021; 185: G43–67.
  8. ↑
    Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velázquez-Villoria Á, Galofré JC. Graves' Ophthalmopathy: VISA versus EUGOGO Classification, Assessment, and Management. J Ophthalmol. 2015;2015:249125. doi: 10.1155/2015/249125. Epub 2015 Aug 17. PMID: 26351570; PMCID: PMC4553342.
  9. ↑ http://www.thyroideyedisease.org
  10. ↑ Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM; European Group on Graves' Orbitopathy (EUGOGO). Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008 Mar;158(3):273-85. doi: 10.1530/EJE-07-0666. PMID: 18299459.
  11. ↑ Bartalena L, Pinchera A, Marcocci C. Management of Graves' ophthalmopathy: reality andperspectives. Endocr Rev 2000;21(2):168‐199. [PMID 10782363]
  12. ↑ Drutel, A., Archambeaud, F., & Caron, P. (2013). Selenium and the thyroid gland: more good news for clinicians. Clinical endocrinology, 78(2), 155-164.
  13. ↑ Douglas, R. S., Kahaly, G. J., Patel, A., Sile, S., Thompson, E. H., Perdok, R., ... & Antonelli, A. (2020). Teprotumumab for the treatment of active thyroid eye disease. New England Journal of Medicine, 382(4), 341-352.
  14. ↑ Smith, T. J., Kahaly, G. J., Ezra, D. G., Fleming, J. C., Dailey, R. A., Tang, R. A., ... & Gigantelli, J. W. (2017). Teprotumumab for thyroid-associated ophthalmopathy. New England Journal of Medicine, 376(18), 1748-1761.
  15. ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 15.11 15.12 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. Thyroid. 2022 Dec;32(12):1439-1470.
  16. ↑ 16.00 16.01 16.02 16.03 16.04 16.05 16.06 16.07 16.08 16.09 16.10 16.11 16.12 Wiersinga WM, Eckstein AK, Žarković M. Thyroid eye disease (Graves' orbitopathy): clinical presentation, epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol. 2025 Jul;13(7):600-614.
  17. ↑ 17.0 17.1 17.2 17.3 Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab. 2005;90(9):5234‑5240.
  18. ↑ 18.0 18.1 18.2 18.3 Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med. 2016;375(16):1552‑1565.
  19. ↑ van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res. 2000;15(6):993‑1000.
  20. ↑ Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology guideline for the prevention and treatment of glucocorticoid‑induced osteoporosis. Arthritis Rheumatol. 2017;69(8):1521‑1537.
  21. ↑ Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J Clin Endocrinol Metab 2015;100(2):432‐ 441. [PMID 25343233]
  22. ↑ Silkiss RZ, Reier A, Coleman M, Lauer SA. Rituximab for thyroid eye disease. Ophthal Plast Reconstr Surg. 2010;26(5):310‐314. [PMID 20562667]
Retrieved from "https://eyewiki.org/w/index.php?title=Thyroid_Eye_Disease&oldid=128262"
The Academy uses cookies to analyze performance and provide relevant personalized content to users of our website.
Learn more
Powered by MediaWiki
Powered by Canasta
Powered by Semantic MediaWiki