Last updated:
03/21/2024
Years published: 2020, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Raymond Douglas, MD, PhD, International Aesthetic Orbit & Oculoplastic Surgeon, for assistance in the preparation of this report.
Summary
Thyroid eye disease (TED) is characterized by progressive inflammation and damage to tissues around the eyes, especially extraocular muscle, connective and fatty tissue. TED has an active disease phase in which progressive inflammation, swelling and tissue changes occur. This phase is associated with a variety of symptoms including pain, a gritty feeling in the eyes, swelling or abnormal positioning of the eyelids, watery eyes, bulging eyes (proptosis) and double vision (diplopia). The active phase can last anywhere from approximately 6 months to 2 years. This is followed by an inactive phase in which the disease progression has stopped. However, some symptoms such as double vision and bulging eyes can remain. In some people, cosmetic changes and significant disability can develop. Although uncommon, in severe instances, vision loss can occur. Thyroid eye disease is an autoimmune disorder. An autoimmune disorder is one in which the body’s adaptive immune system, which protects the body from infectious or other foreign substances, mistakenly attacks healthy tissue instead. Treatment includes reversing hyperthyroidism, specific medications, supportive measures and in some patients, surgery.
Introduction
Thyroid eye disease most commonly occurs as part of Graves’ disease, which is an autoimmune disease that affects the thyroid and often the skin and eyes. The thyroid is a butterfly-shaped gland located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities as well as regulating the heart rate, body temperature and blood pressure. Graves’ disease is characterized by abnormal enlargement of the thyroid (goiter) and increased secretion of thyroid hormone (hyperthyroidism). Less often, thyroid eye disease can occur in people who have or have had an overactive thyroid (hyperthyroidism) or in individuals with an underactive thyroid (hypothyroidism) such as people who have a disorder called Hashimoto thyroiditis.
Although relatively infrequent, TED does not currently fulfill the main criterion for being defined as a rare disease, but several variants of the disease are considered rare diseases.
The signs and symptoms can vary greatly from one person to another. Eye symptoms can range from mild to severe. For some individuals, the symptoms can lead to pain, disfigurement of the eye socket and, eventually, potentially threaten eyesight. The disorder can vary greatly in expression. For some people, the disorder remains little changed for many years, while for others it will worsen or slightly improve. Occasionally people experience repeated episodes of worsening (exacerbations) of the disease, and improvement of the disease (remission).
Initial symptoms include redness, irritation and discomfort of the eyes and eyelids. Dry eyes and pain when moving the eyes may also occur. Eyelid retraction is also common which is when the upper eyelid is positioned too high and/or the lower eyelid too low thus exposing the eye. The most noticeable symptom can be exophthalmos or proptosis, which means that the eyes bulge or protrude outward out of the eye socket. Bulging of the eyes can cause a person to appear as if they are constantly ‘staring’.
Additional symptoms and signs can include blurred vision, double vision (diplopia), misalignment of the eyes (strabismus), chronic bloody eyes, white area of eye inflamed, constant, watery eyes due to the excess formation of tears, swelling near the upper and lower eyelids, an intolerance of bright lights and difficulty moving the eyeballs.
Progressive swelling can cause increased pressure within the eye socket and pain or headaches. In severe cases, additional symptoms can develop including corneal erosion, in which there is an eroded area on the clear (transparent) outer layer of the eye (cornea). In some, enlarged eye muscles can compress and cause damage to the optic nerve (optic neuropathy), which is the main nerve of the eye and carries nerve impulses to the brain. Corneal ulceration and optic neuropathy can, sometimes, progress to cause vision loss.
Thyroid eye disease is a progressive disorder in which progressive damage to various tissues around the eyes can lead to scarring (fibrosis) and tissue remodeling. The extent of scarring and tissue remodeling tends to become apparent during the inactive phase, after inflammation and swelling has subsided. This can change the appearance of the eyes and lead to affected individuals looking tired all the time, or to appear different from people without such changes. These cosmetic issues can have a significant impact on emotional well-being and quality of life.
There may be differences in symptoms in people from certain ethnic backgrounds. For example, Asian patients tend to present with less-pronounced proptosis and diffuse extraocular muscle involvement as well as a tendency for lower lid retraction rather than upper lid retraction.
Thyroid eye disease is an autoimmune disorder, which means that a problem with the body’s adaptive immune system that protects the body from infectious or other foreign substances, mistakenly attacks health tissue instead. The immune system normally produces specialized proteins call antibodies. Antibodies react against foreign materials (e.g. bacteria, viruses, toxins) in the body to destroy them. Antibodies can directly kill microorganisms or coat them so they are more easily destroyed by white blood cells. Specific antibodies are created in response to specific materials or substances. A substance that stimulates an antibody to be produced is called an antigen.
The exact underlying process by which thyroid eye disease occurs is not fully understood. In individuals with Graves’ disease, the immune system creates an abnormal antibody called thyroid-stimulating immunoglobulin. This antibody mimics the function of thyroid-stimulating hormone, which is normally produced by the pituitary gland. These abnormal antibodies also affect the cells surrounding the eyes causing the symptoms associated with the disorder. Researchers think that the affected eye tissue contains proteins that appear similar to proteins of the thyroid gland and the antibodies mistakenly target these proteins. Patients often also have overexpression of a protein called insulin-like growth factor 1 receptor (IGF-1R), and this is thought to play a significant role in the development of the disorder. However, not everyone with thyroid eye disease has these immune system abnormalities suggesting that other abnormal antibodies or other factors can cause thyroid eye disease in some people. Researchers are still investigating the underlying cause of the disorder.
Individuals with thyroid eye disease may have gene variants for, or have a genetic susceptibility to, thyroid eye disease. A person who is genetically predisposed to a disorder has one or more disease-causing gene variants for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors (multifactorial inheritance).
Several risk factors have been found to be associated with an increased chance to develop severe disease, and it is important to identify modifiable risk factors for patients at risk for TED or diagnosed with TED.
Individuals who smoke are at a greater risk of developing thyroid eye disease. Individuals who have undergone radioactive iodine therapy as a prior treatment (e.g. for treatment of hyperthyroidism) are at a greater risk of developing thyroid eye disease. Individuals who have other disorders caused by malfunction of the immune system such as type 1 diabetes or rheumatoid arthritis may be at a greater risk of developing thyroid eye disease. Other risk factors may include selenium and vitamin D deficiency. Obstructive sleep apnea (OSA) is another possible modifiable risk factor.
Thyroid eye disease seems to affect all ethnic groups equally. The estimated prevalence is between 90 and 300/100,000 people. Although relatively infrequent, it does not fulfill the main criterion for being defined as a rare disease in the U.S. (The Orphan Drug Act of 1983 defined rare diseases as disorders affecting fewer than 200,000 Americans, translating to a prevalence of 86 per 100,000). However, several variants of the disease, namely, euthyroid Graves’ orbitopathy and Graves’ orbitopathy associated with thyroid dermopathy or acropachy are far below this threshold and can be considered rare diseases.
Thyroid eye disease affects more females than males, but males are more likely to have a severe form of the disease. There is a genetic component to the disorder and people who have a family member with the disease or a family member with an autoimmune disease are at a greater risk of developing the disorder. The disorder is more likely to occur during middle age.
A diagnosis of thyroid eye disease is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Certain symptoms that occur in thyroid eye disease are often obvious and can lead to a diagnosis upon a physical examination. Some affected individuals have reported that their eyes “didn’t feel right” before symptoms of the disease began.
Individuals suspected of having thyroid eye disease will undergo a complete eye examination. This may include measuring the degree of proptosis (eye bulging) using a device called an exophthalmometer. This small device enables an eye doctor to measure how far forward the eyes have moved (displacement).
Clinical Testing and Workup
In moderate to severe disease, a specialized imaging technique called computerized tomography (CT) scanning may be used to assess whether the optic nerve is compressed by inflamed, enlarged muscles in the eye. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Regular eye tests may be given to assess a person’s clarity of vision (visual acuity).
Affected individuals may undergo thyroid function tests to detect an underlying cause of thyroid eye disease such as Graves’ disease or hypothyroidism. These tests can detect elevated levels of thyroid hormones or antibodies in the blood.
Treatment
Treatment may require the coordinated efforts of a team of specialists, general internists, physicians who specialize in diagnosing and treating eye disorders (ophthalmologists) including eye doctors with experience treating thyroid eye disease, physicians who specialize in diagnosing and treating disorders of the hormone system (endocrinologists), psychologists and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support is essential as well.
In 2020, the U.S. Food and Drug Administration (FDA) approved teprotumumab trbw (Tepezza), the first approved drug indicated to treat thyroid eye disease. Teprotumumab inhibits (or blocks) the activity of the protein insulin-like growth factor-1, which is believed to a play as significant role in the development of the disorder. Affected individuals have shown significant improvement in proptosis, double vision and overall quality of life when taking teprotumumab.
In affected individuals who have underlying Graves’ disease, treatment includes reversing hyperthyroidism. Treating hyperthyroidism of Graves’ disease is important, but will not improve symptoms of thyroid eye disease.
Some individuals with mild thyroid eye disease may be treated with supportive measures such as dark sunglasses to treat sensitivity to light, ointments, artificial tears and/or prisms that are attached to glasses. Prisms can help correct double vision. Some people may wear an eyepatch to manage double vision.
Individuals with moderate-to-severe disease may receive corticosteroids, which are drugs that reduce inflammation and swelling, but do not affect diplopia and proptosis. Prednisone is a common corticosteroid that is used to treat individuals with thyroid eye disease.
The 2021 EUGOGO guidelines have recommended the use of the medication mycophenolate in conjunction with corticoids.
Some individuals with moderate-to-severe disease may eventually require surgery. Surgery is also used to treat individuals with severe disease. Generally, it is recommended to avoid surgery until after the active phase of the disease has ended. Doctors will treat the symptoms to the best of their ability and then perform surgery once the inflammation and swelling has reduced. Surgery may be necessary during the active phase if doctors feel that a person’s vision is at risk by the disease progression.
Surgical options include orbital decompression, motility and lid surgery. During orbital decompression surgery, a surgeon takes out the bone between the eye socket (orbit) and the sinuses. This allows the eye to fall back into its natural position within the eye socket. This surgery is generally reserved for individuals who are at risk of vision loss due to pressure on the optic nerve or in whom other treatment options have not worked.
Surgical options can also help to improve bulging eyes (proptosis) and the position of the eyelids. Motility surgery involves repositioning certain muscles around the eyes to reduce or eliminate double vision.
Thyroid eye disease can cause noticeable changes in a person’s facial appearance that cannot be treated completely. Depression is common in individuals with the disorder and cosmetic changes can cause significant emotional distress and affect emotional well-being. A psychologist is recommended to be part of a treatment plan for individuals with thyroid eye disease to work with affected individuals during and after treatment.
The European Group of Grave’s orbitopathy (EUGOGO) recommendations can be summarized as follows:
• In all cases: general recommendations include smoking cessation, maintenance of normal thyroid status and referral to thyroid eye clinic
• In mild cases: conservative management with artificial tears as needed and selenium supplements for 6 months
• In moderate to severe cases: corticoid (methylprednisolone) with or without mycophenolate sodium and if there is not improvement, consider a second line treatment such as repeating methylprednisolone infusions, orbital radiotherapy, teprotumumab, rituximab and tocilizumab
• In inactive disease cases: Surgical treatments such as orbital decompression, strabismus surgery and eyelid procedures as needed
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials//
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Yu CY, Ford RL, Wester ST, Shriver EM. Update on thyroid eye disease: Regional variations in prevalence, diagnosis, and management. Indian J Ophthalmol. 2022 Jul;70(7):2335-2345 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9426067/
Bartalena L, Piantanida E, Gallo D, Lai A, Tanda ML. Epidemiology, natural history, risk Factors, and prevention of Graves’ orbitopathy. Front Endocrinol (Lausanne). 2020 Nov 30;11:615993. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734282/
Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med. 2020;382:341-352. https://www.nejm.org/doi/full/10.1056/NEJMoa1910434
Douglas R. Teprotumumab, an insulin-like growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye disease: a focus on proptosis. Eye (Lord). 2019;33:183-190. https://www.ncbi.nlm.nih.gov/pubmed/30575804
Roos JCP, Murthy R. Update on the clinical assessment and management of thyroid eye disease. Curr Opin Ophthalmol. 2019;30:401-406. https://www.ncbi.nlm.nih.gov/pubmed/31313753
Wang Y, Patel A, Douglas RS. Thyroid eye disease: how a novel therapy may change the treatment paradigm. Ther Clin Risk Manag. 2019;15:1305-1318. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858302/
Li Z, Cestari DM, Fortin E. Thyroid eye disease: what is new to know? Curr Opin Ophthalmol. 2018;29:529-534. https://www.ncbi.nlm.nih.gov/pubmed/30124533
Strianese D. Update on Graves disease: advances in treatment of mild, moderate and severe thyroid eye disease. Curr Opin Ophthalmol. 2017;28:505-513. https://www.ncbi.nlm.nih.gov/pubmed/28700384
Rao R, Macintosh PW, Yoon MK, Lefebvre DR. Current trends in management of thyroid eye disease. Curr Opin Ophthalmol. 2015;26:484-490. https://www.ncbi.nlm.nih.gov/pubmed/26397888
McAlinden C. An overview of thyroid eye disease. Eye Vis (Lond). 2014;1:9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655452/
Dolman PJ, Rath S. Orbital radiotherapy for thyroid eye disease. Curr Opin Ophthalmol. 2012;23:427-432. https://www.ncbi.nlm.nih.gov/pubmed/22729183
Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc. 1994;92:477– 588. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1298522/
INTERNET
British Thyroid Foundation. Your Guide to Thyroid Eye Disease. Updated: 2019. Available at: https://www.btf-thyroid.org/thyroid-eye-disease-leaflet Accessed February 13, 2020.
Douglas RS. Kellogg Eye Center. Thyroid Eye Disease (TED or Graves Eye Disease). Available at: https://www.umkelloggeye.org/conditions-treatments/thyroid-eye-disease Accessed February 13, 2020.
Davies TF, Burch HB. Clinical features and diagnosis of Graves’ orbitopathy (ophthalmopathy). UpToDate, Inc. 2019 Jun 26. Available at: https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-graves-orbitopathy-ophthalmopathy Accessed February 13, 2020.
Davies TF, Burch HB. Treatment of Graves’ orbitopathy (ophthalmopathy). UpToDate, Inc. 2018 Sep 27. Available at: https://www.uptodate.com/contents/treatment-of-graves-orbitopathy-ophthalmopathy Accessed February 13, 2020.
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