Thyroid Eye Disease (TED) or Graves’ orbitopathy is an autoimmune condition affecting the retroocular (eye) tissue. It usually affects both eyes and often occurs around the time of diagnosis of an overactive thyroid state (hyperthyroidism). About 90% of the cases of TED occur in the setting of hyperthyroidism (Graves’ disease). Eye changes can be observed either before, at the time of diagnosis of Graves’ disease, or later.
Thyroid Eye Disease (TED) is also referred to as Graves’ orbitopathy, Graves’ ophthalmopathy, Graves’ eye disease, thyroid-associated orbitopathy, or thyroid-associated ophthalmopathy.
Endocrine Connection
Graves’ disease is an autoimmune condition caused by immune cells attacking the thyroid gland, which responds by secreting an excess amount of thyroid hormone. This increase in the production of thyroid hormone levels is driven by stimulation of the thyroid-stimulating hormone (TSH) receptor (TSHR), which is mainly located in the thyroid gland but is also found in other tissues such as the tissues around the eyes. Sometimes, the anti-TSHR antibodies, which are present in virtually all patients with TED, also bind to TSH receptors located in tissues around the eyes, resulting in TED. The levels of these antibodies can determine the severity and prognosis of TED.
Approximately one-third of patients with Graves’ disease have some signs and/or symptoms of TED, while only 5% have moderate-to-severe TED. About 90% of patients with TED have hyperthyroidism.
Hyperthyroidism and TED are due to the same underlying autoimmune process. In the active phase of TED, fluctuations in the levels of thyroid hormone (both underactive as well as overactive) can lead to progression of TED. In patients with Graves’ disease who undergo treatment with radioactive iodine therapy, it is important to closely monitor thyroid levels afterwards as untreated hypothyroidism (low thyroid hormone levels) can worsen TED. In hyperthyroidism, there is an excess level of thyroid hormone in the body. This is often characterized by a low thyroid stimulating hormone (TSH) level and high free T4 and T3 levels. Fluctuating levels of thyroid hormone can often worsen the eye disease.
In TED, the immune cells that attack the thyroid gland (to cause Graves’ disease) also attack adipose (body fat) and fibroblast tissues around the eyes. TED, or Graves’ eye disease, is an autoimmune condition that is mainly driven by stimulation of the thyroid-stimulating hormone (TSH) receptor (TSHR). This receptor is mainly located in the thyroid gland but is also found in other tissues in the body such as the tissues around the eyes. The interaction between anti-TSHR antibodies, which are present in virtually all patients with TED, and TSH receptors in tissues around the eyes result in inflammation and swelling of the tissues around the eye. The levels of these antibodies can determine the severity and prognosis of TED.
The anti-TSHR antibodies can also affect the skin (there is a lesser extent of skin involvement than eye involvement), causing a condition known as thyroid dermopathy or pretibial myxedema. This is usually noticed as thickening and puckering of the skin of the shins. Other signs are clubbing of the fingers and toes.
A 7-point clinical activity score can be used to determine whether the TED is in the active or the inactive phase. Elements of the clinical activity score includes presence of pain with eye movement, redness of the eyelids and/or conjunctiva, swelling of the eyelids and/or conjunctiva, decreased eye movements and/or visual acuity, and severity of eye protrusion. A score of >/= 3 is suggestive of active disease. Disease severity can also be based on the likelihood of developing loss in vision and degree/severity of the eye protrusion observed. It is important to identify whether the disease is in the active phase as it is more likely to respond to treatment.
The active phase of TED usually lasts two to three years and requires careful monitoring by an ophthalmologist until the disease is stable. Treatment during the active phase of the disease is focused on preserving sight and the integrity of the cornea.
While some patients may not have any symptoms, at least half the patients with TED will report symptoms, which are due to inflammation and swelling of the tissue around the eye. Eye symptoms include dry eyes, itching and gritty sensation, increased tearing, puffiness around the eyes, redness and double vision. Some individuals may also report light sensitivity. The most common signs of TED are increase prominence or bulging of the eyes, redness in the eyes and eyelid swelling.
A small proportion of patients with TED will have more serious complications including pain, loss of vision (due to compression of the optic nerve), and ulcerations on the cornea (due to incomplete closure of the eyelids).
About 3-5% of patients with TED will have visually threatening complications including loss of vision (when swollen tissues compress the optic nerve) and corneal ulcerations (due to incomplete closure of the eyelids).
Several risk factors have been identified in the development of TED including genetics and family history, sex (women are at a higher risk than men), cigarette smoking, and treatment with radioactive iodine treatment. Both first and second-hand smoking increases the risk of progression of TED and decreases the response to treatment in TED. The risk from smoking is proportional to the number of cigarettes smoked per day. Other conditions such as advanced age, stress, poorly controlled diabetes mellitus and uncontrolled thyroid disease are other likely risk factors.
Prevention of disease progression is usually centered around the avoidance of cigarette smoking and refraining from the use of radioactive iodine for treatment of Graves’ hyperthyroidism in patients with moderate-to-severe or sight-threatening TED.
In addition, trauma is also considered a stimulus for the development of TED.
The goal of treatment is to achieve normal thyroid function. This can be achieved by using medications such as beta-blockers and thioamides. These medications help in reducing the symptoms of an overactive thyroid gland as well as decreasing the production of thyroid hormones. Another option to achieve normal thyroid function is surgery. Radioactive iodine can worsen TED and is generally not recommended in individuals with moderate-to-severe or sight-threatening eye disease. In individuals with mild eye disease, radioactive iodine can be considered as initial treatment. However, this should be done in conjunction with the concurrent use of glucocorticoids especially if they smoke or have high titers of the TSHR antibody.
All patients should be advised to refrain from smoking. The following local measures can be helpful to alleviate some of the symptoms caused by TED: apply cool compresses to the eyes, elevate the head of your bed, use of artificial tears throughout the day and gels or ointments at night to prevent dryness, and protective eyewear and corrective lenses such as prisms for double vision.
For individuals with mild disease, Selenium 100 mcg twice a day has shown some benefit. For individuals with moderate-to-severe or progressive eye disease, glucocorticoids can be used either orally or via the intravenous route. For steroid refractory TED, teprotumumab (insulin-like growth factor-1 antibody) may be a treatment option. Other therapies include external orbital radiation and orbital decompression.
The diagnosis of TED is usually made clinically. To determine the severity of TED, your physician may perform the following tests to assess your vision and the changes in the tissues around your eyes: vision testing, visual fields testing, eyelid measurements, checking the optic nerves, and sometimes photographs. Laboratory finding are performed to evaluate for hyperthyroidism. CT or MRI scans can be performed in individuals who have moderate to severe eye disease to assess the risk of further complications.
Referral to an ophthalmologist for evaluation of TED and subsequent management, and referral to an endocrinologist for evaluation and management of thyroid disease is encouraged.
What are the symptoms that I should be monitoring for to assess for whether the TED is worsening?
When do I seek urgent care?
What can I do to prevent further worsening of the TED?
For patients who also have Graves’ disease and are considering treatment with radioactive iodine: Based on my risk factors, am I a candidate for prophylactic corticosteroid therapy after radioactive iodine to prevent worsening TED?
For patients who have active, progressive TED regardless of their history of prior TED treatment: Based on my current disease state, am I a candidate for teprotumumab?
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