What is Graves Orbitopathy?

Graves’ orbitopathy, also known as Graves’ eye disease or Graves’ ophthalmopathy, is when certain signs and symptoms linked to the eye socket and surrounding areas appear in people with Graves’ disease. Sometimes, it also happens in people who have normal thyroid function (euthyroid) or underactive thyroid (hypothyroid) due to long-term thyroid inflammation. This is caused by the body’s immune system mistakenly attacking tissues behind the eye.

In severe cases, this condition can potentially threaten vision. Therefore, being evaluated promptly and receiving quick treatment is extremely important.

What Causes Graves Orbitopathy?

In Graves’ disease, an antibody called the thyroid-stimulating hormone (TSH) receptor antibody is at fault. This antibody primarily affects TSH receptors in the thyroid. But TSH receptors are also found in other body tissues. In people with Graves disease, these receptors are more concentrated in the tissue behind the eyes.

It’s important to note that people with Graves’ disease may develop eye problems, known as orbitopathy, due to several risk factors. These can be higher levels of TSH receptor antibodies, being female, some genetic factors, or exposure to radioiodine used in the treatment for Graves’ disease. However, the specific genes or mutations causing these risk factors are yet to be identified. Smoking is a high-risk factor that can be controlled. The disease’s eye symptoms tend to be worse and not respond well to treatments that reduce immune system activity in those who smoke. It’s believed that smoking may alter both humoral (pertaining to body fluids) and cell-mediated immunity and suppress so-called ‘killer’ T cells.

In Graves’ orbitopathy, several cell types are involved, including cells known as fibroblasts. These cells are stimulated by TSH receptor antibodies and by T-cells (a type of immune cell) and initiate two processes. The first is the production of substances called glycosaminoglycans (GAGs), primarily hyaluronic acid, which, when accumulated, cause swelling in the eye muscles. The second process is the formation of fat cells. Together, the swelling of the eye muscles and the increase in fat behind the eyes result in eye protrusion and other signs of Graves’ orbitopathy.

Researchers also suggest that IGF-1 receptors, present in fibroblasts, when stimulated by TSH receptor antibodies, can also ramp up GAG production.

Inflammation and scarring of a muscle in the eyelid, known as Müller’s muscle, can cause the upper eyelid to retract. Another scenario causing this is called pseudo-lid retraction, which happens when there’s a restriction of the muscle below the eye and overactivity of the muscle that lifts the eyelid. Normally, the muscles most affected are those below and in the middle of the eye.

Risk Factors and Frequency for Graves Orbitopathy

Graves’ orbitopathy, a condition related to Graves’ disease, affects an estimated 25 to 50% of patients with Graves’ disease. According to a study, clinically obvious Graves orbitopathy is detected in 16 out of every 100,000 females and 2.9 out of every 100,000 males. It’s worth noting that even more patients might have signs of Graves orbitopathy on an MRI scan, even if they don’t show symptoms of the disease.

Signs and Symptoms of Graves Orbitopathy

Graves orbitopathy, a condition affecting the eyes, is typically assessed through a physical examination and patient history. In taking a patient’s history, it’s important to ask if they have been experiencing any symptoms associated with the condition. Some of these symptoms include the feeling of a foreign object in the eyes, tearing, pain or pressure in or behind the eye, and pain when moving the eyes. Visual changes, such as double vision, blurring, changes in color vision, or even complete vision loss, might also be present. Some individuals might also report swelling or redness around their eyes, or an inability to close their eyes completely.

When performing a physical examination, healthcare providers should first inspect the eyes for protrusion, and take note of whether or not this protrusion is symmetrical. They should also check for redness in the conjunctiva (the white part of the eye), swelling of the conjunctiva, and swelling around the eyes. The ability of the patient to fully close their eyes should be tested, as inability to do so can put the patient at risk for corneal damage. The patient’s eye movements should also be checked to identify any pain associated with moving their eyes in certain directions or any difficulty moving their eyes. Testing visual acuity and color vision forms an important part of this comprehensive examination.

Additionally, there are several physical indicators healthcare providers should be aware of when examining a patient for Graves orbitopathy. These include:

Hyperpigmentation of the superior fold of the eyelid (Jellinek’s sign)
Hyperpigmentation of the inferior eyelid (Tella’s sign)
Small tremors of the eyelids when they’re closed (Rosenbach’s sign)
Difficulty focusing on a close object (Moebius’ sign)
Pulsating retinal arteries that can be seen with an exam of the back of the eye (Beck’s sign)
A heart murmur-like sound that can be heard over the closed eyelid using a stethoscope (Snellen-Rieseman’s sign).

Testing for Graves Orbitopathy

After your doctor has done a thorough check-up and understood your medical history, they may order thyroid function tests if not already done. These tests usually include a TSH (thyroid-stimulating hormone) and free T4 (thyroxine) test. Checking the levels of TSH receptor antibodies is also important. This not only confirms the diagnosis of Graves’ disease but also helps to track how severe your condition is and how well you’re responding to treatment.

Graves’ disease, particularly when it affects the eyes (a condition known as Graves’ orbitopathy), is often classified using different scoring methods. These systems help doctors determine the severity and activity of the disease.

One of these methods is a system called NO SPECS, where you’d get scores from 0 to IV. Here’s what they mean:
– Score 0: There are no signs or symptoms of Graves’ disease.
– Score I: You have limited signs such as a retraction or lag of your eyelid.
– Score II: The disease has affected your soft tissues.
– Score III: Your eyes are bulging out (a condition called proptosis).
– Score IV: The disease is affecting the muscles around your eyes.

Other scoring methods include the EUGOGO (developed by the European Group on Graves’ Orbitopathy) and the VISA classification. These systems take into account changes in vision, inflammation, and the appearance of your eye.

Finally, the CAS (clinical activity score) system helps to determine how active your Graves’ orbitopathy is. If your score is 3 or more, this means your condition is active and should be treated immediately. At follow-up visits, a score of 4 or more also means your disease is active.

If you’re diagnosed with Graves orbitopathy, your doctor may also consider doing imaging tests like an MRI (Magnetic Resonance Imaging). This test can help identify if your disease is active and can guide the decision on the type of treatment you may need. MRI is particularly helpful when the disease isn’t presenting typically or affects one eye more than the other. It can also help to rule out other eye conditions. Lastly, if your doctor suspects the disease may be putting pressure on your optic nerve, an MRI can help confirm this.

A CT (Computed Tomography) scan may not be as helpful in determining the activity of the disease, but it can be useful to plan for a surgery called orbital decompression if it becomes necessary.

Treatment Options for Graves Orbitopathy

The treatment options for severe eye disorders are broadly categorized into supportive and specific. Patients with severe eye conditions require supportive care, which includes lubrication with eye drops, use of eye patches for protection, prism correction to aid in double vision, and a raised headrest, which may help to reduce swelling.

Selenium, an essential mineral, has shown to help in mild cases of eye disorders. However, it might be more beneficial in areas where the selenium content in their food and environment is low. Hence, its effectiveness in areas rich in selenium is not entirely certain.

One of the additional treatment options is to help patients quit smoking and normalize their thyroid levels. Approaches to do this include medication, radioactive iodine therapy, or thyroid surgery. In patients with moderate to severe symptoms of Graves’ disease, an autoimmune disorder leading to hyperthyroidism, radioactive iodine therapy is typically not advised. Instead, medications or a specific type of thyroid surgery called total thyroidectomy, which removes more of the thyroid gland, are preferred. Patients with lesser eye symptoms due to Graves’ disease have more options for treatment.

Glucocorticoids are another category of medicines that can be used for patients with active and moderate-to-severe disease. These are available in both oral and intravenous forms, with intravenous therapy being preferred for severe disease. However, careful monitoring is necessary to prevent any side effects associated with long-term use of these drugs.

If the patient doesn’t respond to or cannot tolerate glucocorticoids, alternatives like other types of immunomodulatory drugs (which help to control or adjust the immune system), radiation therapy, or orbital decompression surgery could be considered. The drug called Teprotumumab, which was approved by the FDA in 2020, was found in studies to be very beneficial in patients with active, moderate-to-severe Graves’ eye disease. But it’s important to mention that this drug is administered intravenously and can cause side effects like nausea, diarrhea, hair loss, high blood sugar, fatigue, and muscle spasms.

Patients with severe Graves’ orbitopathy, a condition that affects the eye muscles and other tissues in the orbit and which may threaten vision, should be quickly hospitalized. They will require intravenous glucocorticoids, and, in some cases, may also need urgent orbital decompression surgery.

Orbital decompression surgery, often performed following glucocorticoid treatment, is an option for cases where vision is at risk. This surgery involves removing certain parts of the orbit to alleviate the condition. Some additional surgical procedures could be considered to cope with cosmetic and mobility issues associated with the eye condition due to Graves’ disease.

The use of external beam radiation is generally limited to patients who do not respond to other treatment methods. Its use has been limited due to chronic dry eyes and a theoretic risk of cancer.

In children, the approach to manage Graves’ orbitopathy is very similar to adults, with few modifications. In pregnant patients, the treatment methods are mostly the same as non-pregnant patients. However, radioactive iodine therapy is not recommended, and thyroid surgery can be considered if the Graves’ disease cannot be controlled with maximum dosage of anti-thyroid medication. Steroids and orbital decompression surgery can also be considered if the eye condition worsens.

Possible conditions that could affect the eyes and surrounding muscle structure might include:

Orbital tumors, which could be primary or secondary/metastatic (spread from another part of the body)
Myositis (inflammation) of the extraocular muscles (muscles that control eye movement), which could possibly be due to a condition called sarcoidosis
Orbital cellulitis, which is an infection of the eye or eye area
Ocular myasthenia gravis, a condition that affects the nerves controlling the muscles of the eye
Statin-induced extraocular muscle myopathy, muscle weakness caused by a type of medication known as statins
Hashimoto thyroiditis, an autoimmune disease that could affect the muscles around the eye
Histiocytosis, a rare condition that involves an overproduction of white blood cells known as histiocytes
Carotid cavernous fistula, a rare type of vascular disorder

What to expect with Graves Orbitopathy

The progress and effects of Graves orbitopathy, a condition affecting the eyes, can vary greatly from person to person. Some individuals may find that their condition remains mild without getting worse, whereas others might experience improvements or worsening of the disease over an extended period.

A study found that, over a span of 18 months, the condition developed into a more severe form in about 2.5% of patients. The same study found that 58% of patients with a mild form of the disease went into full recovery.

In cases where the disease has advanced to a moderate or severe stage and requires treatment, steroids like glucocorticoids are commonly used. A scientific review found that using these steroids via an intravenous (IV) method was more effective than taking them orally. Specifically, symptoms reduced by 82% with IV use, compared to a 53% reduction for oral use.

Possible Complications When Diagnosed with Graves Orbitopathy

The side effects of Graves eye disease can vary. Some people may only experience minor symptoms like inflammation of the membrane that lines the eyelids and covers the eyeball, and dry eyes. However, for some, the disease can lead to serious issues that threaten sight. These can include complications where the muscles that move the eye become trapped, ulcers on the clear front surface of the eye, and pressure on the nerve that links the eye to the brain.

Common Side Effects:

Inflammation of the membrane lining the eyelids and covering the eyeball
Dry eyes
Extraocular muscle entrapment
Corneal ulcers
Optic nerve compression

Frequently asked questions

Graves Orbitopathy is a condition where certain signs and symptoms related to the eye socket and surrounding areas appear in people with Graves' disease. It can also occur in individuals with normal or underactive thyroid function due to long-term thyroid inflammation.

Graves Orbitopathy affects an estimated 25 to 50% of patients with Graves' disease.

Some signs and symptoms of Graves Orbitopathy include: - Feeling of a foreign object in the eyes - Tearing - Pain or pressure in or behind the eye - Pain when moving the eyes - Visual changes such as double vision, blurring, changes in color vision, or complete vision loss - Swelling or redness around the eyes - Inability to close the eyes completely During a physical examination, healthcare providers should look for the following signs: - Protrusion of the eyes, noting whether it is symmetrical - Redness in the conjunctiva - Swelling of the conjunctiva and around the eyes - Inability to fully close the eyes - Pain or difficulty moving the eyes - Testing visual acuity and color vision There are also several physical indicators that healthcare providers should be aware of, including: - Hyperpigmentation of the superior fold of the eyelid (Jellinek's sign) - Hyperpigmentation of the inferior eyelid (Tella's sign) - Small tremors of the eyelids when closed (Rosenbach's sign) - Difficulty focusing on a close object (Moebius' sign) - Pulsating retinal arteries that can be seen with an exam of the back of the eye (Beck's sign) - A heart murmur-like sound that can be heard over the closed eyelid using a stethoscope (Snellen-Rieseman's sign)

Graves Orbitopathy can be caused by several risk factors, including higher levels of TSH receptor antibodies, being female, certain genetic factors, exposure to radioiodine used in the treatment for Graves' disease, and smoking. However, the specific genes or mutations causing these risk factors are yet to be identified.

The doctor needs to rule out the following conditions when diagnosing Graves Orbitopathy: - Orbital tumors (primary or secondary/metastatic) - Myositis (inflammation) of the extraocular muscles (possibly due to sarcoidosis) - Orbital cellulitis (infection of the eye or eye area) - Ocular myasthenia gravis (affects nerves controlling eye muscles) - Statin-induced extraocular muscle myopathy (muscle weakness caused by statins) - Hashimoto thyroiditis (autoimmune disease affecting eye muscles) - Histiocytosis (overproduction of white blood cells) - Carotid cavernous fistula (rare vascular disorder)

The types of tests that are needed for Graves Orbitopathy include: 1. Thyroid function tests: These tests include a TSH (thyroid-stimulating hormone) and free T4 (thyroxine) test to assess thyroid function. 2. TSH receptor antibody test: This test checks the levels of TSH receptor antibodies, which confirms the diagnosis of Graves' disease and helps track the severity and response to treatment. 3. Scoring methods: Different scoring methods, such as NO SPECS, EUGOGO, and VISA classification, are used to classify the severity and activity of Graves' disease, particularly when it affects the eyes. 4. Imaging tests: Imaging tests like MRI (Magnetic Resonance Imaging) can help identify the activity of the disease, guide treatment decisions, and rule out other eye conditions. CT (Computed Tomography) scan may be useful for planning orbital decompression surgery if necessary.

Graves Orbitopathy can be treated through various methods depending on the severity of the condition. Supportive care is provided to patients with severe eye conditions, which includes lubrication with eye drops, use of eye patches for protection, prism correction, and a raised headrest. Selenium supplementation may be beneficial in areas where selenium content is low. Quitting smoking and normalizing thyroid levels are important, and medication, radioactive iodine therapy, or thyroid surgery can be used for this purpose. Glucocorticoids are used for patients with active and moderate-to-severe disease, and if they are not effective, alternatives like immunomodulatory drugs, radiation therapy, or orbital decompression surgery can be considered. Hospitalization and intravenous glucocorticoids may be necessary for severe cases. Orbital decompression surgery is an option for cases where vision is at risk, and additional surgical procedures can be considered for cosmetic and mobility issues. External beam radiation is used as a last resort for patients who do not respond to other treatments. The treatment approach for children and pregnant patients is similar with some modifications.

The side effects when treating Graves Orbitopathy can include: - Inflammation of the membrane lining the eyelids and covering the eyeball - Dry eyes - Extraocular muscle entrapment - Corneal ulcers - Optic nerve compression

The prognosis for Graves Orbitopathy can vary greatly from person to person. Some individuals may find that their condition remains mild without getting worse, while others may experience improvements or worsening of the disease over time. In severe cases, prompt evaluation and treatment are important to prevent potential vision-threatening complications.

An ophthalmologist or an endocrinologist.