Thyroid Eye Disease

What is Thyroid Eye Disease?

Thyroid eye disease (TED) is a long-lasting condition caused by inflammation in the eye socket, due to an overactive immune system. It is the leading cause of eyes bulging out in adults, either in one eye (unilateral) or both eyes (bilateral). About a quarter to half of people with Grave disease, a condition that affects the thyroid gland, also have thyroid eye disease.

Thyroid eye disease was first mentioned by Avicenna and Al-Jurjani around the year 1000 AD. They noted it in people with goiter, a condition that causes the thyroid gland in the neck to swell. Later, an Irish doctor named Robert Graves described four young women who showed symptoms of overactive thyroid (such as rapid heartbeat), enlarged thyroid gland, and bulging eyes. This condition, known as Graves’ ophthalmopathy or TED, involves inflammation and infiltration (spread) of the soft tissues of the eye socket. This causes the eyes to bulge and potentially leads to ophthalmoplegia, or weakness or paralysis of the eye muscles.

Our understanding of thyroid eye disease has greatly improved over time, which is crucial for providing appropriate treatment and managing this common condition.

What Causes Thyroid Eye Disease?

The cause of thyroid eye disease (TED) is still not fully known. TED involves a complicated cycle in the eye involving various cells responsible for immune responses, including fibroblasts, adipocytes, and lymphocytes.

The fat tissue in the eye, known as orbital adipose tissue, is unique. When there’s significant inflammation in this area, it results in high levels of certain substances that cause inflammation, like interleukin IL-1 and prostaglandins.

Fibroblasts, a type of cell in the eye, play a significant role in the development of TED. These cells have an increased presence of TSH receptors. These receptors can then transform into mature fat cells. Some fibroblasts produce a particular marker, called Thy-1, in larger amounts. A certain substance, known as transforming growth factor-beta (TGF-B), engages the Thy-1 positive fibroblasts to change into myofibroblasts. On the other hand, fibroblasts that don’t produce Thy-1 transform into fat cells when they come into contact with TGF-B.

The TSH receptor is the primary target of the autoimmune reaction within the eye. The level of specific antibodies, known as TRAb, that attack this receptor, tend to increase with the severity of TED.

Other potential targets include certain molecules like the peroxisome-proliferator-activated receptor-gamma present on Thy-1 negative fibroblasts. It’s responsible for controlling the process of forming new fat cells.

The type 1 insulin-like growth factor receptor (IGF-1R) is another important target that is noticed on Thy-1 positive fibroblasts. The stimulation of this enhances the synthesis of a specific immune signaling protein. The protein promotes the recruitment of specific inflammatory cells to the eye.

In conclusion, the inflammation is a repeating cycle. Thy-1 negative fibroblasts are activated, change into fat cells, and contribute to the ongoing inflammatory process. On the other hand, Thy-1 positive fibroblasts activated by IGF-1R support the recruitment of other immune cells, contributing to the inflammation.

These immune cells also produce substances that stimulate the activity of myofibroblasts and production of a gel-like substance called hyaluronate. More inflammation leads to changes in the eye, including enlargement of fat tissues or even fibrosis, which is a type of tissue scarring.

Interestingly, people younger than 40 tend to have more of the Thy-1 negative response and show an expansion of eye fat. In contrast, individuals over 70 tend to show more of the Thy-1 positive response and display muscle enlargement.

Risk Factors and Frequency for Thyroid Eye Disease

Thyroid eye disease is a condition that affects about 50% of Graves’ disease patients, particularly those of Caucasian descent. In the United States, the disease occurs each year in about 16 out of every 100,000 women and in 2.9 out of every 100,000 men.

There are several factors that can increase the risk of developing thyroid eye disease:

Ethnicity: People of African-American descent have the highest risk, followed by whites and Asians.
Age: The disease most commonly occurs in women between the ages of 40 and 64, and in men between the ages of 45 and 69. Older patients are more likely to experience severe symptoms.
Gender: Women are more likely to develop the disease, but men often experience more severe symptoms and worse outcomes.
Genetics: Certain genes – CTLA-4, HLA-DRB-1, and TNF-a – are often associated with the disease.

There are also several conditions and lifestyle factors that are associated with an increased risk of thyroid eye disease:

Autoimmune disorders: People with conditions like pernicious anemia, lupus, Addison’s disease, vitiligo, celiac disease, and rheumatoid arthritis have a higher risk.
Smoking: Smokers are more likely to develop thyroid eye disease.
Thyroid status: Most people diagnosed with thyroid eye disease are hyperthyroid. A small percentage are euthyroid or have Hashimoto thyroiditis or hypothyroidism.
Radioactive iodine therapy: This treatment can worsen thyroid eye disease in about 24% of cases.
Stress: High levels of stress can exacerbate the disease.
Pregnancy: The condition can appear or worsen in about 30% of Graves’ disease patients after childbirth.
Other factors: Physical trauma and high cholesterol can also increase the risk.

Signs and Symptoms of Thyroid Eye Disease

People with thyroid eye disease often experience symptoms such as eye discomfort, dryness, excessive watering, redness, sensitivity to light, and pain behind the eyes. These symptoms might be accompanied by blurred or double vision. The disease can sometimes show its symptoms before a diagnosis of Graves’ disease. Commonly, discomfort in both eyes is asymmetric.

Eyelid retraction is a tell-tale sign of thyroid eye disease. In addition, there may be changes to the eyelid, including:

Altered upper eyelid contour, known as lateral flare.
Lagging upper eyelid during downward movement, known as lid lag.
Incomplete eyelid closing, known as lagophthalmos.
Lower lid retraction.
Upper lid retraction.

Changes can also occur on the ocular surface, including:

Damage to the tear film.
Inflammation of the lacrimal gland.
Persistent lagophthalmos disrupting the ocular surface.
Dry eyes and watering.
Alteration of cornea and conjunctiva, known as superior limbic keratoconjunctivitis.
Persistent dry eye with keratopathy.

Other severe changes may include corneal ulceration, perforation, and endophthalmitis.

Changes can occur in the orbital region, leading to:

Increased intraorbital pressure due to fat and muscle enlargement.
Forward protrusion of the eyeball, referred to as proptosis.
Venous congestion leading to redness, swelling of the eyelids, chemosis, caruncular edema, and raised intraocular pressure.

Changes to eye muscles (EOM) can include:

Inflammation and infiltration of EOM leading to late-onset fibrosis.
Restrictive strabismus and loss of binocular vision.
Diplopia, which usually worsens in the morning.

Changes to the optic nerve, referred to as dysthyroid optic neuropathy (DON), can lead to blurred vision, altered color vision, diminished contrast sensitivity, and narrowed visual fields due to various factors.

You might notice other distinct eyelid, facial, EOM, and pupillary changes, indicating thyroid eye disease. Changes can include incomplete blinking, absence of forehead creases on up gaze, hyperpigmentation of upper eyelid folds, and absent or disrupted eye movements. In addition to these eye-specific changes, you might observe other body changes related to the disease.

Testing for Thyroid Eye Disease

Thyroid eye disease (TED) is diagnosed based on the activity and severity of the condition. These two factors define how fast the disease progresses and the level of visible damage and loss of function. Several systems have been used to measure and grade the signs of TED.

The NO SPECS classification is a well-known system that assesses the severity of the TED but doesn’t include the activity or inflammation levels of the disease. It divides symptoms into six classes, ranging from no physical signs to severe signs like loss of sight due to optic nerve damage.

The Clinical Activity Score (CAS), introduced in 1989, takes into account the classic signs of inflammation such as pain, redness, and swelling. According to this system, a high score would mean that the disease is active and progressing.

The European Group on Graves Orbitopathy (EUGOGO) proposed a severity assessment protocol that categories the severity of TED into mild, moderate-to-severe, and sight-threatening categories. This system details symptoms such as eyelid swelling, lid margin reactions, and optic nerve complications.

A more recent classification, the VISA system, was introduced in 2006. It evaluates the disease based on four components: Vision, Inflammation/congestion, Strabismus/motility restriction, and Appearance/exposure.

Orbital imaging, such as a CT scan or MRI, can also provide valuable insights into the diagnosis and management of TED. This process can visualize the characteristic changes caused by TED, like the enlargement of eye muscles and changes in the optic nerve.

All these classification systems focus on a qualitative assessment, giving equal weight to all the symptoms, regardless of their diagnostic importance. While helpful, these systems might not accurately reflect the extent of the disease.

In the end, the best way to assess and monitor TED is a combination of these systems and orbital imaging under the guidance of a healthcare professional.

Treatment Options for Thyroid Eye Disease

Preventing and effectively managing thyroid eye disease (TED) requires careful evaluation of the condition. There are several ways to prevent the progression of the disease:

1. Primary Prevention: Quitting smoking helps significantly.
2. Secondary Prevention: Early detection of any thyroid disorder and quick treatment can prevent the disease from getting worse.
3. Tertiary Prevention: Using artificial tears prevents further damage. It’s also important to pay attention to appearance and vision.

For medical treatment:

Returning thyroid function to normal is a key step. Patients with TED may experience symptoms like dry and irritated eyes, which can be helped with artificial tears and similar products. Adding selenium to the diet can also improve patient well-being, reduce inflammation, and slow down the progression of TED.

In cases of mild TED where the eye lid retracts less than 2mm, injections can be done to help correct it. Some of these injections may involve botulinum toxin type A or triamcinolone. Both have shown great results in resolving lid retraction.

If the TED is more severe, it’s important to control the immune response quickly. Steroids are often used first. If steroids aren’t working or can’t be used due to side effects, other drugs that modulate immune response, like methotrexate, azathioprine, and mycophenolate mofetil, can be attempted. Rituximab, an antibody that targets a specific marker on immune cells, has shown extremely promising results, with total symptom resolution in some patients with moderate-to-severe TED.

For inactive TED cases (where the disease is not progressing), eye lubrication is common, along with surgical management for cosmetic reasons.

In severe cases where vision could be threatened, high-dose corticosteroid therapy is the most effective. Orbital radiation therapy can also be helpful in these cases. These therapies can reduce the need for surgical decompression of the eye, which is a procedure that creates more space in the eye socket to relieve pressure.

While surgery is usually reserved for inactive cases that are not responding to other treatments, occasionally someone with active TED will require immediate surgical intervention. The type of surgery used depends on the specific needs of the patient.

Surgery on the eye socket can correct proptosis (bulging eyes), a prominent symptom of TED. After surgery, the patient may also need treatment for misalignment of the eyes and lid retraction. With this multi-step approach, patients can expect a significant improvement in appearance and eye function.

It’s worth noting that the type of surgery used is tailored to the patient’s needs, based on their specific symptoms and the severity of their condition. For instance, surgeries might involve decompression of the lateral walls (sides of the eye socket), medial walls (inner parts of the eye socket), or even floor decompression (bottom part of the eye socket). These techniques all aim to make more space in the eye socket and relieve symptoms.

At times, the removal of fat may also be necessary, especially in cases where the eye socket is dominated by fat. Overall, the goal of surgery is to improve symptoms and enhance the patient’s quality of life.

Non-specific orbital inflammatory disease (NSOID) can cause both eyes to bulge and the tear gland to enlarge. The eye muscles and their attaching tendons also swell. The tear gland can even move out of its normal space. This condition can be linked to autoimmune diseases like polymyositis, dermatomyositis, and diseases related to IGG4. Diagnostic tests for NSOID typically include blood tests and a soft tissue biopsy.

Lymphoma can also cause both eyes to bulge and may be associated with swelling of lymph nodes. Usual blood tests and counts are often normal. A CT scan of the orbit could reveal tissue enlargement on both sides with bony orbit erosion. A diagnosis is typically confirmed with a soft tissue biopsy and further microscopic examination of the tissue to identify cancer cells.

A blow-out fracture of the orbit is another condition that may change the position of the eyeball and limit the movement of the eye muscles. This generally occurs after a trauma and is followed by the eyeball sinking backward into the eye socket and restriction of upward gaze. A CT scan of the orbit will often show a broken bone with trapped tissues.

Amyloidosis can result in both eyes bulging and disease related to nerves. A biopsy showing an abnormal, pinkish substance that shines under polarized light microscopy is key to the diagnosis of Amyloidosis.

What to expect with Thyroid Eye Disease

About 80% of people with thyroid eye disease can be treated just using eye drops to help keep the eyes moisturized. However, around 5% of cases are more severe and need treatment with medications like corticosteroids or other drugs that help to regulate the immune system. Additionally, roughly 20% of patients need some type of surgery to help manage their condition.

Regardless of the treatment needed, it’s crucial for these patients to have regular check-ups and to closely monitor their condition for any complications. This is an important part of the long-term management of thyroid eye disease.

Possible Complications When Diagnosed with Thyroid Eye Disease

People with thyroid eye disease may face some potential complications, which could include:

Dysthyroid optic neuropathy – this is a condition where the optic nerve, which sends visuals from your eye to your brain, is compressed or has reduced blood supply.
Optic atrophy – this involves damage to the optic nerve that can lead to vision loss.
Exposure-keratopathy and keratomalacia – these are forms of damage to the cornea of the eye, which can affect vision.
Open-angle glaucoma – a condition which gradually decreases eyesight due to high eye pressure.
Restrictive strabismus and diplopia – these conditions cause issues with eye alignment and can lead to vision problems including double vision.
Persistent proptosis, lid retraction, and cosmetic disfigurement – these are noticeable physical changes to the appearance of the eyes and eyelids.
Orbital venous stasis and venous occlusions – these involve problems with the veins in the eye area that can affect circulation.

Recovery from Thyroid Eye Disease

Addressing cosmetic concerns is a crucial part of managing Thyroid Eye Disease (TED). When the disease isn’t active, it’s normal for the eyes to feel pushed forward unevenly, or what doctors call “asymmetrical proptosis”. Both of these can be helped by a procedure called surgical orbital decompression, which aims to give your eyes a more balanced look.

The specifics of surgery are planned according to how much your eyes are pushed forward (the amount of proptosis), the pattern of eye deviation (strabismus), and the unique construction of your eye socket (the orbital anatomy). In cases where the muscles controlling eye movement are constrained (restricted EOM), resetting those muscles can help achieve a straight or natural eye position in the primary gaze. If your eyelid needs to be corrected (lid retraction), a final procedure is typically planned at least six months after surgery for strabismus.

Several techniques are commonly used to correct lid retraction; these include Blepharotomy, Blepharomyotomy, Levator recession, and Spacer grafts. These might sound complex, but just note that these are names for different ways your doctor may adjust your eyelids to give them a more natural position and appearance.

Preventing Thyroid Eye Disease

If you have a thyroid disorder, it’s important to be regularly checked for early signs of issues related to your eyes linked with the thyroid, known as thyroid eye disease. Regular check-ups are needed, even if you don’t show any symptoms or if the symptoms are mild. This is important in recognizing and treating any serious complications that could affect your vision.

You should be aware of the early warning signs of a particular complication called DON (Dysthyroid Optic Neuropathy). These signs include changes in color perception, decreased sensitivity to contrast or differences between light and dark, a narrower field of vision than usual, and lower clarity of vision or visual acuity. Having knowledge of these signs can assist in early detection and treatment.

Frequently asked questions

The prognosis for Thyroid Eye Disease varies depending on the severity of the condition. Approximately 80% of people with the disease can be treated with eye drops to keep the eyes moisturized. Around 5% of cases are more severe and require treatment with medications like corticosteroids or other drugs that regulate the immune system. Approximately 20% of patients need some type of surgery to manage their condition. Regular check-ups and close monitoring of the condition are important for long-term management.

There are several factors that can increase the risk of developing thyroid eye disease, including ethnicity, age, gender, genetics, autoimmune disorders, smoking, thyroid status, radioactive iodine therapy, stress, pregnancy, physical trauma, and high cholesterol.

Signs and symptoms of Thyroid Eye Disease include: - Eye discomfort - Dryness - Excessive watering - Redness - Sensitivity to light - Pain behind the eyes - Blurred or double vision - Asymmetric discomfort in both eyes - Eyelid retraction - Altered upper eyelid contour (lateral flare) - Lagging upper eyelid during downward movement (lid lag) - Incomplete eyelid closing (lagophthalmos) - Lower lid retraction - Upper lid retraction - Damage to the tear film - Inflammation of the lacrimal gland - Persistent lagophthalmos disrupting the ocular surface - Dry eyes and watering - Alteration of cornea and conjunctiva (superior limbic keratoconjunctivitis) - Persistent dry eye with keratopathy - Corneal ulceration, perforation, and endophthalmitis (severe changes) - Increased intraorbital pressure due to fat and muscle enlargement - Forward protrusion of the eyeball (proptosis) - Venous congestion leading to redness, swelling of the eyelids, chemosis, caruncular edema, and raised intraocular pressure - Inflammation and infiltration of eye muscles (EOM) leading to late-onset fibrosis - Restrictive strabismus and loss of binocular vision - Diplopia (usually worsens in the morning) - Changes to the optic nerve (dysthyroid optic neuropathy) leading to blurred vision, altered color vision, diminished contrast sensitivity, and narrowed visual fields - Other distinct eyelid, facial, EOM, and pupillary changes, such as incomplete blinking, absence of forehead creases on up gaze, hyperpigmentation of upper eyelid folds, and absent or disrupted eye movements.

The types of tests that are needed for Thyroid Eye Disease include: - Clinical Activity Score (CAS) to assess the activity and progression of the disease based on signs of inflammation. - NO SPECS classification to assess the severity of the disease based on physical signs. - European Group on Graves Orbitopathy (EUGOGO) severity assessment protocol to categorize the severity of TED. - VISA system to evaluate the disease based on vision, inflammation/congestion, strabismus/motility restriction, and appearance/exposure. - Orbital imaging, such as a CT scan or MRI, to visualize characteristic changes caused by TED, such as enlargement of eye muscles and changes in the optic nerve.

The doctor needs to rule out the following conditions when diagnosing Thyroid Eye Disease: 1. Non-specific orbital inflammatory disease (NSOID) 2. Lymphoma 3. Blow-out fracture of the orbit 4. Amyloidosis

When treating Thyroid Eye Disease, there can be potential side effects, including: - Dysthyroid optic neuropathy: Compression or reduced blood supply to the optic nerve, leading to visual impairment. - Optic atrophy: Damage to the optic nerve, resulting in vision loss. - Exposure-keratopathy and keratomalacia: Damage to the cornea, affecting vision. - Open-angle glaucoma: Gradual decrease in eyesight due to high eye pressure. - Restrictive strabismus and diplopia: Issues with eye alignment, causing vision problems such as double vision. - Persistent proptosis, lid retraction, and cosmetic disfigurement: Noticeable physical changes to the appearance of the eyes and eyelids. - Orbital venous stasis and venous occlusions: Problems with the veins in the eye area, affecting circulation.

An ophthalmologist.

Thyroid eye disease affects about 16 out of every 100,000 women and 2.9 out of every 100,000 men in the United States each year.

Thyroid Eye Disease (TED) can be treated through various methods depending on the severity of the condition. In mild cases, injections of botulinum toxin type A or triamcinolone can help correct lid retraction. For more severe cases, controlling the immune response is important, and steroids are often used as the first line of treatment. If steroids are ineffective or cannot be used, other drugs that modulate the immune response, such as methotrexate, azathioprine, and mycophenolate mofetil, can be attempted. In cases where vision is threatened, high-dose corticosteroid therapy and orbital radiation therapy are the most effective treatments. Surgery is usually reserved for inactive cases that do not respond to other treatments, and the specific type of surgery depends on the patient's symptoms and condition. The goal of surgery is to improve symptoms and enhance the patient's quality of life.

Thyroid Eye Disease is a long-lasting condition caused by inflammation in the eye socket, due to an overactive immune system. It is the leading cause of eyes bulging out in adults, either in one eye (unilateral) or both eyes (bilateral).