Thyroid Eye Disease

Thyroid eye disease can develop in any person with Graves’ disease or Hashimoto’s thyroiditis, and occasionally in people with normal thyroid function. The following factors are associated with a higher risk of developing TED or experiencing a more severe course.

• Smoking: the single most impactful modifiable risk factor. Smokers with Graves’ disease have approximately 7.7 times the risk of developing TED compared to non-smokers. Smokers are more likely to develop severe disease, diplopia, proptosis, and optic nerve compression. Their disease responds less well to anti-inflammatory treatments, and they are more likely to relapse. The benefit of quitting smoking applies at any stage.
• Radioactive iodine therapy for Graves’ disease: RAI increases the risk of TED progression by 15–39% compared to antithyroid drugs or thyroid surgery, particularly in patients with pre-existing active orbital disease or who are smokers.
• Poorly controlled thyroid function: Both hyperthyroidism and hypothyroidism worsen TED. Achieving and maintaining normal thyroid hormone levels is the most important ongoing management goal.
• Diabetes mellitus: More than 33% of TED patients with diabetes develop optic nerve compression, compared to less than 4% of TED patients without diabetes. Diabetes impairs the marginal blood flow to the optic nerve, making it far more vulnerable to compression.
• Elevated TSH receptor antibodies (TRAbs): High TRAb levels correlate with more active and more severe TED and with a higher risk of disease reactivation.
• High cholesterol (hyperlipidemia): associated with more active TED. Statin use is associated with approximately a 40% reduction in TED risk.
• Vitamin D deficiency: This deficiency is present in more than 25% of TED patients in large U.S. studies.

There is no single population-wide screening test for TED. Instead, screening follows a structured pathway for patients with known or suspected Graves’ disease. All patients newly diagnosed with Graves’ disease should have a baseline ophthalmology evaluation within three to six months of diagnosis—or sooner if they have any eye symptoms. At every thyroid clinic visit, the clinician should examine the eyelids for retraction, assess whether the eyes appear to protrude, and ask about double vision, eye pain, and visual changes.

When TED is suspected, a comprehensive eye evaluation includes measuring forward displacement of the eye (proptosis) with a Hertel exophthalmometer, scoring inflammation with the CAS, testing color vision and visual fields to screen for early optic nerve compression, and assessing tear film and corneal surface health. Orbital imaging—CT scan for bony anatomy and surgical planning, and magnetic resonance imaging (MRI) for disease activity assessment—is obtained when needed. In the United States, the average patient waits more than a year from first eye symptoms to a definitive TED diagnosis, reflecting a significant gap in recognition and referral. Patients with unexplained eye bulging, lid retraction, or double vision should ask their primary care doctor or endocrinologist about TED screening regardless of whether a thyroid diagnosis has been established.

The hallmark sign of TED—present in more than 90% of patients—is upper eyelid retraction, in which the upper eyelid sits too high, exposing white sclera (the white of the eye) above the colored iris. This gives the face a wide-eyed, staring appearance that is often the first change patients or family members notice. When lower eyelid retraction also occurs—present in about 85% of patients—both the upper and lower lids are pulled away from the normal position, producing the distinctive thyroid stare. Symptoms vary significantly by disease severity and whether the condition is currently in an active or inactive phase.

• Upper eyelid retraction: present in more than 90% of patients. The upper eyelid sits too high, so more of the white of the eye is visible than normal. This may be the only sign in mild disease.
• Lower eyelid retraction: present in about 85% of patients. The lower lid also sits too low, widening the appearance of the eye opening on both the upper and lower borders.
• Proptosis (bulging of the eyes): present in about 60% of patients. The eyeball is pushed forward out of the socket by expanding fat or enlarging eye muscles. It may affect one eye more than the other or both eyes equally. Prominent eye bulging is one of the most distressing features of the condition for many patients.
• Periorbital swelling and puffiness: Swelling of the eyelids, redness, and puffiness around the eyes is caused by lymphatic obstruction and inflammatory fluid accumulation inside the orbit.
• Double vision (diplopia): present in about 35% of patients. The enlarged, stiff extraocular muscles cannot move the eyes fully in all directions, causing the two eyes to misalign and producing double vision. It is most often present in up-gaze or down-gaze rather than in the straight-ahead position.
• Dry eyes, grittiness, and tearing: Ocular surface disease is present in 65–95% of TED patients. Lid retraction and incomplete eyelid closure (lagophthalmos) expose the cornea to air, reducing tear protection. Paradoxically, chronic dryness often triggers reflex tearing.
• Pain or pressure behind or around the eyes: a dull, aching discomfort at rest or with eye movement, present in about 30% of patients. This is a feature of active, inflammatory disease.
• Incomplete eyelid closure (lagophthalmos): The eyelids cannot fully close, particularly during sleep. This leaves the cornea unprotected overnight and can lead to corneal damage.
• Sensitivity to light (photophobia): Corneal exposure and surface inflammation cause discomfort in bright light.
• Elevated eye pressure: This happens particularly when looking upward; caused by restricted inferior rectus muscles and increased pressure in the eye socket veins.
• Facial and periorbital changes: In some patients, orbital fat expands beyond the bony eye socket, causing visible fullness of the cheeks and browline in addition to the orbital findings.

The following symptoms indicate possible optic nerve compression (dysthyroid optic neuropathy––DON) or severe corneal damage and require urgent evaluation—same-day if possible:

• Color vision changes: Colors appear less vivid, washed out, or different between the two eyes. Loss of color saturation is frequently the earliest detectable sign of optic nerve damage in TED and may precede any change in standard visual acuity.
• Visual field loss: a blind spot, shadow, or missing area in the field of vision. Central or paracentral blind spots are the most common pattern in TED-related optic nerve compression.
• Decreased visual acuity: blurring of vision that does not improve with glasses. Less than half of patients with optic nerve compression still have 20/40 vision or better at the time of diagnosis, making earlier detection through color vision and visual field testing critical.
• Transient visual obscurations: brief, passing episodes of vision dimming or blackout. These are caused by momentary impairment of blood flow to the optic nerve from positional pressure.
• An afferent pupillary defect: When light is alternately shone into each eye, the affected pupil responds weakly. This is a highly specific sign of optic nerve damage detected during examination.

Thyroid eye disease is typically diagnosed by an ophthalmologist, oculoplastic surgeon, or neuro-ophthalmologist, usually after a patient with known Graves’ disease presents with eye complaints, or when an endocrinologist identifies eyelid or orbital changes during routine follow-up. Formal diagnosis uses the Bartley criteria: upper eyelid retraction combined with thyroid dysfunction, proptosis, restricted eye movement, or optic nerve dysfunction—or, in the absence of lid retraction, thyroid dysfunction plus at least one of those features. Because TED can present before, during, or after thyroid disease, and because the average U.S. patient waits more than a year for diagnosis after first symptoms, a low threshold for referral is important. Key diagnostic tools include:

• Hertel exophthalmometry: a handheld device that measures how many millimeters the eye protrudes forward from the outer bony orbital rim. Normal values for Caucasian adults are 12 to 21 mm at a standardized base measurement. A reading more than 3 mm above the norm for the patient’s sex and ethnicity, or asymmetry of more than 2 mm between the two eyes, is considered abnormal.
• Margin reflex distance (MRD1 and MRD2): The doctor shines a light at the eye and measures the distance from the pupil’s central light reflex to the upper and lower eyelid margins. An MRD1 greater than 5 mm indicates upper lid retraction; an MRD2 less than 5 mm indicates lower lid retraction. More than 90% of TED patients have some degree of upper lid retraction.
• Clinical Activity Score (CAS): a standardized checklist of seven inflammatory signs at initial evaluation (or ten signs at follow-up), including spontaneous orbital pain, pain with eye movement, eyelid redness, eyelid swelling, conjunctival redness, conjunctival swelling (chemosis), and swelling of the caruncle (the pink tissue at the inner corner of the eye). A score of 3 or more out of 7 indicates active disease.
• Color vision testing: Ishihara or Hardy-Rand-Rittler (HRR) color plates detect early acquired color defects that signal optic nerve dysfunction before visual acuity drops. HRR plates are more sensitive for the type of color defects seen in TED. Any acquired color defect is abnormal and warrants urgent further evaluation.
• Automated visual field testing: a computerized test that maps the full field of vision. Central or paracentral blind spots are the most common finding in TED-related optic nerve compression. Visual field testing is mandatory when optic nerve compression is suspected.
• Pupillary examination for afferent pupillary defect (APD): The swinging flashlight test detects asymmetric optic nerve function between the two eyes. A positive APD is highly specific for optic nerve damage.
• Contrast sensitivity and visual evoked potentials (VEP): These tests detect subclinical optic nerve damage earlier than standard acuity testing and are used in high-risk patients, particularly older men and those with diabetes.
• Tear film assessment: Tear break-up time (TBUT) and Schirmer’s test measure the stability and volume of the tear film to characterize the dry eye disease component of TED, which is present in the great majority of patients.

• TSH, free T4, free T3: to confirm thyroid status and guide antithyroid treatment. Maintaining euthyroidism is critical to orbital disease control.
• TRAbs (TSH receptor antibodies, TBII or thyroid-stimulating immunoglobulin—TSI assay): Detectable in 95–98% of patients with Graves’ disease-related TED using modern third-generation assays. TRAb levels correlate with disease activity and severity. The TSI bioassay provides functional information and correlates specifically with active orbital disease. TRAb testing serves both diagnostic and prognostic purposes.
• Blood glucose and HbA1c: These screen for diabetes, which dramatically increases the risk of optic nerve compression in TED.
• Fasting lipid panel: Hyperlipidemia is a modifiable TED risk factor, and statin use has a protective association.

Thyroid eye disease cannot be cured, but it is highly manageable. Treatment decisions are guided by two questions: Is the disease currently active (is inflammation ongoing) and how severe is it? Active disease responds to anti-inflammatory treatments that target the underlying immune process. Inactive disease does not respond to immunosuppression—residual structural changes are addressed through a specific, ordered sequence of rehabilitative surgeries: first orbital decompression (if needed), then strabismus surgery (if needed), then eyelid surgery. The sequence matters and cannot be reversed. Your care team at a specialized TED center will guide you through each phase and help you understand which treatments are appropriate for your specific stage of disease.

Regardless of disease severity or activity, the following measures protect the eyes and improve comfort throughout the entire course of TED:

• Preservative-free lubricating eye drops: used every one to two hours during the day to protect the exposed corneal surface. Lubricating ointment is used at night for patients with incomplete eyelid closure.
• Nighttime eye taping or moisture chamber goggles: These protect the cornea from exposure during sleep when lagophthalmos (incomplete closure) is present.
• Sunglasses with side shields and prism glasses: Ultraviolet (UV)-blocking wraparound sunglasses reduce photophobia and tear evaporation. Fresnel prism lenses or ground-in prism spectacles can correct stable, small-angle double vision in inactive disease.
• Head-of-bed elevation: Sleeping with the head elevated reduces gravity-dependent fluid accumulation around the eyes overnight.
• Thyroid status optimization: Maintaining euthyroidism with antithyroid drugs (methimazole is preferred for long-term use), beta-blockers for symptom control, or thyroid surgery is the most important ongoing systemic management step.
• Smoking cessation: Counseling and pharmacotherapy to stop smoking must be offered at every visit, as smoking is the most important modifiable driver of severity and treatment resistance.

For patients with mild active TED—a wide-eyed appearance and mild soft tissue swelling without significant proptosis, double vision, or visual threat—selenium supplementation at 200 mcg of sodium selenite daily for six months is the evidence-based first-line treatment, supported by a randomized controlled trial. Selenium reduces inflammation, lowers disease activity scores, and significantly reduces the rate of progression to more severe disease. It is well-tolerated with few side effects. Close monitoring for progression is essential so that treatment can be escalated promptly if needed.

Intravenous methylprednisolone (IV-MP, brand name Solu-Medrol®) is the first-line immunosuppressive treatment for moderate-to-severe active TED, recommended by the European Group on Graves’ Orbitopathy (EUGOGO) guidelines. It is given as an intravenous infusion—not oral pills—because the intravenous route is both more effective and better tolerated than oral steroids at the doses needed to treat orbital inflammation. The standard protocol for moderate-to-severe disease is 500 mg IV once weekly for six weeks, then 250 mg IV once weekly for another six weeks, for a total cumulative dose of 4.5 grams. Liver function tests, blood sugar, and blood pressure are monitored throughout treatment, as elevated liver enzymes, high blood sugar, and high blood pressure are the most important side effects. A more aggressive protocol—higher doses given on three consecutive days, repeated the following week—is used for sight-threatening disease with optic nerve compression. Steroids should never be abruptly discontinued, as reactivation occurs in up to 25% of patients when treatment is stopped prematurely.

Teprotumumab (Tepezza®) is the first and only U.S. Food and Drug Administration (FDA)-approved targeted therapy specifically for TED, approved on January 21, 2020. It works through a fundamentally different mechanism than steroids—it is a monoclonal antibody that blocks the IGF-1R receptor on orbital fibroblasts, directly shutting down the molecular signaling pathway that drives orbital fat expansion, muscle enlargement, and hyaluronic acid buildup. Teprotumumab is given as a series of eight intravenous infusions over approximately 21 weeks (the first infusion at 10 mg/kg body weight, then seven additional infusions at 20 mg/kg, given every three weeks). In the pivotal OPTIC Phase 3 clinical trial, 83% of patients treated with teprotumumab had a meaningful reduction in proptosis (eye bulging of 2 mm or more), compared to only 10% in the placebo group. Double vision improved in significantly more teprotumumab-treated patients. Many patients maintain improvement for a year or more after completing the infusion course. Teprotumumab is also effective in some patients with inactive TED who have not responded to other treatments, though it was originally approved for active disease. Important side effects include muscle cramps and spasms, hearing changes (including sensorineural hearing loss, tinnitus, and a sensation that one’s own voice sounds too loud—called autophony), elevated blood sugar, nausea, hair thinning, and fatigue. A hearing test (audiogram) is recommended before starting teprotumumab and during treatment, particularly for patients with pre-existing hearing concerns. Blood sugar must be monitored carefully in patients with diabetes. Teprotumumab should not be used during pregnancy because the IGF-1R pathway it blocks is critical for normal fetal development.

When IV steroids or teprotumumab are insufficient or not tolerated, additional immunosuppressive medicines are used. Mycophenolate mofetil (CellCept®) is a steroid-sparing immunosuppressant added to or used in place of IV methylprednisolone for moderate-to-severe active TED. Rituximab (Rituxan®) is an anti-CD20 monoclonal antibody that depletes B-cells—the immune cells that produce TRAbs—and is used as a second-line biologic for patients whose disease does not respond to steroids. Tocilizumab (Actemra®) is an IL-6 receptor blocker that has shown benefit in steroid-resistant moderate-to-severe TED, improving proptosis and eye movement in a majority of treated patients.

For eyelid-specific symptoms during the active phase, botulinum toxin (Botox®) injections into the overactive upper eyelid muscles can temporarily reduce lid retraction and protect the corneal surface while waiting for definitive surgical correction. Hyaluronic acid filler injections and injectable corticosteroids can also be used in selected patients for targeted eyelid management. Anti-inflammatory prescription eye drops, including cyclosporine (Restasis®) and lifitegrast (Xiidra®), are used off-label to treat the significant dry eye and ocular surface disease component of TED.

Orbital radiotherapy—delivering a carefully fractionated course of radiation to the eye socket—is used as an adjunct treatment for moderate-to-severe active TED that has not responded adequately to intravenous steroids. The standard protocol delivers 20 Gy per eye in 10 fractions over 10 days using a linear accelerator. The radiation targets the activated immune cells and fibroblasts in the orbit, reducing inflammation and potentially slowing the progression of muscle enlargement. It is generally not used as the sole treatment for active disease but may help certain patients avoid surgery or control disease that has been difficult to manage medically. Orbital radiotherapy is contraindicated in patients with severe high blood pressure or diabetic retinopathy, as these conditions increase the risk of radiation-related vascular damage to the eye.