Ophthalmology – Thyroid Eye Disease

What the Disorder Represents

Thyroid eye disease (TED) is an autoimmune inflammatory disorder of the orbit affecting:

• Extraocular muscles
• Orbital fat
• Orbital connective tissue
• Eyelids
• Lacrimal gland
• Ocular surface

It is also called:

• Graves orbitopathy
• Graves ophthalmopathy
• Thyroid-associated orbitopathy

The classic manifestations are:

• Upper-lid retraction
• Proptosis
• Restrictive strabismus with diplopia
• Exposure keratopathy
• In severe cases, dysthyroid optic neuropathy (DON)

Relationship to Thyroid Function

TED is most commonly associated with:

Graves hyperthyroidism

but can also occur in patients who are:

• Euthyroid
• Hypothyroid
• Occasionally associated with Hashimoto thyroiditis

Therefore:

Normal thyroid hormone levels do not exclude TED.

Ocular disease may:

• Precede thyroid dysfunction
• Develop simultaneously
• Appear after thyroid disease is diagnosed

Who Is Most Often Affected

TED is more common in:

• Women
• Middle-aged adults

but severe disease is disproportionately seen in:

• Men
• Older patients
• Smokers

Disease is usually bilateral but can be:

Markedly asymmetric or apparently unilateral.

The Most Important Modifiable Risk Factor

The strongest established modifiable risk factor is:

Cigarette smoking

Smoking increases:

• Risk of developing TED
• Disease severity
• Risk of progression
• Risk of worsening after radioactive iodine
• Poor response to treatment

Smoking cessation is therefore one of the most important components of management.

Other Factors That Increase Risk or Severity

Relevant factors include:

• Poorly controlled hyperthyroidism
• Hypothyroidism after treatment
• High TSH-receptor antibody levels
• Radioactive iodine in susceptible patients
• Diabetes
• Hypercholesterolemia
• Older age

Rapid normalization and maintenance of a:

Euthyroid state

is important.

Modern Understanding of the Autoimmune Mechanism

TED is driven by autoimmune activation of orbital fibroblasts.

Two particularly important receptors are:

• TSH receptor (TSHR)
• Insulin-like growth factor-1 receptor (IGF-1R)

Autoimmune signaling activates fibroblasts, leading to:

• Cytokine production
• Glycosaminoglycan accumulation
• Tissue edema
• Adipogenesis
• Extraocular muscle enlargement

This explains why therapies targeting:

IGF-1R

can improve proptosis and diplopia in selected patients.

Why the Orbit Becomes Crowded

Inflammatory enlargement of:

• Extraocular muscles
• Orbital fat

occurs within the fixed bony orbit.

This can produce:

• Proptosis
• Venous congestion
• Eyelid retraction
• Restrictive motility
• Corneal exposure
• Compression of the optic nerve at the orbital apex

The Two Broad Disease Phases

TED typically follows a biphasic course.

Active Inflammatory Phase

Characterized by:

• Pain
• Redness
• Swelling
• Chemosis
• Progressive proptosis
• Worsening diplopia

This phase commonly lasts:

Months to a few years

Inactive or Fibrotic Phase

Inflammation subsides, but patients may retain:

• Proptosis
• Restrictive strabismus
• Lid retraction
• Exposure
• Disfigurement

The distinction between:

Activity and severity

is critical for treatment decisions.

How Activity Is Assessed

The Clinical Activity Score (CAS) is commonly used.

Classic CAS features include:

• Spontaneous retrobulbar pain
• Pain on attempted gaze
• Eyelid erythema
• Eyelid swelling
• Conjunctival redness
• Chemosis
• Caruncular or plical inflammation

A score of:

≥3/7

is traditionally considered supportive of active disease at the initial visit.

However:

CAS is not perfect and should not be used in isolation.

Progression in:

• Proptosis
• Diplopia
• Motility restriction
• Soft-tissue inflammation

may indicate active TED even when CAS is relatively low.

How Severity Is Classified

A practical classification is:

Mild

• Minor lid retraction
• Mild soft-tissue involvement
• Mild proptosis
• Little or no diplopia
• Limited impact on daily life

Moderate-to-Severe

• Significant lid retraction
• Moderate/severe soft-tissue disease
• Meaningful proptosis
• Restrictive diplopia
• Significant quality-of-life impairment

Sight-Threatening

• Dysthyroid optic neuropathy
• Severe corneal exposure with ulceration or impending perforation

Sight-threatening TED is an:

Ophthalmic emergency.

The Most Common External Sign

The most characteristic external finding is:

Upper-eyelid retraction

which produces:

• Superior scleral show
• Staring appearance

Lower-lid retraction may also occur.

Lid Lag

Lid lag refers to delayed downward movement of the upper eyelid as the patient looks downward.

This differs from static lid retraction but commonly accompanies it.

Lagophthalmos

Incomplete eyelid closure can result from:

• Proptosis
• Lid retraction
• Fibrosis

This can lead to:

Exposure keratopathy.

Ocular Surface Manifestations

Patients often complain of:

• Grittiness
• Burning
• Tearing
• Foreign-body sensation
• Photophobia
• Fluctuating vision

Findings may include:

• Punctate epithelial keratitis
• Inferior corneal staining
• Exposure keratopathy
• Superior limbic keratoconjunctivitis

Superior Limbic Keratoconjunctivitis

TED is an important association of:

Superior limbic keratoconjunctivitis (SLK)

especially in patients with:

• Tight upper lids
• Lid retraction
• Increased superior conjunctival friction

Proptosis

Proptosis results from enlargement of:

• Orbital fat
• Extraocular muscles
• Both

It is assessed clinically with:

Hertel exophthalmometry

but normal values vary according to:

• Ethnicity
• Facial anatomy
• Instrument base measurement

Change over time is often more useful than a single absolute number.

Restrictive Strabismus

Diplopia results from inflammation and later fibrosis of extraocular muscles.

The classic order of muscle involvement is often remembered as:

Inferior rectus → medial rectus → superior rectus → lateral rectus

but any extraocular muscle can be affected.

Typical Motility Pattern

Inferior rectus restriction causes:

• Limited elevation
• Hypotropia of the affected eye

Medial rectus restriction causes:

• Limited abduction
• Esotropia

Diplopia may initially occur only in:

• Upgaze
• Lateral gaze

before affecting primary position.

Why Diplopia Is Restrictive Rather Than Paretic

The affected muscle is:

Fibrotic and mechanically tight

rather than neurologically weak.

Forced-duction testing may therefore be:

Positive.

Dysthyroid Optic Neuropathy

Dysthyroid optic neuropathy (DON) is the most important vision-threatening complication.

It usually results from:

Compression of the optic nerve by enlarged extraocular muscles at the orbital apex.

It can occasionally occur without dramatic proptosis.

Warning Signs of Optic Neuropathy

Look for:

• Reduced visual acuity
• Reduced color vision
• RAPD if asymmetric
• Reduced contrast sensitivity
• Visual-field defect
• Optic disc edema or pallor

However, the optic disc may appear:

Normal despite significant DON.

A Key Clinical Trap

The amount of proptosis does:

Not reliably predict optic nerve compression.

A patient with relatively little proptosis but a crowded orbital apex may develop severe DON.

Examination Priorities

A complete TED examination should include:

• Visual acuity
• Pupils
• Color vision
• Contrast sensitivity when available
• Ocular motility
• Alignment
• Lid position
• Lagophthalmos
• Corneal exposure
• Exophthalmometry
• IOP
• Optic nerve evaluation

Why IOP May Rise

IOP can increase due to:

• Orbital venous congestion
• Restriction of the inferior rectus
• Increased pressure during upgaze
• Coexisting glaucoma
• Steroid therapy

IOP should ideally be measured in:

Primary gaze

because forced upgaze can artificially increase the reading.

Thyroid Blood Tests

Systemic evaluation typically includes:

• TSH
• Free T4
• T3 when appropriate

Autoimmune markers may include:

• TSH-receptor antibodies (TRAb)
• Thyroid-stimulating immunoglobulin (TSI)

Positive TRAb/TSI supports the diagnosis.

Negative testing does:

Not completely exclude TED.

When Imaging Is Useful

Imaging is particularly helpful when:

• Diagnosis is atypical
• Disease is unilateral
• DON is suspected
• Surgical planning is required
• Another orbital process must be excluded

CT Appearance

Orbital CT classically shows:

Extraocular muscle belly enlargement with relative tendon sparing

producing a spindle-shaped appearance.

The most commonly enlarged muscles are:

• Inferior rectus
• Medial rectus

CT is especially useful for evaluating:

• Bony orbit
• Apical crowding
• Surgical decompression anatomy

MRI Appearance

MRI provides excellent soft-tissue detail and can help assess:

• Extraocular muscle enlargement
• Orbital fat
• Optic nerve compression
• Inflammatory activity

T2/STIR hyperintensity may support:

Active muscle inflammation.

The Classic Imaging Distinction

TED usually causes:

Muscle-belly enlargement with tendon sparing.

Idiopathic orbital myositis more commonly involves:

The muscle and its tendon insertion.

This distinction is helpful but not absolute.

Important Alternative Diagnoses

Consider:

• Idiopathic orbital inflammation
• Orbital lymphoma
• Metastasis
• Carotid-cavernous fistula
• Orbital vascular malformation
• Sarcoidosis
• IgG4-related disease
• Myasthenia gravis

Why Myasthenia Is Important

TED and myasthenia gravis can coexist.

Suspect myasthenia when there is:

• Fluctuating diplopia
• Ptosis
• Variable motility abnormalities
• Findings that do not fit a restrictive pattern

Myasthenia does not cause:

Proptosis or extraocular muscle enlargement typical of TED.

First Priorities for Every Patient

Management begins with:

• Smoking cessation
• Restoration and maintenance of euthyroidism
• Ocular surface protection
• Assessment of activity and severity
• Identification of DON or corneal threat

Treating Ocular Surface Disease

Supportive measures include:

• Preservative-free artificial tears
• Lubricating gel or ointment
• Nighttime ointment
• Moisture chambers
• Eyelid taping during sleep when needed
• Head elevation during sleep

More severe exposure may require:

• Temporary tarsorrhaphy
• Botulinum-induced protective ptosis in selected cases
• Definitive lid surgery after stabilization

Role of Selenium

For mild active TED, particularly in regions or patients with low selenium intake, a limited course of selenium may improve:

• Symptoms
• Quality of life
• Disease progression

Typical studied dosing has been approximately:

100 micrograms twice daily for 6 months

but supplementation should not be indiscriminate because excessive selenium can be toxic.

Its benefit is less certain in selenium-replete populations.

Managing Diplopia Conservatively

Temporary options include:

• Fresnel prism
• Ground-in prism when deviation is small and stable
• Occlusion in difficult cases

Prism is most useful when the deviation is:

• Relatively small
• Comitant enough to correct

Radioactive Iodine and TED

Radioactive iodine treatment for hyperthyroidism can worsen TED in susceptible patients, particularly:

• Smokers
• Patients with active disease
• Patients with high TRAb levels

When radioactive iodine is necessary in a high-risk patient, prophylactic:

Glucocorticoids

may reduce the risk of worsening.

Active Moderate-to-Severe Disease

This group generally requires:

Disease-modifying therapy

rather than observation alone.

Modern treatment options include:

• IV glucocorticoids
• Mycophenolate
• Teprotumumab
• Orbital radiotherapy
• Selected biologic therapy

Choice varies by:

• Disease phenotype
• Availability
• Comorbidities
• Regional guidelines

Intravenous Glucocorticoids

IV methylprednisolone is generally more effective and better tolerated than prolonged high-dose oral steroids for active moderate-to-severe TED.

A commonly used regimen delivers repeated weekly pulses with a total cumulative dose around:

4.5 g

for standard moderate-to-severe active disease.

Exact protocols vary.

Why Very High Steroid Doses Are Avoided

Large cumulative IV methylprednisolone doses increase the risk of:

• Acute liver injury
• Cardiovascular events
• Infection
• Hyperglycemia
• Psychiatric complications

Cumulative doses above approximately:

8 g per treatment course

are generally avoided except in exceptional circumstances.

Mycophenolate

Modern European-style regimens often combine:

IV methylprednisolone + mycophenolate

for active moderate-to-severe disease.

Mycophenolate can:

• Improve inflammatory control
• Reduce relapse
• Reduce steroid exposure

depending on the clinical phenotype.

Teprotumumab

A major modern advance is:

Teprotumumab

a monoclonal antibody targeting:

IGF-1R

It can improve:

• Proptosis
• Diplopia
• Soft-tissue inflammation
• Quality of life

and is particularly attractive when proptosis is a major feature.

Important Teprotumumab Adverse Effects

Potential adverse effects include:

• Hearing impairment
• Hyperglycemia
• Muscle spasm
• Nausea
• Alopecia
• Fatigue
• Infusion reactions

Hearing effects can occasionally persist.

Patients may require:

• Baseline auditory assessment
• Audiologic monitoring
• Glucose monitoring

Pregnancy and Teprotumumab

Teprotumumab can interfere with fetal growth signaling and is:

Contraindicated in pregnancy.

Appropriate pregnancy avoidance is required during treatment and for the recommended period afterward.

Other Biologic or Targeted Options

Selected refractory active disease may be treated with:

• Tocilizumab
• Rituximab

Tocilizumab may be particularly useful in:

Steroid-resistant active TED.

Rituximab evidence is mixed and patient selection is important.

Orbital Radiotherapy

Orbital radiotherapy may improve:

• Active extraocular muscle inflammation
• Restrictive motility
• Diplopia

A common regimen is approximately:

20 Gy divided over 10 fractions

although lower-dose protocols are also used.

Where Radiotherapy Works Best

Radiotherapy tends to be most useful for:

• Active motility restriction
• Inflammatory muscle disease

It is less effective for established:

• Proptosis
• Fibrotic lid retraction

It may be combined with corticosteroids.

When Radiotherapy Is Avoided or Used Cautiously

Caution is appropriate in:

• Younger patients
• Diabetic retinopathy
• Severe hypertension
• Other retinal microvascular disease

because of potential radiation-related ocular complications.

Sight-Threatening Optic Neuropathy

DON requires:

Immediate treatment.

Initial therapy generally consists of:

High-dose IV methylprednisolone

provided there is no major contraindication.

When Orbital Decompression Becomes Urgent

If vision does not improve adequately or promptly after IV steroids, or steroids are contraindicated:

Urgent orbital decompression

is indicated.

Waiting for the disease to become inactive is inappropriate when the optic nerve is threatened.

Corneal Breakdown as a Sight-Threatening Emergency

Severe exposure can cause:

• Persistent epithelial defect
• Ulceration
• Stromal thinning
• Perforation

Treatment may include:

• Intensive lubrication
• Moisture chamber
• Bandage or scleral lens in selected cases
• Temporary tarsorrhaphy
• Eyelid procedure
• Orbital decompression if severe proptosis prevents closure

Rehabilitative Surgery

Once inflammatory disease is inactive and measurements are stable, reconstructive surgery generally follows this sequence:

Orbital decompression → strabismus surgery → eyelid surgery

The order matters because each step can alter the next.

Orbital Decompression

Decompression creates additional orbital volume by removing:

• Bone
• Orbital fat
• Both

Potential walls include:

• Medial wall
• Floor
• Lateral wall

The approach depends on:

• Proptosis severity
• DON
• Pre-existing diplopia
• Surgeon preference

Why Balanced Decompression Is Used

Removing both medial and lateral walls can reduce proptosis while attempting to minimize:

New-onset diplopia

compared with some asymmetric decompression strategies.

No single decompression technique is best for every patient.

Complications of Orbital Decompression

Possible complications include:

• New or worsened diplopia
• Infraorbital numbness
• Sinus complications
• CSF leak, rarely
• Globe displacement
• Vision-threatening hemorrhage, rarely

Strabismus Surgery

Strabismus surgery is usually performed only after:

• Disease is inactive
• Measurements are stable

The goal is mainly to provide single binocular vision in:

• Primary gaze
• Reading position

Perfect single vision in all gaze directions is often unrealistic.

Why Recession Is Common

Restrictive muscles are usually:

Recessed rather than resected

because the problem is excessive tightness rather than weakness.

Adjustable sutures are often useful.

Eyelid Surgery

After orbital and strabismus correction, persistent lid retraction can be treated surgically.

Options include:

• Upper-lid levator/Müller muscle recession
• Lower-lid retractor recession
• Spacer grafts in selected lower-lid cases
• Blepharoplasty when appropriate

Goals include:

• Better corneal protection
• Improved symmetry
• Improved appearance

Timing of Reconstructive Surgery

Elective reconstructive surgery is generally delayed until:

TED has become inactive and measurements have been stable for several months.

The exception is surgery required urgently for:

• Optic neuropathy
• Severe corneal exposure

Monitoring Over Time

Follow-up frequency depends on severity.

During active disease, monitor:

• Visual acuity
• Color vision
• Pupils
• CAS/inflammatory signs
• Proptosis
• Motility
• Diplopia
• Corneal exposure
• IOP
• Optic nerve status

Rapidly changing disease may require review every:

Few weeks or sooner.

Signs Requiring Urgent Review

Patients should seek prompt assessment for:

• Reduced vision
• Faded colors
• New visual-field defect
• Rapidly worsening proptosis
• Increasing diplopia
• Severe exposure
• Corneal pain
• Inability to close the eyelids

These may indicate:

• DON
• Corneal ulceration
• Rapid disease progression

Expected Clinical Course

Most patients have:

Mild disease

requiring mainly:

• Observation
• Lubrication
• Risk-factor modification

A smaller group develops:

• Persistent diplopia
• Disfiguring proptosis
• Significant lid retraction

Only a small minority develop:

Sight-threatening disease.

Factors Associated With Worse Disease

Poorer outcomes are associated with:

• Smoking
• Older age
• Male sex
• Poor thyroid control
• High autoantibody levels
• Diabetes
• Delayed recognition of optic neuropathy

Potential Complications

Important complications include:

• Dysthyroid optic neuropathy
• Exposure keratopathy
• Corneal ulceration or perforation
• Persistent diplopia
• Restrictive strabismus
• Ocular hypertension
• Disfigurement
• Steroid-induced cataract
• Steroid-induced glaucoma
• Treatment-related hearing loss with teprotumumab

High-Yield Takeaways

• Thyroid eye disease is an autoimmune orbital disorder affecting extraocular muscles, orbital fat, connective tissue, eyelids, and the ocular surface.
• TED can occur in hyperthyroid, hypothyroid, or euthyroid patients.
• Upper-lid retraction is the most characteristic external sign.
• The most important modifiable risk factor is smoking, which increases disease risk, severity, treatment resistance, and risk of worsening after radioactive iodine.
• Modern pathogenesis involves both TSH receptor and IGF-1 receptor signaling in orbital fibroblasts.
• The typical imaging finding is extraocular muscle belly enlargement with relative tendon sparing, especially involving the inferior and medial recti.
• TED causes restrictive rather than paralytic strabismus; inferior rectus restriction commonly limits elevation.
• Always assess visual acuity, pupils, color vision, motility, corneal exposure, proptosis, and optic nerve function.
• Dysthyroid optic neuropathy can occur without dramatic proptosis and may have a normal-appearing optic disc.
• CAS is useful for measuring inflammation, but activity should not be determined from CAS alone.
• Mild disease usually requires smoking cessation, euthyroidism, lubrication, and observation; selenium may help selected patients with mild active disease.
• Active moderate-to-severe disease may be treated with IV glucocorticoids, often with mycophenolate, teprotumumab, orbital radiotherapy, or selected biologic therapy.
• Teprotumumab targets IGF-1R and can markedly reduce proptosis and diplopia, but important adverse effects include hearing impairment and hyperglycemia.
• Very high cumulative IV methylprednisolone doses should be avoided because of serious hepatic and cardiovascular toxicity.
• Dysthyroid optic neuropathy is an emergency requiring high-dose IV corticosteroids and urgent decompression if response is inadequate.
• Severe corneal exposure with ulceration is also sight-threatening and requires immediate surface protection.
• Elective rehabilitative surgery usually follows the sequence orbital decompression → strabismus surgery → eyelid surgery after disease becomes inactive.
• Radioactive iodine can worsen TED in susceptible patients; glucocorticoid prophylaxis may be indicated when RAI is necessary.
• Most TED is mild, but early recognition of optic neuropathy and corneal compromise is critical to preventing permanent visual loss.