Thyroid Eye Disease (TED) - Ophthalmology

Clinical Appearance

Thyroid-related orbitopathy with bilateral eyelid retraction, proptosis, and periorbital edema. - Wills Eye Manual, p. 423

Epidemiology & Risk Factors

• Female predominance (5:1), peak in 4th-5th decades
• Smoking is the major modifiable risk factor - risk is dose-dependent and cessation reduces it
• Radioactive iodine (RAI) treatment for hyperthyroidism can worsen TED; concurrent oral steroids mitigate this
• Family history of thyroid dysfunction is common
• Vitamin D deficiency increases risk of progressive orbitopathy

Pathogenesis

1. Pleomorphic cellular infiltration (T-cells, mast cells, macrophages)
2. Increased glycosaminoglycan secretion → osmotic water imbibition
3. Extraocular muscles swell up to 8x normal size
4. Lipogenesis by fibroblasts/preadipocytes → orbital fat expansion
5. Raised intraorbital pressure → possible optic nerve compression
6. Eventual muscle fiber degeneration → fibrosis → restrictive myopathy

Disease Course

Clinical Features

1. Soft Tissue Involvement

• Grittiness, redness, lacrimation, photophobia, retrobulbar discomfort
• Epibulbar hyperaemia over horizontal rectus insertions (sensitive activity marker)
• Periorbital swelling, chemosis, fat prolapse into lids
• Tear insufficiency, superior limbic keratoconjunctivitis (SLK)

2. Eyelid Retraction (present in ~50%)

• Upper lid retraction with lateral flare - highly specific for TED
• Von Graefe sign - lid lag on downward gaze
• Lagophthalmos leading to exposure keratopathy
• Mechanism: Muller muscle sympathetic overstimulation + levator/inferior rectus fibrosis

3. Proptosis

• Usually axial (bilateral or unilateral/asymmetric)
• Myogenic variant: prominent muscle enlargement, minimal proptosis, apical crowding on CT
• Lipogenic variant: severe proptosis, increased fat volume, minimal muscle involvement

4. Restrictive Myopathy

• EOM involvement frequency: Inferior > Medial > Superior > Lateral rectus (mnemonic: "I'M SLow")
• Typically muscle belly enlargement with tendon sparing (distinguishes TED from orbital myositis)
• Elevation and abduction most commonly restricted
• Positive forced duction test

5. Compressive Optic Neuropathy (CON)

• Reduced VA (not always), colour desaturation (sensitive early sign), diminished brightness appreciation
• Relative afferent pupillary defect (RAPD) - "gives cause for marked concern"
• Visual field defects (central/paracentral, nerve fibre bundle)
• Optic disc: normal, swollen, or atrophic
• Critically, axial proptosis is often absent or mild in CON - apical crowding by enlarged muscles is the cause
• VEPs useful when diagnosis uncertain

Systemic Associations

• Hyperthyroidism in ≥80% (TFTs may be normal; euthyroid patients need 6-12 monthly TFTs)
• TED can precede, coincide with, or follow thyroid dysfunction by months to years
• May co-exist with myasthenia gravis - ptosis (rather than retraction) or adduction deficit should raise this possibility

EUGOGO Classification (2021)

• Spontaneous retrobulbar pain
• Pain on attempted up/down gaze
• Redness of eyelids
• Redness of conjunctiva
• Conjunctival/plical swelling (chemosis)
• Swelling of eyelids

Investigation

1. Thyroid function tests (TSH, T3, T4) - may be normal; TSI and TPO antibodies can guide diagnosis and treatment
2. Orbital CT (axial + coronal, without contrast) - indicated for: atypical presentation, unilateral proptosis, severe congestive orbitopathy, optic neuropathy, pre-surgical planning
   • Classic finding: fusiform muscle belly enlargement with tendon sparing
3. Automated visual fields + OCT - screen for subclinical optic neuropathy
4. Colour vision testing / RAPD - at every visit for CON surveillance
5. Serum vitamin D level
6. MRI: superior soft-tissue resolution; preferred in children (no radiation)

CT Appearance in TED

Fig. 4.14 CT showing (A) fusiform medial rectus enlargement on axial view, (B) symmetrical multi-muscle involvement on coronal view - Kanski's Clinical Ophthalmology 10th, p. 136

Treatment

Step 1: All Patients - General Measures

• Smoking cessation - mandatory first step
• Adequate control of thyroid dysfunction (with steroid cover if RAI is used)
• Lubricants, topical anti-inflammatories for ocular surface
• Head elevation at night (3 pillows) to reduce periorbital edema
• Lid taping at night for exposure keratopathy

Mild Active Disease

• Lubricants, topical ciclosporin/NSAIDs
• Selenium 200 µg/day for 6 months (in selenium-deficient areas; reduces progression of mild-moderate TED; use with caution in males due to possible prostate cancer risk)
• Vitamin D supplementation if deficient

Moderate-Severe Active Disease

• IV methylprednisolone (preferred over oral): 500 mg weekly x 6 weeks → 250 mg weekly x 6 weeks (max cumulative dose <8 g to protect liver)
• IV methylprednisolone + mycophenolate sodium (0.72 g/day x 24 weeks) = superior to steroids alone; regimen of choice in specialist centres
• Low-dose orbital radiotherapy: 20 Gy in 10-14 fractions over 2 weeks
  • Second-line; reduces restrictive strabismus progression; ~40% non-responders
  • Avoid or use cautiously in diabetics and vasculopaths (radiation retinopathy risk)
  • Contraindicated in patients <35 years old

Sight-Threatening TED (Optic Neuropathy)

1. Immediate pulsed IV methylprednisolone: 0.5-1 g on 3 successive days, converted to oral
2. If steroids ineffective (20%) or contraindicated → orbital decompression surgery
3. Posterior orbital/apex decompression is most effective for optic neuropathy

Biologics (Second-line / Corticosteroid-Resistant Disease)

Surgical Algorithm (Post-Inflammatory Phase Only)

1. Orbital decompression (if needed)
2. Strabismus surgery (for significant diplopia)
3. Eyelid surgery (retraction repair, blepharoplasty)

Differential Diagnosis of Eyelid Retraction

• Previous lid surgery/trauma
• Contralateral severe ptosis (Hering's law)
• Oculomotor nerve palsy with aberrant regeneration (pseudo-von Graefe sign)
• Parinaud syndrome - dorsal midbrain; lid retraction (Collier sign) + upgaze palsy + convergence-retraction nystagmus + light-near dissociation

Differential Diagnosis of Orbital Myositis vs TED EOM Enlargement

Key Points Summary

• TED is the most common cause of proptosis in adults
• The EOM order of involvement: Inferior > Medial > Superior > Lateral (tendon sparing)
• CON occurs in 5-7% but must be excluded at every visit; color vision loss is an early sensitive sign
• Treatment decisions depend on: activity (CAS), severity (EUGOGO), and disease duration (immunosuppression is much less effective after 18 months)
• Teprotumumab (anti-IGF-1R) is the first FDA-approved biologic for TED (2020)
• Surgical sequence is fixed: decompression → strabismus → eyelid