Thyroid Eye Disease

An autoimmune inflammatory disorder of the orbit, most often with Graves hyperthyroidism, but may occur in euthyroid disease (about 5 to 10 percent) or hypothyroid autoimmune thyroiditis.

• The pathogenesis involves autoantibodies and T cells against the TSH receptor and insulin like growth factor 1 receptor on orbital fibroblasts, causing glycosaminoglycan deposition, adipogenesis and extraocular muscle enlargement.
• Risk factors: smoking (up to 7 times higher risk and worse severity), female sex, age 40 to 60, radioiodine therapy, uncontrolled thyroid dysfunction (hyperthyroid or hypothyroid), high TSH-receptor antibody titres, and genetic susceptibility.
• Natural history: active (inflammatory) phase of 6 to 24 months followed by an inactive (fibrotic) phase with static disease.

• Eyelid retraction (most common sign), lid lag on downgaze, staring appearance.
• Proptosis (exophthalmos), usually bilateral but often asymmetric; lagophthalmos; exposure keratopathy.
• Periorbital oedema, conjunctival injection over the rectus muscle insertions, chemosis, caruncle swelling, retrobulbar pain and pain on eye movement.
• Restrictive myopathy: diplopia and tight muscles (inferior rectus most commonly, then medial rectus), elevated intraocular pressure on upgaze.
• Dysthyroid optic neuropathy (3 to 8 percent): reduced acuity, colour desaturation, relative afferent pupillary defect, visual field defects, optic disc swelling or normal disc, caused by compression from enlarged muscles at the orbital apex; can occur with minimal proptosis.
• Severity: mild (minor signs, no major effect on life), moderate to severe (lid retraction at least 2 mm, moderate or severe soft tissue involvement, proptosis at least 3 mm above normal, inconstant or constant diplopia), sight threatening (optic neuropathy, corneal breakdown).
• Clinical activity score (7 items: spontaneous retrobulbar pain, pain on gaze, eyelid erythema, eyelid swelling, conjunctival redness, chemosis, caruncle swelling): a score of 3 or more indicates active disease.

• Thyroid function: TSH, free thyroxine, free triiodothyronine; thyrotropin receptor antibodies (TSH-receptor antibody or thyroid stimulating immunoglobulin); thyroid peroxidase antibody.
• Exophthalmometry (normal up to 20 mm in white adults; difference between eyes above 2 mm); lid margin reflex distance, Hertel measurement, motility tests, visual fields, colour vision, pupil examination and slit lamp examination of cornea.
• Orbital imaging: CT (muscle belly enlargement sparing tendons, apical crowding) or MRI with fat suppression (STIR sequences show active inflammation).
• Intraocular pressure in primary and upgaze position; optical coherence tomography for disc and macular changes.
• Exclude differentials: orbital myositis, idiopathic orbital inflammation, orbital tumour, carotid cavernous fistula, lymphoma, orbital cellulitis, ocular myasthenia gravis.

• Restore and maintain euthyroidism (carbimazole 15 to 40 mg daily with titration, or block-and-replace; methimazole 10 to 30 mg daily; propylthiouracil 100 to 150 mg three times daily if pregnant in the first trimester). If radioiodine is chosen, give prophylactic prednisolone 0.3 to 0.5 mg/kg daily for 4 to 6 weeks, tapering, particularly in smokers and active eye disease; thyroidectomy is an alternative.
• All patients: stop smoking (strongest modifiable factor), preservative free lubricants every 2 to 4 hours, lubricating ointment at night, sunglasses, head elevation at night, taping the lids at night in lagophthalmos, and cool compresses.
• Mild active disease: selenium 100 micrograms twice daily for 6 months; observation.
• Moderate to severe active disease:
  • Intravenous methylprednisolone 500 mg weekly for 6 weeks, then 250 mg weekly for 6 weeks (cumulative dose 4.5 g); higher cumulative dose up to 8 g only for severe disease. Check liver function, blood pressure, glucose and hepatitis B and C first; maximum single dose 0.75 g, cumulative above 8 g is not recommended due to hepatotoxicity.
  • Teprotumumab (IGF-1 receptor antibody): 10 mg/kg first infusion then 20 mg/kg every 3 weeks for 7 further infusions (total 8). Monitor blood glucose and HbA1c, hearing (hearing loss and tinnitus), muscle cramps, inflammatory bowel disease; avoid in pregnancy.
  • Alternatives: tocilizumab 8 mg/kg IV monthly for 4 doses, rituximab 1 g IV twice 2 weeks apart, mycophenolate 360 mg twice daily with steroids, methotrexate, or orbital radiotherapy (20 Gy in 10 fractions over 2 weeks) in selected patients with motility restriction.
• Sight threatening disease (dysthyroid optic neuropathy, corneal ulceration): intravenous methylprednisolone 500 to 1000 mg daily for 3 days (or on alternate days); if vision does not improve within 1 to 2 weeks, proceed to urgent orbital decompression (medial and floor, or balanced three wall). Corneal exposure: intensive lubrication, tarsorrhaphy, amniotic membrane and urgent decompression.
• Inactive disease (rehabilitation, in this order): orbital decompression (reduces proptosis by 3 to 6 mm, may worsen or create diplopia), then strabismus surgery (recession of tight muscles, adjustable sutures; prisms for small deviations; botulinum toxin sometimes), then eyelid retraction surgery (levator recession, Müllerotomy, spacer grafts to lower lid), then blepharoplasty and brow lifts.
• Follow up every 4 to 12 weeks during active disease; vision and optic nerve monitoring.