thyroid eye disease

**Epidemiology/associations** - Occurs in ~25-50% of Graves disease patients clinically (more on imaging). Can also occur with euthyroid or hypothyroid (Hashimoto) states, and may precede, coincide with, or follow hyperthyroidism. - Women > men, but men often have more severe disease. Peak ages ~40-60. - Risk factors: smoking (strongest modifiable), high TRAb levels, radioactive iodine therapy (can worsen TED, so give prophylactic steroids in at-risk patients), uncontrolled thyroid dysfunction (hyper- or hypothyroidism), and hypercholesterolemia.

**Pathophysiology** - Autoreactive T cells and autoantibodies (TSH receptor Abs, thyroid-stimulating immunoglobulins) target orbital fibroblasts, which express TSH-R and IGF-1R (the two receptors form a signaling complex). - Activated fibroblasts secrete hydrophilic glycosaminoglycans (hyaluronan), causing edema, and differentiate into adipocytes (orbital fat expansion). Extraocular muscles enlarge from inflammation and edema. - Because the bony orbit is rigid, increased volume pushes the globe forward (proptosis) and compresses the optic nerve and vessels. - Cytokines (IFN-γ, TNF-α, IL-1) and CD4+ T cell infiltrates drive the active inflammatory phase. Histology shows lymphocytic infiltrate with GAG accumulation. The disease follows a Rundle curve: active (inflammatory) phase for ~6-24 months, then plateau and an inactive (fibrotic) phase.

**Clinical features** - Eyelid retraction (most common sign; also seen from sympathetic overstimulation in any hyperthyroidism), with lid lag (von Graefe sign) and stare (Dalrymple sign). - Proptosis/exophthalmos (true proptosis is specific to TED). - Periorbital edema, conjunctival injection and chemosis, and caruncle swelling. - Restrictive myopathy with diplopia. Muscle involvement order (mnemonic "I'M SLOW"): Inferior rectus > Medial rectus > Superior > Lateral > Oblique. Upgaze restriction from a tight inferior rectus is classic. Muscle bellies are enlarged with tendon sparing on CT/MRI (unlike orbital myositis, which involves tendons). - Exposure keratopathy, dry eye, and corneal ulceration. - Dysthyroid optic neuropathy (DON): from compression of the optic nerve at the orbital apex, causing decreased visual acuity, color desaturation (early), afferent pupillary defect, and visual field defects. It is a sight-threatening emergency. - Pretibial myxedema (dermopathy) and thyroid acropachy are other extrathyroidal manifestations of Graves disease.

**Diagnosis** - Clinical, supported by thyroid function tests (TSH, free T4/T3), TRAb/TSI. - Orbital CT or MRI when the diagnosis is unclear, with asymmetric or unilateral findings, or when DON is suspected. - Clinical Activity Score (CAS) assesses inflammation (CAS ≥3 of 7 indicates active disease). Severity is graded as mild, moderate-to-severe, or sight-threatening.

**Management** - All patients: achieve euthyroidism, stop smoking, use artificial tears/lubricants, sleep with head elevated, and use selenium supplementation for mild disease (in selenium-deficient areas). - Moderate-to-severe active disease: IV methylprednisolone (preferred over oral steroids), and teprotumumab (IGF-1R inhibitor; reduces proptosis and diplopia; adverse effects include hearing loss/tinnitus, hyperglycemia, muscle spasms, and IBD flares; contraindicated in pregnancy). Other options include mycophenolate, rituximab, tocilizumab, and orbital radiotherapy. - Sight-threatening disease (DON, severe exposure keratopathy): urgent high-dose IV steroids, and orbital decompression if no response. - Inactive/stable disease: rehabilitative surgery in this order: orbital decompression → strabismus surgery → eyelid surgery. - Treating hyperthyroidism: antithyroid drugs or thyroidectomy are preferred in active TED. Radioactive iodine can worsen TED, so it is relatively avoided in moderate-to-severe active disease or given with steroid prophylaxis.

**High-yield board points** - Most common cause of unilateral or bilateral proptosis in adults = thyroid eye disease. - Most common cause of diplopia in Graves disease = restriction of the inferior rectus. - Smoking cessation is the key preventive/modifiable step. - Ocular findings may not improve with treatment of the thyroid disease itself. - Optic neuropathy is the most feared complication.