Thyroid eye disease

Thyroid eye disease (TED), also referred to as Graves’ ophthalmopathy or Graves’ orbitopathy, is an extrathyroidal manifestation of the autoimmune hyperthyroid disorder. It occurs due to inflammatory processes leading to increased soft tissue and muscle volume in the orbital space.

Pathophyisology

In Graves’ disease, the presence of TSH-receptor antibodies (TRAbs) is what stimulates the TSH-receptor to promote thyroid hormone synthesis and secretion (ultimately leading to hyperthyroidism). These TSH-receptors are also found in the orbital fibroblasts as well as orbital adipocytes. Stimulation of these cells by TRAbs leads to activation and proliferation of such cells.

Orbital fibroblasts deposit glycosaminoglycans (GAGs) into the extracellular matrix. It is this deposition of GAGs that leads to tissue expansion. Pro-inflammatory cytokines and cells (such as lymphocytes, mast cells and macrophages) infiltrate the orbital tissue. There is an osmotic shift that occurs with the infiltration of immune cells and GAG deposition that leads to oedema and furthers the expansion of orbital tissues.

Expansion of the orbital contents within the confined spaces of the bony orbit causes an increase in intraorbital pressure. The increase in intraorbital contents and pressure results in eye bulging (proptosis), periorbital oedema and restricted eye movement (due to pressure and fibrosis). The increased pressure can impair venous return and place pressure on the optic nerve, while the restricted ocular motility may result in corneal exposure and ulceration.

The disease has 2 distinct stages:

1. Active/inflammatory stage - this is the acute inflammatory phase in which there is infiltration of immune cells, cytokine release, GAG deposition, proptosis, oedema and swelling. This phase may last from 6 months - 2 years.
2. Inactive/fibrotic stage - in this phase there is less active inflammation and the symptoms may not be as marked, however, the damage that occurred in the inflammatory phases results in fibrosis and scarring of the orbital tissue. This results in persistent symptoms of proptosis, diplopia and restricted eye motility.

⚠️ Risk factors

• Graves’ disease or family history of Graves’ disease - around 90% of patients with TED have Graves’, but 10% are not hyperthyroid and even may be hypothyroid.
• Smoking - this is the single most important risk factor for a patient with Graves’ disease for the development of TED.
• Female sex
• Uncontrolled hyperthyroidism/hypothyroidism
• Genetic factors - such as HLA-DR3, HLA-B8, CTLA4.
• Radioiodine therapy - it may exacerbate TED if in the inflammatory stage. It may also precipitate de novo development of TED.

😷 Presentation

Most patients will have concomitant features of thyrotoxicosis (you can read more on these features here).

• Lid retraction - normally the margin of the upper eyelid lies about 2mm below the limbus (the border between the cornea and sclera). In lid retraction, the eyelid margin lies at the level of or above the superior limbus. Thus the superior portion of the sclera is visible. This may be known as the thyroid stare.
• Exophthalmos (proptosis)
• Ocular motility disturbance - this may cause poor convergence and diplopia due to restricted movement of the extraocular eye muscles.
• Persistent blurred vision - this is suggestive of compressive optic neuropathy and needs immediate investigating as it may lead to permanent vision loss. Symptoms of optic neuropathy include blurred vision, reduced acuity, relevant afferent pupillary defect visual field defects and impaired colour perception.
• Inability to close eyes - this can then lead to exposure keratopathy (with symptoms of photophobia, grittiness, pain)
• Chemosis and conjunctival injection - this may indicate corneal ulceration (and also requires an urgent referral).
• Redness
• Lid lag
• Orbital fat prolapse

🔢 Grading

🔍 Investigations

• Thyroid function tests (TFTs) - normally shows signs consistent with Graves’ disease.
• TSH - low.
• Free T3/T4 - high.
• Thyroid receptor antibodies - positive.
• Slit lamp examination - may show dilated conjunctival vessels, keratoconjunctivitis, and corneal staining.
• 🏆 CT or MRI of the orbits - MRI is better for demonstrating the soft tissue changes but CT may be useful if surgery is planned. It may show exophthalmos, increased orbital adipose tissue, enlarged extra-ocular muscles.
• Hertel exophthalmometer - used to assess and measure exophthalmos.
• Swinging light test - to assess for relevant afferent pupillary defect which may suggest compressive optic neuropathy.
• Hess chart - may be used to assess opthalmoplegia.

🧰 Management

The majority of cases of TED are self-limiting.

🚨 Complications

• Exposure keratopathy
• Compressive optic neuropathy
• Diplopia
• Blindness