Thyroid eye disease (TED) is an autoimmune disorder commonly seen in patients with hyperthyroidism (Graves’ disease). Only about 20–25% of patients present with clinically evident Graves’ ophthalmopathy. It can also occur in patients with hypothyroidism or normal thyroid function.
Strabismus associated with thyroid eye disease results from inflammation and subsequent fibrosis of the extraocular muscles, leading to muscle swelling and thickening that restrict eye movement. 30–50% of patients with thyroid eye disease develop restrictive myopathy.
30–50% of patients with thyroid eye disease develop restrictive myopathy. It is one of the common causes of acquired vertical deviation in adults. On the other hand, motor impairment is rare in children.
The most commonly affected muscle is the inferior rectus, followed in decreasing frequency by the medial rectus, superior rectus, and lateral rectus. The most common deviation patterns are hypotropia and esotropia of the affected eye.
Common Ocular Motor Deficits
Elevation deficit: Most frequently observed due to thickening and contracture of the inferior rectus muscle.
Abduction deficit: Caused by contracture of the medial rectus muscle. Second most common after elevation deficit.
Combined deficit: Impairment in two or more directions, most commonly a combination of elevation and abduction deficits.
Associated ocular findings
Eyelid retraction: The most common sign of thyroid eye disease. Caused by sympathetic overactivity of Müller’s muscle or fibrosis of the levator complex 1).
Proptosis: Normal value is <18mm. In thyroid eye disease patients, it often exceeds 21mm 1).
Compressive optic neuropathy: Occurs in about 5% of cases and requires urgent management 1).
Restriction can be confirmed by forced duction test. As fibrosis progresses, the test becomes strongly positive, with marked deviation of the eye.
Strabismus in thyroid eye disease is primarily caused by restricted eye movement due to inflammation and subsequent fibrosis of the extraocular muscles. Through an autoimmune mechanism, TSH receptor antibodies (TRAb) target orbital tissues, leading to swelling and thickening of the extraocular muscles.
The main risk factors are as follows:
Smoking increases the risk of developing thyroid eye disease in patients with Graves’ disease and makes it more severe. The active phase that threatens vision is prolonged, lasting an average of about 1 year in non-smokers but persisting for 2 to 3 years in smokers.
For the diagnosis of thyroid eye disease, two of the following three signs must be present.
| Differential diagnosis | Key differentiating points |
|---|---|
| Cranial nerve palsy | Paralytic rather than restrictive movement disorder |
| Myasthenia gravis | Fluctuating double vision and ptosis. Positive for AChR antibodies |
| Extraocular myositis | Thickening from the tendon is observed (thyroid eye disease mainly involves the muscle belly) |
| Chronic Progressive External Ophthalmoplegia (CPEO) | Slowly progressive limitation of movement in all directions |
If hyperthyroidism is present, normalization of thyroid hormone levels is the top priority. Not all eye symptoms improve with stabilization of thyroid function, and ophthalmic treatment may be needed concurrently.
When treatment with corticosteroids is not possible or when relapse occurs after steroid therapy, retrobulbar tissue is irradiated with 1.5–2.0 Gy/day for 10 days.
When surgery is necessary, it is usually performed stepwise in the following order.
Stage 1
Orbital decompression: Performed for optic neuropathy or marked proptosis. Since the eye position changes after surgery, this is performed prior to strabismus surgery.
Stage 2
Strabismus surgery: Performed after the deviation has been stable for at least 6 months. The main procedure is recession of the restricted extraocular muscles. Recession of the thickened rectus muscle is performed.
Stage 3
Eyelid surgery: Since vertical muscle surgery affects eyelid position, it is performed for fixed eyelid retraction after strabismus surgery.
Strabismus surgery for diplopia is generally performed during the non-inflammatory phase. The main goal of surgery is to achieve a diplopia-free state in primary gaze and downgaze.
As a general rule, surgery is performed after acute inflammation subsides and the degree of deviation and thyroid function tests have been stable for at least 6 months. However, if daily life is significantly impaired, such as when an extreme compensatory head posture is adopted, surgery may be considered at an earlier stage.
Kinematic success (vertical deviation ≤5Δ and horizontal deviation ≤10Δ) is reported at 69%, and sensory success (no diplopia in primary position) at 58%. The reoperation rate reaches 50%. Under-correction accounts for 59% and over-correction for 41%.
The pathology of thyroid eye disease involves autoimmune inflammation centered on orbital fibroblasts.
Orbital fibroblasts express CD40 receptors that differ from other fibroblasts in the body. When these receptors are activated by T cells bearing CD154, production of inflammatory cytokines such as IL-6, IL-8, and prostaglandin E2 is enhanced. Subsequently, synthesis of hyaluronic acid and glycosaminoglycans (GAGs) increases, leading to inflammation and volume expansion of the orbital contents.
Because orbital fibroblasts are derived from the neural crest embryologically, some have the ability to differentiate into adipocytes. This leads to enlargement of orbital fat, further increasing pressure within the orbital cavity.
The following sequential changes occur in the extraocular muscles.
Fibroblasts express HLA-DR antigens and ICAM-1, but these are not expressed on muscle cells themselves, suggesting that fibroblasts are the target cells of autoimmune inflammation.
When enlarged extraocular muscles compress the optic nerve at the orbital apex, compressive optic neuropathy develops.
Teprotumumab is a human monoclonal antibody targeting the IGF-1 receptor (IGF-1R) and is approved by the US FDA as a treatment for active thyroid eye disease. It has been reported to reduce proptosis and improve diplopia scores.
Cong et al. (2024) reported in a meta-analysis of five studies (411 cases) that the teprotumumab group showed significant improvement in proptosis at 24 weeks compared to the placebo group, and the diplopia response rate was also significantly higher2). The achievement rate of a clinical activity score (CAS) of 0 or 1 was also significantly higher in the teprotumumab group.
The main cause of diplopia in thyroid eye disease is restrictive strabismus due to degeneration of the extraocular muscles. While other biologic agents such as rituximab and tocilizumab have limited effects on diplopia, teprotumumab may show a unique advantage in improving diplopia2).
Recent studies suggest that teprotumumab may also be effective in chronic thyroid eye disease with advanced fibrosis2).
The main side effects of teprotumumab are as follows:
