Thyroid Eye Disease (TED), also known as Graves’ Orbitopathy, is an autoimmune disease. It is most commonly associated with hyperthyroidism, but 4% of cases occur with hypothyroidism and 6% with normal thyroid function.
The annual prevalence of TED is reported as 16 per 100,000 in women and 2.9 per 100,000 in men3). Not all patients with hyperthyroidism develop TED; among those who do, about 15% have symptomatic eye movement disorders. 30–50% of TED patients develop restrictive myopathy1).
The pathogenesis of hypotropia in TED is restrictive strabismus secondary to fibrosis and shortening that occurs after inflammation of the inferior rectus muscle. The course includes an active phase characterized by inflammation and an inactive fibrotic phase that transitions after 1 to 3 years. Signs of TED appear within 6 months before the diagnosis of thyroid disease in 20% of patients, at the time of diagnosis in 20%, and more than 6 months after diagnosis in 40%. The disease is usually bilateral but often asymmetric.
A serious complication is compressive optic neuropathy, which occurs in about 5% of patients3).
Not all patients with hyperthyroidism develop TED. Even if they do, only about 15% present with symptomatic eye movement disorders. However, if thyroid dysfunction is present, ophthalmologic follow-up is recommended.
The clinical presentation of TED differs between the active phase and the fibrotic phase.
Active phase
Periorbital edema: Accompanied by hyperemia and swelling of the eyelids and conjunctiva.
Upper eyelid retraction: The most common sign of TED. It is caused by sympathetic overactivity of Müller’s muscle or fibrosis of the levator complex 3).
Proptosis: Normal value is less than 18 mm. In TED patients, it often exceeds 21 mm 3).
Restriction of eye movement: Presents with transient movement limitation due to inflammatory edema.
Fibrotic stage
Restrictive strabismus: Fibrosis and shortening of the inferior rectus muscle restrict upward gaze. Hypotropia and esotropia are the most common patterns of ocular misalignment1).
Fixation duress: Attempting upward gaze increases brow elevation and lid retraction1).
Excyclotorsion: Increased tension of the inferior rectus muscle can cause excyclotorsion, which may mimic superior oblique palsy1).
Positive forced duction test: This is an important examination finding to confirm mechanical restriction.
The inferior rectus is the most frequently affected extraocular muscle, followed by the medial rectus, superior rectus, and lateral rectus in decreasing order. Therefore, limitation of upward gaze is most common, followed by limitation of abduction. In advanced cases, adhesions between the extraocular muscles and the orbital connective tissue or orbital septum cause further impairment of eye movement.
The VISA (Vision, Inflammation, Strabismus, Appearance) classification and the NOSPECS classification are used for severity grading of TED3).
Because the inferior rectus muscle is fibrotic and shortened, downward gaze is not severely restricted. Upward gaze is mainly limited, causing strong double vision in forward and upward gaze, while in downward gaze the eye misalignment becomes smaller and double vision is reduced.
TED is an autoimmune disease, and the TSH receptor is thought to be involved in the pathology as a common antigen in the thyroid and orbit. Signaling pathways mediated by the insulin-like growth factor 1 receptor (IGF-1R) also play an important role2). Orbital fibroblasts are activated by T cell-derived cytokines, leading to inflammation and fibrosis.
Differences in pathology by age are also observed. In younger individuals, proliferation of adipose tissue is the main cause of proptosis, whereas in middle-aged and older individuals, hypertrophy of the extraocular muscles is more prominent.
The main risk factors for TED are shown below.
| Risk factor | Notes |
|---|---|
| Smoking | Altered T-cell function and hypoxia contribute to TED progression. |
| Thyroid dysfunction | Hyperthyroidism is most common |
| Family history | Genetic predisposition |
| Radioactive iodine therapy | Independent risk factor1) |
| High anti-thyroid antibody titer | Independent risk factor1) |
| Vitamin D deficiency | Independent risk factor1) |
The following are measured to evaluate thyroid function.
It is necessary to distinguish between the differential diagnosis of TED in general and that specific to hypotropia.
| Subject | Differential diagnosis |
|---|---|
| General TED | Carotid-cavernous fistula, idiopathic orbital inflammation, myasthenia gravis, orbital tumor, vasculitis, sarcoidosis |
| Hypotropia | Monocular elevation deficiency, contralateral superior oblique palsy, sagging eye syndrome, isolated superior rectus palsy |
Since some TED patients have concurrent myasthenia gravis, evaluation should be performed if suspected based on clinical findings1).
Restrictive strabismus in TED is characterized by a positive forced duction test and extraocular muscle hypertrophy on imaging, with fixed limitation of eye movement. In contrast, myasthenia gravis involves fatigability, a negative forced duction test, and no extraocular muscle hypertrophy on imaging. Since both diseases can coexist, consider their concurrence if findings are atypical 1).
Normalization of thyroid function is a prerequisite for treatment, and collaboration with an internist is essential. However, even after thyroid function normalizes, the ocular symptoms of TED often do not improve.
TED surgery is generally performed in the following order.
Order of Surgery
Stage 1: Orbital decompression surgery: Performed for optic neuropathy unresponsive to medical treatment or marked proptosis.
Stage 2: Strabismus surgery: Performed after eye position stabilizes. Wait at least 3 months due to eye position changes after decompression.
Stage 3: Eyelid surgery: This is performed last because strabismus surgery can change eyelid position.
Indications for Strabismus Surgery
Thyroid function: Must be normal or stable.
Stable eye alignment: Eye alignment measurements must be stable for at least 6 months1).
Inflammation control: Active inflammation must be resolved.
Persistent diplopia: Double vision remains in primary gaze or reading position.
The standard procedure is inferior rectus recession. Resection is traditionally avoided1).
The main complication is overcorrection (consecutive exotropia), and the following measures are taken.
When TED is bilateral, bilateral asymmetric inferior rectus recession may be selected, also considering the limitation of upward gaze in the contralateral eye. In Japan, the Harada-Ito procedure and a technique combining inferior rectus recession with nasal transposition are also performed.
Surgical success is evaluated by the achievement of binocular single vision in primary position and reading position. The success rate is 66–71% for initial surgery and reaches 89% when including multiple surgeries1).
The success rate of initial surgery is 66–71%, and diplopia may persist in positions other than primary gaze (especially peripheral gaze) 1). Postoperatively, the use of small prisms may be necessary. Due to the unstable nature of the disease, it is important to understand that additional surgery may be required in the future.
The pathology of TED is based on an autoimmune reaction within the orbit. Biopsy specimens show lymphocytic infiltration resembling myositis, and the main target cells are orbital fibroblasts.
The TSH receptor has been proposed as a common autoantigen in the thyroid and orbit. Autoantibodies against the TSH receptor have been detected in patients with thyroid disease, and these are thought to trigger an immune response in orbital tissues as well.
The signaling pathway mediated by IGF-1R (insulin-like growth factor 1 receptor) is also key to the pathology. Activation of IGF-1R promotes the secretion of hyaluronic acid and inflammatory factors 2). Teprotumumab binds to the IGF-1R complex and exerts its therapeutic effect by inhibiting this signaling 2).
T cell-derived cytokines activate fibroblasts, leading to the following cascade.
The most commonly affected extraocular muscle is the inferior rectus, followed by the medial rectus, superior rectus, and lateral rectus1). Fibrosis of the inferior rectus causes limitation of upward gaze, which is the direct cause of hypotropia. When hypertrophied extraocular muscles compress the optic nerve at the orbital apex, compressive optic neuropathy develops.
The CAS has a 7-item version and a 10-item version 2).
The 7-item version consists of conjunctival hyperemia, eyelid swelling, eyelid redness, conjunctival edema, caruncular swelling, pain with forward gaze, and pain with eye movement. A score of 3 or more indicates active TED, a period when anti-inflammatory treatment is effective. As fibrosis progresses, treatment efficacy markedly decreases 2).
The 10-item version adds the following to the above 7 items: an increase in proptosis of 2 mm or more, decreased visual acuity, and a decrease in eye movement of 8 degrees or more (each over the past 1–3 months) 2).
Teprotumumab is a human monoclonal antibody against IGF-1R and has received FDA approval overseas 3).
Cong et al. (2024) reported in a meta-analysis of 5 studies with 411 patients that the teprotumumab group was significantly superior to the placebo group in terms of proptosis reduction at 24 weeks, improvement in diplopia, and achievement of CAS (0 or 1). No significant differences were found between the two groups in the risk of adverse events or serious adverse events 2).
Teprotumumab has been suggested to have a greater improvement effect on diplopia than rituximab or tocilizumab, and this is considered a unique advantage of teprotumumab 2).
Efficacy in chronic TED has also been reported. In a retrospective study by Ugradar involving 31 patients with disease duration >2 years and CAS ≥3, improvements were observed in proptosis, orbital soft tissue volume, diplopia, inflammation, and strabismus2). Furthermore, 63% of patients who did not achieve ≥2 mm improvement in proptosis at week 12 showed significant improvement at week 24, suggesting individual variability in the timing of treatment response2).
As a direct effect on extraocular muscles, a correlation between reduction in extraocular muscle cross-sectional area and improvement in eye movement and diplopia after teprotumumab administration has also been reported1).
Major adverse events include hyperglycemia, muscle cramps, alopecia, nausea, fatigue, headache, dry skin, hearing impairment, and cough. The incidence of hearing impairment is 7–10%, and while most cases are reversible, further investigation into the mechanism and reversibility is needed2). Cost-effectiveness considerations given the high drug price, as well as accumulation of further evidence through large-scale long-term RCTs, remain challenges2).
Tocilizumab (IL-6 inhibitor) is being investigated for refractory TED cases, but its effect on diplopia is considered inferior to teprotumumab3).
