Dysthyroid optic neuropathy (DON) is an optic nerve dysfunction associated with thyroid eye disease (TED). TED, also known as Graves orbitopathy (GO), is an autoimmune disease in which enlargement of the extraocular muscles and orbital fat increases intraorbital pressure, compressing the optic nerve. It is one of the most severe complications of TED and, if left untreated, can lead to permanent vision loss.
DON occurs in 0.9–8.6% of all TED cases1), and approximately 70% of cases are bilateral. More than half of patients maintain a corrected visual acuity of 0.5 or better, but in the worst cases, it can lead to blindness. Since visual function can be expected to recover with appropriate treatment, early diagnosis is extremely important.
Only about 3–8% of all TED cases develop DON, so the majority of TED patients do not progress to DON. However, caution is needed if there are risk factors such as the myopathic phenotype, smoking, or older age. For details, see the section on Causes and Risk Factors.
The initial symptoms of DON are blurred central vision and decreased color vividness (desaturation). The degree of visual loss varies from mild to no light perception, but more than half of patients maintain visual acuity of 0.5 or better.
The main subjective symptoms are listed below.
The main clinical findings of DON and their frequencies are shown below.
| Clinical Finding | Frequency |
|---|---|
| Visual loss | Approximately 80% |
| Color vision loss | Approximately 77% |
| Visual field defect | Approximately 71% |
| Restricted eye movement | Approximately 70% |
| Optic disc edema | Approximately 20% |
Other important clinical findings are listed below.
76% of DON cases are bilateral, and optic disc swelling is absent in about half. Since DON can occur even without optic disc abnormalities, a combination of visual function tests and imaging is essential.
TED is an autoimmune disease caused by autoantibodies against TSH receptors and IGF-1 receptors on the surface of orbital fibroblasts. Antibody binding leads to adipogenesis, T lymphocyte activation, and cytokine release, resulting in deposition of glycosaminoglycans (GAGs) in orbital fat and muscles.
TED is broadly divided into two phenotypes.
Adipogenic Type
Also known as: Type I, adipogenic type
Features: Mainly presents with fat expansion and scarring of the levator palpebrae superioris muscle. Accounts for about two-thirds of TED patients.
Association with DON: Rarely leads to DON unless severe proptosis causes optic nerve stretching.
Myopathic Type
Also known as: Type II, myopathic type
Features: Involves hypertrophy of extraocular muscles, presenting with congestive soft tissue signs and ocular motility disorders. Accounts for about one-third of TED patients.
Association with DON: Prone to optic nerve compression at the orbital apex, a major cause of DON.
TED itself is more common in women (female-to-male ratio 4:1), while DON tends to occur in older men. Major risk factors are listed below.
Thyroid dysfunction correlates with the severity of TED, but there is no clear correlation with the onset or severity of DON. Additionally, DON can occur even if all thyroid autoantibodies are negative.
Smoking is considered the most important risk factor for the progression of TED and the development of DON. The risk of worsening TED after radioactive iodine therapy is also higher in smokers. It is known that smoking cessation reduces treatment resistance in TED.
The diagnosis of DON is based on confirmation of optic nerve dysfunction in TED patients and imaging findings of compression at the orbital apex.
Imaging is essential for definitive diagnosis and surgical planning of DON.
| Test | Main Advantages |
|---|---|
| CT | Excellent bone visualization. Ideal for surgical planning. |
| MRI (STIR) | Useful for assessing inflammatory activity. |
Reports indicate that 96% of patients with recent DON have high titers of thyroid-stimulating immunoglobulin (TSI). However, DON can occur even when all autoantibodies are negative, so serological tests alone cannot rule out the diagnosis.
CT is often the first choice because it provides excellent bone visualization, is quick and inexpensive, and is suitable for surgical planning. On the other hand, MRI STIR sequences are superior for assessing inflammatory activity. The two are complementary and should be used according to the situation.
The first-line treatment for DON is steroid pulse therapy (or half-pulse therapy).
The EUGOGO guidelines (2021) recommend high-dose administration of up to 1 g per day for 3 days, repeated weekly if improvement is seen.
External beam radiotherapy (EBRT) targets lymphocytes and fibroblasts to suppress inflammation. It is not used alone as acute treatment due to lack of rapid effect, and is positioned as an adjunct to steroid therapy. Combined with steroids, it has been reported to prevent the onset of DON.
If optic nerve function does not improve within 2 weeks after starting steroid pulse therapy, emergency orbital decompression surgery is considered. In Japan, 22–38% of DON patients undergo orbital decompression surgery1).
Surgical approaches include the following:
Decompression of the optic nerve is achieved by expanding the volume at the orbital apex, targeting the medial wall, orbital floor, and deep lateral wall. Preoperative CT planning and intraoperative navigation are useful.
Radioactive iodine (RAI) treatment may worsen symptoms in up to 20% of existing TED patients. Prophylactic administration of oral prednisone before RAI is recommended. Factors associated with worsening of TED after RAI include smoking, high pre-treatment T3 levels, post-treatment hypothyroidism, and large goiter.
With appropriate treatment, visual function recovery is achieved in approximately 70% or more of patients. The probability of complete visual recovery is higher when surgical decompression is performed.
If no improvement in optic nerve function is seen within two weeks after starting pulse therapy, emergency orbital decompression is considered. In Japan, 22–38% of DON patients undergo orbital decompression 1).
Multiple mechanisms are involved in the development of DON.
As the underlying pathology of TED, autoantibodies bind to TSH receptors and IGF-1 receptors on orbital fibroblasts with multipotent capacity, leading to the following cascade.
As a result of these processes, the volume within the orbit increases, causing compression or stretching of the optic nerve under the constraints of the bony orbit.
Teprotumumab is a monoclonal antibody that specifically binds to the extracellular domain of the IGF-1 receptor (IGF-1R) and inhibits the immune response in TED.
Cong et al. (2024) reported in a meta-analysis of 5 RCTs (total 411 cases) that teprotumumab significantly reduced proptosis, improved clinical activity score (CAS), and improved diplopia compared to placebo. The risk of adverse events and serious adverse events was not significantly different from the placebo group 2).
For DON, multiple observational studies have reported that teprotumumab was effective in cases resistant to steroids, radiation therapy, and surgery. Future research is expected on the efficacy of teprotumumab in Japanese patients 1).
Evidence for the efficacy of both drugs for DON is limited, and further research is needed.
Mizuochi et al. (2025) reported a case of a 55-year-old woman who transitioned from hypothyroidism to Graves’ disease and developed DON. After three courses of 1 g pulse therapy, she progressed to DON, but additional pulse therapy restored her vision. However, disease activity persisted for more than four years, with a total of five exacerbations. She underwent repeated outpatient 0.5 g once-weekly pulse therapy, and the cumulative dose of methylprednisolone reached 59.5 g, but no serious adverse effects were observed 1).
This report suggests the importance of careful monitoring (CAS, TSAb, orbital MRI) in the long-term management of DON.
Currently, teprotumumab is not established as a standard treatment for DON. However, several observational studies have reported its efficacy in DON cases resistant to steroids or radiation therapy, and future research is expected.
