Dr. SK Wangnoo throws light on thyroid-associated ophthalmopathy (TAO), a condition involving the eyes that frequently manifests with thyroid dysfunction, and is the most common extra-thyroidal manifestation of Graves’ disease. Although usually seen in patients with Graves’ disease, it may also occur in patients with thyroid cancers or autoimmune hypothyroid due to Hashimoto’s thyroiditis, as well as individuals with no thyroid disease.

Epidemiology and pathogenesis

TAO is more common among women and severe ophthalmopathy is more common among men. The age of onset is between 30 and 50, and the disease course is more severe after age 50. Ophthalmopathy is reported to occur in 25 to 50% of patients with Graves’ disease and 2% of patients with Hashimoto’s thyroiditis. Most patients develop ophthalmopathy within 18 months of being diagnosed with Graves’ disease. However, ophthalmopathy onset may occur up to 10 years before and as late as 20 years after the onset of thyroid disease.

Although the pathogenesis of TAO is not completely understood, it is known to be an autoimmune disorder. It has been established that autoimmunity develops against antigens common to the thyroid gland and the orbit. The auto-antibodies against orbital fibroblasts membrane antigen are the main drivers of the disease process. Reactive T lymphocytes that recognise thyroid-orbit common antigens infiltrate the orbit and extraocular muscles leading to the infiltration of the orbit with T lymphocytes. These cytokines stimulate the synthesis and secretion of glycosaminoglycans (GAGs) by fibroblasts. Due to their water-attracting properties, GAGs lead to periorbital oedema, proptosis, and swelling of the extraocular muscles. Fibroblast proliferation stimulated by cytokines also plays a role in the expansion of the orbital contents.

In addition to autoimmunity, genetic and environmental factors are also known to be influential in the pathogenesis of thyroid ophthalmopathy.

Genetic factors

There are many studies investigating the role of genetics in the development of ophthalmopathy. Many studies have reported polymorphisms in protein genes affecting immune function such as HLADR-3, CTLA 4, PTPN22, CD40, interleukin (IL)-2RA, FCRL3, and IL-23R, as well as genes encoding thyroid-specific proteins like TG.

Environmental factors

Cigarette use is the strongest modifiable risk factor - TAO is more common and more severe in smokers, relapse rates are relatively higher and response to treatment is blunted. Strict advice regarding the cessation of smoking is necessary. Ophthalmopathy may be triggered by environmental factors such as stress, infectious agents, iodine, IFN and interleukin therapy, and sex steroids.

Clinical course and signs

Patient evaluation begins with confirming the clinical diagnosis and determining the current disease phase; determining the clinical severity is necessary in order to choose the appropriate treatment.

The natural course of ophthalmopathy is not fully understood, it has an inflammatory active phase that lasts an average of 3-6 months but maybe as long as 3 years, followed by a fibrotic inactive phase. Ophthalmic findings are usually bilateral, but may also be unilateral or asymmetric. Nearly half of Graves’ disease patients have symptoms including dryness and stinging, photophobia, epiphora, diplopia, and a feeling of pressure behind the eyes. Soft tissue inflammation is often the earliest sign of TAO. Soft tissue involvement consists of periorbital oedema, conjunctival hyperemia, and chemosis. Symptoms may include foreign body sensation, epiphora, palpebral and conjunctival hyperemia, and oedema, blurred vision, and retroorbital pain.

Diplopia manifesting as the appearance of overlapping images is common. Optic neuropathy develops as a result of pressure from enlarged muscles on the optic nerve or the vessels that supply it. Fundus examination is usually normal, though optic disc oedema, choroidal folds, optic disc paleness may be observed.

Imaging

Orbital imaging may be done with ultrasound, CT, or MRI. In active disease, the extraocular muscles appear as hyperintense on T2-weighted MRI.“NOSPECS”, Clinical Activity Score (CAS), the VISA, and the EUGOGO classification are commonly used for clinical grading of the severity of ophthalmopathy.

Treatment

Management of TAO may follow the following algorithm (although different institutes may have different approaches and protocols):

1. Euthyroidism should be achieved in all patients (ATDs, radioiodine, or surgery as indicated and decided) with TAO.
2. The most important modifier is smoking – all should be strongly advised to quit smoking.
3. Mild disease may be treated with symptomatic treatments and practices such as topical lubricants, wearing sunglasses, elevating the head during sleep, and using prismatic glasses or botulinum toxin injection.
4. For moderate and severe disease, oral or intravenous steroids in tapering doses with requisite precautions are required. Most patients show improvement in inflammatory soft tissue changes and muscle motility dysfunction with intravenous steroid therapy.
5. For patients who do not respond to steroid therapy, immunosuppressive therapies are an option, and orbital radiotherapy may be preferred for patients with pronounced ocular motility dysfunction.
6. Anti-lymphocyte antibody (rituximab) may be tried in patients who do not respond to conventional immunosuppressive therapy.
7. Orbital decompression surgery may be performed to correct visual abnormalities but requires great expertise.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Subhash Kumar Wangnoo is a Senior Consultant Endocrinologist and Diabetologist from New Delhi.