Graves' ophthalmopathy

In mild disease, patients present with eyelid retraction. In fact, upper eyelid retraction is the most common ocular sign of Graves' orbitopathy. This finding is associated with lid lag on infraduction (Von Graefe's sign), eye globe lag on supraduction (Kocher's sign), a widened palpebral fissure during fixation (Dalrymple's sign) and an incapacity of closing the eyelids completely (lagophthalmos, Stellwag's sign). Due to the proptosis, eyelid retraction and lagophthalmos, the cornea is more prone to dryness and may present with chemosis, punctate epithelial erosions and superior limbic keratoconjunctivitis. The patients also have a dysfunction of the lacrimal gland with a decrease of the quantity and composition of tears produced. Non-specific symptoms with these pathologies include irritation, grittiness, photophobia, tearing, and blurred vision. Pain is not typical, but patients often complain of pressure in the orbit. Periorbital swelling due to inflammation can also be observed.

Eye signs[6]

In moderate active disease, the signs and symptoms are persistent and increasing and include myopathy. The inflammation and edema of the extraocular muscles lead to gaze abnormalities. The inferior rectus muscle is the most commonly affected muscle and patient may experience vertical diplopia on upgaze and limitation of elevation of the eyes due to fibrosis of the muscle. This may also increase the intraocular pressure of the eyes. The double vision is initially intermittent but can gradually become chronic. The medial rectus is the second-most-commonly-affected muscle, but multiple muscles may be affected, in an asymmetric fashion.

In more severe and active disease, mass effects and cicatricial changes occur within the orbit. This is manifested by a progressive exophthalmos, a restrictive myopathy that restricts eye movements and an optic neuropathy. With enlargement of the extraocular muscle at the orbital apex, the optic nerve is at risk of compression. The orbital fat or the stretching of the nerve due to increased orbital volume may also lead to optic nerve damage. The patient experiences a loss of visual acuity, visual field defect, afferent pupillary defect, and loss of color vision. This is an emergency and requires immediate surgery to prevent permanent blindness.

Magnetic resonance imaging of the orbits, showing congestion of the retro-orbital space and enlargement of the extraocular muscles (arrows), consistent with the diagnosis of Graves' ophthalmopathy.

TAO is an orbital autoimmune disease. The thyroid-stimulating hormone receptor (TSH-R) is an antigen found in orbital fat and connective tissue, and is a target for autoimmune assault.

On histological examination, there is an infiltration of the orbital connective tissue by lymphocytes, plasmocytes, and mastocytes. The inflammation results in a deposition of collagen and glycosaminoglycans in the muscles, which leads to subsequent enlargement and fibrosis. There is also an induction of the lipogenesis by fibroblasts and preadipocytes, which causes enlargement of the orbital fat and extra-ocular muscle compartments. This increase in volume of the intraorbital contents within the confines of the bony orbit may lead to dysthyroid optic neuropathy (DON), increased intraocular pressures, proptosis, and venous congestion leading to chemosis and periorbital oedema.[7][8] In addition, the expansion of the intraorbital soft tissue volume may also remodel the bony orbit and enlarge it, which may be a form of auto-decompression.[9]

Graves' ophthalmopathy is diagnosed clinically by the presenting ocular signs and symptoms, but positive tests for antibodies (anti-thyroglobulin, anti-microsomal and anti-thyrotropin receptor) and abnormalities in thyroid hormones level (T3, T4, and TSH) help in supporting the diagnosis.

Orbital imaging is an interesting tool for the diagnosis of Graves' ophthalmopathy and is useful in monitoring patients for progression of the disease. It is, however, not warranted when the diagnosis can be established clinically. Ultrasonography may detect early Graves' orbitopathy in patients without clinical orbital findings. It is less reliable than the CT scan and magnetic resonance imaging (MRI), however, to assess the extraocular muscle involvement at the orbital apex, which may lead to blindness. Thus, CT scan or MRI is necessary when optic nerve involvement is suspected. On neuroimaging, the most characteristic findings are thick extraocular muscles with tendon sparing, usually bilateral, and proptosis.

Not smoking is a common suggestion in the literature. Apart from smoking cessation, there is little definitive research in this area. In addition to the selenium studies above, some recent research also is suggestive that statin use may assist.[11][12]

Even though some people undergo spontaneous remission of symptoms within a year, many need treatment. The first step is the regulation of thyroid hormone levels. Topical lubrication of the eye is used to avoid corneal damage caused by exposure. Corticosteroids are efficient in reducing orbital inflammation, but the benefits cease after discontinuation. Corticosteroids treatment is also limited because of their many side effects. Radiotherapy is an alternative option to reduce acute orbital inflammation. However, there is still controversy surrounding its efficacy. A simple way of reducing inflammation is to stop smoking, as pro-inflammatory substances are found in cigarettes. The medication teprotumumab-trbw may also be used.[13] There is tentative evidence for selenium in mild disease.[14] Tocilizumab, a drug used to suppress the immune system has also been studied as a treatment for TED. However, a Cochrane Review published in 2018 found no evidence (no relevant clinical studies were published) to show that tocilizumab works in people with TED.[15]

Risk factors of progressive and severe thyroid-associated orbitopathy are:

• Age greater than 50 years
• Rapid onset of symptoms under 3 months
• Cigarette smoking
• Diabetes
• Severe or uncontrolled hyperthyroidism
• Presence of pretibial myxedema
• High cholesterol levels (hyperlipidemia)
• Peripheral vascular disease

The pathology mostly affects persons of 30 to 50 years of age. Females are four times more likely to develop TAO than males. When males are affected, they tend to have a later onset and a poor prognosis. A study demonstrated that at the time of diagnosis, 90% of the patients with clinical orbitopathy were hyperthyroid according to thyroid function tests, while 3% had Hashimoto's thyroiditis, 1% were hypothyroid and 6% did not have any thyroid function tests abnormality.[24] Of patients with Graves' hyperthyroidism, 20 to 25 percent have clinically obvious Graves' ophthalmopathy, while only 3–5% will develop severe ophthalmopathy.[25][26]

In medical literature, Robert James Graves, in 1835, was the first to describe the association of a thyroid goitre with exophthalmos (proptosis) of the eye.[27] Graves' ophthalmopathy may occur before, with, or after the onset of overt thyroid disease and usually has a slow onset over many months.

• Infiltrative ophthalmopathy
• Exophthalmos

• Behbehani, Raed; Sergott, Robert C; Savino, Peter J (2004). "Orbital radiotherapy for thyroid-related orbitopathy". Current Opinion in Ophthalmology. 15 (6): 479–82. doi:10.1097/01.icu.0000144388.89867.03. PMID 15523191. S2CID 31340321.
• Boncoeur, M.-P. (2004). "Orbitopathie dysthyroïdienne : imagerie : Orbitopathie dysthyroïdienne" [Imaging techniques in Graves disease : Dysthyroid orbitopathy]. Journal Français d'Ophtalmologie (in French). 27 (7): 815–8. doi:10.1016/S0181-5512(04)96221-3. PMID 15499283. INIST:16100159.
• Boulos, Patrick Roland; Hardy, Isabelle (2004). "Thyroid-associated orbitopathy: A clinicopathologic and therapeutic review". Current Opinion in Ophthalmology. 15 (5): 389–400. doi:10.1097/01.icu.0000139992.15463.1b. PMID 15625899. S2CID 23194226.
• Camezind, P.; Robert, P.-Y.; Adenis, J.-P. (2004). "Signes cliniques de l'orbitopathie dysthyroïdienne : Orbitopathie dysthyroïdienne" [Clinical signs of dysthyroid orbitopathy : Dysthyroid orbitopathy]. Journal Français d'Ophtalmologie (in French). 27 (7): 810–4. doi:10.1016/S0181-5512(04)96220-1. PMID 15499282. INIST:16100158.
• Duker, Jay S.; Yanoff, Myron (2004). "chapt 95". Ophthalmology (2nd ed.). Saint Louis: C.V. Mosby. ISBN 978-0-323-02907-0.
• Morax, S.; Ben Ayed, H. (2004). "Techniques et indications chirurgicales des décompressions osseuses de l'orbitopathie dysthyroïdienne" [Orbital decompression for dysthyroid orbitopathy: a review of techniques and indications]. Journal Français d'Ophtalmologie (in French). 27 (7): 828–44. doi:10.1016/s0181-5512(04)96225-0. PMID 15499287.
• Rose, John G.; Burkat, Cat Nguyen; Boxrud, Cynthia A. (2005). "Diagnosis and Management of Thyroid Orbitopathy". Otolaryngologic Clinics of North America. 38 (5): 1043–74. doi:10.1016/j.otc.2005.03.015. PMID 16214573.