|Bulging eyes and lid retraction from Graves' disease|
Graves ophthalmopathy (also known as thyroid eye disease (TED), dysthyroid/thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO)) is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exophthalmos). It occurs most commonly in individuals with Graves' disease, and less commonly in individuals with Hashimoto's thyroiditis, or in those who are euthyroid.
It is part of a systemic process with variable expression in the eyes, thyroid, and skin, caused by autoantibodies that bind to tissues in those organs. The autoantibodies target the fibroblasts in the eye muscles, and those fibroblasts can differentiate into fat cells (adipocytes). Fat cells and muscles expand and become inflamed. Veins become compressed, and are unable to drain fluid, causing edema.
Annual incidence is 16/100,000 in women, 3/100,000 in men. About 3–5% have severe disease with intense pain, and sight-threatening corneal ulceration or compression of the optic nerve. Cigarette smoking, which is associated with many autoimmune diseases, raises the incidence 7.7-fold.
Mild disease will often resolve and merely requires measures to reduce discomfort and dryness, such as artificial tears and smoking cessation if possible. Severe cases are a medical emergency, and are treated with glucocorticoids (steroids), and sometimes ciclosporin. Many anti-inflammatory biological mediators, such as infliximab, etanercept, and anakinra are being tried, but there are no randomized controlled trials demonstrating effectiveness.
Signs and symptoms
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). 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 in TED
|Abadie's sign||Elevator muscle of upper eyelid is spastic.||Jean Marie Charles Abadie (1842–1932)|
|Ballet's sign||Paralysis of one or more EOM||Louis Gilbert Simeon Ballet (1853–1916)|
|Becker's sign||Abnormal intense pulsation of retina's arteries||Otto Heinrich Enoch Becker (1828–1890)|
|Boston's sign||Jerky movements of upper lid on lower gaze||Leonard Napoleon Boston (1871–1931)|
|Cowen's sign||Extensive hippus of consensual pupillary reflex||Jack Posner Cowen, American ophthalmologist (1906–1989)|
|Dalrymple's sign||Upper eyelid retraction||John Dalrymple (1803–1852)|
|Enroth's sign||Edema esp. of the upper eyelid||Emil Emanuel Enroth, Finnish ophthalmologist (1879–1953)|
|Gifford's sign||Difficulty in eversion of upper lid.||Harold Gifford Sr. (1858–1929)|
|Goldzieher's sign||Deep injection of conjunctiva, especially temporal||Wilhelm Goldzieher, Hungarian ophthalmologist (1849–1916)|
|Griffith's sign||Lower lid lag on upward gaze||Alexander James Hill Griffith, English ophthalmologist (1858–1937)|
|Hertoghe's sign||Loss of eyebrows laterally||Eugene Louis Chretien Hertoghe, Dutch thyroid pathologist (1860–1928)|
|Jellinek's sign||Superior eyelid folds is hyperpigmented||Edward Jellinek, English ophthalmologist and pathologist (1890–1963)|
|Joffroy's sign||Absent creases in the fore head on upward gaze.||Alexis Joffroy (1844–1908)|
|Jendrassik's sign||Abduction and rotation of eyeball is limited also||Ernő Jendrassik (1858–1921)|
|Knies's sign||Uneven pupillary dilatation in dim light||Max Knies, German ophthalmologist (1851–1917)|
|Kocher's sign||Spasmatic retraction of upper lid on fixation||Emil Theodor Kocher (1841–1917)|
|Loewi's sign||Quick Mydriasis after instillation of 1:1000 adrenaline||Otto Loewi (1873–1961)|
|Mann's sign||Eyes seem to be situated at different levels because of tanned skin.||John Dixon Mann, English pathologist and forensic scientist (1840–1912)|
|Mean sign||Increased scleral show on upgaze (globe lag)||Named after the expression of being "mean" when viewed from afar, due to the scleral show|
|Möbius's sign||Lack of convergence||Paul Julius Möbius (1853–1907)|
|Payne–Trousseau's sign||Dislocation of globe||John Howard Payne, American surgeon (1916–1983), Armand Trousseau (1801–1867)|
|Pochin's sign||Reduced amplitude of blinking||Sir Edward Eric Pochin (1909–1990)|
|Riesman's sign||Bruit over the eyelid||David Riesman, American physician (1867–1940)|
|Movement's cap phenomenon||Eyeball movements are performed difficultly, abruptly and incompletely|
|Rosenbach's sign||Eyelids are animated by thin tremors when closed||Ottomar Ernst Felix Rosenbach (1851–1907)|
|Snellen–Riesman's sign||When placing the stethoscope's capsule over closed eyelids a systolic murmur could be heard||Herman Snellen (1834–1908), David Riesman, American physician (1867–1940)|
|Stellwag's sign||Incomplete and infrequent blinking||Karl Stellwag (1823–1904)|
|Suker's sign||Inability to maintain fixation on extreme lateral gaze||George Francis "Franklin" Suker, American ophthalmologist (1869–1933)|
|Topolanski's sign||Around insertion areas of the four rectus muscles of the eyeball a vascular band network is noticed and this network joints the four insertion points.||Alfred Topolanski, Austrian ophthalmologist (1861–1960)|
|von Graefe's sign||Upper lid lag on down gaze||Friedrich Wilhelm Ernst Albrecht von Gräfe (1828–1870)|
|Wilder's sign||Jerking of the eye on movement from abduction to adduction||Helenor Campbell Wilder (née Foerster), American ophthalmologist (1895–1998)|
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.
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. However, some patients with Graves' orbitopathy present with neither anti-microsomal nor anti-thyroglobulin nor anti-TSH receptor antibodies, the antibodies identified in Graves' disease.
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. 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.
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.
Classification of Graves' eye disease
Mnemonic: "NO SPECS":
|Class 0||No signs or symptoms|
|Class 1||Only signs (limited to upper lid retraction and stare, with or without lid lag)|
|Class 2||Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc.)|
|Class 4||Extraocular muscle involvement (usually with diplopia)|
|Class 5||Corneal involvement (primarily due to lagophthalmos)|
|Class 6||Sight loss (due to optic nerve involvement)|
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.
Even though some patients undergo spontaneous remission of symptoms within a year, many need treatment. The first step is the regulation of thyroid hormone levels by a physician.
There is some published evidence that a total or sub-total thyroidectomy may assist in reducing levels of TSH receptor antibodies (TRAbs) and as a consequence reduce the eye symptoms, perhaps after a 12-month lag. However, a 2015 meta review found no such benefits, and there is some evidence that suggests that surgery is no better than medication; and there are risks associated with a Thyroidectomy, as there are with long-term use of anti-thyroid medication.
Topical lubrication of the ocular surface is used to avoid corneal damage caused by exposure. Tarsorrhaphy is an alternative option when the complications of ocular exposure can't be avoided solely with the drops.
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.
Surgery may be done to decompress the orbit, to improve the proptosis, and to address the strabismus causing diplopia. Surgery is performed once the patient's disease has been stable for at least six months. In severe cases, however, the surgery becomes urgent to prevent blindness from optic nerve compression. Because the eye socket is bone, there is nowhere for eye muscle swelling to be accommodated, and, as a result, the eye is pushed forward into a protruded position. In some patients, this is very pronounced. Orbital decompression involves removing some bone from the eye socket to open up one or more sinuses and so make space for the swollen tissue and allowing the eye to move back into normal position and also relieving compression of the optic nerve that can threaten sight.
Eyelid surgery is the most common surgery performed on Graves ophthalmopathy patients. Lid-lengthening surgeries can be done on upper and lower eyelid to correct the patient's appearance and the ocular surface exposure symptoms. Marginal myotomy of levator palpebrae muscle can reduce the palpebral fissure height by 2–3 mm. When there is a more severe upper lid retraction or exposure keratitis, marginal myotomy of levator palpebrae associated with lateral tarsal canthoplasty is recommended. This procedure can lower the upper eyelid by as much as 8 mm. Other approaches include müllerectomy (resection of the Müller muscle), eyelid spacer grafts, and recession of the lower eyelid retractors. Blepharoplasty can also be done to debulk the excess fat in the lower eyelid.
An article in the New England Journal of Medicine reports that treatment with selenium is effective in mild cases.
A large European study performed by the European Group On Graves' Orbitopathy (EUGOGO) has recently shown that the trace element selenium had a significant effect in patients with mild, active thyroid eye disease. Six months of selenium supplements had a beneficial effect on thyroid eye disease and were associated with improvement in the quality of life of participants. These positive effects persisted at 12 months. There were no side effects.
A summary of treatment recommendations was published in 2015 by an Italian taskforce, which largely supports the other studies.
Poor prognostic indicators
Risk factors of progressive and severe thyroid-associated orbitopathy are:
- Age greater than 50 years
- Rapid onset of symptoms under 3 months
- Cigarette smoking
- 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. Of patients with Graves' hyperthyroidism, 20 to 25 percent have clinically obvious Graves' ophthalmopathy, while only 3–5% will develop severe ophthalmopathy.
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. Graves' ophthalmopathy may occur before, with, or after the onset of overt thyroid disease and usually has a slow onset over many months.
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