| Graves ophthalmopathy | |
|---|---|
| Other names | Thyroid eye disease (TED), dysthyroid/thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO) |
 | |
| Bulging eyes and lid retraction from Graves' disease | |
| Specialty | Ophthalmology  |
Graves' ophthalmopathy, also known asthyroid eye disease (TED), is anautoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction,lid lag,swelling, redness (erythema),conjunctivitis, and bulging eyes (exophthalmos).[1] It occurs most commonly in individuals withGraves' disease,[2] and less commonly in individuals withHashimoto's thyroiditis,[3] or in those who are euthyroid.[4]
It is part of a systemic process with variable expression in the eyes, thyroid, and skin, caused byautoantibodies that bind to tissues in those organs. The autoantibodies target thefibroblasts 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, causingedema.[1]
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.[1]
Mild disease will often resolve and merely requires measures to reduce discomfort and dryness, such as artificial tears andsmoking cessation if possible. Severe cases are a medical emergency, and are treated withglucocorticoids (steroids), and sometimesciclosporin.[5] Many anti-inflammatory biological mediators, such asinfliximab,etanercept, andanakinra are being tried.[1] In January 2020, the USFood and Drug Administration approvedteprotumumab-trbw for the treatment of Graves' ophthalmopathy.[6]
In mild disease, patientspresent with eyelid retraction. Upper eyelid retraction is the most common ocular sign of Graves' orbitopathy. This finding is associated withlid lag on infraduction (Von Graefe's sign), eye globe lag on supraduction (Kocher's sign), a widenedpalpebral fissure during fixation (Dalrymple's sign) and inability to close the eyelids completely (lagophthalmos,Stellwag's sign). Owing to theproptosis, eyelid retraction and lagophthalmos, the cornea is more prone to dryness and may present withchemosis,punctate epithelial erosions andsuperior limbic keratoconjunctivitis. The patients also have a dysfunction of the lacrimal gland with a decrease in 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.[citation needed]
| Sign | Description | Named for |
|---|---|---|
| Abadie's sign | Elevator muscle of upper eyelid is spastic. | Jean Marie Charles Abadie (1842–1932) |
| Ballet's sign | Paralysis of one or more extra-ocular muscles | 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 (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 fold is hyperpigmented | Edward Jellinek, English ophthalmologist and pathologist (1890–1963) |
| Joffroy's sign | Absent creases in the forehead on upward gaze. | Alexis Joffroy (1844–1908) |
| Jendrassik's sign | Abduction and rotation of eyeball is also limited | 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, owing 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 with difficulty, 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 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 includemyopathy. The inflammation andedema of the extraocular muscles lead to gaze abnormalities. Theinferior rectus muscle is the most commonly affected muscle and patient may experience verticaldiplopia on upgaze and limitation of elevation of the eyes due tofibrosis 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.[citation needed]
In more severe and active disease, mass effects and cicatricial changes occur within the orbit. This is manifested by a progressiveexophthalmos, 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.[citation needed]
Graves' is an orbitalautoimmune disease. Thethyroid-stimulating hormonereceptor (TSH-R) is anantigen found in orbital fat andconnective tissue, and is a target for autoimmune assault.[citation needed]
On histological examination, there is an infiltration of the orbital connective tissue bylymphocytes,plasmocytes, andmastocytes. The inflammation results in a deposition ofcollagen andglycosaminoglycans in the muscles, which leads to subsequent enlargement andfibrosis. There is also an induction of thelipogenesis byfibroblasts andpreadipocytes, 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 todysthyroid optic neuropathy (DON), increased intraocular pressures,proptosis, and venous congestion leading to chemosis and periorbital oedema.[8][9] 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.[10]
Graves' ophthalmopathy is diagnosed clinically by the presenting ocular signs and symptoms, but positive tests forantibodies (anti-thyroglobulin, anti-microsomal and anti-thyrotropin receptor) and abnormalities inthyroid hormones level (T3, T4, and TSH) help in supporting the diagnosis.[citation needed]
Orbital imaging is an integral 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 theCT scan andmagnetic 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 withtendon sparing, usually bilateral, and proptosis.[citation needed]
Mnemonic: "NO SPECS":[11]
| Class | Description |
|---|---|
| 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 3 | Proptosis |
| 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 suggests that statin use may assist.[12][13]
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 tostop smoking, as pro-inflammatory substances are found in cigarettes. The medicationteprotumumab may also be used.[14][15] There is tentative evidence forselenium in mild disease.[16]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.[17]
In January 2020, the USFood and Drug Administration approvedteprotumumab for the treatment of Graves' ophthalmopathy.[6]
There is some evidence that a total or sub-total thyroidectomy may assist in reducing levels ofTSH receptor antibodies (TRAbs) and as a consequence reduce the eye symptoms, perhaps after a 12-month lag.[18][12][19][20][21] However, a 2015 meta review found no such benefits,[22] and there is some evidence that suggests that surgery is no better than medication.[23]
Surgery may be done to decompress the orbit, to improve the proptosis and to address thestrabismus causing diplopia. Surgery is performed once the patient's disease has been stable for at least six months. In severe cases, however, 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. 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 allow the eye to move back into normal position and also relieve compression of the optic nerve that can threaten sight.[citation needed]
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. Marginalmyotomy oflevator palpebrae muscle can reduce thepalpebral 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 lateraltarsalcanthoplasty is recommended. This procedure can lower the upper eyelid by as much as 8 mm. Other approaches include müllerectomy (resection of theMüller 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.[24]
A summary of treatment recommendations was published in 2015 by an Italian taskforce,[25] which largely supports the other studies.
Risk factors of progressive and severe thyroid-associated orbitopathy are:[citation needed]
The pathology mostly affects persons of 30 to 50 years of age. Females are four times more likely to develop Graves' 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 werehyperthyroid according tothyroid function tests, while 3% hadHashimoto's thyroiditis, 1% werehypothyroid and 6% did not have any thyroid function tests abnormality.[26] Of patients with Graves' hyperthyroidism, 20 to 25 percent have clinically obvious Graves' ophthalmopathy, while only 3–5% will develop severe ophthalmopathy.[27][28]
In medical literature,Anglo-Irish surgeonRobert James Graves, in 1835, was the first to describe the association of a thyroidgoitre withexophthalmos (proptosis) of the eye.[29] Graves' ophthalmopathy may occur before, with, or after the onset of overt thyroid disease and usually has a slow onset over many months.[citation needed]