Graves' ophthalmopathy
Graves' ophthalmopathy, also known as thyroid eye disease, is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, lid lag, swelling, redness, conjunctivitis, and bulging eyes. 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. 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, and sometimes ciclosporin. Many anti-inflammatory biological mediators, such as infliximab, etanercept, and anakinra are being tried. In January 2020, the US Food and Drug Administration approved teprotumumab-trbw for the treatment of Graves' ophthalmopathy.
Signs and symptoms
In mild disease, patients present with eyelid retraction. Upper eyelid retraction is the most common ocular sign of Graves' orbitopathy. This finding is associated with lid lag on infraduction, eye globe lag on supraduction, a widened palpebral fissure during fixation and inability to close the eyelids completely. Owing 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 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.;Eye signs
| Sign | Description | Named for |
| Abadie's sign | Elevator muscle of upper eyelid is spastic. | Jean Marie Charles Abadie |
| Ballet's sign | Paralysis of one or more extra-ocular muscles | Louis Gilbert Simeon Ballet |
| Becker's sign | Abnormal intense pulsation of retina's arteries | Otto Heinrich Enoch Becker |
| Boston's sign | Jerky movements of upper lid on lower gaze | Leonard Napoleon Boston |
| Cowen's sign | Extensive hippus of consensual pupillary reflex | Jack Posner Cowen, American ophthalmologist |
| Dalrymple's sign | Upper eyelid retraction | John Dalrymple |
| Enroth's sign | Edema esp. of the upper eyelid | Emil Emanuel Enroth, Finnish ophthalmologist |
| Gifford's sign | Difficulty in eversion of upper lid. | Harold Gifford |
| Goldzieher's sign | Deep injection of conjunctiva, especially temporal | Wilhelm Goldzieher, Hungarian ophthalmologist |
| Griffith's sign | Lower lid lag on upward gaze | Alexander James Hill Griffith, English ophthalmologist |
| Hertoghe's sign | Loss of eyebrows laterally | Eugene Louis Chretien Hertoghe, Dutch thyroid pathologist |
| Jellinek's sign | Superior eyelid fold is hyperpigmented | Edward Jellinek, English ophthalmologist and pathologist |
| Joffroy's sign | Absent creases in the forehead on upward gaze. | Alexis Joffroy |
| Jendrassik's sign | Abduction and rotation of eyeball is also limited | Ernő Jendrassik |
| Knies's sign | Uneven pupillary dilatation in dim light | Max Knies, German ophthalmologist |
| Kocher's sign | Spasmatic retraction of upper lid on fixation | Emil Theodor Kocher |
| Loewi's sign | Quick Mydriasis after instillation of 1:1000 adrenaline | Otto Loewi |
| Mann's sign | Eyes seem to be situated at different levels because of tanned skin. | John Dixon Mann, English pathologist and forensic scientist |
| Mean sign | Increased scleral show on upgaze | 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 |
| Payne–Trousseau's sign | Dislocation of globe | John Howard Payne, American surgeon, Armand Trousseau |
| Pochin's sign | Reduced amplitude of blinking | Sir Edward Eric Pochin |
| Riesman's sign | Bruit over the eyelid | David Riesman, American physician |
| 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 |
| Snellen–Riesman's sign | When placing the stethoscope capsule over closed eyelids a systolic murmur could be heard | Herman Snellen, David Riesman, American physician |
| Stellwag's sign | Incomplete and infrequent blinking | Karl Stellwag |
| Suker's sign | Inability to maintain fixation on extreme lateral gaze | George Francis "Franklin" Suker, American ophthalmologist |
| 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 |
| von Graefe's sign | Upper lid lag on down gaze | Friedrich Wilhelm Ernst Albrecht von Gräfe |
| Wilder's sign | Jerking of the eye on movement from abduction to adduction | Helenor Campbell Wilder, American ophthalmologist |
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.
Pathophysiology
Graves' is an orbital autoimmune disease. The thyroid-stimulating hormone receptor 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, 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.
Diagnostic
Graves' ophthalmopathy is diagnosed clinically by the presenting ocular signs and symptoms, but positive tests for antibodies and abnormalities in thyroid hormones level help in supporting the diagnosis.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 the CT scan and magnetic resonance imaging, 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
Mnemonic: "NO SPECS":| Class | Description |
| Class 0 | No signs or symptoms |
| Class 1 | Only signs |
| Class 2 | Soft tissue involvement |
| Class 3 | Proptosis |
| Class 4 | Extraocular muscle involvement |
| Class 5 | Corneal involvement |
| Class 6 | Sight loss |