Graves' ophthalmopathy

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Graves ophthalmopathy
Other namesThyroid eye disease (TED), dysthyroid/thyroid-associated orbitopathy (TAO), Graves' orbitopathy (GO)
Proptosis and lid retraction from Graves' Disease.jpg
Bulging eyes and lid retraction from Graves' disease
Specialty Ophthalmology   OOjs UI icon edit-ltr-progressive.svg

Graves' ophthalmopathy, also known as thyroid eye disease (TED), 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). [1] It occurs most commonly in individuals with Graves' disease, [2] and less commonly in individuals with Hashimoto's thyroiditis, [3] or in those who are euthyroid. [4]

Contents

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. [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 and smoking cessation if possible. Severe cases are a medical emergency, and are treated with glucocorticoids (steroids), and sometimes ciclosporin. [5] Many anti-inflammatory biological mediators, such as infliximab, etanercept, and anakinra are being tried. [1] In January 2020, the US Food and Drug Administration approved teprotumumab-trbw for the treatment of Graves' ophthalmopathy. [6]

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, 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.[ citation needed ]

Eye signs [7]
SignDescriptionNamed for
Abadie's signElevator muscle of upper eyelid is spastic. Jean Marie Charles Abadie (1842–1932)
Ballet's signParalysis of one or more EOM Louis Gilbert Simeon Ballet (1853–1916)
Becker's signAbnormal intense pulsation of retina's arteries Otto Heinrich Enoch Becker (1828–1890)
Boston's signJerky movements of upper lid on lower gaze Leonard Napoleon Boston (1871–1931)
Cowen's signExtensive hippus of consensual pupillary reflexJack Posner Cowen, American ophthalmologist (1906–1989)
Dalrymple's signUpper eyelid retraction John Dalrymple (1803–1852)
Enroth's signEdema esp. of the upper eyelidEmil Emanuel Enroth, Finnish ophthalmologist (1879–1953)
Gifford's signDifficulty in eversion of upper lid. Harold Gifford (1858–1929)
Goldzieher's signDeep injection of conjunctiva, especially temporalWilhelm Goldzieher, Hungarian ophthalmologist (1849–1916)
Griffith's signLower lid lag on upward gazeAlexander James Hill Griffith, English ophthalmologist (1858–1937)
Hertoghe's sign Loss of eyebrows laterallyEugene Louis Chretien Hertoghe, Dutch thyroid pathologist (1860–1928)
Jellinek's signSuperior eyelid folds is hyperpigmentedEdward Jellinek, English ophthalmologist and pathologist (1890–1963)
Joffroy's signAbsent creases in the fore head on upward gaze. Alexis Joffroy (1844–1908)
Jendrassik's signAbduction and rotation of eyeball is limited also Ernő Jendrassik (1858–1921)
Knies's signUneven pupillary dilatation in dim lightMax Knies, German ophthalmologist (1851–1917)
Kocher's signSpasmatic retraction of upper lid on fixation Emil Theodor Kocher (1841–1917)
Loewi's signQuick Mydriasis after instillation of 1:1000 adrenaline Otto Loewi (1873–1961)
Mann's signEyes seem to be situated at different levels because of tanned skin.John Dixon Mann, English pathologist and forensic scientist (1840–1912)
Mean signIncreased 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 signDislocation of globeJohn Howard Payne, American surgeon (1916–1983), Armand Trousseau (1801–1867)
Pochin's signReduced 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 phenomenonEyeball movements are performed difficultly, abruptly and incompletely
Rosenbach's signEyelids are animated by thin tremors when closed Ottomar Ernst Felix Rosenbach (1851–1907)
Snellen–Riesman's signWhen 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 signIncomplete and infrequent blinking Karl Stellwag (1823–1904)
Suker's signInability to maintain fixation on extreme lateral gazeGeorge Francis "Franklin" Suker, American ophthalmologist (1869–1933)
Topolanski's signAround 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 signUpper lid lag on down gaze Friedrich Wilhelm Ernst Albrecht von Gräfe (1828–1870)
Wilder's signJerking of the eye on movement from abduction to adductionHelenor 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.[ citation needed ]

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.[ citation needed ]

Pathophysiology

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. Graves Ophthalmopathy MRT 01.jpg
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.

Graves' 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.[ citation needed ]

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. [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]

Diagnostic

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.[ 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 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.[ citation needed ]

Classification

Mnemonic: "NO SPECS": [11]

ClassDescription
Class 0No signs or symptoms
Class 1Only signs (limited to upper lid retraction and stare, with or without lid lag)
Class 2Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc.)
Class 3Proptosis
Class 4Extraocular muscle involvement (usually with diplopia)
Class 5Corneal involvement (primarily due to lagophthalmos)
Class 6Sight loss (due to optic nerve involvement)

Prevention

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. [12] [13]

Treatment

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. [14] [15] There is tentative evidence for selenium 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 US Food and Drug Administration approved teprotumumab-trbw for the treatment of Graves' ophthalmopathy. [6]

Surgery

There is some 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. [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 the strabismus causing diplopia. Surgery is performed once the person'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. 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.[ 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. 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. [24]

A summary of treatment recommendations was published in 2015 by an Italian taskforce, [25] which largely supports the other studies.

Prognosis

Risk factors of progressive and severe thyroid-associated orbitopathy are:[ citation needed ]

Epidemiology

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 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. [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]

History

In medical literature, Anglo-Irish surgeon Robert James Graves, in 1835, was the first to describe the association of a thyroid goitre with exophthalmos (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 ]

See also

Related Research Articles

<span class="mw-page-title-main">Hyperthyroidism</span> Clinical syndrome caused by excessive thyroid hormone

Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.

<span class="mw-page-title-main">Graves' disease</span> Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter or Basedow’s disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.

<span class="mw-page-title-main">Thyroidectomy</span> Surgical procedure involving partial or complete removal of the thyroid

A thyroidectomy is an operation that involves the surgical removal of all or part of the thyroid gland. In general surgery, endocrine or head and neck surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other condition of the thyroid gland or goiter. Other indications for surgery include cosmetic, or symptomatic obstruction. Thyroidectomy is a common surgical procedure that has several potential complications or sequelae including: temporary or permanent change in voice, temporary or permanently low calcium, need for lifelong thyroid hormone replacement, bleeding, infection, and the remote possibility of airway obstruction due to bilateral vocal cord paralysis. Complications are uncommon when the procedure is performed by an experienced surgeon.

<span class="mw-page-title-main">Orbit (anatomy)</span> Cavity or socket of the skull in which the eye and its appendages are situated

In anatomy, the orbit is the cavity or socket/hole of the skull in which the eye and its appendages are situated. "Orbit" can refer to the bony socket, or it can also be used to imply the contents. In the adult human, the volume of the orbit is about 28 millilitres, of which the eye occupies 6.5 ml. The orbital contents comprise the eye, the orbital and retrobulbar fascia, extraocular muscles, cranial nerves II, III, IV, V, and VI, blood vessels, fat, the lacrimal gland with its sac and duct, the eyelids, medial and lateral palpebral ligaments, cheek ligaments, the suspensory ligament, septum, ciliary ganglion and short ciliary nerves.

<span class="mw-page-title-main">Eye surgery</span> Surgery performed on the eye or its adnexa

Eye surgery, also known as ophthalmic surgery or ocular surgery, is surgery performed on the eye or its adnexa. Eye surgery is part of ophthalmology and is performed by an ophthalmologist or eye surgeon. The eye is a fragile organ, and requires due care before, during, and after a surgical procedure to minimize or prevent further damage. An eye surgeon is responsible for selecting the appropriate surgical procedure for the patient, and for taking the necessary safety precautions. Mentions of eye surgery can be found in several ancient texts dating back as early as 1800 BC, with cataract treatment starting in the fifth century BC. It continues to be a widely practiced class of surgery, with various techniques having been developed for treating eye problems.

<span class="mw-page-title-main">Diplopia</span> Double vision

Diplopia is the simultaneous perception of two images of a single object that may be displaced horizontally or vertically in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often voluntary. However, when occurring involuntarily, it results from impaired function of the extraocular muscles, where both eyes are still functional, but they cannot turn to target the desired object. Problems with these muscles may be due to mechanical problems, disorders of the neuromuscular junction, disorders of the cranial nerves that innervate the muscles, and occasionally disorders involving the supranuclear oculomotor pathways or ingestion of toxins.

<span class="mw-page-title-main">Exophthalmos</span> Bulging of the eye anteriorly out of the orbit

Exophthalmos is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral or unilateral. Complete or partial dislocation from the orbit is also possible from trauma or swelling of surrounding tissue resulting from trauma.

<span class="mw-page-title-main">Enucleation of the eye</span> Type of ocular surgery

Enucleation is the removal of the eye that leaves the eye muscles and remaining orbital contents intact. This type of ocular surgery is indicated for a number of ocular tumors, in eyes that have sustained severe trauma, and in eyes that are otherwise blind and painful.

Ocular myasthenia gravis (MG) is a disease of the neuromuscular junction resulting in hallmark variability in muscle weakness and fatigability. MG is an autoimmune disease where anomalous antibodies are produced against the naturally occurring acetylcholine receptors in voluntary muscles. MG may be limited to the muscles of the eye, leading to abrupt onset of weakness/fatigability of the eyelids or eye movement. MG may also involve other muscle groups.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

<span class="mw-page-title-main">Orbital cellulitis</span> Inflammation of eye tissues

Orbital cellulitis is inflammation of eye tissues behind the orbital septum. It is most commonly caused by an acute spread of infection into the eye socket from either the adjacent sinuses or through the blood. It may also occur after trauma. When it affects the rear of the eye, it is known as retro-orbital cellulitis.

Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain.

Infiltrative ophthalmopathy is found in 5-10% of patients with Graves disease and resembles exophthalmos, except that the blurry or double vision is acquired because of weakness in the ocular muscles of the eye. In addition, there is no known correlation with the patient's thyroid levels. Exophthalmos associated with Grave's disease disappears when the thyrotoxicosis is corrected. Infiltrative ophthalmopathy at times may not be cured. Treatments consist of high dose glucocorticoids and low dose radiotherapy. The current hypothesis is that infiltrative ophthalmopathy may be autoimmune in nature targeting retrobulbar tissue. Smoking may also have a causative effect.

<span class="mw-page-title-main">Idiopathic orbital inflammatory disease</span> Medical condition

Idiopathic orbital inflammatory (IOI) disease refers to a marginated mass-like enhancing soft tissue involving any area of the orbit. It is the most common painful orbital mass in the adult population, and is associated with proptosis, cranial nerve palsy, uveitis, and retinal detachment. Idiopathic orbital inflammatory syndrome, also known as orbital pseudotumor, was first described by Gleason in 1903 and by Busse and Hochheim. It was then characterized as a distinct entity in 1905 by Birch-Hirschfeld. It is a benign, nongranulomatous orbital inflammatory process characterized by extraocular orbital and adnexal inflammation with no known local or systemic cause. Its diagnosis is of exclusion once neoplasm, primary infection and systemic disorders have been ruled out. Once diagnosed, it is characterized by its chronicity, anatomic location or histologic subtype.

The signs and symptoms of Graves' disease generally result from the direct and indirect effects of hyperthyroidism, although they can also be caused by other thyroidal conditions, such as Graves' ophthalmopathy, goitre and pretibial myxedema. These clinical manifestations can involve virtually every system in the body.

Teprotumumab, sold under the brand name Tepezza, is a medication used to treat adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to bulge outwards.

<span class="mw-page-title-main">IgG4-related ophthalmic disease</span> Medical condition

IgG4-related ophthalmic disease (IgG4-ROD) is the recommended term to describe orbital manifestations of the systemic condition IgG4-related disease, which is characterised by infiltration of lymphocytes and plasma cells and subsequent fibrosis in involved structures. It can involve one or more of the orbital structures.

Alan Brown Scott was an American ophthalmologist specializing in eye muscles and their disorders, such as strabismus. He is best known for his work in developing and manufacturing the drug that became known as Botox, research described as "groundbreaking" by the ASCRS.

Exposure keratopathy is medical condition affecting the cornea of eyes. It can lead to corneal ulceration and permanent loss of vision due to corneal opacity.

<span class="mw-page-title-main">Orbital emphysema</span> Medical condition

Orbital emphysema is a medical condition that refers to the trapping of air within the loose subcutaneous around the orbit that is generally characterized by sudden onset swelling and bruising at the impacted eye, with or without deterioration of vision, which the severity depends on the density of air trapped under the orbital soft tissue spaces.

References

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  26. ↑ Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA (March 1996). "Clinical features of Graves' ophthalmopathy in an incidence cohort". American Journal of Ophthalmology. 121 (3): 284–290. doi:10.1016/s0002-9394(14)70276-4. PMID   8597271.
  27. ↑ Davies TF, Burch HB (September 2009). Ross DS, Martin KA (eds.). "Pathogenesis and clinical features of Graves' ophthalmopathy (orbitopathy)". UpToDate.
  28. ↑ Bartalena L, Marcocci C, Pinchera A (April 2002). "Graves' ophthalmopathy: a preventable disease?". European Journal of Endocrinology. 146 (4): 457–461. doi: 10.1530/eje.0.1460457 . PMID   11916611.
  29. ↑ Robert James Graves at Who Named It?

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