Graves’ ophthalmopathy, also known as thyroid eye disease (TED), is an
autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction,
lid lag Lid lag is the static situation in which the upper eyelid is higher than normal with the globe in downgaze. It is most often a sign of thyroid eye disease
Graves’ ophthalmopathy, also known as thyroid eye disease (TED), is an autoimmune infla ...
,
swelling, redness (
erythema
Erythema (from the Greek , meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not asso ...
),
conjunctivitis
Conjunctivitis, also known as pink eye, is inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may occur. The ...
, and bulging eyes (
exophthalmos
Exophthalmos (also called exophthalmus, exophthalmia, proptosis, or exorbitism) is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral (as is often seen in Graves' disease) or unilateral (as is often seen in ...
).
It occurs most commonly in individuals with
Graves' disease, and less commonly in individuals with
Hashimoto's thyroiditis
Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. Early on, symptoms may not be noticed. Over time, the thyroid may enlarg ...
, or in those who are
euthyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
.
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
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
). 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
Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. As a result, nicotine withdrawal often m ...
if possible. Severe cases are a medical emergency, and are treated with
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every verteb ...
s (steroids), and sometimes
ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...
. Many anti-inflammatory biological mediators, such as
infliximab
Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...
,
etanercept
Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It ...
, and
anakinra
Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a recombinant and slightly modif ...
are being tried.
In January 2020, the US
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
approved
teprotumumab-trbw for the treatment of Graves’ ophthalmopathy.
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 Lid lag is the static situation in which the upper eyelid is higher than normal with the globe in downgaze. It is most often a sign of thyroid eye disease
Graves’ ophthalmopathy, also known as thyroid eye disease (TED), is an autoimmune infla ...
on infraduction (
Von Graefe's sign
Von Graefe's sign is the lagging of the upper eyelid on downward rotation of the eye, indicating exophthalmic goiter (Graves' disease).Cline D; Hofstetter HW; Griffin JR. ''Dictionary of Visual Science''. 4th ed. Butterworth-Heinemann, Boston 199 ...
), eye globe lag on supraduction (
Kocher's sign Kocher's sign is a medical sign that denotes an eyelid phenomenon in hyperthyroidism
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occur ...
), a widened
palpebral fissure
The palpebral fissure is the elliptic space between the medial and lateral canthi of the two open eyelids. In simple terms, it is the opening between the eyelids. In adult humans, this measures about 10 mm vertically and 30 mm horizontally.
Va ...
during fixation (
Dalrymple's sign Dalrymple's sign is a widened palpebral (eyelid) opening, or eyelid spasm, seen in thyrotoxicosis (as seen in Graves' disease, exophthalmic goitre and other hyperthyroid conditions), causing abnormal wideness of the palpebral fissure. As a resul ...
) and an incapacity of closing the eyelids completely (
lagophthalmos
Lagophthalmos is the inability to close the eyelids completely. Cline D; Hofstetter HW; Griffin JR. ''Dictionary of Visual Science''. 4th ed. Butterworth-Heinemann, Boston 1997.
Blinking covers the eye with a thin layer of tear fluid, thereby p ...
,
Stellwag's sign
Stellwag's sign is a sign of infrequent or incomplete blinking associated with exophthalmos or Graves orbitopathy. It is accompanied by Dalrymple's sign, which is a retraction of the upper eyelids resulting in an apparent widening of the palpebra ...
). Due to the
proptosis
Exophthalmos (also called exophthalmus, exophthalmia, proptosis, or exorbitism) is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral (as is often seen in Graves' disease) or unilateral (as is often seen i ...
, eyelid retraction and lagophthalmos, the cornea is more prone to dryness and may present with
chemosis
Chemosis is the swelling (or edema) of the conjunctiva. The term derives from the Greek ''chem-'' meaning chemical and ''-osis'' meaning denoting action. A chemical reaction, or in this case, a chemical reaction of the conjunctiva which is du ...
,
punctate epithelial erosions
Punctate epithelial erosions are a pathology affecting the cornea.
Signs and symptoms
It is a characterized by a breakdown or damage of the epithelium of the cornea in a pinpoint pattern, which can be seen with examination with a slit-lamp. ...
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 symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
s with these pathologies include irritation, grittiness,
photophobia
Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of ...
, 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 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
The inferior rectus muscle is a muscle in the orbit near the eye. It is one of the four recti muscles in the group of extraocular muscles. It originates from the common tendinous ring, and inserts into the anteroinferior surface of the eye. It ...
is the most commonly affected muscle and patient may experience vertical
diplopia
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 v ...
on upgaze and limitation of elevation of the eyes due to
fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
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
Exophthalmos (also called exophthalmus, exophthalmia, proptosis, or exorbitism) is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral (as is often seen in Graves' disease) or unilateral (as is often seen in ...
, 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
The visual field is the "spatial array of visual sensations available to observation in introspectionist psychological experiments". Or simply, visual field can be defined as the entire area that can be seen when an eye is fixed straight at a point ...
defect,
afferent pupillary defect, and loss of color vision. This is an emergency and requires immediate surgery to prevent permanent blindness.
Pathophysiology
![Graves Ophthalmopathy MRT 01](https://upload.wikimedia.org/wikipedia/commons/8/8d/Graves_Ophthalmopathy_MRT_01.jpg)
TAO is an orbital
autoimmune disease. The
thyroid-stimulating hormone
Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism ...
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
(TSH-R) is an
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
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
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...
. The inflammation results in a deposition of
collagen and
glycosaminoglycans in the muscles, which leads to subsequent enlargement and
fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
. There is also an induction of the
lipogenesis
In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride syn ...
by
fibroblasts
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...
and
preadipocytes
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. ...
, 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
Exophthalmos (also called exophthalmus, exophthalmia, proptosis, or exorbitism) is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral (as is often seen in Graves' disease) or unilateral (as is often seen i ...
, 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 (anti-thyroglobulin, anti-microsomal and anti-thyrotropin receptor) and abnormalities in
thyroid hormones
File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4
rect 376 268 820 433 Thyroid-stimulating hormone
rect 411 200 849 266 Thyrotropin-releasing hormone
rect 297 168 502 200 Hypothalamus
rect 66 216 386 25 ...
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
Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies fr ...
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
A tendon or sinew is a tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone. It is able to transmit the mechanical forces of muscle contraction to the skeletal system without sacrificing its ability ...
sparing, usually bilateral, and proptosis.
Classification
Mnemonic: "NO SPECS":
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.
[
]
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. There is tentative evidence for selenium
Selenium is a chemical element with the symbol Se and atomic number 34. It is a nonmetal (more rarely considered a metalloid) with properties that are intermediate between the elements above and below in the periodic table, sulfur and tellurium, ...
in mild disease. 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.
In January 2020, the US Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
approved teprotumumab-trbw for the treatment of Graves' ophthalmopathy.
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. However, a 2015 meta review found no such benefits, and there is some evidence that suggests that surgery is no better than medication.
Surgery may be done to decompress the orbit, to improve the proptosis, and to address the strabismus
Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...
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.
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
Myotomy is a List of surgical procedures, surgical procedure in which muscle is cut. A common example of a myotomy is the Heller myotomy.
See also
* List of surgeries by type References
Surgical procedures and techniques
{{Treatmen ...
of levator palpebrae
The levator palpebrae superioris ( la, elevating muscle of upper eyelid) is the muscle in the orbit that elevates the upper eyelid.
Structure
The levator palpebrae superioris originates from inferior surface of the lesser wing of the sphenoid bon ...
muscle can reduce the palpebral fissure
The palpebral fissure is the elliptic space between the medial and lateral canthi of the two open eyelids. In simple terms, it is the opening between the eyelids. In adult humans, this measures about 10 mm vertically and 30 mm horizontally.
Va ...
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
The canthus (pl. canthi, palpebral commissures) is either corner of the eye where the upper and lower eyelids meet. More specifically, the inner and outer canthi are, respectively, the medial and lateral ends/angles of the palpebral fissure.
Th ...
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
Blepharoplasty (Greek: ''blepharon'', "eyelid" + ''plassein'' "to form") is the plastic surgery operation for correcting defects, deformities, and disfigurations of the eyelids; and for aesthetically modifying the eye region of the face. With t ...
can also be done to debulk the excess fat in the lower eyelid.
A summary of treatment recommendations was published in 2015 by an Italian taskforce, which largely supports the other studies.
Prognosis
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
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
* Severe or uncontrolled hyperthyroidism
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 hyperthyroidis ...
* Presence of pretibial myxedema
Pretibial myxedema (myxoedema in British English, also known as Graves' dermopathy, thyroid dermopathy, Jadassohn-Dösseker disease or myxoedema tuberosum) is an infiltrative dermopathy, resulting as a rare complication of Graves' disease, with a ...
* High cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
levels (hyperlipidemia
Hyperlipidemia is abnormally elevated levels of any or all lipids (fats, cholesterol, or triglycerides) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also used as an umbre ...
)
* Peripheral vascular disease
Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular dise ...
Epidemiology
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
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
, while 3% had Hashimoto's thyroiditis
Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. Early on, symptoms may not be noticed. Over time, the thyroid may enlarg ...
, 1% were hypothyroid
Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...
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.
History
In medical literature, Robert James Graves
Robert James Graves, F.R.C.S. (27 March 1796 – 20 March 1853) was an eminent Irish surgeon after whom Graves' disease takes its name. He was President of the Royal College of Physicians of Ireland, Fellow of the Royal Society of London and t ...
, in 1835, was the first to describe the association of a thyroid goitre
A goitre, or goiter, is a swelling in the neck resulting from an enlarged thyroid gland. A goitre can be associated with a thyroid that is not functioning properly.
Worldwide, over 90% of goitre cases are caused by iodine deficiency. The term is ...
with exophthalmos
Exophthalmos (also called exophthalmus, exophthalmia, proptosis, or exorbitism) is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral (as is often seen in Graves' disease) or unilateral (as is often seen in ...
(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.
See also
* Infiltrative ophthalmopathy
* Exophthalmos
Exophthalmos (also called exophthalmus, exophthalmia, proptosis, or exorbitism) is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral (as is often seen in Graves' disease) or unilateral (as is often seen in ...
References
Further reading
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External links
{{Authority control
Thyroid disease
Eye diseases
Autoimmune diseases
Thyroid