Graves ophthalmopathy
Synonyms and keywords: Thyroid eye disease (TED); Dysthyroid/Thyroid-associated orbitopathy (TAO); Graves' orbitopathy

# Overview
Graves ophthalmopathy, also known by any of the combinations of Graves~/thyroid~/thyroid-associated~/dysthyroid~ with ~ophthalmopathy/~orbitopathy/~exophthalmos, is an autoimmune inflammatory disorder affecting the orbit, with or without thyroid disorder.

# Historical Perspective
The first case of thyroid-associated ophthalmopathy (TAO) may have been in the sixth century, affecting Bodhidharma, who was the founder of Zen Buddhism and Kung Fu.   In the medical literature, Robert James Graves, in 1835, was the first to describe the association of a thyroid goitre with exophthalmos 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.

# Classification

# Pathophysiology
TAO is an orbital autoimmune disease.  The thyroid stimulating hormone receptor (TSH-R) is an antigen found in orbital fat & connective tissue, and is a target for autoimmune assault.  However, some patients with Graves orbitopathy present with neither anti-microsomal, anti-thyroglobulin nor anti-TSH receptor, 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 orbital volume enlargement due to fat deposition.

# Causes

# Differentiating Graves Ophthalmopathy from other Diseases

# Epidemiology and Demographics
The pathology mostly affects persons of 30-50 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.

# Risk Factors
Risk factors of progressive and severe thyroid-associated orbitopathy are:
- Male gender
- Age greater than 50 years
- Rapid onset of symptoms under 3 months
- Cigarette smoking
- Diabetes
- Severe or uncontrolled hyperthyroidism
- Presence of pretibial myxedema
- High cholesterol levels (hyperlipidemia)
- Peripheral vascular disease

# Natural History, Complications and Prognosis

# Diagnosis

## Diagnostic Criteria
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.

## 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 (Von Graefe's sign),a widened palpebral fissure  during fixation (Dalrymples 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.
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 which 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.

## Physical Examination

## Laboratory Findings

## Imaging Findings

## Other Diagnostic Studies

# Treatment

## Medical Therapy
Even though some patients undergo spontaneous remission of symptoms within a year, many need treatment.  The first step is the regulation of thyroid hormones levels by an endocrinologist.
Topical lubrification 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.  Unfortunately, there is still controversy surrounding its efficacy.
A simple way of reducing inflammation is smoking cessation, as pro-inflammatory substances are found in cigarettes.

## Surgery
Surgery may be done to decompress the orbit, to improve the proptosis and to address the strabismus causing diplopia.  Surgery is performed once the patients disease has been stable for at least six months.  In severe cases, however, the surgery becomes urgent to prevent blindness from optic nerve compression.
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 patients 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 mullerectomy (resection of muller 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.

## Prevention