Graves' ophthalmopathy

Graves ophthalmopathy
Classification and external resources
ICD-10	H06.2*
ICD-9	xxx
DiseasesDB	5419
eMedicine	oph/237 ent/169 neuro/476 radio/485
MeSH	D049970

Graves' ophthalmopathy (also known as thyroid eye disease (TED), dysthyroid/thyroid-associated orbitopathy (TAO), Graves' orbitopathy) is an autoimmune inflammatory disorder affecting the orbit around the eye, characterized by upper eyelid retraction, swelling (edema), redness (erythema), conjunctivitis, and bulging eyes (proptosis).

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, and generally occurs with hyperthyroidism. The most common form of hyperthyroidism is Graves' disease. About 10% of cases do not have Graves' disease, but do have autoantibodies.

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.

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 glucocorticoid (steroids), and sometimes cyclosporine. Many autoimmune and anti-inflammatory biological mediators, such as infliximab, etanercept, and anakinra are being tried, but there are no randomized controlled trials demonstrating effectiveness.

History

In 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.

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, while 3% had Hashimoto's thyroiditis, 1% were hypothyroid 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.

Pathophysiology

TAO 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. 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.

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). 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.

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.

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.

Classification of Graves' eye disease

Mnemonic: "NO SPECS":

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)

Treatment

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 lubrication 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 may be done to decompress the orbit, to improve the proptosis and to address the strabismus causing diplopia. Surgery is performed once the patient’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. In some patients this is very pronounced. Orbitial decompression involves removing some bone from the eye socket to open up one or more sinus's 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 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.

Poor prognostic indicators

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

See also

• Infiltrative ophthalmopathy
• Exophthalmos

References

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• Boncoeur MP (2004). "[Dysthyroid orbitopathy: imaging]". Journal français d'ophtalmologie (in French). 27 (7): 815–8. doi:10.1016/S0181-5512(04)96221-3. PMID 15499283. CS1 maint: Unrecognized language (link)
• Boulos PR, Hardy I (2004). "Thyroid-associated orbitopathy: a clinicopathologic and therapeutic review". Current opinion in ophthalmology. 15 (5): 389–400. doi:10.1097/01.icu.0000139992.15463.1b. PMID 15625899. 
• Camezind P, Robert PY, Adenis JP (2004). "[Clinical signs of dysthyroid orbitopathy]". Journal français d'ophtalmologie (in French). 27 (7): 810–4. doi:10.1016/S0181-5512(04)96220-1. PMID 15499282. CS1 maint: Multiple names: authors list (link) CS1 maint: Unrecognized language (link)
• Duker, Jay S.; Yanoff, Myron (2004). "chapt 95". Ophthalmology (2nd ed.). Saint Louis: C.V. Mosby. ISBN 0-323-02907-8. CS1 maint: Multiple names: authors list (link)
• Martinuzzi, A, Sadun AA (1991). "Marginal myotomies of levator with lateral tarsal canthoplasty in the treatment of Graves' lid retraction". Ital J Ophth. 1: 23–29. CS1 maint: Multiple names: authors list (link)
• Morax S, Ben Ayed H (2004). "[Orbital decompression for dysthyroid orbitopathy: a review of techniques and indications]". Journal français d'ophtalmologie (in French). 27 (7): 828–44. PMID 15499287. CS1 maint: Unrecognized language (link)
• Rose JG, Burkat CN, Boxrud CA (2005). "Diagnosis and management of thyroid orbitopathy". Otolaryngol. Clin. North Am. 38 (5): 1043–74. doi:10.1016/j.otc.2005.03.015. PMID 16214573. CS1 maint: Multiple names: authors list (link)