Graves' Orbitopathy
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Graves’ orbitopathy is also known as thyroid-associated orbitopathy or dysthyroid orbitopathy. It is an autoimmune inflammatory disorder affecting the orbit, with or without thyroid disorder. The first case of thyroid-associated orbitopathy may have been in the sixth century, affecting Bodhidharma, who was the founder of Zen Buddhism and Kung Fu. In the medical literature, Graves, in 1835, was the first to describe the pathology. Graves’ orbitopathy may precede, coincide, or follow the systemic complications of dysthyroidism. The onset is typically insidious with a gradual progression over months.
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[edit] Epidemiology
The pathology mostly affects persons of 30-50 years of age. Females are four times more likely to develop Graves’ orbitopathy than males. When males are affected, they tend to have a later onset and a poor prognosis. A study (Bartley, 1996) 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.
[edit] Pathophysiology
Graves’ orbitopathy 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.
[edit] 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 (Von Graefe'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.
[edit] Diagnostic
Graves’ orbitopathy 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’ orbitopathy 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.
[edit] 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 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 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.
Eyelid surgery is the most common surgery performed on Graves' orbitopathy 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 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.
[edit] 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
[edit] References
Rose JG Jr, Burkat CN, Boxrud CA, Diagnosis and management of thyroid orbitopathy. Otolaryngol Clin North Am. 2005 Oct;38(5):1043-74. Review.
Boulos PR, Hardy I, Thyroid-associated orbitopathy: a clinicopathologic and therapeutic review. Curr Opin Ophthalmol. 2004 Oct;15(5):389-400. Review
Behbehani R, Sergott RC, Savino PJ. Orbital radiotherapy for thyroid-related orbitopathy. Curr Opin Ophthalmol. 2004 Dec;15(6):479-82. Review.
Morax S, Ben Ayed H, Orbital decompression for dysthyroid orbitopathy: a review of techniques and indications J Fr Ophtalmol. 2004 Sep;27(7):828-44. Review. French.
Boncoeur MP, Dysthyroid orbitopathy: imaging J Fr Ophtalmol. 2004 Sep;27(7):815-8. Review. French.
Camezind P, Robert PY, Adenis JP. Clinical signs of dysthyroid orbitopathy, J Fr Ophtalmol. 2004 Sep;27(7):810-4. Review. French.
Ing E, Bednarczuk T., Thyroid ophthalmopathy, http://www.emedicine.com/NEURO/topic476.htm
Yanoff M, Duker JS, Ophthalmology 2e Edition, (C.V. Mosby 2004),chapt 95
Bartley G, Fatourechi V, Kadrmas E, Clinical features of Graves’ ophthalmopathy in an incidence cohort. Am J Ophthalmol 1996; 121: 284-90.
Martinuzzi, A, Sadun AA, Marginal myotomies of levator with lateral tarsal canthoplasty in the treatment of Graves' lid retraction, Ital J Ophth, 1991; V/1: 23-29
