REVIEW ARTICLE

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THYROID ASSOCIATED OPHTHALMOPATHY – A REVIEW

CLINICAL CLASSIFICATION OF DISEASE SEVERITY

There are several classifications available to grade the severity of thyroid ophthalmopathy. The symptoms and signs of TAO are often classified with the modified NO SPECS system.44 (Table 1).The CAS system (clinical activity score) is another system which was developed for the selection of therapy, especially for deciding whether or not immunosuppressive therapy should be instituted.45

Table 1. Abridged classification of eye changes of Graves’ disease

Class
Definition

0

No physical signs and symptoms

I

Only signs, no symptoms (signs limited to upper eyelid retraction, stare and lid lag)

II

Soft tissue involvement (signs and symptoms)

III

Proptosis (3 mm or more)

IV

Extraocular muscle involvement

V

Corneal involvement
VI
Sight loss (optic nerve involvement)

Adapted from Werner44

DIAGNOSIS

The diagnosis of TAO is clinical and is based on the triad of characteristic eye findings, thyroid dysfunction, and imaging studies.46  In majority of cases, ophthalmopathy occurs in association with hyperthyroidism. TAO is also said to occur in 5% of patients with Hashimoto’s thyroiditis. However in 5% to 10% of cases, ophthalmopathy occurs in the absence of thyroid disease (euthyroid disease). This could be due to lack of TSH control of thyroid function in patients with ophthalmic Graves’ disease. Even in patients without overt thyroid disease further tests like triiodothyronine (T3) suppression test, anti-thyroid antibodies abnormal thyroid-releasing hormone stimulation test and TSH antibody tests will demonstrate abnormalities in about 30% of patients.47,48 Patients with a euthyroid disease can even become hyper or hypothyroid after sometime. All these findings suggest that thyroid associated ophthalmopathy is heterogeneous either due to different phase of presentation or different pathogenesis in different patients.46

The most characteristic findings in TAO are enlargement of the extra ocular muscles, without involvement of their tendons. Ultrasound B-scan of the eye, CT-scan orbit and MRI can be used to show thickened muscles, however CT scan is currently the imaging study of choice. MRI is sensitive for showing compression of the optic nerve.

DIFFERENTIAL DIAGNOSIS

The clinical features of thyroid associated ophthalmopathy are usually identified easily if it is bilateral and associated with hyperthyroidism, however in patients with euthyroid disease and unilateral it is essential to rule out other causes of lid retraction and proptosis. The differential diagnosis of proptosis include vascular conditions like cavernous haemangioma, orbital varices, lymphomas, inflammatory conditions which may be pseudotumour, orbital cellulitis, sarcoidosis, primary orbital tumours like lacrimal gland tumour and metastatic tumours. The other causes of lid retraction include aberrant regeneration of third nerve, Parinaud’s syndrome and use of sympathomimetic drugs.49

TREATMENT OF GRAVES’ OPHTHALMOPATHY

The hyperthyroidism and the eye disease should be treated independently. Most of the mild to moderate TAO cases shows improvement with treatment of the underlying hyperthyroidism. The decision to treat TAO depends on the severity and the activity of the disease. The principal goals of therapy for TAO include pain relief, protection of vision and cosmetic improvement. The major therapeutic options include corticosteroids, radiotherapy and surgical intervention. TAO is categorized as severe and non-severe for treatment purposes. Severe disease can be either active or inactive. Features of severe ophthalmopathy are marked proptosis, diplopia in primary gaze or reading, exposure keratopathy, corneal ulceration or perforation and compressive optic neuropathy. Treatment options for severe, active cases include either medical decompression (steroids or radiotherapy) or surgical decompression. Majority of them prefer high doses of steroids first and surgical decompression if it fails. For severe, inactive disease, surgical decompression is the only option. Management options for non-severe cases are mainly supportive and are shown in Table 2. Lid retraction in TAO is caused by sympathetic stimulation of the Muller’s muscle. Guanethidine or β-blocker eye drops has been tried for the treatment of lid retraction with varying degree of success. In patients with severe ophthalmopathy, if the disease is active the treatment is medical decompression by either steroids or radiotherapy and if the TAO is inactive orbital decompression and rehabilitative surgery is the choice.

Table 2 : Treatment of non-severe TAO

Signs / Symptoms
Management Options

Peri-orbital oedema

Elevation head of the bed, anti-diuretics

Dryness, foreign body sensation

Artificial eye drops and ointment

Lagophthalmos

Nocturnal eye taping, eyes shield

Eyelid retraction

Topical Guanethidine or β-blockers eye drops

Diplopia

Prisms

Photophobia

Sunglasses

Glucocorticoids

Corticosteroids therapy is the mainstay and is effective against active disease, soft tissue inflammatory changes and optic neuropathy.50 It has no much role to play in long-standing and inactive disease (fibrotic stage). Favourable response rate ranges from 63% -73%. The beneficial effects of steroids are due to its anti-inflammatory, immunosuppressive.51 and ability to reduce gycoaminoglycans synthesis.52 Corticosteroid can be administered orally, locally (subconjunctival or retrobulbar) and intravenously. Intravenous steroids given by weekly pulse doses have a favourable response than daily oral steroids. Intravenous steroids have higher tolerability and success rates.53 Retrobulbar steroids are not preferred as it is associated with pain and increase in the intraocular pressure. Intravenous methylprednisolone 0.5 to 1 g every other day for 3 cycles is associated with much higher tolerability. The dose of oral steroids is 60-100 mg (7-14 days) and dose reduction over several months. The disadvantages of steroids are the frequency and severity of side-effects like Cushingoid features, glucose intolerance, gastritis, hypertension, hepatitis, depression and fatty liver.54 Recurrences after cessation or withdrawal of steroids are common.

Orbital radiotherapy

It is effective in for congestive signs, optic neuropathy and extraocular muscle involvement, not very effective against proptosis, eyelid retraction. It has a non-specific anti-inflammatory effect, and reduces the synthesis of glycoaminoglycans. Orbital lymphocytes are highly radiosensitive.55 The standard dose is 20 Gy per eye fractionated in ten daily doses for 2 weeks or 1 Gy per week for 20 weeks.56,57 Favourable responses are seen in 60% of cases. Radiotherapy is associated with increased inflammation causing temporary exacerbation of the ocular signs. This can be lessened by concomitant administration of steroids. Radiotherapy combined with intravenous steroids is more effective than other modalities of treatment.58 Cataract formation, radiation retinopathy, radiation induced optic neuropathy and carcinogenesis are some of the possible risks of radiation of the orbit. Young patients and patients with diabetic retinopathy are contraindications for radiotherapy.

Orbital decompression

It is also known as surgical decompression and involves removal of bony walls of the orbit to increase the orbital space to accommodate the orbital contents. The main indications are optic neuropathy, proptosis, severe orbital inflammation, corneal ulceration and cosmetic improvement. The orbit consists of four walls and in orbital decompression one to four walls can be removed depending on the clinical severity. There are several approaches for doing the decompression procedure. Transantral approach is the most preferred approach for most patients with optic neuropathy. Another approach, the transorbital can be used alone or in combination with transantral approach.59 Decompression can be done by either surgical techniques or endoscopically. The complications of surgical decompression are sensory disturbances, sinusitis, oroantral fistula, facial neuralgia, vision loss and diplopia.

Rehabilitative surgery

It is usually done when the TAO is stable and inactive for at least 4-6 months. It is usually done in the following order strabismus surgery, lid-lengthening surgery and blepharoplasty. Strabismus surgery is done to minimize diplopia in primary and reading positions. Lid-lengthening surgeries decreases corneal exposure and blepharoplasty is done to reduce the excess skin and soft tissue.

Other treatment modalities

Somatostatin analogues

Octreotide and lanreotide are synthetic somatostatin analogues which have shown to be beneficial in patients with TAO.60 TAO patients with somatostatin-receptor-bearing cells can be identified by orbital scintigraphy and can be subjected to treatment with the somatostatin analogues.

Immunosupressive agents

Cyclosporin, cyclophosphamide, azathioprine and ciamexone have been tried for the management of TAO due to its auto-immune nature. The results are varying with no clear conclusive evidence for their role. Cyclosporine along with glucocorticoids was found to be effective in patients with either persistent disease or steroid resistance.61

Intravenous immunoglobulins

Immumoglobulins have better side-effect profile than steroids. It has a beneficial role to play in many autoimmune disorders including TAO, due to its effect on autoantibodies, complement and phagocytes.62

Plasmapheresis

It has shown beneficial effect in patients with severe disease, especially severe progressive ophthalmopathy.

PREVENTION

Refraining from smoking plays a very vital role in primary, secondary and also tertiary prevention of TAO. Smoking influences almost all stages of thyroid eye disease. Stopping smoking prevents Graves’ ophthalmopathy (primary prevention).63 In patients who already have TAO, the chances of remission is much less in patients who quit smoking (secondary prevention) and the outcome of immunosuppressive treatment is beneficial in non-smokers than smokers63 (tertiary prevention).

CONCLUSION

Thyroid eye disease even in its mildest form affects the quality of life of the individual considerably. All the currently available treatment modalities for TAO are associated with serious side-effects and complications. Identification of the risk factors and its elimination can help to modify the disease outcome. As smoking is one of the strongest risk factor found to be associated with TAO, refraining from smoking can help to reduce the magnitude of this problem both in developed and developing countries.

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