Thyroid Eye Disease

It is also known as Graves' ophthalmopathy, ophthalmic Graves' disease, thyroid associated ophthalmopathy, Basedow's disease (in German speaking parts) and TED.

The pathogenesis of the disease is poorly understood and there are no adequate animal models. Thyrotoxicosis results from an IgG autoantibody called LATS (long acting thyroid stimulant) that attaches to the TSH receptors on the thyroid gland with a more prologed and potent effect than TSH and without the negative feedback. There is a postulated exophthalmos producing factor (EPS) but it has not been identified. TSH receptors have been found in the eye and affected skin. Antibodies, cell mediated immunity and cytokines are thought to be involved.

• Graves' disease or thyrotoxicosis, has a prevalence of between 1 and 2.7%.¹
• The ophthalmic complication affects between 25 and 50% of those with the disease.
• There is a female preponderance of 5:1 but this reflects the higher incidence of thyrotoxicosis in women.
• For those with Graves' disease, there is an equal risk between the sexes of developing ophthalmic complications.
• The eye disease can be more severe in men over the age of 60.
• Extrapolation of these figures gives an estimated 400,000 cases in the UK.
• The usual age of onset is between 30 and 50.

Smoking is an important risk factor.² The risk increases with number of cigarettes smoked and reduces on quitting.³ Smoking also increases the risk of ophthalmopathy after radioiodine but this can be reduced by corticosteroids.³ It also reduces the efficacy of the usual methods of treatment such as steroids and radiotherapy.⁴

Symptoms and signs may be in addition to those of thyrotoxicosis.

Symptoms

The symptoms will be a reflection of the intensity of the inflammatory reaction and the severity of the anatomical, functional and cosmetic aspects.

• Eye pain or discomfort behind the eye, which may feel gritty.
• There may be photophobia.
• Diplopia can result from restricted ocular mobility, initially involving the inferior rectus muscles.

Signs

• Lid retraction or lid lag, allows the sclera to be seen above the cornea.
• There is also soft tissue inflammation with forward displacement of the eye (proptosis) and myopathy of the extraocular muscles.
• Active disease is associated with conjunctival injection and oedema and lid oedema.
• There is inability to close the lids properly. This may cause sight-threatening exposure keratopathy.
• There may be an early increase in intraocular pressure.
• Proptosis may stretch the optic nerve and this may be made worse by steroids. The optic disc often appears normal but may be atrophic in long-standing cases with irreversible loss of vision.

As disease activity rather than duration of disease is the prime determinant of the outcome of treatment, a clinical assessment score has been developed.⁵ The presence of each of the following scores one of a possible 10.

Extraorbital Features

Dermatological features may appear including inflammatory skin reactions called thyroid associated dermopathy. The commonest site for this is the pretibial region when it is called pretibial myxoedema but it can occur on sites of skin trauma.

Thyroid acropathy may also be seen. Clinically it is like clubbing of the nails.

Thyroid eye disease is bilateral whereas proptosis from such important pathology as a retro-orbital tumour, is usually unilateral. It is usually associated with thyroid disease but occasionally it may precede it.

Lid lag is a common feature of thyrotoxicosis and is not the same as exophthalmos. It is due to excessive sympathetic activity causing retraction of the elevator of the eyelids. To demonstrate it, stand to the side of the patient at eye level and hold her head so that she has to move her eyes rather than her head to change her gaze. Holding her head with one hand, ask her to follow your index finger on the other. Move it up and then down. As it descends, a rim of white sclera is seen above the iris. There is no protrusion of the globe and this sign will disappear when the disease is treated.

• Thyroid stimulating hormone (TSH), and free thyroxine (FT4). If normal, free tri-iodothyronine.
• Antithyroid peroxidase, anti-thyroglobulin, and thyroid stimulating antibodies.
• CT or preferably MRI of orbits. MRI is better at showing soft tissue.
• Thyroid uptake scan or orbital biopsy are sometimes required.

This is almost invariably associated with thyrotoxicosis although it may not present until after the thyroid disease has been treated.

A committee of the American Thyroid Association made the following recommendation to grade severity with the acronym NOSPECS.⁷

Class 0 No signs or symptoms
Class 1 Only signs (eg lid retraction ±lid lag)
Class 2 Soft tissue involvement (conjunctival oedema, injection etc)
Class 3 Proptosis
Class 4 Extraocular muscle involvement (ie diplopia)
Class 5 Corneal involvement (primarily due to lid lag)
Class 6 Sight loss (optic nerve involvement).

Ideally, the condition should be managed in a joint endocrinology and ophthalmology clinic where there is much experience and expertise in the condition. Surgical treatment is not often needed but early referral is advised as medical treatment is most effective when the eye is acutely inflamed.

If the patient smokes, this must cease. As mentioned above, smoking aggravates the condition,² it reduces the effect of treatment³ and cessation has a beneficial effect.⁴

Most patients have a mild, self-limiting disease which only requires symptomatic treatment. Usual advice it to avoid dust, use optical lubricants and sleep propped up. Prismatic spectacles may be required for diplopia.

Between about 10 and 35% will need further treatment but trials of therapies need to have good controls⁸ as there is a strong tendency for natural remission and it is important to distinguish between the effects of intervention and natural history. The aim of treatment it to modulate the immune response. The usual technique is steroids at high dosages and orbital radiotherapy. Orbital decompression surgery can be used in the acute phase to treat compression of the optic nerve, and in the inactive phase to improve residual functional and cosmetic features. However, these treatments are currently inadequate. After treatment more than half the patients have diplopia, more than a third are dissatisfied with the appearance of their eyes, and more than a quarter have low visual acuity.

Steroids

There are not good RCTs for the use of steroids in the condition and as it is reported that between a third and two thirds of patients improve, it is uncertain if ethics committee approval would be obtained. The dose is usually started high and titrated down to the lowest effective dose. Steroid sparing may be achieved with drugs including cyclosporin, methotrexate and azathioprine possibly in combination.⁹ Steroids are a particular problem in diabetes.

New Drugs

Reducing the inflammation with anti-TNFα drugs such as enteracept is logical and promising¹⁰ but more good RCTs are required.

Orbital Radiotherapy

This is a controversial mode of treatment that has received much criticism recently. It seems that early trials were inadequately controlled and much apparent improvement was natural remission. More recent prospective, placebo controlled trials have shown little or no improvements after radiotherapy.^{11 12 13} The last of those trials also reported follow up. They found no benefit 3 years after treatment but there were adverse effects.¹⁴ They found microvascular abnormalities.¹⁵

Various reports of adverse events after radiotherapy include cataracts (12% incidence after a median of 11 years), radiation retinopathy (usually, but not always, as a result of incorrect radiation doses or targeting), and malignancy (calculated risk of 1.2%).¹ Radiotherapy is contraindicated in diabetic patients with pre-existing retinopathy.

Surgery

Surgery is indicated only for more severe disease under the following conditions:

• Sight is threatened and the disease is unresponsive to other treatments
• For functional and cosmetic reasons once the disease has "burnt out."

The usual procedure is an inferior orbital decompression. A defect is created in the floor and medial wall of the orbit, allowing some of the orbital contents to prolapse down into the maxillary sinus and reduce the tissue volume within the orbit. Although this improves proptosis, a need for eyelid surgery often arises at a later date, to improve appearance and function. It is used in about 5% of patients.

Surgery is sometimes required for strabismus but it is best delayed for 6 months, until the condition is stable.

Various "plastic surgery" procedures may be required to improve the coverage of the coverage of the lid over the eye to protect it.

Endoscopic orbital decompression is an effective and safe procedure that may have potential for the future.¹⁶

• Corneal exposure
• Strabismus
• Pressure on the optic nerve
• Poor cosmetic result.

In uncomplicated disease there is a benign natural course over about a year.

Robert Graves was an Irish physician who was born in 1797 and died in 1853. He delivered a series of lectures in 1834 that were published in 1835, in which he described patients with palpitations, enlarged thyroids, and in one, protruding eyes. "The eyeballs were visibly enlarged, to such a degree the eyelids were unable to shut during sleep and when trying to close the eye. When the eyes were open the white of the eyes could be seen in the breadth of several lines around all of cornea."

Karl von Basedow described the occurrence of exophthalmos through hypertrophy of the cellular tissue of the eyes in 1840. In the English language, it is usually referred to as Graves' disease.

Robert Graves travelled extensively and was a great linguist. He introduced the concept of bedside teaching and gave his lectures in English rather than Latin.