Post date: 
Tuesday, 17 May 2016
Thyroid eye disease
Thyroid eye disease

Radhika Holmström explains the clinical trials that could change the way we treat Thyroid Eye Disease.

Over the past seven years, thyroid eye disease (TED) or Graves’ Orbitopathy (thyroid disease is often known as Graves’ Disease) has finally started to get the attention it needs. The European Group On Graves’ Orbitopathy (EUGOGO) has led an international drive to improve the care of patients with TED, and 84 organisations co-signed the 1999 Amsterdam Declaration for people with TED, pledging to improve patient care. 

TED is in fact a surprisingly prevalent condition: specialists estimate that it affects up to 40 per cent of people with a malfunctioning thyroid, leaving 10 to 20 per cent of those people with some degree of vision damage which can be permanent. Around 2,500 new patients are now diagnosed in the UK every year: more commonly women, and people of white or Asian origin. However, there are probably other cases who are not diagnosed at all, and certainly many of the people who do get a diagnosis have had to wait some time, and/or received an earlier misdiagnosis of allergy or conjunctivitis.
The disease
The thyroid is a small gland at the front of the neck which produces different hormones. These mainly control growth in children, and controlling the metabolism (the rate at which the body’s chemistry works). When the control of the metabolism malfunctions this is usually the result of auto-immune disease, where the body’s immune system starts attacking its own tissues with auto-antibodies. 
TED is usually linked to an overactive thyroid (though some people with the condition have normal or low thyroid function). The auto-antibodies attacking the thyroid gland also attack the tissues around the eyes, which are very similar to those of the thyroid gland. It’s not known, at the moment, why this happens though some research has found specific problems in the immune system.
The effects on the eyes
The ‘active’ phase of TED usually lasts for two to three years. The most common first problem is dry eyes, because the tissues being attacked include the lachrymal gland, which produces tears. The eyes feel gritty and uncomfortable and at the same time, they can also water more than normal.  Then, as the tissues become further inflamed the eyes become red and inflamed.
As a result of the inflammation, the tissues of the eye expand and become congested. The lids swell up, and the muscles and fat around the eye swell as well, pushing the eyes forward to bulge out of their sockets. This is uncomfortable at best, or extremely painful at worst. In addition, the swelling that pushes the eyes forward also causes them to move at different rates, which can result in double vision (diplopia). Patients also develop fibrosis, which means that the eyelid muscles pull back or ‘retract’, so that they appear to have a constant stare - and this, combined with the swelling, can also make the dry eye symptoms worse. At its worst, the combination of eyes bulging forward and scarring from retracted lids can mean that the cornea ulcerates; or the pressure of thick, inflamed and/or scarred muscles can damage the optic nerve and this is particularly serious.  
In the ‘burnt-out’ phase, some people’s vision returns to pretty well normal. However, people whose eyes have been more severely affected may be left with scarring, staring prominent eyes, retracted lids and/or double vision.
Diagnosis and treatments
One major priority has been to get TED diagnosed as early as possible, so that patients can get the best treatment; and, following that, to directing people towards the most appropriate, specialist treatment. In the UK, the Thyroid Disease Amsterdam Declaration Implementation Group (TEAMeD) has made this a priority (and won a Judges’ Special Award in the Bayer Ophthalmology Honours 2015).   
TEAMed member Dr Anna Mitchell of Newcastle University is leading a team developing a clinical assessment tool called DiaGO (Diagnosis of Graves’ Orbitopathy) which is designed for use by health professionals who are not ophthalmologists. “It’s been developed using the expert consensus on signs and symptoms,” she explains. “The first section is a list of questions that patients can answer for themselves, either ‘yes’ or ‘no’. The second is an eye examination that can be performed by GPs, people working in endocrinology clinics, and so on. And having this tool also acts as a prompt for patients themselves to think about eye symptoms. If they wake up with double vision or gritty eyes, they may not realise this is connected to their thyroid disease.” DiaGO has already been tested in a small pilot study and is now about to be tested across more sites. “We’re investigating whether there are other, subtle signs that we should also be picking up,” says Mitchell. 
Once the diagnosis is made, there’s a range of treatments. During the active phase, the focus is on two things: retaining as much sight as possible, and protecting the cornea. The Royal College of Ophthalmologists advises ‘simple, low-cost interventions’ including selenium supplements and ‘meticulous attention to controlling the thyroid’; artificial tears and ointments for dry eyes also help, and some people use eye covers or tape to hold the eye shut at night if the retracted lid makes it difficult to close. If these are not enough, patients with vision problems may be given anti-inflammatory drugs or immuno-suppressants – or, in some cases, radiotherapy. These do not eliminate all the damage to the soft tissue but do make it significantly less severe. 
For some people, however, surgery is the only option if they still have damaged tissue - scarring, staring prominent eyes, retracted lids and/or double vision – in the burnt-out phase. Surgeons operate in the hope of restoring the position of the eyeball and the lid, and/or straightening up the muscles to correct double vision (or at least make it possible for the person to have single vision when they’re looking straight ahead). The most major treatment is orbital decompression surgery, to correct the position of the eyeball as well as any pressure on the optic nerve; this involves removing bone from the walls of the eye socket to create more room for the soft tissues, including the eyeball, to settle back.
Research and developments 
Moorfields consultant Jimmy Uddin is the primary investigator for the CIRTED trial, which has been investigating the use of radiotherapy and immuno-suppressants in treating TED. “Radiotherapy is controversial, as studies show differing results as to whether it’s effective or not,” he explains. “TED is effectively an orbital inflammatory disease, and as with a lot of inflammatory conditions there’s a cellular over-activity. The radiotherapy in our trial is aimed at targeting the over-active inflammatory cells just behind the eye, with the aim of driving the inflammation down.”
Uddin is also the president of the International Thyroid Eye Disease Society, and outlines some of the other research into tackling TED. “We are doing a number of studies into different drugs for treating moderate to severe disease, of which the most popular is rutiximab – a lymphoma drug also used for rheumatoid arthritis. Other work is looking at antibodies: addressing the immune system, but in a much more specific, targeted manner than steroids do.” 
Being seen
Uddin adds: “There have also been quite a lot of advances in surgery; we do minimally invasive surgery, which has phenomenally improved, and we are much more receptive to helping the patient look better.” This is crucially important because TED does not only affect the way people see: it affects the way they are seen. There has not been much research into this so far, but one investigation of psychosocial distress in a preliminary cohort of the CIRTED trial found that ‘patients with TED were significantly more affected than patients with facial burns, head and neck cancer and other maxillofacial conditions’. 
 “Many people are devastated by what TED does to their appearance; there are very high levels of anxiety, depression and social avoidance,” says Dan Ezra, another consultant at Moorfields. “We’ve always concentrated on getting the surgery right in terms of the vision, but we need to think about quality of life more broadly and develop psychological interventions too. A lot of research shows it’s not necessarily how you look that determines your quality of life, but the underlying psychological issues.”   
Further information
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