Referral, Assessment and Treatment of Thyroid Eye Disease (TED)

• Summary of Guideline
• Aims
• Background
• Diagnosis
• Investigations
• Treatment and Management

Summary of Guideline

Please ensure that you include a summary which may include the following:

Patients with all but the mildest of thyroid eye (TED) disease benefit from being managed in a joint endocrine/eye clinic.

Patients can present with a variety of symptoms and signs ranging from swelling of the soft tissues around the eyes to ocular surface discomfort, diplopia and orbital pain.

The degree of activity of a patient’s thyroid eye disease is determined by the clinical activity score (CAS). Patients scoring 3 or above are generally deemed to be active. The severity of the eye disease can then be classified on the basis of lid retraction, exophthalmos, soft tissue signs around the eye, corneal involvement and diplopia. Rarely patients may be at risk of sight loss, principally from dysthyroid optic neuropathy or corneal exposure.

Treatment and management of the disease is aimed at controlling the active inflammatory phase before dealing with the long term sequelae of the disease such as lid malposition and strabismus. Steroids form the mainstay of treatment of the active inflammatory component although radiotherapy and surgery may be useful adjuncts. Novel therapies including anti TNFα and monoclonal antibody agents remain promising but lack a proven evidence base at present. 

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Aims

To improve the diagnosis and management of Thyroid Eye Disease (TED)

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Background

Glossary of terms

TED: Thyroid eye disease
DON: Dysthyroid optic neuropathy
GO: Graves ophthalmopathy/orbitopathy
PPI: Proton pump inhibitor
CAS: Clinical activity score

Thyroid-eye disease, or dysthyroid-associated orbitopathy is a disease of the eyes and surrounding soft tissues.
It is an autoimmune inflammatory disorder affecting the tissues within the eye socket, characterised by pain, swelling, redness, watering, retraction of the upper eyelids, conjunctivitis, bulging eyes, double vision and, in rare circumstances, decreased vision.

Thyroid-eye disease may occur before or after the onset of overt thyroid disease, and can start suddenly or more slowly. The yearly incidence is 16/100,000 in women, 3/100,000 in men, and the disease is more frequent in smokers.

Although patients may undergo spontaneous remission of symptoms within a year, many still need treatment. The first step of treatment aims to regulate thyroid hormone levels and a block and replace regime is often used for this. It is imperative that patients cease smoking. Topical treatments such as lubricating eye drops can be used to alleviate symptoms in very mild disease.

In more active disease, signs or symptoms increase. In most cases steroids are effective but are used conservatively because of their side effects. In severe cases the vision may be threatened due to optic nerve compression or corneal ulceration related to lagophthalmos and exposure. About 3-5 % of patients have severe disease which may need treatment urgently with high dose intravenous steroids and/or surgery for refractory cases.

Management of the active stage of the disease may take several years. Following this, patients may be left with numerous sequelae including double vision, protruding eyes, eye bags and lid retraction. Many of these aspects of the patient’s appearance are amenable to surgery but this is undertaken in a step-wise process and again may take a long time to complete.

Thyroid-eye disease is a rare but treatable disease that causes a significant decrease in quality of life. In all but the very mildest of cases patients benefit from a multi-disciplinary approach and should be managed in specialised clinics with endocrine, ophthalmic and orthoptic expertise. It is hoped that this document will improve the referral of patients into our joint clinics so that patient’s treatment and outcomes can be optimised and unnecessary follow-up minimised.

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Diagnosis

Establishing a diagnosis and assessing the activity of thyroid eye disease

Patients with thyroid eye disease may present with any number of the signs and symptoms outlined below:

• Redness of the eyelids and conjunctivae
• Swelling of the lids
• Swelling of the conjunctivae (chemosis)
• Swelling of the carruncle (the fleshy lump of tissue at the nasal aspect of the eyelids)
• Lid retraction and scleral show
• Signs of corneal exposure
• Puffy eyelids

• Eye pain at rest

• Pain on eye movements

• Double vision

• Itchy / Burning / Stinging eyes

Other conditions that may present in a similar fashion should form part of your differential diagnosis:

• Allergic Conjunctivitis
• Myasthenia Gravis
• Orbital mass
• Orbital Pseudotumour
• Carotico-cavernous fistula
• Orbital Myositis

Once a diagnosis of thyroid-eye disease has been established then a rational approach to treatment should be pursued. The first stage is to establish the degree of inflammatory activity using the clinical activity score outlined below:

Components of the clinical activity score

• Spontaneous retrobulbar pain
• Pain with eye movement
• Redness of the eyelids
• Redness of the conjunctiva
• Swelling of the eyelids
• Swelling of the caruncle
• Conjunctival oedema (chemosis)

A score is given out of 7 with each component scoring 1 point

The severity of disease can then be assessed using the following algorithm:

Adapted from

www.eugogo.eu

Bartalena 2009, NEJM; 360: 994

When to refer to the joint thyroid eye clinic

You should consider referral of patients suffering with thyroid-eye disease to the joint thyroid eye clinic in the following circumstances.

Urgent Referral:

• Sudden proptosis
• Impaired colour vision
• Decreased acuity
• Lids fail to close (lagophthalmos)
• Corneal ulceration
• Optic disc abnormalities

Routine Referral:

• Progressive proptosis
• Diplopia
• Ocular Pain
• Gritty sensation
• Limitation of eye movements
• Abnormal head posture
• Eyelid swelling and redness
• Conjunctiva swelling and redness

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Investigations

• MRI can be requested in cases of unilateral signs and symptoms to rule out other orbital pathology but is otherwise not routinely indicated
• Thyroid antibodies are not required unless a diagnosis of Graves’ disease is unclear.

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Treatment and Management

If you are uncertain of the diagnosis and concerned that a patient has active thyroid eye disease then referral to the joint clinic for a confirmatory opinion may be undertaken.

Management of mild disease (local measures that can be implemented by non-specialists)

• Preservative free topical lubricants and artificial tears
• Systemic Diuretics (Bendroflumethiazide is most commonly used)

Management of moderate to severe disease (should only be implemented in specialist clinics ie: Oculoplastics / Orbital clinic or Joint TED clinic

•Topical steroids are rarely used (mild disease)

•Intravenous methyl prednisolone is preferable to high dose oral steroid. Most commonly used regimen:

–Methyl-prednisolone 500 mg weekly for 6 weeks then 250 weekly for 6 weeks (4.5 g, total dose not exceeding 6.5 g). Lower dose IVMP can be used with mycophenolate.

–Blood tests at baseline, then weeks 1, 2, 4, 6, 8 and 12:

•FBC, LFTs, U&Es, Glucose

•In general a PPI is required for gastric protection, and bone protection will be needed for anyone on steroids for more than 3 months

Alternative options to high dose IV steroids:

Radiotherapy (only to be implemented in specialist clinics as described above)

•Around two third of patients respond to10-20 Gy in divided doses over 2-20 weeks)
•Efficacy is increased by combining with steroids (oral or IV)
•Radiotherapy should not be considered in the following circumstances:

–Below the age of 40 years in LTHT

–Diabetes Mellitus – diabetes remains a relative contraindication to radiotherapy and if radiotherapy is to be considered then diabetic retinopathy must be absent)

–Uncontrolled hypertension

•Radiotherapy is given as a single treatment if required for TED and cannot be repeated)

Surgical Intervention (only to be implanted in specialist clinics)

• Urgent orbital decompression is reserved for sight threatening active disease with dysthroid optic neuropathy or corneal exposure which has proved refractory to high dose steroid treatment
• Elective surgery is implemented to deal with the sequelae of thyroid eye disease once the active inflammatory phase has passed. A rational approach to this involves surgery in the following order:

1. Orbital decompression surgery
2. Squint Surgery
3. Lid Surgery

Marcocci JCEM 2001, 86: 3562
Kahaly JCEM 2005, 90:5234
Bartalena NEJM 2009, 360:994

Systemic Immune Suppressants as steroid sparing agents and Biologics (to be implemented by specialist clinics only)

•Ciclosporin

–Is less effective than oral steroids when used as a single agent
–Can helps to reduce the overall steroid dose required for disease control (a steroid sparing agent)
–Use of Ciclosporin requires the following to be monitored:

•Baseline: BP, U&Es, LFTs, glucose, lipids, HbA1c
•U&Es, LFTs (2 weekly at initiation and following dose adjustment)
•Lipid profile and glucose should be monitored with long-term use

•Azathioprin
–Limited efficacy
–Monitor FBC, LFTs

•Rituximab
–Anti-CD20 monoclonal Ab resulting in inhibition of B cell activation and differentiation
–Has been used in sporadic cases of TED with some success (no RCT to date)

•Etanercept
–Anti-TNFa
–Has been used in sporadic TED cases (no RCT to date)

Bonara, Clin Rev Allerg Immunol 2008, 34:118

Paridaens, Eye 2005, 19:1286

• Teprotumamab (FDA approved) IGF-1R antagonist/blocker is a new agent not available in UK except on trial basis. Can reverse proptosis.

Douglas, RS. Teprotumamab, an insulin growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye diseas: a focus on proptosis. Eye 2019; 33(2): 183-190.

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