Introduction

Thyroid Eye Disease (TED) is an autoimmune disease characterised by extraocular muscle swelling and orbital fat expansion¹.  It affects approximately 50,000 people in the UK, most commonly occurring in those diagnosed with Graves’ disease, although a minority of cases do affect euthyroid or hypothyroid patients^1,2.  

Symptoms may include lid retraction, proptosis, watery eyes and double vision³.

In addition to visual impairment, TED can significantly impact patients’ quality of life through psychological distress associated with reduced self-image and social wellbeing⁴.

In severe cases, it can lead to sight-threatening complications such as exposure keratopathy or optic nerve compression⁵.

Assessing the severity of symptoms, the presence of visual complications and ensuring timely referral to ophthalmology is therefore important.

Pathophysiology

TED has an initial active inflammatory phase, which may last up to 2 years, followed by an inactive fibrotic phase, where the disease is considered ‘burnt out’.

The orbital inflammation is thought to be mediated by Anti-Thyroid Stimulating Hormone Receptor (anti-TSHr) antibodies. These bind to TSHr expressed on orbital fibroblasts, which in turn secrete hydrophilic glycosaminoglycans and differentiate into myofibroblasts. There is resultant oedema and remodelling of extra-ocular muscle and fat tissue. This process is further propagated through T-cell mediated release of cytokines such as TNF-alpha^5,6.

Risk Factors

• Females are more likely to develop TED
• Smoking  increases risk of developing TED and worsens disease severity Smoking cessation could improve prognosis through reducing disease severity and improving treatment response.
• Abnormal thyroid function
• Older age
• Radioiodine used to treat Graves’  Disease, may worsen TED

Signs and Symptoms  (incl. red flags)

• Eyelid retraction
• Proptosis
• Eyelid swelling
• Eye redness
• Watery eyes
• Gritty sensation
• Diplopia
• Pain at rest or on eye movement

Assess for symptoms of hyperthyroidism such as agitation, palpitations, heat intolerance, weight loss and diarrhoea, although noting that TED can occur in euthyroid or hypothyroid patients.2

Red flags (sight-threatening features)⁵

• Unable to close eyelids
• Decrease in colour vision
• Visual field loss
• Globe subluxation

The inability to fully close eyelids means the patient is at risk of developing corneal ulcers⁵.

Loss of colour vision or visual fields suggest damage to the optic nerve, which can be compressed due to extraocular muscle and fat swelling. This compression occurs in approximately 5% of patients⁵.

Red flag symptoms should prompt urgent referral to ophthalmology⁸.

Investigations

Examination⁸

• Inspect the eyes for signs such as peri-orbital oedema and conjunctival hyperaemia
• Assess if the patient can fully close their eyelids
• Check pupillary light reflexes
• Test visual fields
• Test visual acuity using a Snellen Chart and colour vision with Ishihara Plates.
• Assess for any signs of Graves’ hyperthyroidism including goitre and pretibial myxoedema.

An ophthalmologist may perform a slit-lamp examination to assess for corneal ulceration and optic nerve damage.

Laboratory tests

TFTs

• T4, T3, TSH (Useful in confirming thyroid dysfunction or identifying poor control of function in known patients)³
• TSHr antibody levels (1 – To diagnose Graves’ Disease; 2 – May be useful in correlating with disease severity and assessing treatment response)⁹

Most patients with TED have associated Graves’ hyperthyroidism, but an approximate 10% may be euthyroid or hypothyroid⁹.

Imaging

This is often requested by ophthalmologists, who opt for either non-contrast CT or MRI Orbits. Indications include exclusion of differential diagnoses such as orbital tumours in atypical TED, unilateral disease, severe disease or surgical planning⁸.

Both CT and MRI can reveal swelling of the extra-ocular muscle bellies, with characteristic sparing of the tendons⁸.

Clinicians may opt for MRI for its better soft tissue visualisation, to identify active inflammation and complications such as optic nerve compression.  Meanwhile non-contrast CT offers better bone visualisation and may be used for surgical planning in the fibrotic phase.

Management

A multidisciplinary approach is key to providing patients holistic care for their eye disease, systemic thyroid dysfunction and impact on quality of life. This may involve ophthalmology, endocrinology, orthoptics and, where appropriate, counselling services⁸.

If you suspect a case of thyroid eye disease, with sight-threatening red flag features present, obtain immediate advice from ophthalmology¹⁰.

In the absence of sight-threatening features, arrange a routine referral to ophthalmology and consider endocrinology referral if thyroid function is abnormal¹⁰.

You may wish to initiate conservative management in the meantime, including¹⁰:

• Smoking cessation
• Lubricating eye drops
• Simple analgesia
• Protective eye shields for the cornea if unable to close eyelids
• Head elevation during sleep, to reduce swelling

What happens next?

• During the active inflammatory phase, specialist medical management of TED may involve an ophthalmologist initiating immunosuppression¹¹.

• Systemic steroids or steroid-sparing agents such as mycophenolate mofetil or cyclosporine are used.
• The aim is to shorten the active phase and reduce symptom severity.

• Ongoing monitoring and correction of thyroid function from the Endocrinologist or GP remains important, regardless¹¹.

• Surgical management options include orbital decompression surgery, which is aimed at reducing  proptosis¹¹.

• This procedure may involve partial removal of the bony orbit walls and excision of orbital fat to reduce orbital pressure.
  • It is indicated acutely in sight-threatening disease where there is optic nerve compression, and IV glucocorticoids have not shown improvement.
  • Otherwise, surgical options to address proptosis are performed electively once the disease has ‘burnt out’ (i.e. inactive and thyroid function stable).

• Following decompressive surgery, squint surgery may be performed to correct diplopia, through appropriate lengthening and recession of the extraocular muscles¹².

• Additionally, eyelid surgery can correct lid retraction¹².

Take-home messages

1. TED involves immune-mediated swelling of extraocular muscle and fat tissue
2.  It can have sight-threatening complications

These include corneal ulceration and optic neuropathy.

• Assess for red flags

The presence of reduced visual acuity, reduced colour vision, visual field loss, inability to close eyelids or globe subluxation, require immediate ophthalmology advice.

• TED requires a multidisciplinary approach

Arrange appropriate referrals to ophthalmology and endocrinology.

• Offer smoking cessation advice

This is a key aspect of conservatively managing the incidence and severity of TED.

References

1. Thyroid Eye Disease [Internet]. EyeWiki. Available from: https://eyewiki.org/Thyroid_Eye_Disease#Disease_entity
2. British Thyroid Foundation. Thyroid Eye Disease (TED). [Internet]. Available from: https://www.btf-thyroid.org/listing/category/thyroid-eye-disease-ted 
3. Hyperthyroidism: diagnosis [Internet]. NICE Clinical Knowledge Summaries. Available from: https://cks.nice.org.uk/topics/hyperthyroidism/diagnosis/diagnosis/
4. Yeatts RP. Quality of life in patients with Graves ophthalmopathy. Trans Am Ophthalmol Soc. 2005;103:368-411. PMID: 17057811; PMCID: PMC1447582.
5. Clinical features and diagnosis of thyroid eye disease [Internet]. UpToDate. Available from: https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-thyroid-eye-disease
6. Bahn RS. Graves’ Ophthalmopathy. New England Journal of Medicine. 2010;362(8): 726–738. Available from: https://doi.org/10.1056/NEJMra0905750.
7. Thornton J, Kelly SP, Harrison RA, Edwards R. Cigarette smoking and thyroid eye disease: a systematic review. Eye. 2007;21(9): 1135–1145. Available from: https://doi.org/10.1038/sj.eye.6702603.
8. Burch HB, Perros P, Bednarczuk T, Cooper DS, Dolman PJ, Leung AM, et al. Management of thyroid eye disease: a Consensus Statement by the American Thyroid Association and the European Thyroid Association. European Thyroid Journal. 2022;11(6). Available from: https://doi.org/10.1530/ETJ-22-0189.
9. Bartalena L, Gallo D, Tanda ML, Kahaly GJ. Thyroid Eye Disease: Epidemiology, Natural History, and Risk Factors. Ophthalmic Plastic & Reconstructive Surgery. 2023;39(6S): S2–S8. https://doi.org/10.1097/IOP.0000000000002467.
10. Hyperthyroidism: management [Internet]. NICE Clinical Knowledge Summaries. Available from: https://cks.nice.org.uk/topics/hyperthyroidism/management/management/#managing-suspected-graves-orbitopathy
11. Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, et al. The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. European Journal of Endocrinology. 2021;185(4): G43–G67. Available from: https://doi.org/10.1530/EJE-21-0479.
12. Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C, et al. The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. European Thyroid Journal. 2016;5(1): 9–26. https://doi.org/10.1159/000443828.

Written by Dr Sri Harsha Dintakurti (FY2) and reviewed by Dr Nima Ghadiri (Consultant Medical Ophthalmologist)