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Thyroid Eye Disease
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Synonyms: TED, thyroid ophthalmopathy, dysthyroid eye disease, Graves' ophthalmopathy, ophthalmic Graves' disease, Basedow's disease (in German-speaking parts).
This record will give you an overview of thyroid eye disease, a condition associated with various forms of thyroid dysfunction. You may also find the following records relevant:
This is an organ-specific idiopathic auto-immune disease.It is characterised by an active inflammatory orbital phase lasting months to years, followed by an 'inactive' fibrotic phase.2 It can be sight-threatening as acute progressive disease affects the optic nerve and cornea. Sight loss still occurs despite advanced medical care systems; this is primarily due to delay in starting treatment.3 It may also be disfiguring with possible psychological sequelae.3
Most patients with thyroid eye disease (TED) have clinical and/or biochemical evidence of hyper/hypothyroidism but some are euthyroid (at least at the time of presentation). Therefore, thyroid dysfunction can precede, proceed or be co-existent with TED.
The exact pathogenesis of the disease is poorly understood and there are no adequate animal models. The presence of one or more shared auto-antigens between the thyroid and the orbit may explain why retro-orbital tissues are affected.3 An IgG auto-antibody called a long-acting thyroid stimulant (LATS) attaches to the thyroid stimulating hormone (TSH) receptors on the thyroid gland with a more prolonged 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. Cell mediated immunity and cytokines are also thought to be involved. A cascade of events is triggered, the end point being the proliferation of orbital fibroblasts, expansion of adipose tissue and secretion of glycosaminoglycans from fibroblasts.4
The course of the disease is described by Rundle's curve: there is progressive deterioration over a few months in the initial phase, followed by a peak before spontaneously improving. It ends in a chronic 'burn-out' phase where further changes are unlikely.3 The importance of this concept lies in treatment options: medical management is only available in the active, early phase in this curve. When the disease becomes inactive (no acute inflammation), surgery is the only option. Note that activity is not the same as severity (see 'Staging' below).
- The incidence of TED is 2.9 to 16 cases/100,000/year.3
- The ophthalmic complications of Graves' disease or thyrotoxicosis affects between 25% and 50% of those with the disease.
- There is a female preponderance of 4:1; 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 usual age of onset is between 30 and 50.
- TED can be more severe in men over the age of 60.
Risk factors
Smoking is an important risk factor.5 It increases the risk of developing thyroid eye disease by seven- to eight-fold.3 The risk increases with number of cigarettes smoked and reduces on quitting.6 Smoking increases the risk of ophthalmopathy after radio-iodine but this can be reduced by corticosteroids.6 It also reduces the efficacy of the other methods of treatment such as steroids and radiotherapy.7 Other risk factors include:
- Female sex
- Middle age
- HLA-DR3, HLA-B8 and the genes for CTLA4 and the TSH receptor
- Auto-immune thyroid disease
- Uncontrolled thyroid dysfunction
Radio-iodine therapy is associated with progressive Graves' ophthalmopathy3 but has a place in the treatment of hyperthyroidism.4 Thus it can only be used in the inactive phase of the eye disease (see 'Description' above).
Most patients present with concurrent thyrotoxicosis due to Graves’ disease. About 10-20% of patients develop eye problems in the months before becoming thyrotoxic; about 10-15% present with current or previous hypothyroidism and occasionally, thyroid eye disease precedes thyroid dysfunction by several years.3
Ophthalmic features

The symptoms will be a reflection of the intensity of the inflammatory reaction and the severity of the anatomical, functional and cosmetic aspects. Initially, they relate to an increasingly 'crowded' orbit:
- Ocular irritation
- Ache (worse in the mornings) behind the eye
- Red eyes
- Cosmetic changes
- Diplopia (restricted ocular mobility, initially involving the inferior rectus muscles)
Gradually, proptosis (exophthalmos) may develop accompanied by:
- Lid retraction and lid lag
- Conjunctival injection and chemosis (oedema)
- Orbital fat prolapse
- Exposure keratopathy (photophobia, tearing, grittiness, pain) due to incomplete lid closure
It is worth noting that exophthalmos does not always develop and does not correlate with disease severity. Some patients with minimal exophthalmos are at high risk of optic nerve compression.3 Elderly patients may present with relatively inactive orbitopathy and progressive strabismus.2
Acute progressive optic neuropathyIf the involved tissues (mainly muscle) begin to compress the optic nerve and if the nerve is further stretched due to proptosis, visual loss can occur. Features of possible optic neuropathy require urgent referral to an ophthalmologist because the shorter the duration of visual loss, the better the chance of a good outcome of treatment.8 These features include:
See record on Examination of the Eye for details on how to assess these. See also urgent referral criteria below under 'Referral' heading. |
Systemic features
These depend on the thyroid status and the underlying disease. See links at beginning of record for more information about dysthyroid states.
This is straightforward in patients with obvious bilateral eye disease and a background of thyroid function abnormalities. It can be more tricky in unilateral disease or when the patient is euthyroid. Diagnosis is confirmed with blood biochemistry and orbital imaging - see 'Investigations' below.
Thyroid eye disease is more often bilateral whereas proptosis from such important pathology as a retro-orbital tumour, is usually unilateral. Allergic conjunctivitis is a common misdiagnosis when periorbital swelling and conjunctival injection are predominant: the give-away is restricted eye movement, lid retraction ± blurred vision.3 Another misdiagnosis in very early disease is dry eye.9 Other differentials include:2,3
- Orbital myositis
- Chronic progressive external ophthalmoplegia
- Idiopathic orbital inflammatory disease
- Lymphoproliferative disorders
- Caroticocavernous fistula
- Myasthenia gravis (in elderly males with inactive disease)
- Cushing's syndrome4
Obesity can sometimes result in a similar clinical picture.4
- TSH and free thyroxine (FT4). If normal but clinical suspicion strong, free tri-iodothyronine (T3).
- Thyroid auto-antibodies: anti-TSH receptor, anti-thyroid peroxidase and anti-thyroglobulin antibodies (although these have poor sensitivity and specificity).
- CT or preferably MRI of orbits. MRI is better at showing soft tissue; CT will be helpful if surgery for orbital decompression is planned. There will be enlarged extra-ocular muscles (with tendon sparing) ± an increase in orbital fibro-adipose tissue.4
- Thyroid uptake scan or orbital biopsy are sometimes required.
- Ophthalmologists will organise an orthoptist review to assess fully the ocular movement and visual fields.
TED is most commonly associated with Graves' disease. Clinically recognised Graves' ophthalmopathy occurs in about 50% of cases of Graves' disease, is clinically relevant in 20-30% and sight-threatening (dysthyroid optic neuropathy, corneal breakdown or both) in 3-5%. Even in the absence of clinical signs, imaging reveals subtle orbital changes in most cases.4 The other important association is with auto-immune thyroiditis, such as in Hashimoto's thyroiditis where it occurs in about 3% of cases.1
Disease activity
Disease activity rather than duration of disease is the prime determinant of the outcome of treatment.10 The presence of each of the following, scores one of a possible 10.
Clinical Assessment Score | |
|---|---|
| Pain | Painful, oppressive feeling on or behind eye over past 4 weeks |
| Pain on attempted eye movement over past 4 weeks | |
| Redness | Eyelid(s) red |
| Diffuse conjunctival injection covering at least one quadrant of eyeball | |
| Swelling | Swollen eyelid(s) |
| Swollen caruncle | |
| Proptosis increasing > 2 mm over past 1-3 months | |
| Chemosis | |
| Loss of Function | Reduced eye movements (> 5° in any direction over 1-3 months) |
| Reduced visual acuity (e.g. 1 line on Snellen's chart over 1-3 months) | |
Disease severity
This is assessed using the NOSPECS classification (more commonly used by physicians than ophthalmologists but a helpful guide):
| Score | NOSPECS abbreviation | Feature |
| 0 | N | No symptoms or signs |
| 1 | O | Only signs, no symptoms |
| 2 | S | Soft tissue involvement |
| 3 | P | Proptosis |
| 4 | E | Extraocular muscle involvement |
| 5 | C | Corneal involvement |
| 6 | S | Sight loss (decreased visual acuity) |
General points
Ideally, the condition should be managed in a joint endocrinology and ophthalmology clinic where there is experience and expertise in the condition. However, the general practitioner can have a role by:
- Identifying sight-threatening eye complications early if the patient is not already under specialist care and referring early (see 'Referral' below)
- Supporting the patient to stop smoking
- Achieving and maintaining euthyroidism (following local protocol)
- Prescribing ocular lubricants where there are symptoms of corneal exposure
- Reminding patients to try sleeping propped up and avoid dusty conditions
- Providing support group information (see 'Internet and further reading' below)
Additional measures in the eye department will include prisms for diplopia.
Referral3
Patients with a history of Graves’ disease, who have neither symptoms nor signs of thyroid eye disease, require no further ophthalmological assessments and need not be referred to a specialist. Where there is suspected TED, early referral is important because medical treatment is most effective when the eye is acutely inflamed.
- Refer urgently if any of the following are present:
- Unexplained deterioration in vision
- Awareness of change in intensity or quality of colour vision in one/both eyes
- History of eye(s) suddenly ‘popping out’ (globe subluxation)
- Obvious corneal opacity
- Inability to close eyelids sufficiently to cover cornea
- Swollen optic disc
- Symptoms
- Signs
- Refer non-urgently if any of the following are present:
- Abnormal light sensitivity: troublesome or deteriorating over 1-2 months
- Excessively gritty eyes, not improving after 1 week of topical lubricants
- Orbital ache or pain: troublesome or deteriorating over 1-2 months
- Altered appearance of eyes or eyelids over 1-2 months
- Patient concerned by appearance of eyes
- Double vision troublesome or deteriorating
- Troublesome eyelid retraction
- Abnormal swelling or redness of eyelids or conjunctiva
- Restricted eye movements
- Tilting of head (especially chin elevation) to avoid double vision
- Symptoms
- Signs
Medical treatment1
Immunosuppression is the mainstay of treatment in active disease, particularly if motility or function is threatened. This is often systemic corticosteroids (in sight-threatening eye disease, high dose intravenous treatment may be needed)4 but ciclosporin, methotrexate and azathioprine may all be used.
Radiotherapy
Radiotherapy is a controversial mode of treatment that has received some criticism. Early trials were inadequately controlled and much apparent improvement was natural remission. 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%).11 However, it still has a place in adjunctive treatment (particularly where there is dysmotility)4 and is used in a number of centres. Radiotherapy is contra-indicated in diabetic patients with pre-existing retinopathy, patients under 35 years of age and severe hypertensives.4
Surgical treatment
Orbital decompression surgery can be used in the acute phase to treat compression in acute progressive optic neuropathy. It is used in about 5% of patients. In the inactive phase, surgery may improve residual functional and cosmetic features 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. Endoscopic orbital decompression is an effective and safe procedure that may have a greater role in the future.
Although this orbital decompression surgery improves proptosis, a need for eyelid surgery often arises at a later date, to improve appearance and function (particularly related to corneal cover). Eye muscle surgery can usefully improve or restore binocular vision in almost 90% of patients.3 A minority of patients will require all three types of surgery (i.e. orbital, lid and eye muscle).
After surgical treatment, up to 15% of patients have new diplopia and visual loss may occur (< 1:1,000 cases).2 Other complication risks are low. Surgery is also sometimes required for strabismus but it is best delayed for ≥ 6 months, until the condition is stable.
- Corneal exposure
- Strabismus
- Pressure on the optic nerve
- Poor cosmetic result
The natural history of the disease is variable: ocular symptoms may progress, remain unchanged or improve spontaneously.4 Most patients have a mild, self-limiting disease which only requires symptomatic treatment and resolves over 1 to 5 years.1 For those with more severe disease, good long-term outcome is dependent on timely intervention in the acute phase with attention to avoiding sight-threatening complications. Poor prognostic factors include:1
- Older age at onset
- Rapid progression at onset
- Longer duration of active disease
- Drop in visual acuity during active phase
- Male gender
- Smoker
- Diabetes
More than a third are dissatisfied with the appearance of their eyes and more than a quarter have low visual acuity. Between about 10% and 35% will need further treatment.
Much work is being done with regards to the treatment of TED. Rituximab has had promising results in a small scale study and anti-oxidants may have a role in mild to moderate disease. Reducing the inflammation with anti-TNF-α drugs such as enteracept is logical and promising12 but more good RCTs are required. Other new potential candidates for medical treatment have included somatostatin analogues and intravenous immune globulin.4
Document references
- Denniston AKO, Murray PI. Oxford Handbook of Ophthalmology, OUP (2008).
- Jackson TL. Moorfields Manual of Ophthalmology, Mosby (2008).
- Perros P, Neoh C, Dickinson J; Thyroid eye disease. BMJ. 2009 Mar 6;338:b560. doi: 10.1136/bmj.b560.
- Bartalena L, Tanda ML; Clinical practice. Graves' ophthalmopathy. N Engl J Med. 2009 Mar 5;360(10):994-1001.
- Vestergaard P; Smoking and thyroid disorders--a meta-analysis. Eur J Endocrinol. 2002 Feb;146(2):153-61. [abstract]
- Bartalena L, Marcocci C, Tanda ML, et al; Cigarette smoking and treatment outcomes in Graves ophthalmopathy. Ann Intern Med. 1998 Oct 15;129(8):632-5. [abstract]
- Bartalena L, Marcocci C, Bogazzi F, et al; Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med. 1998 Jan 8;338(2):73-8. [abstract]
- Bahn RS, Bartley GB, Gorman CA; Emergency treatment of Graves' ophthalmopathy. Baillieres Clin Endocrinol Metab. 1992 Jan;6(1):95-105. [abstract]
- Gupta A, Sadeghi PB, Akpek EK; Occult thyroid eye disease in patients presenting with dry eye symptoms. Am J Ophthalmol. 2009 May;147(5):919-23. Epub 2009 Feb 10. [abstract]
- Mourits MP, Prummel MF, Wiersinga WM, et al; Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf). 1997 Jul;47(1):9-14. [abstract]
- Cawood T, Moriarty P, O'Shea D.; Recent developments in thyroid eye disease.; BMJ. 2004 Aug 14;329(7462):385-90.
- Paridaens D, van den Bosch WA, van der Loos TL, et al; The effect of etanercept on Graves' ophthalmopathy: a pilot study. Eye. 2005 Dec;19(12):1286-9. [abstract]
Internet and further reading
- Ing E; Thyroid Ophthalmopathy. emedicine, April 2008.
- RNIB; Thyroid eye disease
- British Thyroid Foundation; Patient-led charitable organisation dedicated to helping those with thyroid disorders.
- whonamedit.com; Robert James Graves
Document ID: 2868
Document Version: 23
Document Reference: bgp1597
Last Updated: 16 Jun 2009
Planned Review: 16 Jun 2011
The authors and editors of this article are employed to create accurate and up to date content reflecting reliable research evidence, guidance and best clinical practice. They are free from any commercial conflicts of interest. Find out more about updating.
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