oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
Synonyms: TED, thyroid ophthalmopathy, dysthyroid eye disease, Graves' ophthalmopathy, ophthalmic Graves' disease, Basedow's disease (in German-speaking parts)
This article will give you an overview of thyroid eye disease, a condition associated with various forms of thyroid dysfunction. You may also find the following separate articles relevant:Thyroid Function Tests, Hyperthyroidism, Hyperthyroidism in Pregnancy, Hyperthyroid Crisis (Thyrotoxic Storm), Hypothyroidism, Hashimoto's Thyroiditis and Eye in Systemic Disease.
This is an organ-specific idiopathic autoimmune disease. It is characterised by an active inflammatory orbital phase lasting months to years, followed by an 'inactive' fibrotic phase. 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. It may also be disfiguring with possible psychological sequelae.
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 basic pathogenesis is thought to involve an autoimmune reaction to thyroid stimulating hormone (TSH) receptors, modulated by T-cell lymphocytes. Infiltration of lymphocytes into orbital tissue stimulates the release of cytokines (eg, tumor necrosis factor (TNF), interleukin 1 (IL-1)) which in turn promote the release of mucopolysaccharides from fibroblasts.The resulting hyperosmotic shift results in oedema of the orbital fat and extraocular muscles, forcing the eyeball forward and leading to the typical appearance of exophthalmos. There are underlying genetic factors which are currently being researched.
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. 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).
- A Welsh study reports the incidence of TED as 16 cases/100,000 in females and 2.9/100,000 in males. The approximate prevalence is 0.25%.
- The higher preponderance in females reflects the higher incidence of thyrotoxicosis in women.
- The ophthalmic complications of Graves' disease or thyrotoxicosis affect between 25% and 50% of those with the disease.
- 10-15% of patients have never been hyperthyroid and some are hypothyroid at the time the orbitopathy presents.
Smoking is an important risk factor. It increases the risk of developing TED by seven- to eight-fold. The risk increases with the number of cigarettes smoked and reduces on quitting. Smoking increases the risk of ophthalmopathy after radio-iodine but this can be reduced by corticosteroids. It also reduces the efficacy of the other methods of treatment such as steroids and radiotherapy. Other risk factors include:
- Female sex.
- Middle age.
- HLA-DR3, HLA-B8 and the genes for CTLA4 and the TSH receptor.
- Autoimmune thyroid disease.
- Uncontrolled thyroid dysfunction.
Radio-iodine therapy is associated with progressive Graves' ophthalmopathy but has a place in the treatment of hyperthyroidism. 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 20% of patients develop eye problems in the months before becoming thyrotoxic; about 10% present with current or previous hypothyroidism and occasionally, TED precedes thyroid dysfunction by several years.
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. Elderly patients may present with relatively inactive orbitopathy and progressive strabismus.
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. These features include:
- Blurred vision.
- Impaired perception of colour.
- Reduced visual acuity.
- A relative afferent papillary defect.
- Visual field defect.
These depend on the thyroid status and the underlying disease. See the links at the beginning of this article 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.
TED 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. Another misdiagnosis in very early disease is dry eye. Other differentials include:
- Orbital myositis.
- Chronic progressive external ophthalmoplegia.
- Idiopathic orbital inflammatory disease.
- Lymphoproliferative disorders.
- Caroticocavernous fistula.
- Myasthenia gravis (in elderly males with inactive disease).
- Cushing's syndrome.
Obesity can sometimes result in a similar clinical picture.
- TSH and free thyroxine (FT4). If normal but clinical suspicion is 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 the 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.
- 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. The other important association is with autoimmune thyroiditis, such as in Hashimoto's thyroiditis, where it occurs in about 3% of cases.
Various methods of staging have been developed over the years. The prevailing system is that outlined in the European Group on Grave's Orbitopathy (EUGOGO) Consensus statement 2008. This is based on a combination of activity measures and severity measures, as follows:
- Spontaneous retrobulbar pain.
- Pain on attempted up or down gaze.
- Redness of the eyelids.
- Redness of the conjunctiva.
- Swelling of the eyelids.
- Inflammation of the caruncle and/or plica.
- Conjunctival oedema.
Scoring one for each measure, a score of 3 or more indicates active Graves' orbitopathy.
- Lid aperture (distance between the lid margins in mm with the patient looking in the primary position, sitting relaxed and with distant fixation).
- Swelling of the eyelids (absent/equivocal, moderate, severe).
- Redness of the eyelids (absent/present).
- Redness of the conjunctivae (absent/present).
- Conjunctival oedema (absent, present).
- Inflammation of the caruncle or plica (absent, present).
- Exophthalmos (measured in mm using the same Hertel exophthalmometer and same intercanthal distance for an individual patient).
- Subjective diplopia score (0 = no diplopia; 1 = intermittent, ie diplopia in primary position of gaze, when tired or when first awakening; 2 = inconstant, ie diplopia at extremes of gaze; 3 = constant, ie continuous diplopia in primary or reading position).
- Eye muscle involvement (ductions in degrees).
- Corneal involvement (absent/punctate keratopathy/ulcer).
- Optic nerve involvement (best-corrected visual acuity, colour vision, optic disc, relative afferent pupillary defect (absent/present), plus visual fields if optic nerve compression is suspected).
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 to avoid dusty conditions.
- Providing support group information (see 'Further reading & references', below).
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.
- Corneal exposure.
- Pressure on the optic nerve.
- Poor cosmetic result.
EUGOGO also recommend urgent referral where:
- There is unexplained deterioration in vision.
- Colour vision changes in one or both eyes.
- Sudden exophthalmos.
- Obvious corneal opacity.
- Restriction of eye movement.
- Disc swelling.
There are a number of options for treating orbitopathy, including:
- Prisms to control diplopia.
- Botulinum toxin to reduce upper lid swelling.
- Medical treatments - systemic steroids for severe cases, octreotide, ciclosporin, intravenous immunoglobulin.
- Emerging treatments - selenium (antioxidant), rituximab, anti-tumour necrosis factor.
- Orbital radiation.
- Surgical interventions - orbital decompression, strabismus surgery, lid-lengthening surgery, blepharoplasty.
The natural history of the disease is variable: ocular symptoms may progress, remain unchanged or improve spontaneously. In thyrotoxic patients, 90% of proptosis improves and 30% of restrictive myopathy improves but proptosis rarely improves without further treatment. Typically the disease runs its course over a 12- to 24-month period. Poor prognostic factors include:
- Older age at onset.
- Rapid progression at onset.
- Longer duration of active disease.
- Drop in visual acuity during the active phase.
- Male gender.
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.
Further reading & references
- Thyroid eye disease, Royal National Institute of Blind People (RNIB)
- British Thyroid Foundation
- EUropean Group On Graves' Orbitopathy, 2012
- Ing E; Thyroid-Associated Orbitopathy, Medscape, Jan 2012
- Bothun ED, Scheurer RA, Harrison AR, et al; Update on thyroid eye disease and management. Clin Ophthalmol. 2009;3:543-51. Epub 2009 Oct 19.
- Perros P, Neoh C, Dickinson J; Thyroid eye disease. BMJ. 2009 Mar 6;338:b560. doi: 10.1136/bmj.b560.
- Bartley GB; Rundle and his curve. Arch Ophthalmol. 2011 Mar;129(3):356-8.
- Lazarus JH; Epidemiology of Graves' orbitopathy (GO) and relationship with thyroid disease. Best Pract Res Clin Endocrinol Metab. 2012 Jun;26(3):273-9.
- Bartalena L; Prevention of Graves' ophthalmopathy. Best Pract Res Clin Endocrinol Metab. 2012 Jun;26(3):371-9.
- Chan W, Wong GW, Fan DS, et al; Ophthalmopathy in childhood Graves' disease. Br J Ophthalmol. 2002 Jul;86(7):740-2.
- Ponto KA, Zang S, Kahaly GJ; The tale of radioiodine and Graves' orbitopathy. Thyroid. 2010 Jul;20(7):785-93.
- Krassas GE, Wiersinga W; Smoking and autoimmune thyroid disease: the plot thickens. Eur J Endocrinol. 2006 Jun;154(6):777-80.
- Maheshwari R, Weis E; Thyroid associated orbitopathy. Indian J Ophthalmol. 2012 Mar-Apr;60(2):87-93.
- Bartalena L, Tanda ML; Clinical practice. Graves' ophthalmopathy. N Engl J Med. 2009 Mar 5;360(10):994-1001.
- Chong K, Thyroid Eye Disease: a Comprehensive Review, Medical Bulletin, The Federation of Medical Societies of Hong Kong, Vol 15, No 10. 2010.
- Behbehani R; Clinical approach to optic neuropathies. Clin Ophthalmol. 2007 Sep;1(3):233-46.
- Tucker S et al; Thyroid Orbitopathy, Chapter 36, Duane's Ophthalmology, 2006.
- Findling J et al, Screening and Diagnosis of Cushing’s Syndrome, Endocrinol Metab Clin N Am 34 (2005) 385–402
- Smolders MH, Graniewski-Wijnands HS, Meinders AE, et al; Exophthalmos in obesity. Ophthalmic Res. 2004 Mar-Apr;36(2):78-81.
- Bartalena L, Baldeschi L, Dickinson A, et al; Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008 Mar;158(3):273-85.
- De Hoog J, Stravers S, Kalmann R; Recession of the inferior rectus muscle in Graves' orbitopathy. Eye (Lond). 2010 Jun;24(6):1011-7. Epub 2009 Nov 13.
- Cawood T, Moriarty P, O'Shea D; Recent developments in thyroid eye disease. BMJ. 2004 Aug 14;329(7462):385-90.
Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.
Dr Laurence Knott
Dr Laurence Knott
Prof Cathy Jackson