Recent developments in thyroid eye disease
http://www.100md.com
《英国医生杂志》
1 Department of Endocrinology, St Vincent's University Hospital, Elm Park, Dublin 4, Republic of Ireland, 2 Royal Victoria Eye and Ear Hospital, Dublin 2
Correspondence to: T Cawood tomjcawood@eircom.net
Introduction
Sources of information
We retrieved from Medline papers with "thyroid" and "eye'" anywhere in the abstract and drew further information from leading medical textbooks. We also consulted with recognised experts (R Bahn, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA; P Kendall-Taylor, Department of Endocrinology, University of Newcastle, Newcastle upon Tyne; A P Weetman, Department of Medicine, Clinical Sciences Centre, University of Sheffield; and W M Wiersinga, Department of Endocrinology, Academic Medical Centre, University of Amsterdam, Netherlands).
Clinical features
Thyroid eye disease is also known as Graves' ophthalmopathy and thyroid associated ophthalmopathy and is usually associated with autoimmune hyperthyroidism (Graves' disease). Its typical ocular manifestations are recognised by a variety of clinical features including pain, gritty eyes, photophobia, chemosis, diplopia, and exophthalmos. Compression of the optic nerve can, in extreme cases, lead to blindness.
Risk factors
The symptoms of thyroid eye disease depend on how active the disease is (intensity of acute inflammatory reactions) and its severity (extent of anatomical, functional, and cosmetic features). Common symptoms are pain, an oppressive feeling behind the eye, a gritty sensation in the eye, double vision, and photophobia.
The accompanying signs include oedema of the conjunctiva and eyelid, proptosis, and diplopia owing to involvement of extraocular muscles. As the disease progresses the acute inflammation recedes, but signs and symptoms improve only partially because of the residual fibrosis and scarring of the orbital contents (fig 1).
Fig 1 Activity and severity of thyroid eye disease, adapted from Rundle 195713 and Prummel and Wiersinga 200214. The lower panel shows the possible outcome of treatment (indicated by the single arrow) which has 50% efficacy, given at 50% of maximal disease severity, and 95% disease activity. Treatment given later, when the disease is less active, is likely to have much less effect on disease severity
The intensity of inflammation can be measured by using the clinical activity score (box 1) which can be used to assess disease progression and help guide immunosuppressive treatment.11 w10 The severity of eye changes is often classified by using the "NO SPECS" system (box 2).
Box 1: Clinical activity score11
A score of 1 is given for each feature present.
Pain
Painful, oppressive feeling on or behind the globe during the last 4 weeks
Pain on attempted up, side or down gaze during the past 4 weeks
Redness
Redness of the eyelid(s)
Diffuse redness of the conjunctiva, covering at least one quadrant
Swelling
Swelling of the eyelid(s)
Chemosis
Swollen caruncle
Increase by 2 mm or more in proptosis during a period of one to three months
Impaired function
Decrease in eye movements in any direction of 5 degrees or more during a period of one to three months
Decrease in visual acuity (1 or more lines on Snellen chart, using a pinhole) during a period of one to three months
High vigilance for any features of possible optic neuropathy (such as blurred vision, impaired perception of colour, reduced visual acuity, a relative afferent papillary defect, or visual field loss) is important. Any such findings should prompt urgent review by an ophthalmologist, because the shorter the duration of visual loss, the better the chance of a good outcome of treatment.15
Extraorbital features
In addition to the eye features, an inflammatory reaction can occur in the skin at various sites. The most common site is the pretibial region (pretibial myxoedema), but sites of skin trauma can also be affected. The skin manifestations are known as thyroid associated dermopathy. Changes can also occur in the fingers nails (acropachy), which are clinically indistinguishable from finger clubbing.
Box 2: "NO SPECS" classification of thyroid eye disease, abbreviated from Werner12
Class 0: No signs or symptoms
Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag)
Class 2: Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc)
Class 3: Proptosis
Class 4: Extraocular muscle involvement (usually with diplopia)
Class 5: Corneal involvement (primarily due to lagophthalmos)
Class 6: Sight loss (due to optic nerve involvement)
Diagnosis of thyroid eye disease
Thyroid eye disease should be managed under the supervision of a specialist with particular expertise and experience of thyroid eye disease, preferably in a combined clinic for thyroidology and ophthalmology. This provides the ideal setting for the accurate and detailed assessment of disease activity and response to treatment that is required. Patients should be referred promptly, as the medical treatment of thyroid eye disease is more likely to be effective when given while the eye tissue is acutely inflamed.
Most patients experience mild disease that requires only symptomatic measures, such as artificial tears, avoiding dust, and sleeping propped up. Smokers should stop smoking, as smoking may influence the course of thyroid eye disease in a dose dependent manner during treatment. The response to treatment is delayed and considerably poorer in smokers.16
A sizeable minority of patients (10-35%) require medical treatment.17 18 w11 This is aimed at modulating the immune response and consists of steroids at high dosages and orbital radiotherapy. Orbital decompression surgery can be used in the acute phase to treat compression of the optic nerve, and in the inactive phase to improve residual functional and cosmetic features. However, these treatments are currently inadequate. After treatment more than half the patients have diplopia, more than a third are dissatisfied with the appearance of their eyes, and more than a quarter have low visual acuity.w12 w13
Judging the effect of treatment in thyroid eye disease is difficult without carefully controlled randomised trials, because, even if no treatment is given, the condition will improve to a variable degree.
Steroids
No large randomised placebo controlled trials of steroids in thyroid eye disease have been conducted, and the observation that steroids dampen down the acute inflammation (response rates to steroids in thyroid eye disease range from 33%w14 to 66%w15) would arguably make such a trial unethical. It is not clear to what degree steroids improve thyroid eye disease, or whether they just shorten the time to recovery without improving the final end point.
In general, high doses of steroids are required, but the dosage is titrated against the response and kept to the lowest effective dose, given for as short a time as possible. This should be determined by a specialist using detailed methods for assessment. This approach aims to minimise the potentially serious side effects of steroids, and some centres also use steroid sparing agents such as azathioprine.
Orbital radiotherapy
The role of orbital radiotherapy is controversial. Its use has stemmed from numerous retrospective, uncontrolled studies. Some of these studies may have wrongly attributed the improvements after radiotherapy to the radiotherapy, rather than just the natural course of the disease. Recent, prospective, placebo controlled trials have shown few or no improvements after radiotherapy.19-21 In mild thyroid eye disease, radiotherapy does not prevent progression of disease or improve patients' quality of life.20 The reported side effects of radiotherapy include cataracts (12% incidence after a median 11 yearsw16), radiation retinopathy (usually, but not always, as a result of incorrect radiation doses or targetingw17 w18), and malignancy (calculated risk of 1.2%w19). Radiotherapy is contraindicated in diabetic patients with pre-existing retinopathy. In light of the recent trials the use of radiotherapy for thyroid eye disease may diminish, and currently it should be limited to people with motility defects.19
Surgery
Surgery is indicated only for more severe disease, either when the disease is sight threatening and unresponsive to other treatment modalities, or for functional and cosmetic reasons once the disease has "burnt out." The usual procedure is an inferior orbital decompression (fig 3), during which 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, so reducing the tissue volume within the orbit. Although this improves proptosis, a need for eyelid surgery often arises at a later date, to improve appearance and function.
Fig 3 Patient after bilateral orbital decompression, lower lid hard palate grafts, and upper lid recessions
Pathogenesis of thyroid eye disease
The signs and symptoms of thyroid eye disease are explained by the orbital accumulation of glycosaminoglycans (GAG) and hypertrophy of adipose tissue, and the orbital fibroblast appears to play a key role in both of these processes.
These fibroblasts have been shown to increase their production of GAG under stimulation from certain cytokines.w27-w31 The messenger RNA of a number of cytokines has been detected in orbital samples taken at surgical decompression (IL-1, TNF-, IL-8, IL-10, and interferon),w32-w34 but the individual functions of these cytokines remains unclear.
Involvement of T cells and activation of fibroblasts have been shown to occur in the early stages of the disease process.22 Successful interruption of the acute inflammatory process therefore probably needs to occur early in the evolution of an individual patient's thyroid eye disease.
There is evidence of increased adipogenesis in the orbits of patients with thyroid eye disease, and a subpopulation of orbital fibroblasts can differentiate into adipose cells with appropriate stimulation.w35 w36 Interestingly, peroxisome proliferator activated receptor (PPAR) agonists (such as the thiazolidinediones) have been shown in vitro to stimulate orbital adipogenesis and increase orbital expression of TSH receptors.24 w37 A clinical case is known of a patient who was treated with pioglitazone, who subsequently experienced an exacerbation of his thyroid eye disease that had been stable and inactive for more than two years. As a consequence it has been proposed that PPAR agonists may be contraindicated in thyroid eye disease.24
The future
Over recent years important steps have been taken towards understanding thyroid eye disease, and several potential therapeutic targets have been identified. Further progress in the laboratory is likely to translate into real improvement in the treatment options for patients with this challenging condition.
References w1-w38 are on bmj.com
We thank all the patients for allowing us to use their words, scans, and pictures; D E Malone, consultant radiologist, Royal Victoria Eye and Ear Hospital and St Vincent's University Hospital, for providing the computed tomography scans; and R Bahn, P Kendall-Taylor, A P Weetman, and W M Wiersinga for their help and advice.
Contributors: TC and DO'S wrote the text, with editorial input and clinical images from PM. DO'S is guarantor.
Funding: None.
Competing interests: None declared.
References
Weetman AP. Hyperthyroidism and Graves' Disease. In: Besser GM, Thorner MO. Comprehensive clinical endocrinology. 3rd ed. Edinburgh: Mosby, 2002.
Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977;7: 481-93.
Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med 1993;329: 1468-75.
Vestergaard P. Smoking and thyroid disorders—a meta-analysis. Eur J Endocrinol 2002;146: 153-61.
Bartalena L, Marcocci C, Tanda ML, Manetti L, Dell'Unto E, Bartolomei MP, et al. Cigarette smoking and treatment outcomes in Graves ophthalmopathy. Ann Intern Med 1998;129: 632-5.
Bartalena L, Pinchera A, Marcocci C. Management of Graves' ophthalmopathy: reality and perspectives. Endocr Rev 2000;21: 168-99.
Perros P, Crombie AL, Matthews JN, Kendall-Taylor P. Age and gender influence the severity of thyroid-associated ophthalmopathy: a study of 101 patients attending a combined thyroid-eye clinic. Clin Endocrinol (Oxf) 1993;38: 367-72.
Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell'Unto E, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med 1998;338: 73-8.
Manso PG, Furlanetto RP, Wolosker AM, Paiva ER, de Abreu MT, Maciel RM. Prospective and controlled study of ophthalmopathy after radioiodine therapy for Graves' hyperthyroidism. Thyroid 1998;8(1): 49-52.
Farid NR, Marga M. Genetics of thyroid-associated ophthalmopathy: a play in search of a cast of characters. J Endocrinol Invest 2003;26: 570-4.
Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf) 1997;47(1): 9-14.
Werner SC. Modification of the classification of the eye changes of Graves' disease: recommendations of the Ad Hoc Committee of the American Thyroid Association. J Clin Endocrinol Metab 1977;44: 203-4.
Rundle FF. Management of exophthalmos and related ocular changes in Graves' disease. Metabolism 1957;6: 36-47.
Prummel MF, Wiersinga WM. Graves' ophthalmopathy and dermopathy. In: Wass JAH, Shalet SM, eds. Oxford textbook of endocrinology and diabetes. 1st ed. Oxford: Oxford University Press, 2002.
Bahn RS, Bartley GB, Gorman CA. Emergency treatment of Graves' ophthalmopathy. Baillieres Clin Endocrinol Metab 1992;6(1): 95-105.
Eckstein A, Quadbeck B, Mueller G, Rettenmeier AW, Hoermann R, Mann K, et al. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J Ophthalmol 2003;87: 773-6.
Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Endocrinol (Oxf) 1995;42(1): 45-50.
Noth D, Gebauer M, Muller B, Burgi U, Diem P. Graves' ophthalmopathy: natural history and treatment outcomes. Swiss Med Wkly 2001;131: 603-9.
Mourits MP, van Kempen-Harteveld ML, Garcia MB, Koppeschaar HP, Tick L, Terwee CB. Radiotherapy for Graves' orbitopathy: randomised placebo-controlled study. Lancet 2000;355: 1505-9.
Gorman CA, Garrity JA, Fatourechi V, Bahn RS, Petersen IA, Stafford SL, et al. A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy. Ophthalmology 2001;108: 1523-34.
Prummel MF, Terwee CB, Gerding MN, Baldeschi L, Mourits MP, Blank L, et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy. J Clin Endocrinol Metab 2004;89(1): 15-20.
Pappa A, Lawson JM, Calder V, Fells P, Lightman S. T cells and fibroblasts in affected extraocular muscles in early and late thyroid associated ophthalmopathy. Br J Ophthalmol 2000;84: 517-22.
Otto EA, Ochs K, Hansen C, Wall JR, Kahaly GJ. Orbital tissue-derived T lymphocytes from patients with Graves' ophthalmopathy recognize autologous orbital antigens. J Clin Endocrinol Metab 1996;81: 3045-50.
Starkey K, Heufelder A, Baker G, Joba W, Evans M, Davies S, et al. Peroxisome proliferator-activated receptor-gamma in thyroid eye disease: contraindication for thiazolidinedione use? J Clin Endocrinol Metab 2003;88(1): 55-9.
Bartalena L, Marcocci C, Pinchera A. Cytokine antagonists: new ideas for the management of Graves' ophthalmopathy. J Clin Endocrinol Metab 1996;81: 446-8.(Tom Cawood, specialist re)
Correspondence to: T Cawood tomjcawood@eircom.net
Introduction
Sources of information
We retrieved from Medline papers with "thyroid" and "eye'" anywhere in the abstract and drew further information from leading medical textbooks. We also consulted with recognised experts (R Bahn, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA; P Kendall-Taylor, Department of Endocrinology, University of Newcastle, Newcastle upon Tyne; A P Weetman, Department of Medicine, Clinical Sciences Centre, University of Sheffield; and W M Wiersinga, Department of Endocrinology, Academic Medical Centre, University of Amsterdam, Netherlands).
Clinical features
Thyroid eye disease is also known as Graves' ophthalmopathy and thyroid associated ophthalmopathy and is usually associated with autoimmune hyperthyroidism (Graves' disease). Its typical ocular manifestations are recognised by a variety of clinical features including pain, gritty eyes, photophobia, chemosis, diplopia, and exophthalmos. Compression of the optic nerve can, in extreme cases, lead to blindness.
Risk factors
The symptoms of thyroid eye disease depend on how active the disease is (intensity of acute inflammatory reactions) and its severity (extent of anatomical, functional, and cosmetic features). Common symptoms are pain, an oppressive feeling behind the eye, a gritty sensation in the eye, double vision, and photophobia.
The accompanying signs include oedema of the conjunctiva and eyelid, proptosis, and diplopia owing to involvement of extraocular muscles. As the disease progresses the acute inflammation recedes, but signs and symptoms improve only partially because of the residual fibrosis and scarring of the orbital contents (fig 1).
Fig 1 Activity and severity of thyroid eye disease, adapted from Rundle 195713 and Prummel and Wiersinga 200214. The lower panel shows the possible outcome of treatment (indicated by the single arrow) which has 50% efficacy, given at 50% of maximal disease severity, and 95% disease activity. Treatment given later, when the disease is less active, is likely to have much less effect on disease severity
The intensity of inflammation can be measured by using the clinical activity score (box 1) which can be used to assess disease progression and help guide immunosuppressive treatment.11 w10 The severity of eye changes is often classified by using the "NO SPECS" system (box 2).
Box 1: Clinical activity score11
A score of 1 is given for each feature present.
Pain
Painful, oppressive feeling on or behind the globe during the last 4 weeks
Pain on attempted up, side or down gaze during the past 4 weeks
Redness
Redness of the eyelid(s)
Diffuse redness of the conjunctiva, covering at least one quadrant
Swelling
Swelling of the eyelid(s)
Chemosis
Swollen caruncle
Increase by 2 mm or more in proptosis during a period of one to three months
Impaired function
Decrease in eye movements in any direction of 5 degrees or more during a period of one to three months
Decrease in visual acuity (1 or more lines on Snellen chart, using a pinhole) during a period of one to three months
High vigilance for any features of possible optic neuropathy (such as blurred vision, impaired perception of colour, reduced visual acuity, a relative afferent papillary defect, or visual field loss) is important. Any such findings should prompt urgent review by an ophthalmologist, because the shorter the duration of visual loss, the better the chance of a good outcome of treatment.15
Extraorbital features
In addition to the eye features, an inflammatory reaction can occur in the skin at various sites. The most common site is the pretibial region (pretibial myxoedema), but sites of skin trauma can also be affected. The skin manifestations are known as thyroid associated dermopathy. Changes can also occur in the fingers nails (acropachy), which are clinically indistinguishable from finger clubbing.
Box 2: "NO SPECS" classification of thyroid eye disease, abbreviated from Werner12
Class 0: No signs or symptoms
Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag)
Class 2: Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc)
Class 3: Proptosis
Class 4: Extraocular muscle involvement (usually with diplopia)
Class 5: Corneal involvement (primarily due to lagophthalmos)
Class 6: Sight loss (due to optic nerve involvement)
Diagnosis of thyroid eye disease
Thyroid eye disease should be managed under the supervision of a specialist with particular expertise and experience of thyroid eye disease, preferably in a combined clinic for thyroidology and ophthalmology. This provides the ideal setting for the accurate and detailed assessment of disease activity and response to treatment that is required. Patients should be referred promptly, as the medical treatment of thyroid eye disease is more likely to be effective when given while the eye tissue is acutely inflamed.
Most patients experience mild disease that requires only symptomatic measures, such as artificial tears, avoiding dust, and sleeping propped up. Smokers should stop smoking, as smoking may influence the course of thyroid eye disease in a dose dependent manner during treatment. The response to treatment is delayed and considerably poorer in smokers.16
A sizeable minority of patients (10-35%) require medical treatment.17 18 w11 This is aimed at modulating the immune response and consists of steroids at high dosages and orbital radiotherapy. Orbital decompression surgery can be used in the acute phase to treat compression of the optic nerve, and in the inactive phase to improve residual functional and cosmetic features. However, these treatments are currently inadequate. After treatment more than half the patients have diplopia, more than a third are dissatisfied with the appearance of their eyes, and more than a quarter have low visual acuity.w12 w13
Judging the effect of treatment in thyroid eye disease is difficult without carefully controlled randomised trials, because, even if no treatment is given, the condition will improve to a variable degree.
Steroids
No large randomised placebo controlled trials of steroids in thyroid eye disease have been conducted, and the observation that steroids dampen down the acute inflammation (response rates to steroids in thyroid eye disease range from 33%w14 to 66%w15) would arguably make such a trial unethical. It is not clear to what degree steroids improve thyroid eye disease, or whether they just shorten the time to recovery without improving the final end point.
In general, high doses of steroids are required, but the dosage is titrated against the response and kept to the lowest effective dose, given for as short a time as possible. This should be determined by a specialist using detailed methods for assessment. This approach aims to minimise the potentially serious side effects of steroids, and some centres also use steroid sparing agents such as azathioprine.
Orbital radiotherapy
The role of orbital radiotherapy is controversial. Its use has stemmed from numerous retrospective, uncontrolled studies. Some of these studies may have wrongly attributed the improvements after radiotherapy to the radiotherapy, rather than just the natural course of the disease. Recent, prospective, placebo controlled trials have shown few or no improvements after radiotherapy.19-21 In mild thyroid eye disease, radiotherapy does not prevent progression of disease or improve patients' quality of life.20 The reported side effects of radiotherapy include cataracts (12% incidence after a median 11 yearsw16), radiation retinopathy (usually, but not always, as a result of incorrect radiation doses or targetingw17 w18), and malignancy (calculated risk of 1.2%w19). Radiotherapy is contraindicated in diabetic patients with pre-existing retinopathy. In light of the recent trials the use of radiotherapy for thyroid eye disease may diminish, and currently it should be limited to people with motility defects.19
Surgery
Surgery is indicated only for more severe disease, either when the disease is sight threatening and unresponsive to other treatment modalities, or for functional and cosmetic reasons once the disease has "burnt out." The usual procedure is an inferior orbital decompression (fig 3), during which 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, so reducing the tissue volume within the orbit. Although this improves proptosis, a need for eyelid surgery often arises at a later date, to improve appearance and function.
Fig 3 Patient after bilateral orbital decompression, lower lid hard palate grafts, and upper lid recessions
Pathogenesis of thyroid eye disease
The signs and symptoms of thyroid eye disease are explained by the orbital accumulation of glycosaminoglycans (GAG) and hypertrophy of adipose tissue, and the orbital fibroblast appears to play a key role in both of these processes.
These fibroblasts have been shown to increase their production of GAG under stimulation from certain cytokines.w27-w31 The messenger RNA of a number of cytokines has been detected in orbital samples taken at surgical decompression (IL-1, TNF-, IL-8, IL-10, and interferon),w32-w34 but the individual functions of these cytokines remains unclear.
Involvement of T cells and activation of fibroblasts have been shown to occur in the early stages of the disease process.22 Successful interruption of the acute inflammatory process therefore probably needs to occur early in the evolution of an individual patient's thyroid eye disease.
There is evidence of increased adipogenesis in the orbits of patients with thyroid eye disease, and a subpopulation of orbital fibroblasts can differentiate into adipose cells with appropriate stimulation.w35 w36 Interestingly, peroxisome proliferator activated receptor (PPAR) agonists (such as the thiazolidinediones) have been shown in vitro to stimulate orbital adipogenesis and increase orbital expression of TSH receptors.24 w37 A clinical case is known of a patient who was treated with pioglitazone, who subsequently experienced an exacerbation of his thyroid eye disease that had been stable and inactive for more than two years. As a consequence it has been proposed that PPAR agonists may be contraindicated in thyroid eye disease.24
The future
Over recent years important steps have been taken towards understanding thyroid eye disease, and several potential therapeutic targets have been identified. Further progress in the laboratory is likely to translate into real improvement in the treatment options for patients with this challenging condition.
References w1-w38 are on bmj.com
We thank all the patients for allowing us to use their words, scans, and pictures; D E Malone, consultant radiologist, Royal Victoria Eye and Ear Hospital and St Vincent's University Hospital, for providing the computed tomography scans; and R Bahn, P Kendall-Taylor, A P Weetman, and W M Wiersinga for their help and advice.
Contributors: TC and DO'S wrote the text, with editorial input and clinical images from PM. DO'S is guarantor.
Funding: None.
Competing interests: None declared.
References
Weetman AP. Hyperthyroidism and Graves' Disease. In: Besser GM, Thorner MO. Comprehensive clinical endocrinology. 3rd ed. Edinburgh: Mosby, 2002.
Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977;7: 481-93.
Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med 1993;329: 1468-75.
Vestergaard P. Smoking and thyroid disorders—a meta-analysis. Eur J Endocrinol 2002;146: 153-61.
Bartalena L, Marcocci C, Tanda ML, Manetti L, Dell'Unto E, Bartolomei MP, et al. Cigarette smoking and treatment outcomes in Graves ophthalmopathy. Ann Intern Med 1998;129: 632-5.
Bartalena L, Pinchera A, Marcocci C. Management of Graves' ophthalmopathy: reality and perspectives. Endocr Rev 2000;21: 168-99.
Perros P, Crombie AL, Matthews JN, Kendall-Taylor P. Age and gender influence the severity of thyroid-associated ophthalmopathy: a study of 101 patients attending a combined thyroid-eye clinic. Clin Endocrinol (Oxf) 1993;38: 367-72.
Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell'Unto E, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med 1998;338: 73-8.
Manso PG, Furlanetto RP, Wolosker AM, Paiva ER, de Abreu MT, Maciel RM. Prospective and controlled study of ophthalmopathy after radioiodine therapy for Graves' hyperthyroidism. Thyroid 1998;8(1): 49-52.
Farid NR, Marga M. Genetics of thyroid-associated ophthalmopathy: a play in search of a cast of characters. J Endocrinol Invest 2003;26: 570-4.
Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf) 1997;47(1): 9-14.
Werner SC. Modification of the classification of the eye changes of Graves' disease: recommendations of the Ad Hoc Committee of the American Thyroid Association. J Clin Endocrinol Metab 1977;44: 203-4.
Rundle FF. Management of exophthalmos and related ocular changes in Graves' disease. Metabolism 1957;6: 36-47.
Prummel MF, Wiersinga WM. Graves' ophthalmopathy and dermopathy. In: Wass JAH, Shalet SM, eds. Oxford textbook of endocrinology and diabetes. 1st ed. Oxford: Oxford University Press, 2002.
Bahn RS, Bartley GB, Gorman CA. Emergency treatment of Graves' ophthalmopathy. Baillieres Clin Endocrinol Metab 1992;6(1): 95-105.
Eckstein A, Quadbeck B, Mueller G, Rettenmeier AW, Hoermann R, Mann K, et al. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J Ophthalmol 2003;87: 773-6.
Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Endocrinol (Oxf) 1995;42(1): 45-50.
Noth D, Gebauer M, Muller B, Burgi U, Diem P. Graves' ophthalmopathy: natural history and treatment outcomes. Swiss Med Wkly 2001;131: 603-9.
Mourits MP, van Kempen-Harteveld ML, Garcia MB, Koppeschaar HP, Tick L, Terwee CB. Radiotherapy for Graves' orbitopathy: randomised placebo-controlled study. Lancet 2000;355: 1505-9.
Gorman CA, Garrity JA, Fatourechi V, Bahn RS, Petersen IA, Stafford SL, et al. A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy. Ophthalmology 2001;108: 1523-34.
Prummel MF, Terwee CB, Gerding MN, Baldeschi L, Mourits MP, Blank L, et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy. J Clin Endocrinol Metab 2004;89(1): 15-20.
Pappa A, Lawson JM, Calder V, Fells P, Lightman S. T cells and fibroblasts in affected extraocular muscles in early and late thyroid associated ophthalmopathy. Br J Ophthalmol 2000;84: 517-22.
Otto EA, Ochs K, Hansen C, Wall JR, Kahaly GJ. Orbital tissue-derived T lymphocytes from patients with Graves' ophthalmopathy recognize autologous orbital antigens. J Clin Endocrinol Metab 1996;81: 3045-50.
Starkey K, Heufelder A, Baker G, Joba W, Evans M, Davies S, et al. Peroxisome proliferator-activated receptor-gamma in thyroid eye disease: contraindication for thiazolidinedione use? J Clin Endocrinol Metab 2003;88(1): 55-9.
Bartalena L, Marcocci C, Pinchera A. Cytokine antagonists: new ideas for the management of Graves' ophthalmopathy. J Clin Endocrinol Metab 1996;81: 446-8.(Tom Cawood, specialist re)