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Thyroid Ophthalmopathy
Yash Shah
hyroid ophthalmopathy often termed as Graves ophthalmopathy, is a part of an autoimmune process that can affect the orbital and periorbital tissue, the thyroid gland and rarely the pretibial skin or digits.1 The condition primarily effects women and has an incidence of approximately 4/10,000 per annum. During their lifetime approximately 1% of the population is affected. The condition has disfiguring and sight threatening complications and its the commonest cause of unilateral and bilateral axial proptosis in young and middle aged adults. Though the condition is associated with hyperthyroidism in 90% of patients, 6% are euthyroid.2 Smoking is associated with an increased risk of development and severity of thyroid eye disease by seven to eight fold.3,4,5

Introduction
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orbitopathy and thyroid induced sensitization of Mullers muscle to circulating catecholamines resulting in a staring look (Fig. 2). Soft tissue signs: These are common in active eye disease and include eyelid oedema (Fig. 3) and conjunctival erythema and chemosis. Dilated episcleral veins over insertion of recti can be seen in inactive disease. Proptosis: Proptosis is commonly seen in thyroid eye disease. Its extent is partly dependent on compliance of orbital septum. Choroidal folds can occasionally be seen and there is often an increased resistance to retropulsion. Proptosis combined with lid retraction and inferior rectus restriction may lead to corneal exposure and ulceration. (Fig. 4 ) Restrictive extraocular myopathy: This is due to oedema, inflammation and fibrosis due to lymphocytic infiltration of the extraocular muscles. This causes tethering of the globe by the tight recti muscles. The muscles (recti) involved in decreasing order of severity and frequency are the inferior rectus, superior rectus and lateral rectus. Anterior segment signs: They include superficial punctuate keratitis, superior limbic keratoconjunctivitis, conjunctival injection usually over the rectus muscle insertions, and conjunctival chemosis. With severe proptosis, corneal exposure with frank corneal ulceration may occur. A chronic, often recurrent condition of ocular irritation, which may be attributable to mechanical trauma transmitted from the upper eyelid to the superior bulbar and tarsal conjunctiva and is purpoted to be a prognostic marker for severe thyroid ophthalmopathy is superior limbic keratoconjunctivitis. Strabismus is common and it often represents as hypotropia or esotropia because the inferior rectus muscle and the medial rectus muscle are the most commonly involved extraocular muscles. Since asymmetric proptosis and lid retraction may mask the true relative positions of the globes, corneal light reflexes should be examined closely. Forced ductions or elevated intraocular pressure with eye movement (e.g. upgaze in hypotropic patients) can help confirm restrictive myopathy in cases in which the diagnosis of thyroid ophthalmopathy is difficult. Inferior rectus muscle restriction may mimic double elevator palsy. Pseudo-fourth nerve palsies have been described with thyroid ophthalmopathy. Although esotropia is a more common finding with thyroid ophthalmopathy, convergence insufficiency has been described. In patients with thyroid ophthalmopathy and exotropia, the possibility of concurrent myasthenia gravis should be considered.

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Pathophysiology
The underlying pathophysiology is thought to be an antibody-mediated reaction against the TSH receptor with orbital fibroblast modulation of T- cell lymphocytes. The T-cell lymphocytes are believed to react against thyroid follicular cells with shared antigenic epitopes in the retrobulbar space.1 The lymphocytic infiltration leads to the activation of cytokine networks and inflammation and interstitial oedema of the extraocular muscles.5 Excess secretion of glycosaminoglycans by orbital fibroblasts seems to be an important contributor. The end result is expansion of the volume of extraocular muscles, retrobulbar fat and connective tissue. Similar changes affect the eyelids and anterior periorbital tissues.6

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Signs and Symptoms

The sign and symptoms may vary and depend on the stage that the patient is experiencing. Initially, an acute or sub acute stage of active inflammation occurs. A patient with thyroid ophthalmopathy may progress from an acute or sub-acute stage to a more quiescent stage, characterized by fibrosis.7 Patients may complain of the ocular symptoms as shown in Table 1. 7.

Signs
The clinical signs are characteristic and include a combination of eye lid retraction, lid lag, globe lag, proptosis, restrictive extraocular myopathy and optic neuropathy.2, 9 1. Lid signs: Lid lag and lid retraction (Fig. 1) result from involvement of levator palpebrae superioris due to Table 1 : Ocular symptoms of thyroid ophthalmopathy
Dry eyes Puffy eyelids Proptosis Eyelid retraction Diplopia, especially at extreme gaze5 Visual loss Field loss Dyschromatopsia Photopsia on upgaze Ocular pressure or pain Lacrimation Exposure keratitis8

Medical Director - Total Eye Care, E 1st Floor, Bhaveshwar Vihar, SVP Road, Prarthna Samaj, Opp. Hurkisondas Hospital, Mumbai 400004, India; Hon. Consultant, Bhatia Hospital, Conwest Jain Hospital, Jagjivanram Western Railway Hospital,

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Optic nerve compression may occur with seemingly mild proptosis. Also, in most cases of compressive thyroid optic neuropathy visible optic nerve oedema occurs. For this

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Fig 1 : Dalrymple sign Lid retraction

Fig. 4 : Exophthalmos, proptosis

Fig 5 : Moebius sign- weakness of convergence Fig 2 : Kochers sign - Staring look

Fig. 3 : Puffiness of eyes

Fig 6 : Exophthalmometry

reason, documenting visual acuity, colour vision, and the presence or absence of a relatively afferent papillary defect is important during each visit. 9. Glaucoma may result from decreased episcleral venous outflow. restrictive myopathy may cause an increase in intraocular pressure of more than 8mm Hg on upgaze (differential IOP).

dramatic, cutaneous signs of dysthyroidism. Many a times, in cases of periorbital swelling and conjunctival redness as the predominant features, thyroid eye disease is often misdiagnosed as allergic conjunctivitis. Differentiating between the thyroid eye disease and other causes of periorbital edema is possible by (exophthalmometry Fig. 6) examining the presence of eyelid retraction and restricted eye movements, which occurs in thyroid eye disease.5

10. Choroidal folds may be seen with thyroid ophthalmopathy. 11. Other eponymous signs are associated with thyroid ophthalmopathy, including the following: Vigouroux sign (eyelid fullness) Stellwag sign (incomplete and infrequent blinking) Grave sign (resistance to pulling down the retracted upper lid) Goffory sign (absent creases in the forehead on superior gaze) Mobius sign (poor convergence) (Fig. 5) Ballet sign (restriction of one or more extraocular muscles)

Differential Diagnosis
Allergic conjunctivitis Myasthenia gravis Orbital myositis Chronic progressive external ophthalmoplegia Orbital tumors (primary or secondary). Carotid cavernous fistula Any inflammatory orbitopathy Sarcoidosis Preseptal cellulitis Orbital cellulitis

12. Deep glabellar rhytids has been found to be significantly associated with thyroid ophthalmopathy, presumably as a result of hypertrophy of brow depressor muscles compensating for lid retraction. 13. Pretibial dermopathy and thyroid acropachy (which mimics the appearance of clubbing) are less commonly encountered

Classification for Thyroid Ophthalmopathy

Simplest classification for thyroid ophthalmopathy is1:

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Table 2: NOSPECS classification (signs and symptoms).

Score 0 1 2 Grade No signs or symptoms Only signs Soft tissue involvement, with symptoms and signs Absent Minimal Moderate Marked Proptosis <23mm 23-24mm 25-27mm 28mm Extraocular muscle involvement Absent Limitation of motion in extremes of gaze Evident restriction of movement Fixed eyeball Corneal involvement Absent Stippling of cornea Ulceration Clouding Sight loss Absent 20/20 20/60 20/70 20/200 <20/200

Table 3: Point system used for Clinical Activity Score (CAS)

Pain Painful, oppressive feeling on or behind the globe during the last 2 weeks. Pain on attempted up, side or down gaze during the last 4 weeks. Redness Redness of the eye lids. Diffuse redness of the conjunctiva covering at least one quadrant. Swelling Swelling of the eyelids. Chemosis Swollen caruncle Increase of proptosis 2mm during a period of 1-3 months. Impaired Function Decrease of eye movements in any direction 5 during a period of 1-3 months. Decrease of visual acuity of 1 line on the Snellen chart (using a pin hole) during a period of 1-3 months.

0 a b c 3 0 a b c 4 0 a b c 5 0 a b c 6 0 a b c

Diagnosis
blood In screening for thyroid disease, the combination of T4 (thyroxine) and TSH (thyroid-stimulating hormone) or serum TSH (thyrotropin) are highly sensitive and specific. Serum TSH is useful to establish a diagnosis of hyperthyroidism and hypothyroidism. The TSH is low in hyperthyroidism and high in hypothyroidism. Other blood tests that may be useful include calculated free T4 index, thyroid-stimulating immunoglobulin, antithyroid antibodies and serum T3. Thyroid peroxidase antibodies and antibodies to thyroglobulin may be useful when trying to associate eye findings with a thyroid abnormality, such as euthyroid Graves disease.

Type 1 is characterized by minimal inflammation and restrictive myopathy. Type 2 is characterized by significant orbital inflammation and restrictive myopathy

NOSPECS classification (Table 2) for remembering clinical features10 N - No signs or symptoms O - Only signs (such as lid retraction), no symptoms S - Soft tissue involvement P - Proptosis E - Extraocular muscle C - Corneal involvement S - Sight loss

Imaging Studies Ultrasound Orbital ultrasound can quickly confirm if the patient has thickened muscles or an enlarged superior ophthalmic vein. CT Scan and MRI If the diagnosis of thyroid ophthalmopathy can be established clinically, then it is not necessary to routinely order a CT scan or an MrI. If the above studies are required, obtain axial and coronal views.12 Neuroimaging usually reveals thick muscles with tendon sparing. The inferior rectus muscles and the medial rectus muscle usually are involved. Isolated rectus muscle involvement may occur in upto 6% of patients. In this sub group of patients, the superior rectus muscle may be the most frequently involved muscle. Bilateral muscle enlargement is the norm; unilateral cases usually represent asymmetric involvement rather than normality of the less involved side

Disease Activity
The assessment of disease activity is important as it is believed that immunosuppression would be useful only in the early active phase of disease. Disease activity can be assessed by using the Clinical Activity Score (CAS) which was proposed by Mauritz in 1989.11 Clinical Activity Score (CAS) has been found to be of value in predicting the outcome of immunosuppressive treatment and immunotherapy because of its high specificity and high positive predictive value. For each item in the Table 3, one point is given. The sum of these points is the CAS. Studies have shown that with CAS 4 were more responsive to treatment as compared to patients with CAS<4.

Neuroimaging may show a dilated superior ophthalmic vein Apical crowding of the optic nerve is well visualized on

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Fig 7 : CT scan (coronal section) showing thyroid associated orbitopathy

neuroimaging MRI is more sensitive for showing optic nerve. CT scan is performed prior to bony decompression because it shows better bony architecture. Occasionally the proptosis results in straightening of the optic nerve.
Fig 8 : CT scan (axial view) showing thyroid ophthalmopathy

Monitor for visual loss from corneal exposure and optic neuropathy and for strabismus development. Visual field and colour vision testing may help in early detection of visual loss.

Atypical features requiring confirmation of the diagnosis of thyroid eye disease by orbital imaging (CT or MrI) 5 :- (Fig. 7, 8) Unilateral disease Unilateral or bilateral disease in patients with no previous or present evidence of thyroid dysfunction Absence of upper eyelid retraction Divergent strabismus Diplopia sole manifestation History of diplopia worsening towards the end of the day Lymphocytic cell infiltration Enlargement of fibroblasts Accumulation of mucopolysaccharides Interstitial oedema Increased collagen production Fibrosis with degenerative changes in the eye muscles

If a patient has dry eye symptoms, consider using tears during the day, lubricating ointment at night and punctual plugs. Morning lid edema may be reduced by sleeping on a bed with its head slightly elevated. Patients should be encouraged to stop smoking in order to reduce the risk of congestive orbitopathy.

Histologic findings

Severe form of disease may need more aggressive management. Whereas patients with active and progressive disease may benefit from immunosuppression, patients with inactive burnt out disease are only amenable to surgical intervention.14 Radiotherapy This has a non specific anti- inflammatory effect and destroys the radiosensitive lymphocytes and reduces glycosaminoglycans production.15, 16, 17 Usually a cumulative dose of 20 Gy per eye fractioned in 10 daily doses over a two week period is used. Orbital radiotherapy may cause a transient exacerbation of inflammation, but this can be prevented by concomitant glucocorticoid administration.17 Glucocorticoids These are highly effective in soft tissue changes and optic neuropathy, whereas decrease in proptosis and ocular motility is less impressive.16 Intravenous glucocorticoids seem to be associated with higher success rate and better tolerability as compared to oral glucocorticoids.18,19 Since recurrences are not infrequent, treatment may prolong.9,19 Patients may be treated with one gram of intravenous methyl prednisolone daily for three days followed by oral steroids which may be tapered as condition improves. Antioxidants Treatment with anti oxidants like nicotinamide and allopurinol, has shown encouraging results in mild and moderately severe newly diagnosed active disease.20 Nicotineamide and allopurinol have been used in doses of 300mg daily. The effect was found to be more pronounced in cigarette smokers. Though soft tissue inflammation responds well to treatment, effect on proptosis is not very impressive.16

Management
TEArS mnemonic for remembering initial management.5 T Tobacco abstinence is immensely important E Euthyroidism must be achieved and maintained A Artificial tears are helpful for the majority of the patients and can afford rapid relief from symptoms of corneal exposure r referral to a specialist centre with experience and expertise in treating thyroid eye disease is indicated in all but the mildest of cases S Self help groups can provide valuable additional support Medical care Inform patients that thyroid ophthalmopathy usually runs a self limited but prolonged course over 1 or more years. Patient should realize that no immediate care is available.13 Most patients with thyroid ophthalmopathy should be observed and the follow up interval depends on disease activity.

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Somatostatin analogues These receptors can be visualized in Vivo in orbital tissue of Graves ophthalmopathy patients.21,22 Somatostatin analogues are postulated to bind to certain somatostatin receptors on surface of various orbital cells like lymphocytes, fibroblasts and muscle cells, thereby altering their immunologic and metabolic activities.20 recent studies have shown successful therapy with octreotide and lanreotide in patients with moderately severe Graves ophthalmopathy and a positive Octreoscan, but the number of treated patients is too small to draw conclusions.21,23,24 Monoclonal antibodies rituximab, a chimeric monoclonal antibody, is being evaluated for its possible role in Graves ophthalmopathy.25,26 rituximab causes an immediate depletion of circulating b cells which usually lasts for 4-6 months but may last upto 4 years. T cells and natural killer cells are usually not affected.27, 28 Immunosuppressive drugs The autoimmune origin of Graves ophthalmopathy has prompted the use of immunosuppressive drugs however their efficacy is yet to be proven. Cyclosporine has a lower effectiveness than glucocorticoids but a combination may be more effective than either treatment alone.15 Low dose treatment with Methotrexate is being used with apparent success, however data to conclusively prove its efficacy is still lacking. 29,30 Other drugs that have been tried include Azathioprine and cyclophosphamide.31, 32 However these drugs are yet to prove their efficacy. In patients with diplopia, prisms may be beneficial to those with small angle and relatively comitant deviations. Tape occlusion of one lens or segment of the glasses may be helpful. An occluder or an eye patch can also be tried, but with care not to compress the orbit. Oral steroids usually are reserved for patients with severe inflammation or compressive optic neuropathy. Steroids may decrease the production of mucopolysaccharides by the fibroblasts. Pulse intravenous steroids may be considered. This procedure sometimes is prescribed for moderate to severe inflammatory symptoms, diplopia and visual loss. The radiation is administered via lateral fields with posterior angulation. radiation is believed to damage orbital fibroblasts or perhaps lymphocytes. radiation requires several weeks to take effect, and it may transiently cause increased inflammation. Thus, most patients are maintained on steroids during the first few weeks of treatment. Better response to radiation is observed in patients with active inflammation who are treated within 7 months of thyroid ophthalmopathy onset. radiation may be more effective if combined with steroid treatment. Cataract, radiation retinopathy and radiation optic neuropathy are possible risks. They are not common if treatment is appropriately fractioned and the eyes are shielded. In Marquezs study, 12% of patients developed cataracts after irradiation with median follow up of 11years.33 Wakelkamp also believed that orbital irradiation is a -

safe treatment modality, except possibly for patients with diabetes mellitus.34 Although improvement of motility disturbances can occur with radiotherapy, radiation is limited when used in isolation to treat diplopia. Compressive optic neuropathy may present with blurry vision, visual loss, dyschromatopsia or field loss. Patients may not have marked proptosis but they usually show markedly decreased retropulsion. If necessary, high-dose steroids and higher intravenous doses are given. In case of non-response to high-dose steroids and higher intravenous doses after 24 hours, it must be borne in mind that steroids may not work. Such patients should undergo surgical decompression while being maintained on steroids. If a good steroid response occurs, orbital radiation may be considered. In severe cases, combined steroids, radiation and surgery may be required.

Optic nerve compression -

Surgical care Few patients may require surgical care. Patients must be informed that surgical care will involve multiple staged procedures.35 Orbital decompression Patients undergoing surgical care should be explained the probable complications that may occur with orbital decompression prior to the procedure. These include blindness, haemorrhage, diplopia, periorbital numbness, globe malposition, sinusitis, and lid malposition. In patients with compressive optic neuropathy, orbital decompression may be employed as initial therapy or if medical treatment is found to be ineffective. A medical and surgical treatment may be required in compressive optic neuropathy. Strabismus surgery Although studies have described the practice of early strabismus surgery during active thyroid ophthalmopathy, this is not preferred. Strabismus surgery generally is delayed until ophthalmopathy is inactive and the prism measurements have been stable for a minimum of 6 months. Patients should be informed of the expectations after strabismus surgery; the goal of surgery is to minimize diplopia in primary and reading positions and expecting binocular single vision in all positions of gaze may be unrealistic. Strabismus surgery predominantly involves recessions rather than resections because of the presence of restrictive myopathy. Adjustable suture surgery is recommended in all possible cases. Lid-lengthening surgery Lid-lengthening surgery should be considered if restoration of the euthyroid state does not improve lid retraction. Corneal exposure is reduced by this surgery which helps in camouflaging mild-to-moderate proptosis. A muller muscle excision can be used to ameliorate a 2 to 3 mm upper lid retraction. The temporal flare may be reduced by employing lateral levator tenotomy. For further lid recession, levator recession is a good option. blepharoplasty This is the last phase of restorative surgery in thyroid ophthalmopathy. Lower lid blepharoplasty can be approached transconjunctivally if no excess lower lid skin is present.

Orbital radiation -

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Upper lid blepharoplasty is performed transcutaneously with conservative skin excision. Brow fat resection may be considered. Dacryopexy may be required if lacrimal gland prolapsed occurs.

Ophthalmopathy: a pilot study. Eye (Lond) 2005;19:1286-9. 5. Krassas GE, Heufelder AE. Immunosuppressive therapy in patients with thyroid eye disease: an overview of current concepts. Eur J Endocrinol 2001;144:311-8. Marcocci C, Marino M, rochi r, et al. Novel aspects of immunosuppressive and radiotherapy management of Graves ophthalmopathy. J Endocrinol Invest 2004;27:272-80. Bartalena L, Wiersinga WM, Pinchera A. Garves ophthalmopathy: state of the art and perspectives. J Endocrinol Invest 2004;27:295301. Marcocci C, Bartalena L, Tanda L. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiopathy in management of severe Graves ophthalmopathy: results of a prospective, single blind, randomized study. J Clin Endocrinol Metab 2001;86:3562-7. Wiersinga WM, Prummel MF. Graves ophthalmopathy: a rational approach to treatment. Trends Endocrinol Metab 2002;13:280-7. Wiersinga WM. Immunosuppressive treatment of Graves ophthalmopathy. Trends Endocrinol Metab 1990;1:377-81. Bouzas EA, Karadimas P, Mastorakos G, et al. Antioxidant agents in the treatment of Graves ophthalmopathy. Am J Ophthalmol 2000;129:618-22. Kahaly G, Diaz M, Just M, et al. rolw of octreoscan and correlation with Mr imaging in /graves Ophthalmopathy. Thyroid 1995;29:17584. Krassas KE, Dumas A, Pontikides N, et al. Somatostatin receptor scintigraphy and octreotide treatment in patients with thyroid eye disease. Clin Endocrinol (oxf) 1995;42:571-80. Chang TC, Kao SCS, Huang KM,. Octreotide and Graves ophthalmopathy and pretibial myxedema. Br Med J 1992;304:158. Kung AVC, Michon J, Tai KS, et al. the effect of somatostatin versus corticosteroids in the treatment of Graves ophthalmopathy. Thyroid 1996;6:381-4. Bartalena L, Tanda L. Immunotherapy for Graves orbitopathy: easy enthusiasm but lets keep trying. J Endocrinol Invest 2006;29:1012-6. Nielsen Ch, El Fassi D, Hasselbalch HC, et al. B-cell depletion with rituximab in the treatment of autoimmune diseases. Graves ophthalmopathy the latest addition to an expanding family. Expert Opin Biol Ther 2007;7:1061-78. reff ME, Carner K, Chambers KS. Depletion of B cells in vivo by chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435-45. Boye J, Elter T, Engert T, et al. An overview of the current clinical use of anti Cd20 monoclonal antibody ritumiximab. Ann Oncol 2003;14:520-35. Tanikawa T, Okada y, Tanaka y. Inravenous cyclophosphamide pulse therapy is effective for refactory Graves ophthalmopathy. J Uoeh 2006;28:185-91. Durrani K, Papaliodis GN, Foster CS. Pulse IV cyclophosphamide in ocular inflammatory disease. Ophthalmology 2004;111:960-5. Clements PJ, yu DTy, Levy J, et al. Effects of cyclophosphamide on B and T lymphocytes in rheumatoid arthritis. Arthritis Rheum 1974;10:347-53. Cupps Tr, Edgar LC, Fauci AS. Suppression of human B lymphocyte function by cyclophosphamide. J Immunol 1982;128:2453-7. Marquez S.D., et al. Long- term results of Irradiation for Patients with Progressive Graves Ophthalmopathy. Int J Radiat Oncol Biol Phys 2001;51:766-74. Wakelkamp IM, et al. Orbital Irradiation for Graves Ophthalmopathy: Is it Safe? A Long Term Follow Up Study Ophthalmology 2004;111:1557-62. Tang IP, et al. Endoscopic orbital decompression for optic neuropathy in thyroid ophthalmopathy. Med J Malaysia 2008;63:3378.

Consultations
Patients with thyroid ophthalmopathy benefit from consultation and follow up care with an endocrinologist. When endoscopic procedures are contemplated together with orbital decompression, an otorhinolaryngologist should be part of the surgical team. Neurosurgical consultation is required when decompression of the orbital roof is performed.

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Conclusion
Thyroid ophthalmopathy (Graves ophthalmopathy), is an autoimmune disorder with clinical signs which are characteristic and include a combination of eye lid retraction, lid lag, globe lag, proptosis, restrictive extraocular myopathy and optic neuropathy. Diagnosis is confirmed on various clinical signs and investigative studies like ultrasonography, CT scan and MrI. The primary protocol of managing thyroid eye disease is patient counseling emphasizing the self limited but prolonged course of disease with not immediate care available. Various pharmacotherapy and surgical options are available depending on the various stages of ophthalmopathy.

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References
1. 2. 3. 4. 5. Ing E, Abuhaleeqa K. Graves Ophthalmopathy (thyroid-associated orbitopathy). Clinical and Surgical Ophthalmology 2007;25:386-92 Graves ophthalmopathy. Basic and Clinical Science Course. American Academy of Ophthalmology 2002;7:44-51. Bartalena L, Marcocci C, Tanda L, et al. Management of thyroid eye disease. Eur J Med Mol Imaging 2002;29:S458-65. Bartalena L, Smoking and Graves disease. J Endocrinol Invest 2002;25:42. Boboridis K, Perros P General management plan. In: Weirsinga WM, Kahaly GJ, eds. Graves Ophthalmopathy: A multidisciplinary approach. Basel: Karger 2008:88-95. Perros P, Neoh C, Dickinson J, Thyroid Eye Disease: Clinical review, BMJ 2009;338:3-8. Konuk EB, Konuk O., et al. Expression of cyclogenase-2 in orbital fibroadipose connective tissues of Graves Ophthalmopathy Patients. Eur J Endocrinol 2006;155:681-5. Singer P, Cooper D, et al, Treatment Guidelines for Patients with Hyperthyroidism and Hypothyroidism. JAMA 1995;273:808-12. Steel HW, Potts MJ. Thyroid Eye Disease. Oxford Textbook of Ophthalmology 1999;722-30. Werner SC. Classification of the eye changes of Graves disease. Am J Ophthalmol 1969;68:646-8. Mauritz MP, Koorneer L., Weirsinga WM, et al. Clinical criteria for the assessment of disease activity in Graves ophthalmopathy: a novel approach. British Journal of Ophthalmology 73:639-44. Dodds NI., et al, Use of High-resolution MrI of the Optic Nerve in Graves Ophthalmopathy. Br J Radiol 2009;82:541-4. Paridaens D., et al. The Effect of Etanercept on Graves

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