History

Fact Explanation
Abnormal potrusion of the eyeball Abnormal protrusion of the eyeball is called exophthalmos. The causes are endocrine, inflammatory, vascular, infective, neoplastic and traumatic. When exophthalmos occurs in Graves disease it usually occurs in young females. [1] [2] [3] [4] [5] [6] [7]
Protrusion of the eye ball [1] [2] [3] [4] [7] The eye ball is in a rigid bony compartment and the only place where protrusion can occur is from the front. [1] [2] [3] [4] [7]
Pain in the eye [1] [2] [3] [4] [7] There's an increase in volume within the fixed bony orbit and this may press on nerves and cause pain. The cause could also be trauma or inflammation which themselves cause pain. [1] [2] [3] [4] [7]
Change in visual acuity or refraction [1] [2] [3] [4] [7] Inflammation of the orbital tissue may result in change in visual acuity and refraction. [1] [2] [3] [4] [7]
Diplopia, and decreased fields of vision [1] [2] [3] [4] [7] Extra ocular muscles gets weakened due to inflammatory process and the eye movements get defective resulting in double vision [1] [2] [3] [4] [7]
Transient visual loss or blackout periods [1] [2] [3] [4] [7] This usually suggests optic nerve compression due to increased volume within the orbit. [1] [2] [3] [4] [7]
Goitre, Anxiety, heat intolerance, weight loss [5] [6] These are symptoms of hyperthyroidism. There are auto antibodies in Graves disease which damage tissues in the orbital mainly the fat and the extraocular muscles. [5] [6]
References
  1. JONES D. I. R.. THE EFFECT OF METRONIDAZOLE ON EXOPHTHALMOS IN MAN. Journal of Endocrinology [online] 1968 August, 41(4):609-610 [viewed 24 August 2014] Available from: doi:10.1677/joe.0.0410609
  2. LUBIN J. R., JALLOW S. E., WILSON W. R., GROVE A. S., ALBERT D. M.. Rhinoscleroma with exophthalmos: a case report.. British Journal of Ophthalmology [online] 1981 January, 65(1):14-17 [viewed 24 August 2014] Available from: doi:10.1136/bjo.65.1.14
  3. DOCHERTY P T. Acute endocrine exophthalmos.. British Journal of Ophthalmology [online] 1976 June, 60(6):481-485 [viewed 24 August 2014] Available from: doi:10.1136/bjo.60.6.481
  4. CHATTERJEE B H, GHOSH P K. Intermittent exophthalmos- report of three cases. Indian J Ophthalmol [online] 1966,14:246-9. [viewed 24 Aug 2014] Available from: http://www.ijo.in/text.asp?1966/14/6/246/38665
  5. ARISAKA O., HOSAKA A., ARAI H., FUJIWARA S., TADOKORO R., YABUTA K.. Graves' disease associated with exophthalmos, cerebral ventricular dilatation and accelerated growth. Archives of Disease in Childhood [online] 1997 January, 76(1):62-64 [viewed 24 August 2014] Available from: doi:10.1136/adc.76.1.62
  6. STRIANESE DIEGO, et al. Unilateral proptosis in thyroid eye disease with subsequent contralateral involvement: retrospective follow-up study. Array [online] 2013 December [viewed 24 August 2014] Available from: doi:10.1186/1471-2415-13-21
  7. KUBICKY R. A., FAERBER E. N., DE CHADAREVIAN J.-P., WU S., REZVANI I., DE LUCA F.. An Adolescent With a Mediastinal Mass, Diagnosed With Graves Disease and Thymic Hyperplasia. PEDIATRICS [online] December, 125(2):e433-e437 [viewed 24 August 2014] Available from: doi:10.1542/peds.2009-2204

Examination

Fact Explanation
Proptosis of the eye [6] [7] [8] [9] The eye ball is in a rigid bony compartment and the only place where protrusion can occur is from the front. [6] [7] [8] [9]
Eyelid lesions and tenderness in palpation [1] [2] [3] [4] [5] [6] [7] [8] [9] Traumatic or inflammatory lesions in the eyelids are noted in inspection and tenderness can be elicited in palpation [1] [2] [3] [4] [5] [6] [7] [8] [9]
Chemosis [4] [5] [6] [7] [8] [9] Seen in graves ophthalmopathy due to inflammation. [4] [5] [6] [7] [8] [9]
Engorged conjunctival vessels [4] [5] [6] [7] [8] [9] Inflammation may cause this [4] [5] [6] [7] [8] [9]
incomplete lid closure [6] [7] [8] [9] As the eye ball is protruded to front, eyelids may be difficult to be closed [6] [7] [8] [9]
Pulsations of the globe on palpation [6] [7] [8] [9] Arterio-venous malformations may cause pulsations specially seen in cavernous sinus thrmobosis [6] [7] [8] [9] [10]
Regional lymph nodes [6] [7] [8] [9] Infective/ inflammatory cause or malignancy cause lymph node enlargement. [6] [7] [8] [9]
high flow state on auscultation of the orbit [6] [7] [8] [9] Orbital bruits may be heard in conditions like cavernous sinus thrombosis, fistulas [6] [7] [8] [9] [10]
Decreased visual acuity, change of refraction [4] [5] [6] [7] [8] [9] Inflammation of the orbital contents may result in change in visual acuity and refraction [4] [5] [6] [7] [8] [9]
Eye ball movement defects [4] [5] [6] [7] [8] [9] This indicates dysfunction of the extraocular muscles due to weakening associated with inflammation [4] [5] [6] [7] [8] [9]
Dilated fundoscopic examination [4] [5] [6] [7] [8] [9] Optic atrophy due to long standing optic nerve compression may be observed. [4] [5] [6] [7] [8] [9]
Goitre, tremors, increased sweating, tachycardia [1] [2] [3] These are symptoms of hyperthyroidism. The auto antibodies in Graves disease attack the fat and extra ocular muscles and resultant inflammation produces exophthalmos [1] [2] [3]
References
  1. ARISAKA O., HOSAKA A., ARAI H., FUJIWARA S., TADOKORO R., YABUTA K.. Graves' disease associated with exophthalmos, cerebral ventricular dilatation and accelerated growth. Archives of Disease in Childhood [online] 1997 January, 76(1):62-64 [viewed 24 August 2014] Available from: doi:10.1136/adc.76.1.62
  2. STRIANESE DIEGO, et al. Unilateral proptosis in thyroid eye disease with subsequent contralateral involvement: retrospective follow-up study. Array [online] 2013 December [viewed 24 August 2014] Available from: doi:10.1186/1471-2415-13-21
  3. KUBICKY R. A., FAERBER E. N., DE CHADAREVIAN J.-P., WU S., REZVANI I., DE LUCA F.. An Adolescent With a Mediastinal Mass, Diagnosed With Graves Disease and Thymic Hyperplasia. PEDIATRICS [online] December, 125(2):e433-e437 [viewed 24 August 2014] Available from: doi:10.1542/peds.2009-2204
  4. LUBIN J. R., JALLOW S. E., WILSON W. R., GROVE A. S., ALBERT D. M.. Rhinoscleroma with exophthalmos: a case report.. British Journal of Ophthalmology [online] 1981 January, 65(1):14-17 [viewed 24 August 2014] Available from: doi:10.1136/bjo.65.1.14
  5. CHATTERJEE B H, GHOSH P K. Intermittent exophthalmos- report of three cases. Indian J Ophthalmol [online] 1966,14:246-9. [viewed 24 Aug 2014] Available from: http://www.ijo.in/text.asp?1966/14/6/246/38665
  6. DOCHERTY P T. Acute endocrine exophthalmos.. British Journal of Ophthalmology [online] 1976 June, 60(6):481-485 [viewed 24 August 2014] Available from: doi:10.1136/bjo.60.6.481
  7. KWAN A. S L, WILKINSON E., ADAMS G. G W. Recurrent proptosis and thyroid eye disease. Postgraduate Medical Journal [online] 1999 November, 75(889):689-691 [viewed 24 August 2014] Available from: doi:10.1136/pgmj.75.889.689
  8. DESAI BOBBY. A Case of Traumatic Proptosis. Case Reports in Emergency Medicine [online] 2013 December, 2013:1-3 [viewed 24 August 2014] Available from: doi:10.1155/2013/514328
  9. TOMASETTI P., JACBOSEN C., GANDER T., ZEMANN W.. Emergency decompression of tension retrobulbar emphysema secondary to orbital floor fracture. Journal of Surgical Case Reports [online] December, 2013(3):rjt011-rjt011 [viewed 24 August 2014] Available from: doi:10.1093/jscr/rjt011
  10. WEBER FP. Case of Exophthalmos probably caused by Non-suppurative Cavernous Sinus Thrombosis Proc R Soc Med [online] 1923, 16(Clin Sect):41-43 [viewed 05 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2103857

Differential Diagnoses

Fact Explanation
Orbital cellulitis [5] Infection of the orbit due to various organisms present with can present with pain in the eye, reduced vision, and double vision [5]
Carotid Cavernous fistula [6] There's abnormal connection between internal or external carotid arteries and the cavernous sinus resulting in fistula formation. Double vision, redness, bruits are observed[6]
Cavernous Hemangioma [7] This is benign tumor that presents in adults and it's not painful [7]
Orbital Fractures [1] [2] Fractures of the bones which line the orbit can cause double vision, and difficulty to move the eye [1] [2]
Thyroid Ophthalmopathy [3] Graves disease causes exophthalmos which present with redness, double vision, along with other symptoms suggestive of hyperthyroidism. . [3]
Pleomorphic lacrimal gland adenoma [8] This is a tumor in the eye and may present with protrusion of the eye ball.[8]
Malignancies such as leukemia [4] Soft tissue infiltration of malignant cells in Acute myeloid leukemia (AML) occurs in the orbit as well therefore can cause ocular symptoms [4]
References
  1. TOMASETTI P., JACBOSEN C., GANDER T., ZEMANN W.. Emergency decompression of tension retrobulbar emphysema secondary to orbital floor fracture. Journal of Surgical Case Reports [online] December, 2013(3):rjt011-rjt011 [viewed 24 August 2014] Available from: doi:10.1093/jscr/rjt011
  2. DESAI BOBBY. A Case of Traumatic Proptosis. Case Reports in Emergency Medicine [online] 2013 December, 2013:1-3 [viewed 24 August 2014] Available from: doi:10.1155/2013/514328
  3. KWAN A. S L, WILKINSON E., ADAMS G. G W. Recurrent proptosis and thyroid eye disease. Postgraduate Medical Journal [online] 1999 November, 75(889):689-691 [viewed 24 August 2014] Available from: doi:10.1136/pgmj.75.889.689
  4. MURTHY RAMESH, VEMUGANTI GEETA K, HONAVAR SANTOSH G, NAIK MILIND, REDDY VIJAYANAND. Extramedullary leukemia in children presenting with proptosis. Array [online] 2009 December [viewed 24 August 2014] Available from: doi:10.1186/1756-8722-2-4
  5. BERGIN D J, WRIGHT J E. Orbital cellulitis.. British Journal of Ophthalmology [online] 1986 March, 70(3):174-178 [viewed 24 August 2014] Available from: doi:10.1136/bjo.70.3.174
  6. KAPLAN JOSHUA B, BODHIT AAKASH N, FALGIANI MICHAEL L. Communicating carotid-cavernous sinus fistula following minor head trauma. Array [online] 2012 December [viewed 24 August 2014] Available from: doi:10.1186/1865-1380-5-10
  7. MURRONE DOMENICO, DE PAULIS DANILO, MILLIMAGGI DANIELE F, DEL MAESTRO MATTIA, GALZIO RENATO J. Cavernous hemangioma of the frontal bone: a case report. Array [online] 2014 December [viewed 24 August 2014] Available from: doi:10.1186/1752-1947-8-121
  8. CATES C. A. Pleomorphic adenoma of the lacrimal gland in a 10 year old girl. [online] 2002 February, 86(2):249-250 [viewed 24 August 2014] Available from: doi:10.1136/bjo.86.2.249

Investigations - for Diagnosis

Fact Explanation
Thyroid function studies [1] [2] [3] [7] [8] Patients with exophthalmos should undergo thyroid function studies to assess the thyroid status. Usually elevated free T4, T3 is seen with reduced TSH. [1] [2] [3] [7] [8]
Full blood count [4] [5] When orbital cellulitis is suspected, full blood count may show high white blood cell counts. [4] [5]
Blood culture [4] [5] When orbital cellulitis is suspected, blood for cultures are taken. [4] [5]
Nasal culture [4] [5] When orbital cellulitis is suspected, nasal secretions are taken to identify the portal of entry of the organism and to isolate the organism [4] [5]
Intra-ocular pressure measurement [7] Intra-ocular pressure may be high in Graves disease therefore measurement is done. [7]
CT scan of the orbit [6] [8] This helps in evaluation of the orbit and to detect any masses if present. [6] [8]
MRI of the orbit [6] [8] Excellent soft tissue enhancement is an advantage to do MRI even though it;s expensive or neither widely available. [6] [8]
Ocular ultrasonography [8] This helps to visualize masses if present and when combined with Doppler it's particularly useful to detect increased blood flow.[8]
References
  1. KWAN A. S L, WILKINSON E., ADAMS G. G W. Recurrent proptosis and thyroid eye disease. Postgraduate Medical Journal [online] 1999 November, 75(889):689-691 [viewed 24 August 2014] Available from: doi:10.1136/pgmj.75.889.689
  2. ARISAKA O., HOSAKA A., ARAI H., FUJIWARA S., TADOKORO R., YABUTA K.. Graves' disease associated with exophthalmos, cerebral ventricular dilatation and accelerated growth. Archives of Disease in Childhood [online] 1997 January, 76(1):62-64 [viewed 24 August 2014] Available from: doi:10.1136/adc.76.1.62
  3. STRIANESE DIEGO, et al. Unilateral proptosis in thyroid eye disease with subsequent contralateral involvement: retrospective follow-up study. Array [online] 2013 December [viewed 24 August 2014] Available from: doi:10.1186/1471-2415-13-21
  4. GOODYEAR P W A. Periorbital swelling: the important distinction between allergy and infection. Emergency Medicine Journal [online] 2004 March, 21(2):240-242 [viewed 24 August 2014] Available from: doi:10.1136/emj.2002.004051
  5. GONZALEZ MO, DURAIRAJ VD. Understanding pediatric bacterial preseptal and orbital cellulitis. Middle East Afr J Ophthalmol [online] 2010 Apr, 17(2):134-7 [viewed 24 August 2014] Available from: doi:10.4103/0974-9233.63074
  6. CHATTERJEE B H, GHOSH P K. Intermittent exophthalmos- report of three cases. Indian J Ophthalmol [online] 1966,14:246-9. [viewed 24 Aug 2014] Available from: http://www.ijo.in/text.asp?1966/14/6/246/38665
  7. KALMANN R., MOURITS M. P.. Prevalence and management of elevated intraocular pressure in patients with Graves' orbitopathy. British Journal of Ophthalmology [online] 1998 July, 82(7):754-757 [viewed 24 August 2014] Available from: doi:10.1136/bjo.82.7.754
  8. FICHTER N., GUTHOFF R. F., SCHITTKOWSKI M. P.. Orbital Decompression in Thyroid Eye Disease. ISRN Ophthalmology [online] 2012 December, 2012:1-12 [viewed 24 August 2014] Available from: doi:10.5402/2012/739236

Investigations - Fitness for Management

Fact Explanation
Thyroid function studies [2] [3] [4] [5] Patients with Graves disease should undergo the thyroid function studies to assess the thyroid status prior to surgical management of the goitre. [2] [3] [4] [5]
Full blood count [1] To exclude anemia prior to surgery [1]
Coagulation studies [1] To exclude any coagulopathy prior to surgery [1]
Renal function tests ( Serum Creatinine, eGFR, Blood urea nitrogen) [1] To assess the fitness for anesthesia prior to surgery [1]
References
  1. KUMAR A, SRIVASTAVA U. Role of routine laboratory investigations in preoperative evaluation J Anaesthesiol Clin Pharmacol [online] 2011, 27(2):174-179 [viewed 24 August 2014] Available from: doi:10.4103/0970-9185.81824
  2. KWAN A. S L, WILKINSON E., ADAMS G. G W. Recurrent proptosis and thyroid eye disease. Postgraduate Medical Journal [online] 1999 November, 75(889):689-691 [viewed 24 August 2014] Available from: doi:10.1136/pgmj.75.889.689
  3. ARISAKA O., HOSAKA A., ARAI H., FUJIWARA S., TADOKORO R., YABUTA K.. Graves' disease associated with exophthalmos, cerebral ventricular dilatation and accelerated growth. Archives of Disease in Childhood [online] 1997 January, 76(1):62-64 [viewed 24 August 2014] Available from: doi:10.1136/adc.76.1.62
  4. STRIANESE DIEGO, et al. Unilateral proptosis in thyroid eye disease with subsequent contralateral involvement: retrospective follow-up study. Array [online] 2013 December [viewed 24 August 2014] Available from: doi:10.1186/1471-2415-13-21
  5. FICHTER N., GUTHOFF R. F., SCHITTKOWSKI M. P.. Orbital Decompression in Thyroid Eye Disease. ISRN Ophthalmology [online] 2012 December, 2012:1-12 [viewed 24 August 2014] Available from: doi:10.5402/2012/739236

Investigations - Followup

Fact Explanation
Thyroid function tests [1] [2] [3] [4] Patients with Graves disease should undergo the thyroid function studies to assess the thyroid status and this test is done in the follow up to assess thyroid status. [1] [2] [3] [4]
References
  1. KWAN A. S L, WILKINSON E., ADAMS G. G W. Recurrent proptosis and thyroid eye disease. Postgraduate Medical Journal [online] 1999 November, 75(889):689-691 [viewed 24 August 2014] Available from: doi:10.1136/pgmj.75.889.689
  2. ARISAKA O., HOSAKA A., ARAI H., FUJIWARA S., TADOKORO R., YABUTA K.. Graves' disease associated with exophthalmos, cerebral ventricular dilatation and accelerated growth. Archives of Disease in Childhood [online] 1997 January, 76(1):62-64 [viewed 24 August 2014] Available from: doi:10.1136/adc.76.1.62
  3. STRIANESE DIEGO, et al. Unilateral proptosis in thyroid eye disease with subsequent contralateral involvement: retrospective follow-up study. Array [online] 2013 December [viewed 24 August 2014] Available from: doi:10.1186/1471-2415-13-21
  4. FICHTER N., GUTHOFF R. F., SCHITTKOWSKI M. P.. Orbital Decompression in Thyroid Eye Disease. ISRN Ophthalmology [online] 2012 December, 2012:1-12 [viewed 24 August 2014] Available from: doi:10.5402/2012/739236

Management - General Measures

Fact Explanation
Patient education [1] [2] [3] [4] Patient education plays an important role and the patient should be educated regarding the etiology, nature, course and prognosis, available treatment options and importance of follow up. Advices should be given to avoid smoking as it has showed to increase the risk of ocular disease. [1] [2] [3] [4]
Elevation of the head end of the bed and taping of the eye lids [3] This is thought to reduce the peri-orbital edema associated with exophthalmos also inability to close the eye completely during sleep [3]
Wearing sungalsses [3] If patient is having inability/ pain to look at light, sunglasses during the day light is helpful [3]
Ocular lubricants [1] [2] This will reduce the dryness of the eyes. [1] [2]
References
  1. BARTALENA L., et al. Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. European Journal of Endocrinology [online] 2008 March, 158(3):273-285 [viewed 24 August 2014] Available from: doi:10.1530/EJE-07-0666
  2. OESTREICHER JAMES, MEHTA SONUL. Complications of Blepharoplasty: Prevention and Management. Plastic Surgery International [online] 2012 December, 2012:1-10 [viewed 24 August 2014] Available from: doi:10.1155/2012/252368
  3. MCNAB A. A. Does radiotherapy have a role in the management of thyroid orbitopathy?. [online] 2002 January, 86(1):102-107 [viewed 24 August 2014] Available from: doi:10.1136/bjo.86.1.102
  4. JURECKA-LUBIENIECKA BEATA, et al. Association between Polymorphisms in the TSHR Gene and Graves' Orbitopathy. PLoS ONE [online] 2014 July [viewed 24 August 2014] Available from: doi:10.1371/journal.pone.0102653

Management - Specific Treatments

Fact Explanation
Treatment for underlying Graves disease [1] [6] [7] [8] [10] Medical therapy as Carbimazole, Proplythiouracil, Radio iodine treatment are helpful. Total thyroidectomy can also be an option [1] [6] [7] [8] [10]
Immunosuppressants [1] [6] [9] Corticosteroids are inflammatory agents, therefore reduce the inflammation and Methotrexate is also used sometimes. [1] [6] [9]
Selenium therapy [11] [13] Increased generation of free radicals is thought to be seen in Graves disease and Selenium acts as an anti-oxidant. Studies have shown that it improves quality of life and slows the progression of the disease in patients with mild Graves' ophthalmopathy. [11] [13]
Orbital radiotherapy [2] [10] This can be given if there's poor response to corticosteroids and can be used in conjunction with corticosteroids as well [2] [10]
Surgical management [3] Surgical management may vary depending on the cause. Cavernous sinus fistula can be repaired and also thyroidectomy for Graves disease can be done. Sometimes extra ocular muscle surgery is also carried out. [3]
Orbital decompression surgery [4] [5] Orbital bone segments may be removed in order to reduce the compression [4] [5]
Management of any underlying malignancy which causes exophthalmos [12] Treatment depends on the type of tumour which causes exophthalmos [12]
References
  1. FARLING P. A.. Thyroid disease. [online] 2000 July, 85(1):15-28 [viewed 24 August 2014] Available from: doi:10.1093/bja/85.1.15
  2. MCNAB A. A. Does radiotherapy have a role in the management of thyroid orbitopathy?. [online] 2002 January, 86(1):102-107 [viewed 24 August 2014] Available from: doi:10.1136/bjo.86.1.102
  3. KAPLAN JOSHUA B, BODHIT AAKASH N, FALGIANI MICHAEL L. Communicating carotid-cavernous sinus fistula following minor head trauma. Array [online] 2012 December [viewed 24 August 2014] Available from: doi:10.1186/1865-1380-5-10
  4. FICHTER N., GUTHOFF R. F., SCHITTKOWSKI M. P.. Orbital Decompression in Thyroid Eye Disease. ISRN Ophthalmology [online] 2012 December, 2012:1-12 [viewed 24 August 2014] Available from: doi:10.5402/2012/739236
  5. TOMASETTI P., JACBOSEN C., GANDER T., ZEMANN W.. Emergency decompression of tension retrobulbar emphysema secondary to orbital floor fracture. Journal of Surgical Case Reports [online] December, 2013(3):rjt011-rjt011 [viewed 24 August 2014] Available from: doi:10.1093/jscr/rjt011
  6. KWAN A. S L, WILKINSON E., ADAMS G. G W. Recurrent proptosis and thyroid eye disease. Postgraduate Medical Journal [online] 1999 November, 75(889):689-691 [viewed 24 August 2014] Available from: doi:10.1136/pgmj.75.889.689
  7. ARISAKA O., HOSAKA A., ARAI H., FUJIWARA S., TADOKORO R., YABUTA K.. Graves' disease associated with exophthalmos, cerebral ventricular dilatation and accelerated growth. Archives of Disease in Childhood [online] 1997 January, 76(1):62-64 [viewed 24 August 2014] Available from: doi:10.1136/adc.76.1.62
  8. STRIANESE DIEGO, et al. Unilateral proptosis in thyroid eye disease with subsequent contralateral involvement: retrospective follow-up study. Array [online] 2013 December [viewed 24 August 2014] Available from: doi:10.1186/1471-2415-13-21
  9. STRIANESE DIEGO, et al. Methotrexate for the Treatment of Thyroid Eye Disease. Journal of Ophthalmology [online] 2014 December, 2014:1-5 [viewed 24 August 2014] Available from: doi:10.1155/2014/128903
  10. GWINUP GRANT. Effect on Exophthalmos of Various Methods of Treatment of Graves' Disease. JAMA [online] 1982 April [viewed 24 August 2014] Available from: doi:10.1001/jama.1982.03320400047033
  11. DUNTAS LEONIDAS H.. The Evolving Role of Selenium in the Treatment of Graves' Disease and Ophthalmopathy. Journal of Thyroid Research [online] 2012 December, 2012:1-6 [viewed 24 August 2014] Available from: doi:10.1155/2012/736161
  12. ECKARDT ANDRĂ© M, LEMOUND JULIANA, RANA MAJEED, GELLRICH NILS-CLAUDIUS. Orbital lymphoma: diagnostic approach and treatment outcome. Array [online] 2013 December [viewed 24 August 2014] Available from: doi:10.1186/1477-7819-11-73
  13. MARCOCCI CLAUDIO, et al. Selenium and the Course of Mild Graves' Orbitopathy. N Engl J Med [online] 2011 May, 364(20):1920-1931 [viewed 07 September 2014] Available from: doi:10.1056/NEJMoa1012985