Thyroid eye disease

1. Thyroid eye disease B.Eshraghi M.D Associate professor of ophthalmology Ophthalmic plastic and reconstructive surgeon TUMS

3. Definition • TED is an heterogeneous autoimmune disorder affecting the thyroid, eyes and skin • Clinically apparent ophthalmopathy occurs in 25-50% of patients with GD • 3–5% of patients suffer from intense painand inflammation with double vision or even loss of vision • Thyroid eye disease, is a potentially progressive but generally self-limited autoimmune process • Approximately 10% of patients with GO donot have hyperthyroidism • some degree of ocular involvement may be detected by sensitive imaging techniques (MRI or CT) in almost all patients with Graves’ disease

4. It is the most common cause of proptosis ( 85% of bilateral and 50% of unilateral exophthalmos in adults) • Graves’ disease has a strong female preponderance, with a female: male ratio of approximately 4:1 - 9:1 • Affected men tend to progress more rapidly and severely • average age in the 40s (Age peaks: the 5th and 7th decades) • Children are rarely affected

6. Pathological findings • Many of the clinical symptoms and signs of GO can beexplained on a mechanical basis by an increase in the volume of both: 1.Orbital fatty connective tissues 2.Extraocularmuscle bodies

7. Sever proptosis with increased orbital adipose tissue

8. TED with large muscles

9. Clinical features Blurred vision Orbital pain Diplopia Lid edema Lacrimation Ocular discomfort Photophobia • Lid edema • Chemosis • Conjunctinal injection • SLK • Keratopathy • Proptosis • Lid retraction • Lagophthalmos • High IOP • Abnormal disc • Choroidal folds • Extraocularmuscle dysfunction

10. Diagnosis of TED

11. Diagnosis is made when 2 of the following 3 signs are present : • Thyroid dysfunction; • Graves hyperthiroidism • Hashimoto thyroiditis • Presence of circulating thyroid antibodies without a coexisting dysthyroid state • (TSH-R ab, TBII, TSI, antimicrosomlAb (Anti TPO) • Orbital signs: • Unilateral or bilateral eyelid retraction with typical temporal flare (± lagophthalmos) 90% • Bilateral proptosis 60% • Restrictive strabismus in a typical pattern 40% • Compressive optic neuropathy 6% • Fluctuating eyelid edema/ erythema • Chemosis/ caruncular edema

12. 3. radiographic evidence of TAO : • Unilateral or bilateral fusiform enlargement of one or more of the following; • MR muscle • IR muscle • SR muscle

13. Thyroid status: • Hypertyroidism (90%) • Eutyroidism (6%) • Hypothyroidism and hashimatu (4%) • 20% coincidence • In 60% eye disease occurs within one year of onset of thyroid disease • In others the risk of thyroid disease is 25% in one year and 50% in 5 years

14. Evaluation • Classification: • Activity • Severity • Different types of classification : • NOSPECS (1969 by Werner ) • CAS (1989by Mourits ) • EUGOGO (1999) • VISA (developed by Dolman and Rootman in 2006)

16. Activity measures Activity measures based on the classical features of inflammation (it consists of two symptoms and five signs): 1. Spontaneous retrobulbar pain 2. Pain on attempted up or down gaze 3. Redness of the eyelids 4. Redness of the conjunctiva 5. Swelling of the eyelids 6. Inflammation of the caruncle and/or plica 7. Conjunctival edema A CAS ≥3/7 indicates active GO

17. Patients assessed after follow-up (1–3 months) can be scored out of 10: • 8- Increased of >2mm proptosis • 9- Decrease in uniocular ocular excursion in any one direction of >8° • 10- Decrease of acuity equivalent to 1 Snellen line

18. Is there any problem with activity scores? • A 48 year old woman presented with: • Chemosis 3+ • Lid edema 3+ • Conjunctival injection 3+ A 56 year old man presented with: • Conjunctival injection 2+ • caruncle inflammation 1+ • Mild retrobulbar pain

20. Severity classification: • Mild TED • Moderate to sever TED • Sight threatening

21. Mild TED • 1. minor lid retraction (<2 mm), • 2.exophthalmos <3 mm above normal for race and gender, • 3. mild soft tissue involvement • 4. transient or no diplopia • 5. corneal exposure responsive to lubricants • Features of GO have only a minor impact on daily life and they do not need immunosuppressive except in the presence of low QOL score.

22. Mild inactive TED

23. Sight threatening TED 1- Dysthyroid optic neuropathy (DON) 2- Corneal breakdown • Immediate intervention is necessary in this category

24. Moderate to severe TED 1. lid retraction ≥2 mm, 2. moderate or severe soft tissue involvement, 3. exophthalmos ≥3 mm above normal for race and gender 4. inconstant, or constant diplopia. IN this group eye disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive).

25. Moderate to severe inactive TED

26. Management: • TED is often mild and self-limiting • Active inflammation usually lasts between 6 months to 2 years • Reactivation can occurs in 5% even after 7 years • All patients with GO, except for the mildest cases, should either be managed by a physician with particular expertise in managing GO or better be referred to a combined thyroid eye clinics for further assessment and management

27. Risk Factors for severity • Tobacco • Male • Older age • Sever thyroid dysfunction • Thyroid dermopathy • Higher serum triiodothyroxine

28. Is correction of thyroid dysfunction important forGO? • Patients with uncontrolled thyroid function (both hyper- and hypothyroidism) are more likely to have more severe TED than patients with euthyroidism • Antithyroid drug (ATD) therapy and thyroidectomy do not affect the course of TED • surgical thyroidectomy, alone or in combination with medical therapy, was associated with a 74% decreased risk for TED development compared with radioactive iodine therapy alone in GD • J. D. Stein, D. Childers, S. Gupta et al., “Risk factors for developing thyroid-associated ophthalmopathyamong individuals with Graves disease,” JAMA Ophthalmology, vol. 133, no. 3, pp. 290–296, 201

29. Radioiodine… • 15% develop new eye disease or experience the progression of pre-existing GO within 6 months after radioiodine therapy • In 5% of patients, worsening persisted at 1 year and required additional treatment • This risk is almost eliminated by giving a short course (3 months) of oral glucocorticoids (GCs) after radioiodine therapy • Steroid cover can be avoided in patients with inactive eye disease, when other risk factors for GO progression, including smoking,high free thyroid hormone level and/or TSH receptor autoantibodies,hyperthyroidism of recent onset

30. Radioiodine can cause NLD obstruction • Hyper or Hypothyroidism should be treated

31. Smoking • The mechanisms involved in the association between smokingand GO are unclear • Smoking is the most important risk factor amenable to modification in patients with GO • The odds ratio, relativeto controls, has been reported to be as high as 20.2 for currentsmokers • Development of GO • Deterioration of pre-existing disease • Effectiveness of treatment • More sever disease • Progression after radioiodone

32. General consideration • Elevation of head • Low salt diet • Lubrication (dry eye is common because of evaporation and lacrimal gland inflammation) • Sunglasses • Patching • Prism • Botulinum toxin

33. Botulinum toxininjection in upper lid retraction

35. Management of mild active GO • Watching waiting is appropriate for the majority of patients • 15% of the patients with mild disease may experience progression • 6-month course with oral selenium (100 μg twice daily) significantly improves quality of life in active disease • Glucocorticoids are rarely justified in mild GO • If quality of life has been profoundly affected treatment is similar to moderate to severe GO

36. Management of active moderate to sever GO Other modalities (IVIG ,biologic agents , somatostatin analogues…..

38. Oral prednisolone 60-80 mg 2 to 4weeks 40mg 2weeks 30mg 2 weeks 20mg 4weeks tapered off 2.5 10 mg / week Course of therapy 4- 8 months

39. IV includes: • fewer side effects , more effective , less relapse , shorter duration of treatment • 500-1000mg pulse methylprednisolone for 3 days followed by oral prednisolone • 500mg pulse methylprednisolone weekly for 6 weeks then 250mg for another 6 weeks.(4.5 gr) • 500 mg IV for 3 days ,Repeat every 4 weeks for three months,0-4 -8 -12 (6 gr) • 750 mg pulse methylprednisolone weekly for 6 weeks then 500 mg for another 6 weeks.(7.5 gr)

40. Patients with recent hepatitis, liver dysfunction, severe cardiovascular morbidity, or severe hypertension must be excluded • Liver enzymes,(viral markers for hepatitis) ,glucose levels, and blood pressure should be monitored before starting and then monthly during treatment • Idiosyncratic hepatic failure and arrhythmia might occur at cumulative doses over 8g • Safety data suggest that single dose should not exceed .75gr ,cumulative dose should be less than 8 gr and consecutive day -therapy should be avoided

41. Oral prednisolone

42. Radiotherapy • It takes about 4 weeks to observe acceptable response • RT probably alters helpers/suppressor T lymphocyte ratio • orbital radiotherapy combined with corticosteroids has an effective and sustained response and is protective against disease progression to restrictive myopathy and compressive optic neuropathy • Patient with sever HTN or diabetic retinopathy should not be treated with radiation • DM without DR should be regarded as a relative contraindication • RT should be avoided in patients younger than 35 years old • It is better to preserve for sever active TED

43. Protocols • 2 GY/day over 2 weeks for a total dose of 20 GY • 1 GY/day over 2 weeks for a total dose of 10 GY • 1 GY weekly over 10 weeks for a total dose of 10 GY • 2 GY weekly over 10 weeks for a total dose of 20 GY • Response is similar to oral GC cataract occurs in 12% of patients

44. Other options…… • Steroid-sparing agents =nonsteroidimmunosuppresant(e.g. methotrexate, azathioprine, rapamycin, cyclosporin, cyclophospamide) • Immunomodulator (e.g.ciamexone) • Newer biologics (e.g. rituximab,adalimumab) • Somatostatin analogs,(e.g. octreotide and lanreotide). • Oral antioxidan(allopurinol ,nicotinamide) • Cytokine blocking agent(pentoxifylline) • IVIG • Plasmapheresis

45. When should you start second line treatment? Use adjuvant immunosuppressive drugs or cyclosporine in patients who may not have responded to other measures or are diabetic In patients with persistent active disease despite a full course of steroid treatment

46. Cyclosporine has lower effectiveness than prednisone as a single-agent treatment, but a combination of cyclosporine and prednisone may be more effective than either treatment alone • In some cases, the use of topical cyclosporine has aided in reducing ocular surface irritation

47. Cyclosporine is administered 50 mg twice a day with an upper range of 200 mg twice a day. The usual dosage is 100 mg twice a day. • Some authors have suggested that early combinations of corticosteroids and immunosuppressive drugs may reduce disease severity. • Cyclosporine, although shown to be less effective than oral glucocorticoids in a randomized trial, may help to reduce the dose of glucocorticoids

48. Immunobiologic therapy (Rituximab,Adalimumab,Tocilizumab) • Immunobiologic therapy that targets specific components of the immune system with genetically engineered monoclonal antibodies may provide acute and long-term efficacy and a safe form of therapy. • Rituximab is an intravenously administered chimeric mouse-human monoclonal antibody that targets the CD20 antigen on pre-B and mature B lymphocytes.

49. 2 courses of rituximab(1000 mg ) over a 2-week period, and there were no adverse effects of the rituximab infusions and no reported side effects during the 1-year post infusion observation period. • The concluded that at present, high cost, and potential side effects do not support use of rituximab in uncomplicated Graves’ disease

50. Refractory case before and after Rituximab