Thyroid eye disease ( Graves Ophthalmopathy )

Overview of the clinical diagnostic and treatment options in thyroid eye disease (Graves Ophthalmopathy).

1. Thyroid Eye Disease Raed Behbehani , MD FRCSC

2. Thyroid Eye Disease 1-2% of women , 0.5% of men Female : Male ratio , 5:1 Infiltration of immune effector cells and thyroid-antigen-specific T cells into thyroid and TSH receptors carrying tissues TSHR is found on thyroid epithelial cells , adipocytes and bone cells. Fibroblast activation is caused by inflammatory cytokines released by T-cells and macrophages.

3. Pathology Infiltration of connective tissue with mononuclear cells (lymphocytes, macrophages , plasma cells) Activation of CD4+ and CD8+ T-cells and integration with B cells, plasmas cells and macrophages. Release of pro-inflammatory cytokines. Accumulation of GAG in the EOM and fat. CD34 + fibrocytes key in the pathogenesis , Antigen in orbit : Thyroglobulin TSHR is found on thyroid follicles and orbital fibroblasts

4. Systemic Signs and Symptoms Symptoms : Hyperactivity , hear intolerance , palpitations , weight loss and gain (increased appetite) , Diarrhea . Signs : Tachycardia , atrial fibrillations , tremor , goiter , warm moist skin, lid retraction and lag , exophthalmos. Eye signs usually start within a year of hyperthyroidism (75%) Occasionally eye signs start years later.

5. Laboratory investigations Endocrine : low or borderline TSH ,normal or elevated T4 , elevated T3, TSHR autoantibodies T3 toxicosis . T4 toxicosis (excess iodine intake) Eleveated bilirubin , liver enzymes , ferritin (diagnostic confusion) Microcystic anemia and thrombocytopenia.

6. TSHR Auto-antibodies Antibodies that bind to TSH receptors. Binding assay : measures both Thyroid stimulating and thyroid blocking antibodies Cell-based assay : can distinguish thyroid stimulating and thyroid blocking antibodies by their effect on cyclic AMP production in cell lines. (more useful to measure activity and prognosis)

7. Imaging in TED Enlargement of EOM, orbital fat expansion , increase lacrimal gland size. CT is the study of choice (Bone and soft tissues)

8. CT in TED For initial diagnosis and for planing for decompression surgery Bone remodeling (medial wall) Enlargement of EOM , lacrimal glands, anterior soft tissue swelling , prominent SOV maybe seen

9. MRI in TED Quantitative and qualitative Assess disease activity Increased T2 in EOM - good response to XRT and steroids Increased T2 in EOM - active stage ( high water content) Low T2 in EOM- inactive fibrotic stage

10. Ultrasound in TED A and B-scan operator dependent Normal muscle - low internal reflectivity Active phase - lower internal reflectivity (swelling) Fibrotic phase- irregular high reflectivity (scar)

11. Medical Management of Hyperthyroidism Anti-thyroid drugs : thinoamides (PTU) , carbimazole , methimazole. Thionamides inhibit synthesis of thyroid hormones. Need 6-8 weeks to achieve euthyroid state Side effects of anti-thyroid drugs : Skin rash , urticarial , arthralgia , Fever

12. Natural History of Thyroid Eye Disease Rundle’s curve Progressive phase lasting for up to 18 months Stable (inactive) phase

13. Clinical Features – Lid retraction Pathogenesis : sympathetic stimulation , overaction of LPS alone with SR compensating for IR restriction , inflammation and fibrosis of LPS.

14. Clinical Features-Proptosis Due to expansion of orbital fat and muscles. Complete subluxation of the globe (sometimes) Prolapse of the lacrimal glands Corneal exposure/ epithelial defects Absence of Bell’s phenomenon (tight IR)

15. Strabismus 30% of patients with TED Diplopia can be intermittent or constant During the active phase : enhancement of fat surrounding affected muscles Inferior Recti , Medial Recti (most common) Any type of Strabismus ( ET and HopT most common) Oblique muscle involvement more common.

16. Compressive Optic Neuropathy 5%-7% of TED Direct compression of the optic nerve at the orbital apex Dyschromatopsia , RAPD ( absent if bilateral) Disc edema in 40% Visual fields Often in the active phase of the disease Proptosis may be minimal (tight lids)

17. Thyroid CON

18. Clinical Activity NOSPECS – not very useful EUGOGO classification : Mild : eyelid swelling , lid retraction, proptosis Moderate-Severe : Active disease (EOM dysfunction, diplopia , proptosis >25 mm) Very severe : CON , Corneal exposure (needs emergent surgery)

19. Clinical Activity Clinical Activity Score (CAS) : -Binary scale -1 point for each periocular soft tissue inflammatory sign -Points for proptosis ( 2 mm or more) , decreased motility (8 degrees or more) or decreased visual acuity over last 3 months. -CAS > 4 means 80% PPV for response to steroids

20. CAS Limitations Score does not correlate with significant complications (CON) , each sign has equal point weight Patients with low CAS may develop severe complications (like CON) Cannot measure response to therapy

21. VISA classification V (Vision) , I (inflammation), S (Strabismus) , A (Appearance) Vision/CON Inflammation/Congestion : based on documented change of inflammation rather than absolute value Strabismus/Motility : measuring ductions and alignments Appearance/Exposure Score of 5 or more —> Active disease or progression (Consider Steroids)

22. VISA Classification

23. VISA Classification

24. Risk Factors for Progression Smoking Life stressors Hypothyroidism following radio-iodine treatment Positive family history of auto-immune disease Increasing age

25. Medical Management of TED Assessment of clinical severity of disease. CAS : 4 of 10 points (80% PPV to steroids) VISA classification : popular in N America (>5 of 10) GO-QOL : to assess effects of disease on personal and professional life. Simple measures for mild TED ( lubricants , cold compressors)

26. Selenium 200 ug/day for 6 months For Mild disease Antioxidant effect Immunomodulatory effect : reduce thyroid autoantibodies Reduce severity of disease and improve QOL

27. Corticosteroids Intravenous , Oral IV pulses are more effective and has less side effects IV dose (max 8 grams) : 500 mg weekly for 6 weeks and then 250 mg weekly for 6 weeks Relapse is common (20%) Steroid response is evident usually 2-4 weeks later Moderate to severe TED : 71% respond to IV steroid vs 51% oral with SS improvement of VA , chemosis and QOL. IV steroids for compressive ON

28. Orbital Radiation Mechanism : lymphocyte sterilization, destruction of tissue monocytes 20 Gy in 10 divided sessions over 2 weeks May have a role in patients with TED who have restricted ocular motility or active disease Some studies have shown benefit (controversial) More suited for patients > 35 years of age Contra-indicated in pre-existing retinopathy (diabetes , hypertensive)

29. Rituximab Chimeric mono-clonal antibody targets CD20 CD20 is expressed on more than 95% of B cells and plasma cells RTX removes B cells and short-lived plasma cells RTX depletes 95% of mature B cells , blocks Ab production , and decrease inflammatory cytokine release For steroid-refractory disease Side effects : Allergic reaction (mild) PML (severe)

30. Botulinum Toxin Neurotoxin , inhibits acetylcholine release For upper lid retraction (transconjunctival , transcutaneous route) Effect on Muller’s muscle and LPS Side effects of Botox : bruising , ptosis and diplopia

31. Orbital Decompression for TED In TED , expansion of fat and muscles. Decompression usually in stable phase of disease. Cosmetic for rehabilitation and or for severe TED. Need to discuss goals of surgery with patients. Post-operative complications (diplopia, vision loss) Outcome is variable : degree of fibrosis , fat expansion , bone available , duration of optic neuropathy etc Decompression —> Muscle Surgery —> Lid surgery

32. Orbital Decompression Fat only (First Wall) 2-3 mm Lateral Wall 3-6 mm Medial Wall 4-7 Orbital Roof 5-9 mm

33. Strabismus Surgery for TED In the stable phase with stable alignments for 6 months Press-on Fresnel/Botox as temporizing measure Single binocular vision in primary and reading position “More is less and less is More” Conjunctival dissection is challenging Adjustable vs Fixed sutures Relaxed EOM positioning Oblique surgery can increase area of single binocular vision

34. Complications of Strabismus Surgery in TED Scleral perforation Anterior segment ischemia (>2 muscles , old age , Atherosclerosis) — preoperative Iris FA Slipped/lost muscles (IR) Under-/overcorrections Re-operation rate around 50% in TED Intraoperative assessment of oblique muscle involvement (to increase area of binocularity)

35. Crowing of Eyebrows /Lid Complex Fat expansion/prolapse of the lacrimal glands

36. Lower Lid retraction Can improve with decompression and removal of the floor basin. Lower lid recession with decompression. Spacer (ear cartillage or hard palate/allogenic material Lower retraction repair can be combined with inferior rectus recession

37. Upper Lid Retraction Levator recession / Mullerectomy Full-thickness blepharotomy Botox injections into Muller’s muscle Filler (Hyaloronic acid) in subcinjunctival space (0.1-0.2 ml)

38. Psychological Impact of TED Disfigurement/altered facial appearance Misinterpretation as hostile or angry Almost 50% of TED suffer depression and/or anxiety 90% of TED have appearance concerns (young females) 44% have self-confidence issues Quality of life measures and questionnaires Multidisciplinary approach (psychiatric included) Support groups

39. Psychological Disturbances in TED

40. GO-QOL Questionnaire

41. Graves disease Mimickers Inflammatory (IOIS , CCF , Orbital Vascular lesions, Sarcoidosis) Neoplastic (Lymphoma , lacrimal gland tumors , meningioma) Motility (Myasthenia , cranial nerve palsy , Orbital Myositis , orbital apex and cavernous sinus lesions) Lid retraction (Parinaud's syndrome)

42. Graves Ophthalmopathy Mimickers

43. Graves Ophthalmopathy

44. Graves Ophthalmopathy Mimickers

45. Graves Ophthalmopathy Mimickers