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