Thyroid Eye Disease Dr Bijay Vaidya Dept of Endocrinology, Royal Devon & Exeter Hospital,  Exeter
Thyroid Eye Disease <ul><li>Is an autoimmune disorder </li></ul><ul><li>25-50% Graves’ disease </li></ul><ul><li>3-5% seve...
Pathogenesis of TED NEJM, 2000
CT Orbits TED Normal
The Case <ul><li>65/F </li></ul><ul><li>Recurrent Graves’ thyrotoxicosis </li></ul><ul><li>Smoker </li></ul><ul><li>TSH 0....
How to Assess TED?
Severity of TED: NO-SPECS <ul><li>Class 0:  N o signs or symptoms  </li></ul><ul><li>Class 1:  O nly   signs (lid retracti...
EUGOGO Classification of TED Severity <ul><li>Sight-threatening </li></ul><ul><ul><li>Optic neuropathy </li></ul></ul><ul>...
Identification of Sight-threatening TED <ul><li>Deterioration of vision  </li></ul><ul><li>Colour desaturation </li></ul><...
Activity vs. Severity of TED BMJ, 2004
Predictive Indicators of TED Activity <ul><li>Short duration of eye disease </li></ul><ul><li>Increasing severity </li></u...
Clinical Activity Score (Mourits et al.) <ul><li>Pain on or behind the globe </li></ul><ul><li>Pain on eye movement </li><...
How to Manage Thyrotoxicosis in a patient with TED?
Progression of TED After Radioiodine <ul><li>Randomised study </li></ul><ul><ul><li>26 RAI alone </li></ul></ul><ul><ul><l...
Progression of TED After Radioiodine <ul><li>Randomised study </li></ul><ul><ul><li>Radioiodine (n=39) </li></ul></ul><ul>...
Progression of TED After Radioiodine <ul><li>443 Graves’ patients with slight or no TED  </li></ul><ul><li>Randomised to: ...
TED After Radioiodine in Smokers & Non-smokers Bartalena, Ann Intern Med, 1998 % Progression of TED (n=82) (n=68) 23% 6%
Early Thyroxine After Radioiodine & Progression of TED <ul><li>Group A (First 2yrs) </li></ul><ul><ul><li>248 patients </l...
Radioiodine Treatment in Patients with Inactive TED * * * Perros et al., JCEM 2005
Radioiodine & TED <ul><li>In patients with active TED, defer radioiodine or use with steroids </li></ul><ul><li>In patient...
How to Treat?
General Measures <ul><li>Stop smoking </li></ul><ul><li>Avoid radioiodine in active TED </li></ul><ul><li>Maintain euthyro...
Is TED Related to Smoking? % Hagg & Asplund, BMJ, 1987 83% 46% 31%
Smoking & Risk of TED Odds Ratio P<0.01 1.9 4.4 EJE, 2002
Smoking & Response to Treatment Ann Intern Med, 1998
Established Therapies for Active Moderate-Severe TED <ul><li>Systemic corticosteroids </li></ul><ul><li>Orbital radiothera...
Oral Steroids in TED <ul><li>High dose prednisolone (60-100mg/d) for several months </li></ul><ul><li>Interfere with T & B...
Efficacy of Oral Steroids in TED %
Problems with Oral Steroids <ul><li>Not effective in all patients </li></ul><ul><li>Need for high dose, often for long dur...
Intravenous Steroids in TED <ul><li>High dose iv methylprednisolone (0.5-1g) at different intervals </li></ul><ul><li>More...
Efficacy of IV Steroids in TED %
Intravenous vs. Oral Steroids <ul><li>IV steroid more effective (Kahaly et al.) </li></ul><ul><li>Rapid response </li></ul...
IV Methylprednisolone Protocol <ul><li>Methylprednisolone 500mg IVI over 30min for 3 consecutive days </li></ul><ul><li>Da...
Orbital Radiotherapy in TED <ul><li>Non-specific anti-inflammatory effect  </li></ul><ul><li>20 Gy per eye in 10 daily dos...
Efficacy of Radiotherapy in TED %
Controlled Trials of Orbital Radiotherapy  <ul><li>Radiotherapy more effective than sham irradiation (Mourits et al.) </li...
Complications of Radiotherapy <ul><li>Transient exacerbation of orbital oedema, conjunctival injection, chemosis </li></ul...
Other Medical Treatments <ul><ul><li>Azathioprine </li></ul></ul><ul><ul><li>Methotrexate  </li></ul></ul><ul><ul><li>Cycl...
Somatostatin Analogues <ul><li>Receptors on immune cells & fibroblasts in the eyes </li></ul><ul><li>Uptake on octreotide ...
Randomised Controlled Trial of Octreotide-LAR JCEM, 2004 -8 Octreotide Placebo Octreotide Screening 0 16 32 Weeks 56
Clinical Activity Score placebo LAR *** *** ***p <.001
Management of Sight-threatening Active TED <ul><li>Immediate treatment </li></ul><ul><li>Optic Neuropathy </li></ul><ul><u...
Role of Rehabilitative Surgery
Impact of TED on Quality of Life Thyroid, 1997
% How does/did your TED affect your quality of life?
Summary: Management of TED Stop smoking, maintaining euthyroidism & supportive measures All stages IV methylprednisolone d...
Who to Refer to Specialist TED Clinic?
Urgent Referral <ul><li>Unexplained deterioration in vision </li></ul><ul><li>Awareness of reduced colour vision </li></ul...
Routine Referral <ul><li>Eyes abnormally sensitive to light (1-2mo) </li></ul><ul><li>Excessive grittiness </li></ul><ul><...
Routine Referral <ul><li>Troublesome eyelid retraction </li></ul><ul><li>Abnormal swelling or redness of eyelid or conjunc...
The UK TED Patient Survey: Attend/Attended Specialist TED Clinic? %
*p<0.05, ** p<0.01 The UK TED Patients Survey: Specialist TED clinic vs. No Sp TED Clinic % % % % % ** * * *
Further Reading: Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbito...
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  • Ted.Dec08

    1. 1. Thyroid Eye Disease Dr Bijay Vaidya Dept of Endocrinology, Royal Devon & Exeter Hospital, Exeter
    2. 2. Thyroid Eye Disease <ul><li>Is an autoimmune disorder </li></ul><ul><li>25-50% Graves’ disease </li></ul><ul><li>3-5% severe disease </li></ul><ul><li>Can present before, with or after thyrotoxicosis </li></ul><ul><li>Rarely in euthyroid or hypothyroid patients </li></ul>
    3. 3. Pathogenesis of TED NEJM, 2000
    4. 4. CT Orbits TED Normal
    5. 5. The Case <ul><li>65/F </li></ul><ul><li>Recurrent Graves’ thyrotoxicosis </li></ul><ul><li>Smoker </li></ul><ul><li>TSH 0.03 mu/L, FT4 34 pmol/L </li></ul><ul><li>Red eyes, excessive watering, squint & double vision </li></ul>
    6. 6. How to Assess TED?
    7. 7. Severity of TED: NO-SPECS <ul><li>Class 0: N o signs or symptoms </li></ul><ul><li>Class 1: O nly signs (lid retraction, stare ± lid lag) </li></ul><ul><li>Class 2: S oft tissue involvement </li></ul><ul><li>Class 3: P roptosis </li></ul><ul><li>Class 4: E xtraocular muscle involvement </li></ul><ul><li>Class 5: C orneal involvement </li></ul><ul><li>Class 6: S ight loss (optic nerve involvement) </li></ul>
    8. 8. EUGOGO Classification of TED Severity <ul><li>Sight-threatening </li></ul><ul><ul><li>Optic neuropathy </li></ul></ul><ul><ul><li>Corneal breakdown </li></ul></ul><ul><li>Moderate-Severe </li></ul><ul><ul><li>Lid retraction ( ≥ 2mm), moderate-severe soft tissue involvement, proptosis ( ≥ 3mm), diplopia </li></ul></ul><ul><li>Mild </li></ul>
    9. 9. Identification of Sight-threatening TED <ul><li>Deterioration of vision </li></ul><ul><li>Colour desaturation </li></ul><ul><li>Relative afferent pupillary defect (RAPD) </li></ul><ul><li>Papilloedema </li></ul><ul><li>Visual field, VEP, MRI </li></ul><ul><li>Corneal opacity </li></ul><ul><li>Cornea visible on closing eyelids </li></ul>
    10. 10. Activity vs. Severity of TED BMJ, 2004
    11. 11. Predictive Indicators of TED Activity <ul><li>Short duration of eye disease </li></ul><ul><li>Increasing severity </li></ul><ul><li>High clinical activity score </li></ul><ul><li>High titres of TBII antibodies </li></ul><ul><li>Positive octreoscans </li></ul><ul><li>Oedematous extra-ocular muscles on USG or MRI </li></ul>
    12. 12. Clinical Activity Score (Mourits et al.) <ul><li>Pain on or behind the globe </li></ul><ul><li>Pain on eye movement </li></ul><ul><li>Redness of the eyelids </li></ul><ul><li>Redness of the conjunctiva </li></ul><ul><li>Swelling of the eyelids </li></ul><ul><li>Chemosis </li></ul><ul><li>Swollen caruncle </li></ul><ul><li>Increase of proptosis </li></ul><ul><li>Decreased eye movement </li></ul><ul><li>Decreased visual acuity </li></ul>Pain Redness Swelling Function
    13. 13. How to Manage Thyrotoxicosis in a patient with TED?
    14. 14. Progression of TED After Radioiodine <ul><li>Randomised study </li></ul><ul><ul><li>26 RAI alone </li></ul></ul><ul><ul><li>26 RAI & prednisolone </li></ul></ul><ul><li>Assessment at 3 & 18 months </li></ul><ul><li>No control group treated with ATD </li></ul>% Bartalena et al., NEJM, 1989
    15. 15. Progression of TED After Radioiodine <ul><li>Randomised study </li></ul><ul><ul><li>Radioiodine (n=39) </li></ul></ul><ul><ul><li>Subtotal thyroidectomy (n=37) </li></ul></ul><ul><ul><li>Methimazole for 18 months (n=38) </li></ul></ul><ul><li>Assessment at 24 months </li></ul>% P=0.02 Tallstedt et al., NEJM, 1992
    16. 16. Progression of TED After Radioiodine <ul><li>443 Graves’ patients with slight or no TED </li></ul><ul><li>Randomised to: </li></ul><ul><ul><li>radioiodine (n=150) </li></ul></ul><ul><ul><li>radioiodine plus prednisolone (n=145) </li></ul></ul><ul><ul><li>methimazole (n=148) </li></ul></ul><ul><li>Progression of TED monitored for 12 month </li></ul>Bartalena, NEJM, 1998
    17. 17. TED After Radioiodine in Smokers & Non-smokers Bartalena, Ann Intern Med, 1998 % Progression of TED (n=82) (n=68) 23% 6%
    18. 18. Early Thyroxine After Radioiodine & Progression of TED <ul><li>Group A (First 2yrs) </li></ul><ul><ul><li>248 patients </li></ul></ul><ul><ul><li>T4 when hypothyroid </li></ul></ul><ul><li>Group B (Second 2yrs) </li></ul><ul><ul><li>244 patients </li></ul></ul><ul><ul><li>T4 50mcg after 2 wks, 100mcg after 4 wks </li></ul></ul><ul><li>Assessment at 18 months </li></ul>% P=0.03 Tallstedt et al., EJE, 1994
    19. 19. Radioiodine Treatment in Patients with Inactive TED * * * Perros et al., JCEM 2005
    20. 20. Radioiodine & TED <ul><li>In patients with active TED, defer radioiodine or use with steroids </li></ul><ul><li>In patients with inactive TED, radioiodine may be considered without steroids </li></ul><ul><li>Avoid hypothyroidism & advise against smoking </li></ul>
    21. 21. How to Treat?
    22. 22. General Measures <ul><li>Stop smoking </li></ul><ul><li>Avoid radioiodine in active TED </li></ul><ul><li>Maintain euthyroidism </li></ul><ul><li>Symptom relief </li></ul><ul><ul><li>Lubricating eye drops, dark glasses, occlusive pads, prism </li></ul></ul><ul><li>Reassurance </li></ul>
    23. 23. Is TED Related to Smoking? % Hagg & Asplund, BMJ, 1987 83% 46% 31%
    24. 24. Smoking & Risk of TED Odds Ratio P<0.01 1.9 4.4 EJE, 2002
    25. 25. Smoking & Response to Treatment Ann Intern Med, 1998
    26. 26. Established Therapies for Active Moderate-Severe TED <ul><li>Systemic corticosteroids </li></ul><ul><li>Orbital radiotherapy </li></ul>
    27. 27. Oral Steroids in TED <ul><li>High dose prednisolone (60-100mg/d) for several months </li></ul><ul><li>Interfere with T & B lymphocyte functions </li></ul><ul><li>Decrease GAG synthesis & release </li></ul><ul><li>Effective on soft tissue changes & optic neuropathy </li></ul><ul><ul><li>Not for proptosis & ocular dysmotility </li></ul></ul>
    28. 28. Efficacy of Oral Steroids in TED %
    29. 29. Problems with Oral Steroids <ul><li>Not effective in all patients </li></ul><ul><li>Need for high dose, often for long duration </li></ul><ul><li>Frequent relapse of active eye disease </li></ul><ul><li>Side-effects </li></ul><ul><ul><li>Cushing’s syndrome, weight gain, diabetes, hypertension, osteoporosis, infections etc </li></ul></ul>
    30. 30. Intravenous Steroids in TED <ul><li>High dose iv methylprednisolone (0.5-1g) at different intervals </li></ul><ul><li>More effective on inflammatory changes & optic nerve involvement </li></ul><ul><li>More effective in severe eye disease than mild disease (Mori et al.) </li></ul>
    31. 31. Efficacy of IV Steroids in TED %
    32. 32. Intravenous vs. Oral Steroids <ul><li>IV steroid more effective (Kahaly et al.) </li></ul><ul><li>Rapid response </li></ul><ul><li>Better tolerated by patients </li></ul><ul><li>Reduced requirement for further therapy (Kauppinen-Makelin et al.) </li></ul><ul><li>More expensive </li></ul><ul><li>Acute hepatitis </li></ul>
    33. 33. IV Methylprednisolone Protocol <ul><li>Methylprednisolone 500mg IVI over 30min for 3 consecutive days </li></ul><ul><li>Daily electrolytes, glucose, LFT </li></ul><ul><li>Reducing dose of oral prednisolone (40mg 2wks, 30mg 1wk, 20mg 1 wk, to continue) </li></ul><ul><li>Lansoprazole, bisphosphonates </li></ul><ul><li>Up to 3 pulses </li></ul>
    34. 34. Orbital Radiotherapy in TED <ul><li>Non-specific anti-inflammatory effect </li></ul><ul><li>20 Gy per eye in 10 daily doses over a 2-week period </li></ul><ul><li>Beneficial for soft tissue inflammation, ocular dysmotility & optic neuropathy </li></ul><ul><li>Little effect on proptosis </li></ul>
    35. 35. Efficacy of Radiotherapy in TED %
    36. 36. Controlled Trials of Orbital Radiotherapy <ul><li>Radiotherapy more effective than sham irradiation (Mourits et al.) </li></ul><ul><li>No difference between the irradiated orbit and sham-irradiated fellow orbit (Gorman et al.) </li></ul><ul><li>Combined radiotherapy & systemic steroid more effective than either single agents (Marcocci et al.) </li></ul>
    37. 37. Complications of Radiotherapy <ul><li>Transient exacerbation of orbital oedema, conjunctival injection, chemosis </li></ul><ul><li>Radiation-induced retinopathy (C/I: diabetes & hypertension) </li></ul><ul><li>Cataract </li></ul><ul><li>Theoretical risk of tumour induction (not used in patients <35yr) </li></ul>
    38. 38. Other Medical Treatments <ul><ul><li>Azathioprine </li></ul></ul><ul><ul><li>Methotrexate </li></ul></ul><ul><ul><li>Cyclophosphamide </li></ul></ul><ul><ul><li>Plasmapheresis </li></ul></ul><ul><ul><li>IV immunoglobulins </li></ul></ul><ul><ul><li>Pentoxifylline </li></ul></ul><ul><ul><li>Bromocriptine </li></ul></ul><ul><ul><li>Anti-cytokines (Etanercept) & monoclonal antibodies (Rituximab) </li></ul></ul>
    39. 39. Somatostatin Analogues <ul><li>Receptors on immune cells & fibroblasts in the eyes </li></ul><ul><li>Uptake on octreotide scan in active TED </li></ul><ul><li>Small uncontrolled studies shown beneficial effects </li></ul>
    40. 40. Randomised Controlled Trial of Octreotide-LAR JCEM, 2004 -8 Octreotide Placebo Octreotide Screening 0 16 32 Weeks 56
    41. 41. Clinical Activity Score placebo LAR *** *** ***p <.001
    42. 42. Management of Sight-threatening Active TED <ul><li>Immediate treatment </li></ul><ul><li>Optic Neuropathy </li></ul><ul><ul><li>IV Methylprednisolone </li></ul></ul><ul><ul><li>Orbital decompression </li></ul></ul><ul><li>Corneal breakdown </li></ul><ul><ul><li>Hourly topical lubricant </li></ul></ul><ul><ul><li>Temporary eye closure </li></ul></ul><ul><ul><li>Botulinum toxin injections </li></ul></ul>
    43. 43. Role of Rehabilitative Surgery
    44. 44. Impact of TED on Quality of Life Thyroid, 1997
    45. 45. % How does/did your TED affect your quality of life?
    46. 46. Summary: Management of TED Stop smoking, maintaining euthyroidism & supportive measures All stages IV methylprednisolone decompression Sight-threatening Rehabilitative surgery Moderately severe (inactive) Immuno-suppression and/or radiotherapy Moderately severe (active) ‘ Wait-and-see’ Mild
    47. 47. Who to Refer to Specialist TED Clinic?
    48. 48. Urgent Referral <ul><li>Unexplained deterioration in vision </li></ul><ul><li>Awareness of reduced colour vision </li></ul><ul><li>Globe subluxation </li></ul><ul><li>Obvious corneal opacity </li></ul><ul><li>Corneal exposure when eyelids are closed </li></ul><ul><li>Disc swelling </li></ul>EUGOGO, 2008
    49. 49. Routine Referral <ul><li>Eyes abnormally sensitive to light (1-2mo) </li></ul><ul><li>Excessive grittiness </li></ul><ul><li>Pain in or behind the eyes (1-2mo) </li></ul><ul><li>Progressive change in appearance (1-2mo) </li></ul><ul><li>Appearance of eyes causing concern to the patient </li></ul><ul><li>Double vision </li></ul>EUGOGO, 2008
    50. 50. Routine Referral <ul><li>Troublesome eyelid retraction </li></ul><ul><li>Abnormal swelling or redness of eyelid or conjunctiva </li></ul><ul><li>Restriction of eye movements or squint </li></ul><ul><li>Tilting of the head to avoid double vision </li></ul>EUGOGO, 2008
    51. 51. The UK TED Patient Survey: Attend/Attended Specialist TED Clinic? %
    52. 52. *p<0.05, ** p<0.01 The UK TED Patients Survey: Specialist TED clinic vs. No Sp TED Clinic % % % % % ** * * *
    53. 53. Further Reading: Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy. Eur J Endocrinol. 2008 Mar;158(3):273-85.

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