Downloaded 60 times
More Related Content
Similar to Graves Orbitopathy
Graves Orbitopathy
- 1. Graves Orbitopathy Raed Behbehani, MD FRCSC
- 2. Graves Orbitopathy • 1-2%of women , 0.5% of men • Female : Male ratio , 5:1
- 3. GD Pathophysiology Smith TJet al. ENJM 2017
- 4. Systemic Signs andSymptoms • Eye signs usually start within a year of hyperthyroidism (75%) • Occasionally eye signs start years later.
- 5. Keratopathy Superficial Punctate KeratitisSuperior Limbic Keratoconjunctivitis
- 6. Lid retraction Pathogenesis :sympathetic stimulation , overaction of LPS alone with SR compensating for IR restriction , inflammation and fibrosis of levator palpebrae superioris muscle.
- 7. Clinical Features-Proptosis • Dueto expansion of orbital fat and muscles. • Complete subluxation of the globe (sometimes) • Prolapse of the lacrimal glands • Corneal exposure/ epithelial defects
- 8. CT in TED •Enlargement of EOM , lacrimal glands, anterior soft tissue swelling , prominent superior ophthalmic vein. • Bone remodeling (medial wall)
- 9. MRI in TED •High T2 in EOM - active stage ( high water content) , good prognostic sign for response to XRT and steroids • Low T2 in EOM- inactive fibrotic stage
- 10. Strabismus • 30% ofpatients with TED. • Diplopia can be intermittent or constant • Inferior Recti , Medial Recti (most common)
- 11. Compressive Optic Neuropathy •5%-7% of TED • Direct compression of the optic nerve at the orbital apex • Dyschromatopsia , RAPD . • Optic Disc edema in 40% • Visual fields • Often in the active phase of the disease • Proptosis may be minimal (tight lids)
- 12.
- 13. Natural History ofThyroid Eye Disease • Rundle’s curve • Progressive phase lasting for up to 18 months • Stable (inactive) phase
- 14. Risk Factors forGraves Orbitopathy • Smoking • Hypothyroidism following radio-iodine treatment • Positive family history of auto-immune disease • Increasing age • Life stressors
- 15. Smoking and TED •A meta-analysis showed smoking increases the risk of TED Vestergaard at al. 2002 Odds ratio (95% CI) GD vs Controls Current smoker vs Never Smoker 3.3 (2.09-5.22) GO vs Controls Ever smoker vs never smoker 4.4 (2.88-6.73) GO = Graves Ophthalmopathy GD= Graves disease
- 16. Smoking and TED– Dose Response • Relative risk of proptosis increased with smoking. (Pfeilschifter et al. Clin Endocrnol. 1996) • Smoking was predictive of severe TED (OR= 6.57) and optic neuropathy (OR=10) (Lee JH et al. Korean J Ophthalmol 2010) Smoking cig/day Relative risk of Proptosis 1-10 1.8 11-20 3.8 >20 7
- 17. Smoking risk forTED specific GD. • OR for toxic nodular goitre is only 1.22 . • Smoking is associated with lower occurrence of anti-TPO and anti- thyroglobulin Ab (Hashimoto’s thyroiditis). • Confounding factors (iodine intake , stressors, alcohol)
- 18. Smoking and TED •A 30 year old man with protruding eyes for 5 months. • He was diagnosed with GD 6 months ago and started on Inderal and neomercazole. • Euthyroid • Heavy smoker (2-3 packs/day)
- 19.
- 20. Radio-iodine ablation (RAI)and TED • RAI is associated with 15% chance of TED . (Bartalena et al. NEJM 1998) • Risk is reduced with a course of steroids. (Traisk et al. J Clin Enocrinol Metab. 2009) • Smoking increase risk of worsening post-RAI 4-fold vs. non-smokers. • Response to steroids is 4-fold less likely in smokers vs. non-smokers.
- 21. RAI and TED •Risk of development or worsening GO with RAI vs ATD (OR 2.25) • Steroid prophylaxis reduced risk by 60%. • Total Thyroid ablation (near total thyroidectomy or RAI) did show significant beneficial effect on the improvement of GO (OR 6.0) • Early administration of levothyroxine after RAI therapy reduces the occurrence of GO. (Tallstedt L et al. Eur J Endocrinol 1994)
- 22. RAI and TED •EUGOGO : Post-RAI steroid prophylaxis with risk factors for worsening of TED (pre-treatmemt FT3, smoking, pre-exsiting TED, hypothyroidism). • Steroid Dose: 0.3—0.5 mg/kg prednisone for 4-6 weeks
- 23. Clinical Activity • EUGOGOAssessment • CAS • VISA
- 24. Clinical Activity (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. • Active GO = CAS ≥3 • CAS > 4 means 80% PPV for response to steroids
- 25. VISA classification • V(Vision) , I (inflammation), S (Strabismus) , A (Appearance) • Score of 5 or more —> Active disease or progression (Consider Steroids)
- 26.
- 27.
- 28. EUGOGO Assessment • Mild– minor impact of daily life , lid retraction <2 mm, Proptosis <3 mm , mild soft tissue swelling. • Moderate-to-Severe - Significant impact on daily life , lid retraction >2 mm , Proptosis > 3mm , moderate-severe soft tissue swelling , Diplopia • Sight-threatening – Optic Neuropathy , Severe corneal exposure
- 29. Selenium • 200 ug/dayfor 6 months • For Mild disease • Antioxidant effect • Immunomodulatory effect : reduce thyroid autoantibodies • Reduce severity of disease and improve QOL
- 30. Corticosteroids • IV pulsesare more effective than oral (70%-80% vs 50%) with less adverse events (39 vs. 81%.) (Zang S et al. J Clin Endocrinol Metab 2011; Stiebel-Kalish at al. J Clin Endocrinol Metab 2009) • IV dose (max 8 grams) : 500 mg weekly for 6 weeks and then 250 mg weekly for 6 weeks. • Improvement is related to cumulative dose. • Steroid response is evident usually 2-4 weeks late
- 31. Rituximab • Chimeric mono-clonalCD20 antibody . • CD20 is expressed on more than 95% of B cells and plasma cells • For steroid-refractory disease • Side effects : Allergic reaction (mild) PML (severe)
- 32. Rituximab • At 24weeks 100% of RTX patients improved compared with 69% after IV Steroids (P < .001) (Salvi et al. J Clin Endocrinol Metab 2015) • RTX offered no additional benefit over placebo to our patients with active and moderate-to-severe GO (Stan MN et al. J Clin Endocrinol Metab 2015)
- 33. Orbital Radiation (OR) •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)
- 34. Orbital Decompression forTED • In severe corneal exposure or/or compressive optic neuropathy. • Cosmetic for rehabilitation in stable phase. • Post-operative complications (diplopia, vision loss) • Outcome is variable : degree of fibrosis , fat expansion , bone available, duration of optic neuropathy .
- 35. Orbital Decompression Fat only(First Wall) 2-3 mm Lateral Wall 3-6 mm Medial Wall 4-7 Orbital Roof 5-9 mm
- 36. Orbital Decompression Before surgery After3 wall decompression
- 37. Strabismus Surgery forTED • 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 • Conjunctival dissection is challenging.
- 38. Upper Lid Retraction •Levator recession / Mullerectomy • Full-thickness blepharotomy • Botox injections into Muller’s muscle (transient) • Filler (Hyaloronic acid) in subcinjunctival space (0.1-0.2 ml)
- 39. 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)
- 40. Psychological Impact andQuality of Life in TED • Studies suggest low QOL equivalent to diabetes and cancer(Kahaly GJ et al. Clin Endocrinol Oxf 2005) • Disfigurement/altered facial appearance • Almost 50% of TED suffer depression and/or anxiety • 90% of TED have appearance concerns (young females)
- 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 (contralteral ptosis)
- 42.
- 43.
- 44.
- 45.
- 46.
- 47.
- 48. Summary • Graves isinflammatory orbital disease characterized by proptosis , lid retraction and changes in the periorbital tissues. • Smoking is a risk factor for severe TED and poor response to therapy. • RAI is associated with GO and risk is minimized with steroids and post- hypothyroidism treatment. • IV steroids are more effective and safer than oral steroids. • Surgery for GO is indicated for corneal exposure and optic neuropathy and cosmetic rehabilitation • Multidisciplianary , patient-focused approach is important.
- 49. Case • A 53year old presents on 28/1/2017 with “sudden onset of proptosis” started 5/12/2016. • He denies any pain , diplopia or decreased vision. • He was seen by an ophthalmologist and diagnosed as “orbital pseudotumor” and received IV steroids followed by oral steroids for 2 months. • No improvement of proptosis following steroids. • Thyroid functions were “normal” , except at one time , and it then normalized again. • Family history of thyroid disease in sister.
- 50. Case Hertel Exophthalmometry 20 OD28 OS Base 115
- 51.
- 52. Case Test 26/1/2017 8/1/201729/11/2016 Reeference TSH 0.623 0.441 0.005 0.27-4.2 mIU/L Free T4 13.2 12.6 21.8 12-22 pmol/L Anti-Thyroperoxidase Ab negative Anti-TSH Receptor Ab negative
- 53.
Editor's Notes
- #3 Thyroid eye disease , Thyroid Orbitopathy , Graves eye, Thyroid-related eye disease all same condition
- #4 Infiltration of immune effector cells and thyroid-antigen-specific and integration with B cells, plasmas cells and macrophages cells into thyroid and TSH and IGF-recptor receptors carrying tissues TSHR is found on thyroid epithelial cells , adipocytes and bone cells. CD34 + fibrocytes key in the pathogenesis and its activation is caused by inflammatory cytokines released by T-cells and macrophages. Also impoartantly , IGF and IGF-receptor activity is required for some of the down-stream signaling initiated through TSHR. Emerging new mono-clonal antibodies are being developed to target these . Final results is Accumulation of GAG in the EOM and fat and fibrosis of orbital tissues and EOM
- #5 There is no correlation between the timing of hyperthyroidism . Most of the times they are occur with hypertgroidism but many times there can be months or even years between TED and systemic hyperthyroidism.
- #6 lacrimal gland physiologically expresses TSH receptor, which, in active GO, can bind with circulating anti-TSHR autoantibodies and contribute to lacrimal gland impairment. High tear osmolarity leading to rapid evaporation and dry eyes.
- #7 Lid retraction is the most common eye sign of TED and the mechanism behind it is speculative but can due to many things.
- #8 The second most common eye sign is proptosis or exophthalmos …
- #9 CT is the study of choice (Bone and soft tissues) and it will show Enlargement of EOM, orbital fat expansion , increase lacrimal gland size. Radiologic findings frequently are seen in majority of TED without clinical signs Coronal views is important in order to assess the muscle size and orbital fat expansion..
- #10 MRI is useful in that it not only gives you a structural view of the disease effects but also also it can assess disease activity….
- #11 Most of the times the eye is down and In (Esotropia and Hypotropia) but any eye muscle can be involved and you can have any type of strabismus.
- #12 This is a rare but vision-threatening complication of TED. The other typical thing about most of these patients is that proptosis is not marked and the eye settle in in this tight orbit and therefore you have compression of the optic nerve.
- #13 This is a young patient who presented with progressive loss of vision over several months. As you can see how the optic nerve is being compressed by the enlarged EOM at the orbital apex. Her vision was CF in both eyes but fortunately for her she had not yet developed optic atrophy and her vision returned back to normal following a combined nasal enodscopic and trans-orbital decompression.
- #14 You are probably all familiar with the Randle’s curve.. In practice , though , many of those patients do not strictly follow this curve but rather go phases of remission and relapses than can last for years before stabilization .
- #15 Two out of these stand out and are very important ; smoking and post-RAI
- #16 This is a metanalysis which showed that OR to develop severe TED is increased even for past smokers (ever smoked) and not only current smokers.
- #17 This is another study that showed that the number of cigarettes/day correlates well with the degree proptosis and was predictive of severe TED. Smoking was also associated with higher risk of compressive optic neuropathy
- #18 What is interesting is that smoking only increases the risk of TED in GD and not in Toxic Goitre , or other auto-immune thyroid disorders such as Hasimoto’s thyroiditis .. It is important to remember that there maybe other confounding factors associated with smoking that are also reposnsible..
- #21 The other big trigger of course is RAI… This can be reduced with steroids of course but again in patient who smoke , the risk is higher and steroids do not work as well and they still more likely to have worsening of TED…
- #22 Recent metanalysis of 9 large RCT. Risk of TED is higher with RAI vs Drugs ”Ride the storm” . TTA was more beneficial for GO than TX alone in inducing earlier and steadier GO improvement but In the long term (approximately 18 months after surgery), GO outcome was found to be similar in both groups. Finally, post-RAI hypothyroidism
- #23 This is the EUGOGO recommendation for post-RAI steroid prophylaxis and which patients are at higher risk.
- #25 GO activity assessment according CAS (redness of eyelids and conjunctiva, swelling of caruncle, eyelid , and conjunctiva ) The main limitation of CAS is that score does not correlate with significant complications (CON) , each sign has equal point weight.
- #26 Vision/CON Inflammation/Congestion : based on documented change of inflammation rather than absolute value Strabismus/Motility : measuring ductions and alignments Appearance/Exposure
- #29 The EUGOGO clssification , which what I do probably in the clinic and how I would classify most of the patients I see. For mild – topical lubricants , cold compressors , selenium Moderate-Severe- IV Steroids Sight-threatening- IV Steroids +- Surgery
- #30 This has been shown in RCT to improved ocular comfort and also reduce the incidence of progression from mild to severe disease . Patients of recent onset and short duration NOT chronic long-standing disease who are better managed with rehabilitative surgery.
- #31 Several RCT have shown that IV steroids are more effective and have less side effects than oral. EUGGO have looked at three different different regimen in an RCT using 3 different regimens (7.47, 4.98 and 2.25) and the improvement was best seen in the highest dose but probably at the cost more toxicity ( cardiovascular and hepatic) Shorter more intensive coursed may have lower efficacy (Logistics) For moderate to severe disease I tend to give 4.5-6 g total dose over 6-8 weeks or so. If the patient has CON, I would give the dose over a shorter period of time and follow up the patient to see if he needs decompression
- #32 RTX depletes 95% of mature B cells , blocks Ab production , and decrease inflammatory cytokine release Most of the data is from uncontrolled studies on patients with active severe TED , some of whom refractory to steroids The dose that was used was variable 500 mg to 1000 mg q 2weeks based on peripheral B cell depletion
- #33 There were two RCT one Italian (Salvi) and US (Stan) with somewhat conflicting results. The two studies had different study populations (Italian were younger and had higher prevalence of smoking . Of note also is that some patients who used Rituximab still went to develop CON and required surgery Rituximab is probably more effective in inactivating TED and preventing relapses than IV steroids. However, At this point Rituximab should be used as a second line therapy for patients with severe disease who have failed IV steroids.
- #34 OR might be effective in reducing 7-CAS and ocular motility disturbances. No significant improvement in proptosis or eyelid retraction should be expected from this treatment.
- #35 In TED , expansion of fat and muscles and this what we remove during surgery. I have a long discussion with the patients trying to set the expectation and goals , which are quite different in a case where you are trying to save vision versus cosmetic rehabilitation. I always tell patients that this is typically a multistage process and patients frequentlty require 2-3 surgeries for cosmetic rehabilitation .
- #37 And sometimes we get spectacular results but often we fall short of the high expectations of patient. Decompression will relief of ocular pain and tension and reduces vascular congestion . Main complications are new diplopia requiring strabismus surgery
- #40 Hard palate graft or ear cartilage for lower lid support. Homologous acellular dermal matrix hard-palate mucosa, but unfortunately it is not available in Kuwait.
- #41 Many of these patients are young ladies who are disfigured. Some patients with TED go into full blown clinical depression because of their appearance to the extent of sometimes not willing to take necessary treatment like RAI fearing the risk of GO. There has to be a individualized patient approach that deals with the individual issues .
- #53 He repeated these tests one month later and the TFT were normal and thyroid auto-antibodies were negative. He was seen in India by another physician who has recommended orbital decompression.