Thyroid Eye Disease Raed Behbehani , MD FRCSC

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.

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

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.

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.

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)

Imaging in TED• Enlargement of EOM, orbital fat expansion , increase lacrimal gland

size.• CT is the study of choice (Bone and soft tissues)

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

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

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)

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

Natural History of Thyroid Eye Disease

• Rundle’s curve• Progressive phase lasting for up to 18 months• Stable (inactive) phase

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

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)

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.

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)

Thyroid CON

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)

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

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

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)

VISA Classification

VISA Classification

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

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)

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

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

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)

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)

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

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

Orbital Decompression Fat only (First Wall)

2-3 mm

Lateral Wall 3-6 mm

Medial Wall 4-7

Orbital Roof 5-9 mm

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

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)

Crowing of Eyebrows /Lid Complex

Fat expansion/prolapse of the lacrimal glands

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

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)

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

Psychological Disturbances in TED

GO-QOL Questionnaire

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)

Graves Ophthalmopathy Mimickers

Graves Ophthalmopathy

Graves Ophthalmopathy Mimickers

Graves Ophthalmopathy Mimickers