Thyroid Eye Disease Dr Bijay Vaidya Dept of Endocrinology, Royal Devon & Exeter Hospital, Exeter

Thyroid Eye Disease Is an autoimmune disorder 25-50% Graves’ disease 3-5% severe disease Can present before, with or after thyrotoxicosis Rarely in euthyroid or hypothyroid patients

Is an autoimmune disorder

25-50% Graves’ disease

3-5% severe disease

Can present before, with or after thyrotoxicosis

Rarely in euthyroid or hypothyroid patients

Pathogenesis of TED NEJM, 2000

CT Orbits TED Normal

The Case 65/F Recurrent Graves’ thyrotoxicosis Smoker TSH 0.03 mu/L, FT4 34 pmol/L Red eyes, excessive watering, squint & double vision

65/F

Recurrent Graves’ thyrotoxicosis

Smoker

TSH 0.03 mu/L, FT4 34 pmol/L

Red eyes, excessive watering, squint & double vision

How to Assess TED?

Severity of TED: NO-SPECS Class 0: N o signs or symptoms Class 1: O nly signs (lid retraction, stare ± lid lag) Class 2: S oft tissue involvement Class 3: P roptosis Class 4: E xtraocular muscle involvement Class 5: C orneal involvement Class 6: S ight loss (optic nerve involvement)

Class 0: N o signs or symptoms

Class 1: O nly signs (lid retraction, stare ± lid lag)

Class 2: S oft tissue involvement

Class 3: P roptosis

Class 4: E xtraocular muscle involvement

Class 5: C orneal involvement

Class 6: S ight loss (optic nerve involvement)

EUGOGO Classification of TED Severity Sight-threatening Optic neuropathy Corneal breakdown Moderate-Severe Lid retraction ( ≥ 2mm), moderate-severe soft tissue involvement, proptosis ( ≥ 3mm), diplopia Mild

Sight-threatening

Optic neuropathy

Corneal breakdown

Moderate-Severe

Lid retraction ( ≥ 2mm), moderate-severe soft tissue involvement, proptosis ( ≥ 3mm), diplopia

Mild

Identification of Sight-threatening TED Deterioration of vision Colour desaturation Relative afferent pupillary defect (RAPD) Papilloedema Visual field, VEP, MRI Corneal opacity Cornea visible on closing eyelids

Deterioration of vision

Colour desaturation

Relative afferent pupillary defect (RAPD)

Papilloedema

Visual field, VEP, MRI

Corneal opacity

Cornea visible on closing eyelids

Activity vs. Severity of TED BMJ, 2004

Predictive Indicators of TED Activity Short duration of eye disease Increasing severity High clinical activity score High titres of TBII antibodies Positive octreoscans Oedematous extra-ocular muscles on USG or MRI

Short duration of eye disease

Increasing severity

High clinical activity score

High titres of TBII antibodies

Positive octreoscans

Oedematous extra-ocular muscles on USG or MRI

Clinical Activity Score (Mourits et al.) Pain on or behind the globe Pain on eye movement Redness of the eyelids Redness of the conjunctiva Swelling of the eyelids Chemosis Swollen caruncle Increase of proptosis Decreased eye movement Decreased visual acuity Pain Redness Swelling Function

Pain on or behind the globe

Pain on eye movement

Redness of the eyelids

Redness of the conjunctiva

Swelling of the eyelids

Chemosis

Swollen caruncle

Increase of proptosis

Decreased eye movement

Decreased visual acuity

How to Manage Thyrotoxicosis in a patient with TED?

Progression of TED After Radioiodine Randomised study 26 RAI alone 26 RAI & prednisolone Assessment at 3 & 18 months No control group treated with ATD % Bartalena et al., NEJM, 1989

Randomised study

26 RAI alone

26 RAI & prednisolone

Assessment at 3 & 18 months

No control group treated with ATD

Progression of TED After Radioiodine Randomised study Radioiodine (n=39) Subtotal thyroidectomy (n=37) Methimazole for 18 months (n=38) Assessment at 24 months % P=0.02 Tallstedt et al., NEJM, 1992

Randomised study

Radioiodine (n=39)

Subtotal thyroidectomy (n=37)

Methimazole for 18 months (n=38)

Assessment at 24 months

Progression of TED After Radioiodine 443 Graves’ patients with slight or no TED Randomised to: radioiodine (n=150) radioiodine plus prednisolone (n=145) methimazole (n=148) Progression of TED monitored for 12 month Bartalena, NEJM, 1998

443 Graves’ patients with slight or no TED

Randomised to:

radioiodine (n=150)

radioiodine plus prednisolone (n=145)

methimazole (n=148)

Progression of TED monitored for 12 month

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 Group A (First 2yrs) 248 patients T4 when hypothyroid Group B (Second 2yrs) 244 patients T4 50mcg after 2 wks, 100mcg after 4 wks Assessment at 18 months % P=0.03 Tallstedt et al., EJE, 1994

Group A (First 2yrs)

248 patients

T4 when hypothyroid

Group B (Second 2yrs)

244 patients

T4 50mcg after 2 wks, 100mcg after 4 wks

Assessment at 18 months

Radioiodine Treatment in Patients with Inactive TED * * * Perros et al., JCEM 2005

Radioiodine & TED In patients with active TED, defer radioiodine or use with steroids In patients with inactive TED, radioiodine may be considered without steroids Avoid hypothyroidism & advise against smoking

In patients with active TED, defer radioiodine or use with steroids

In patients with inactive TED, radioiodine may be considered without steroids

Avoid hypothyroidism & advise against smoking

How to Treat?

General Measures Stop smoking Avoid radioiodine in active TED Maintain euthyroidism Symptom relief Lubricating eye drops, dark glasses, occlusive pads, prism Reassurance

Stop smoking

Avoid radioiodine in active TED

Maintain euthyroidism

Symptom relief

Lubricating eye drops, dark glasses, occlusive pads, prism

Reassurance

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 Systemic corticosteroids Orbital radiotherapy

Systemic corticosteroids

Orbital radiotherapy

Oral Steroids in TED High dose prednisolone (60-100mg/d) for several months Interfere with T & B lymphocyte functions Decrease GAG synthesis & release Effective on soft tissue changes & optic neuropathy Not for proptosis & ocular dysmotility

High dose prednisolone (60-100mg/d) for several months

Interfere with T & B lymphocyte functions

Decrease GAG synthesis & release

Effective on soft tissue changes & optic neuropathy

Not for proptosis & ocular dysmotility

Efficacy of Oral Steroids in TED %

Problems with Oral Steroids Not effective in all patients Need for high dose, often for long duration Frequent relapse of active eye disease Side-effects Cushing’s syndrome, weight gain, diabetes, hypertension, osteoporosis, infections etc

Not effective in all patients

Need for high dose, often for long duration

Frequent relapse of active eye disease

Side-effects

Cushing’s syndrome, weight gain, diabetes, hypertension, osteoporosis, infections etc

Intravenous Steroids in TED High dose iv methylprednisolone (0.5-1g) at different intervals More effective on inflammatory changes & optic nerve involvement More effective in severe eye disease than mild disease (Mori et al.)

High dose iv methylprednisolone (0.5-1g) at different intervals

More effective on inflammatory changes & optic nerve involvement

More effective in severe eye disease than mild disease (Mori et al.)

Efficacy of IV Steroids in TED %

Intravenous vs. Oral Steroids IV steroid more effective (Kahaly et al.) Rapid response Better tolerated by patients Reduced requirement for further therapy (Kauppinen-Makelin et al.) More expensive Acute hepatitis

IV steroid more effective (Kahaly et al.)

Rapid response

Better tolerated by patients

Reduced requirement for further therapy (Kauppinen-Makelin et al.)

More expensive

Acute hepatitis

IV Methylprednisolone Protocol Methylprednisolone 500mg IVI over 30min for 3 consecutive days Daily electrolytes, glucose, LFT Reducing dose of oral prednisolone (40mg 2wks, 30mg 1wk, 20mg 1 wk, to continue) Lansoprazole, bisphosphonates Up to 3 pulses

Methylprednisolone 500mg IVI over 30min for 3 consecutive days

Daily electrolytes, glucose, LFT

Reducing dose of oral prednisolone (40mg 2wks, 30mg 1wk, 20mg 1 wk, to continue)

Lansoprazole, bisphosphonates

Up to 3 pulses

Orbital Radiotherapy in TED Non-specific anti-inflammatory effect 20 Gy per eye in 10 daily doses over a 2-week period Beneficial for soft tissue inflammation, ocular dysmotility & optic neuropathy Little effect on proptosis

Non-specific anti-inflammatory effect

20 Gy per eye in 10 daily doses over a 2-week period

Beneficial for soft tissue inflammation, ocular dysmotility & optic neuropathy

Little effect on proptosis

Efficacy of Radiotherapy in TED %

Controlled Trials of Orbital Radiotherapy Radiotherapy more effective than sham irradiation (Mourits et al.) No difference between the irradiated orbit and sham-irradiated fellow orbit (Gorman et al.) Combined radiotherapy & systemic steroid more effective than either single agents (Marcocci et al.)

Radiotherapy more effective than sham irradiation (Mourits et al.)

No difference between the irradiated orbit and sham-irradiated fellow orbit (Gorman et al.)

Combined radiotherapy & systemic steroid more effective than either single agents (Marcocci et al.)

Complications of Radiotherapy Transient exacerbation of orbital oedema, conjunctival injection, chemosis Radiation-induced retinopathy (C/I: diabetes & hypertension) Cataract Theoretical risk of tumour induction (not used in patients <35yr)

Transient exacerbation of orbital oedema, conjunctival injection, chemosis

Radiation-induced retinopathy (C/I: diabetes & hypertension)

Cataract

Theoretical risk of tumour induction (not used in patients <35yr)

Other Medical Treatments Azathioprine Methotrexate Cyclophosphamide Plasmapheresis IV immunoglobulins Pentoxifylline Bromocriptine Anti-cytokines (Etanercept) & monoclonal antibodies (Rituximab)

Azathioprine

Methotrexate

Cyclophosphamide

Plasmapheresis

IV immunoglobulins

Pentoxifylline

Bromocriptine

Anti-cytokines (Etanercept) & monoclonal antibodies (Rituximab)

Somatostatin Analogues Receptors on immune cells & fibroblasts in the eyes Uptake on octreotide scan in active TED Small uncontrolled studies shown beneficial effects

Receptors on immune cells & fibroblasts in the eyes

Uptake on octreotide scan in active TED

Small uncontrolled studies shown beneficial effects

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 Immediate treatment Optic Neuropathy IV Methylprednisolone Orbital decompression Corneal breakdown Hourly topical lubricant Temporary eye closure Botulinum toxin injections

Immediate treatment

Optic Neuropathy

IV Methylprednisolone

Orbital decompression

Corneal breakdown

Hourly topical lubricant

Temporary eye closure

Botulinum toxin injections

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 decompression Sight-threatening Rehabilitative surgery Moderately severe (inactive) Immuno-suppression and/or radiotherapy Moderately severe (active) ‘ Wait-and-see’ Mild

Who to Refer to Specialist TED Clinic?

Urgent Referral Unexplained deterioration in vision Awareness of reduced colour vision Globe subluxation Obvious corneal opacity Corneal exposure when eyelids are closed Disc swelling EUGOGO, 2008

Unexplained deterioration in vision

Awareness of reduced colour vision

Globe subluxation

Obvious corneal opacity

Corneal exposure when eyelids are closed

Disc swelling

Routine Referral Eyes abnormally sensitive to light (1-2mo) Excessive grittiness Pain in or behind the eyes (1-2mo) Progressive change in appearance (1-2mo) Appearance of eyes causing concern to the patient Double vision EUGOGO, 2008

Eyes abnormally sensitive to light (1-2mo)

Excessive grittiness

Pain in or behind the eyes (1-2mo)

Progressive change in appearance (1-2mo)

Appearance of eyes causing concern to the patient

Double vision

Routine Referral Troublesome eyelid retraction Abnormal swelling or redness of eyelid or conjunctiva Restriction of eye movements or squint Tilting of the head to avoid double vision EUGOGO, 2008

Troublesome eyelid retraction

Abnormal swelling or redness of eyelid or conjunctiva

Restriction of eye movements or squint

Tilting of the head to avoid double vision

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' orbitopathy. Eur J Endocrinol. 2008 Mar;158(3):273-85.