Thyroid Eye Disease : A Review for the Postgraduates

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Dr. Amber Dubey Postgraduate Trainee, Sankara Nethralya, Chennai

Dr. Vazhipokkil Anju Chandran Fellow, Department of Oculoplasty, Sankara Nethralaya

Dr. Nisar Sonam Poonam Associate Consultant, Department of Oculoplasty, Sankara Nethralaya

Published Online: April 1st, 2021 | Read Time: 23 minutes, 15 seconds

Introduction:

Thyroid eye disease (TED) or thyroid-associated orbitopathy (TAO) also called Basedow-Grave’s disease. It is an autoimmune inflammatory disorder characterized by enlargement of the orbital fat and extraocular muscles.¹ It is a consequence of thyroid gland dysfunction, where antibodies are targeted against thyrotropin receptors (TSHR) known as thyroid-stimulating globulin(TSI).¹ It is independent of the serum level of the circulating hormone levels.²

TED is characterized by an active or inflammatory stage and an inactive or fibrotic stage. The active or the inflammatory stage is characterized by inflammation, adipogenesis, and accumulation of extracellular fluid, glycosaminoglycans which in turn causes enlargement of the extraocular muscles and expansion of the orbital fat. Once the inflammation settles, there is predominant scarring of the orbital tissues which marks the onset of the fibrotic stage.

The natural course of the disease is quite variable. The majority of TED patients show a mild, self-limiting course, while 3–7% of TED patients exhibit a severe sight-threatening disease secondary to compressive optic neuropathy or corneal exposure.^2,3 A spectrum of patients fall between these two extremes and present with lid signs, proptosis motility restriction, diplopia with or without strabismus which has an adverse effect on their quality of life, both functionally and aesthetically.

Epidemiology:

About 90% of TED cases are associated with hyperthyroidism, 5% with hypothyroidism (such as Hashimoto’s thyroiditis) and about 5% are euthyroid.²

Age Between 3^rd – 5^th decade with greater severity in older patients.⁴

Sex

Female preponderance, with M: F - 1:4.
Men tend to have late-onset but a more severe disease as compared to females.⁴

Race Caucasians have greater severity of disease as compared to Asians. ⁴

NON-MODIFIABLE

RISK FACTORS

Race
Gender and age
Radioactive iodine (RAI) therapy
Positive family history
Thyroid dysfunction and presence of TSH receptor antibodies

MODIFIABLE RISK FACTORS

Smoking^1,6 (Stimulates hyaluronic acid production and an increase in adipogenesis)

Smokers with Grave’s are 7.7 times more likely to develop TED than non-smokers
Smoking cessation is considered as the strongest modifiable risk factor for TED

Selenium deficiency

Selenium helps in the protection of oxidative damage and metabolism of thyroid hormones
Selenium levels were shown to be significantly lower in Graves’ disease and associated with increased severity of TED
Dose 100 mcg twice a day for 3-6 months⁷

High serum cholesterol

Life stressors

Pathophysiology:

Orbital fibroblasts are the main effector cells. In TED patients, orbital fibroblasts can differentiate into mature adipocytes or myofibroblasts.⁵

Figure 1: Pathogenesis of Thyroid Eye DiseaseAPC=Antigen-presenting cells, GDIgGs = Graves Disease Immunoglobulins, OF=orbital ﬁbroblasts, TNF= Tumor necrosis factor, IL=interleukin

Both Thyroid-stimulating hormone receptor (TSHR) and Insulin-like growth factor-1R (IGF-1R) are antigens expressed by orbital fibroblasts. which activate the PI3K/AKT pathway to upregulate peroxisome proliferator-activated receptor-γ (PPAR-γ) expression, differentiation, and proliferation of adipocytes and enhance adipogenesis.(Figure no. 1)

Risk factors 1:

Clinical Features:

TED can be divided based on the stage of the disease into active and inactive or quiescent disease.(Figure no. 2)

Figure 2: Rundle's curve: Describes the disease course.

ACTIVE DISEASE

Lasts for about 6 to 24 months

Proptosis

Episcleral injection (at the insertion of muscles)

Conjunctival injection and chemosis

Diplopia

Sight threatening complication secondary to corneal ulceration or compressive optic neuropathy

QUIESCENT DISEASE

Progressive fibrosis

Stable proptosis

Eyelid retraction

Persistent restrictive strabismus

No signs of inflammation

Corrective Surgical management to be planned

Symptoms

The prominence of the eye
Grittiness, redness, photophobia, tearing and puffy lids
Retrobulbar dull aching pain and pain on eye movements
Diurnal variation (worse in the morning)
- Staring look, difficulty in closing eyes and ocular surface symptoms
- Double vision, discomfort in certain positions of gaze
- Diminution of vision

Figure 3: Clinical external picture depicting right eye axial proptosis. Note the tell-tale signs of TED. (Right upper lid and lower retraction, superior and inferior scleral show and upper lid lateral flare)

Soft Tissue Inflammation

Signs

Congestion
Caruncular edema
Chemosis
Periorbital fullness and edema
Upper/ lower lid fat prolapse
Lacrimal gland enlargement

Cause

Intense focal hyperemia at the insertion of horizontal recti
Edema and infiltration behind orbital septum associated with lid edema and chemosis.
Increase in orbital fat volume and increased intra orbital pressure

Eyelid

Signs

Superior/ inferior Scleral show +
Lid retraction
Diagnosed as MRD 1 is ≥5 mm [average MRD1(normal population) = 4-5mm] or palpebral fissure height >11mm.
Lateral flare
Lid lag in downgaze
Lagophthalmos
Named signs - Refer table*

Cause

Fibrosis and contracture of levator palpebrae and inferior rectus
The increased sympathetic activity of Muller’s muscle (causing lateral flare)
Secondary overaction due to hypertropia or hypotropia

Ocular Surface Discomfort

Signs

Superior limbic keratoconjunctivitis (SLK), punctate epithelial erosion,
Keratitis, Corneal ulcer and subsequent diminution of vision
Dry eye [Fluorescein stain and Schirmer’s test]

Cause

Lid retraction/ proptosis/ lagophthalmos
Increased corneal exposure-related changes

Proptosis (Exophthalmos)

FEATURES

Usually bilateral, often asymmetrical
The most common cause of unilateral and bilateral axial proptosis in adults⁴. [Hertel exophthalmometer, Nafziger’s view and worms hole view]

CAUSE

Orbital tissue proliferation
Deposition of GAGs leading to edema
Increased orbital fat and extraocular muscle volume

Ocular Motility Restrictions

FEATURES

The most common muscle involved Inferior rectus > Medial rectus > Superior rectus > Lateral rectus (I’M So Lucky)

Lead to restrictive strabismus and diplopia
Braley sign- increase in (intraocular pressure) IOP ≥ 6mmHg on attempted gaze towards direction of limitation from 1^o position

CAUSE

In active phase due to inflammatory oedema of the muscle later secondary to fibrosis

Diplopia

FEATURES

Gorman grading for the severity of diplopia:

no diplopia - 1
intermittent diplopia - 2
Gaze‐evoked diplopia - 3
Constant diplopia in the primary position or on reading - 4

CAUSE

Proptosis

Mechanical

Restrictive strabismus

Intraocular Pressure⁸

FEATURES

Categorized into

Ultrashort term (seconds or minutes)
short-term (hours or days)
long-term fluctuations (months or years)

Differential IOP – Increase IOP in up gaze (> 6mm Hg- significant)

Management –Treatment of Grave’s orbitopathy. Topical Antiglaucoma medication.

CAUSE

Ultra-short term and short-term increase: due to eyeball compression by enlarged and infiltrated extra-ocular muscles
Long term: episcleral venous pressure elevation secondary to intra-orbital content and pressure increase

Compressive Optic Neuropathy

SIGNS

Impaired visual acuity
Abnormal colour vision
Abnormal contrast sensitivity
RAPD +/-
Optic disc changes
Abnormal visual field
Abnormal visual evoked potential

CAUSE

Increased intra-orbital pressure
Increased orbital volume
Mechanical stretching of the nerve due to severe proptosis

Signs
Eyelid signs	Kocher’s – Staring Appearance Vigouroux – Fullness of eyelids Rosenbach’s – Tremors of the eyelids while closed Reisman’s – Bruit over the eyelids
Upper lid signs	Von Graefe’s – Lid lag on downgaze Dalrymples’s – Lid retraction Stellwag’s – Incomplete and infrequent blinking Grove – Resistance to pulling the retracted upper lid Boston – Jerky movements of the lid on downward gaze
Lower lid signs	Gellineck’s – Abnormal pigmentation of the upper lid Gifford’s – Difficulty in inverting the upper lid
Extraocular movements signs	Moebius – the inability to converge eyes Ballet’s – Restriction of one or more EOM Sulker’s – Poor fixation on abduction Jendrassik’s – Paralysis of all EOM
Facial signs	Joffroy’s sign – Absent creases on the forehead on upward gaze
Pupillary and conjunctival signs	Knies – Uneven pupillary dilatation in dim light Cowen’s – Jerky contraction of the pupil to light Goldzeiher’s – conjunctival injection

Classification

A. No Specs/ Werners Classification ⁹

Grades

0 No signs or symptoms

1 Only signs, no symptoms (signs limited to upper lid retraction and stare, with or without lid lag and proptosis)

2 Soft tissue involvement (symptoms and signs)

3 Proptosis

4 Extraocular muscle involvement

5 Corneal involvement

6 Sight loss (optic nerve involvement)

B. CAS (Clinical Activity Score)⁹

Initial Visit (1 point each)

Spontaneous orbital pain in the last 4 weeks
Gaze-evoked orbital pain in the last 4 weeks
Eyelid swelling
Eyelid erythema
Conjunctival injection
Chemosis
Inflammation of caruncle or plica semilunaris

CAS ≥ 3 → "Active"

Follow-up Visit (1 point each)

Criteria 1-7

Increase ≥ 2mm proptosis
The decrease in uniocular motility in any one direction of ≥ 8°
The decrease in visual acuity equivalent to 1 Snellen line

CAS ≥ 4 → "Active"

C. EUGOGO Severity Scale (European Group On Graves Orbitopathy) based on clinical features^7,9

Management category	Criteria
Mild	Eyelid retraction Mild proptosis Minimal muscle involvement
Moderate to severe	Greater proptosis (>25mm) Inflammation Significant motility restriction
Sight threatening	Dysthyroid optic neuropathy Corneal ulceration

D. VISA’ Classification / ITEDS (International Thyroid Eye Disease Study) ⁹– grades disease activity and severity based on the subjective and objective evaluation of Vision, Inflammation, Strabismus and Appearance⁹. More than 4 signifies activity. VISA form

CAS and VISA inflammatory score depicts the disease activity while NOSPECS, EUGOGO, VSA score of VISA define the severity of the disease.^9,10

Management:

TED is a self-limiting disease, with patients moving from the active to quiescent phase within 1-3 years with a 5-10% risk of recurrence.

Systemic investigations	Ocular investigation
Thyroid function test (Free T3, T4, TSH)	Vision, color vision
Antibody to thyroid peroxidase (TPO) and thyroglobulin	Fundus evaluation
Rule out other associated auto-immune conditions: Myasthenia Gravis and Pernicious Anemia	Diplopia charting
Ultrasound neck (To looks for thyroid gland)	Visual fields perimetry, VEP fundus photo (DON)

Orbital imaging

Ultrasound orbit – (seldomly used) can be used for distinguishing active enlargement of extraocular muscles with lower internal reflectivity from the quiescent stage showing high reflectivity.
Computed Tomography (CT) orbit
- Useful to understand the orbital bony architecture, floor, and adjacent sinuses and enables proper surgical management.¹¹
Magnetic resonance imaging (MRI)
- Preferred for soft tissue delineation.
- Gives a measure of fat hypertrophy and extraocular muscle enlargement.
- Detects apical crowding and early optic nerve compression.
- Radiological activity – inflammatory oedema and activity of extraocular muscles appear hyperintense on T2 weighted images while in fibrotic stage, they appear hypointense on T2W
- Aids in monitoring response to treatment
- Barrett’s index – Using a mid-orbit scan, vertical muscle index was calculated using the superior rectus muscle–levator muscle complex (A) and inferior rectus muscles(B) along with the perpendicular orbital height (C).
- The vertical muscular index = ([A+B/C] ×100)
- The horizontal muscular index is expressed as a percentage of the sum of the horizontal recti muscles and orbital width were measured to determine the horizontal muscle index ([D+E/F]). The larger of the two was taken as muscle index with 67% or more indicating optic nerve apical compression¹¹.
- Coco-cola bottle sign¹² – The bellies of the extraocular muscles are enlarged sparing the tendons which give an appearance similar to the Coco- cola^TM bottle.
- Fat effacement – is a measure of apical crowding measured on coronal images. The amount of effacement of perineural fat planes by enlarged extraocular muscles in percentage is graded into 0 -none, 1- (up to 25%), 2-(25-50%), 3-(more than 50%)¹⁰. (Figure no.4)

Figure 4: MRI orbits T2- weighted image (A: Coronal, B: Axial cut) showing enlargement of the extraocular muscle right orbit with intramuscular T2 hyperintense signal suggestive of radiological activity. Extraocular muscle thickness > 4 mm is considered significant.Note the classical Coco-cola bottle (B) sign depicting the tendon sparing enlargement of the muscles on axial cut.

Treatment depends on

The stage of the disease
Disease activity and severity based on clinical and radiological findings.

Based on various classifications available, the therapeutic protocol was charted out for mild, moderate-severe, and sight-threatening disease.

The primary goal in the active phase:

preserve visual function
prevent complications and sequelae

Disease severity	Management
Mild	Topical lubricants Home vision monitoring Behavioral modifications Quit smoking Salt restricted diet to prevent water accumulation Dark glasses to prevent photophobia and avoiding direct sun exposure Head elevation to reduce periorbital oedema Cool compresses Diplopia management - with prisms/ occlusion till disease stabilization Oral antioxidants – selenium 100mcg twice a day for 6 months⁷
Moderate - Severe	Medical decompression Intravenous methylprednisolone (IVMP) pulse: Initial 500 mg/week × 6 weeks Followed by 250 mg/week × 6 weeks (IVMP -8 g of maximum cumulative dosage)13
Sight threatening [DON (Dysthyroid optic neuropathy)]	IVMP 1gm daily for 3 days followed by pulse IVMP
Non- responders / Steroid dependent	Immunomodulator drugs Orbital radiotherapy (20Gy in 10 divided fractions) Surgical decompression

Medical Management (Progressive Disease)

Corticosteroids

The mainstay of treatment in active disease.
Intravenous corticosteroids
- Mechanism of action – steroids act on fibroblasts, B and T cells and reduce the release of pro-inflammatory cytokines, reduced prostaglandin release and fibroblast activity.¹⁰
- First-line therapy for compressive optic neuropathy
- (Refer Table for dosage).
- Earlier oral corticosteroids were used but are now less popular due to reduced efficacy as compared to intravenous steroids and increased systemic adverse effects.

Immunosuppressive therapy

Drugs:

Azathioprine (50mg twice a day for 1 week up to three times a day)
Methotrexate (525mg once per week)
Cyclophosphamide i. v. (500-100mg every 4-8 weeks) or oral 12mg/kg every day
Cyclosporine (50mg twice a day, increase up to 200mg twice a day)
- Regular monitoring of hematological profile, kidney and liver functions.⁴

Newer drugs in the management of TED¹⁰

Drug	MOA
Teprotumumab	Inhibits insulin-like growth factor 1 receptor (IGF1R) signalling
Rituximab	a monoclonal antibody that targets CD20
Tocilizumab	humanized monoclonal antibody against the IL-6 receptor
Belimumab (ongoing trials)	A monoclonal antibody directed towards the B cell-activating factor

Orbital Irradiation

Indications: Active disease - clinically or radiologically.

Treatment regimen: 2000 cGy or 20 Gy over 10 sessions in divided fractions, during a 2-week time course (standard regime)

Can be administered with concurrent oral or intravenous steroids

Contraindications –
- Younger patients (<35 yrs)
- Patients with microvascular retinopathy (diabetic or hypertensive retinopathy)
Adverse ophthalmic effects
- Dry eye, cataract, worsening of retinopathy, optic neuropathy, long term secondary tumours.

Orbital Decompression

Indications

Active disease

Sight threatening (DON), severe disease
No response to medical management
Severe progressive active disease with gross proptosis and exposure keratopathy

Quiescent phase

Cosmetic

Approach

External- transconjunctival
Endoscopic

Surgical Decompression	Reduction in Proptosis (mm)
Fat Removal Orbital decompression (FROD)	2-3mm
Bone removal Orbital decompression (BROD) 1 wall 2 walls 3 walls	2-3 mm 4-5 mm 6-7 mm
FROD + 3 wall decompression + lateral rim removal Balanced decompression – Medial + lateral wall (cosmetic)	10-12 mm¹⁴

Bony Decompression	Bones removed
Lateral wall decompression	Zygomatic bone – lateral to inferior orbital fissure Greater wing of the sphenoid bone Frontal bone – Lacrimal gland fossa
Medial wall decompression	Segments of the ethmoid bone Orbital contents extend into the ethmoid sinus
Orbital floor decompression	Posteromedial part of the floor - maxillary bone Expansion of orbital content into the maxillary sinus

Care should be taken to avoid damage to the neurovascular bundle, the inferior oblique muscle along the floor, and more importantly the inferomedial orbital strut to prevent hypoglobus.

Complications:

Intraoperative	Postoperative
Bleeding	Early – Infection Bleeding Retrobulbar haemorrhage Diminution of vision Diplopia Scarring
Lacrimal/supraorbital/infraorbital nerve injury
Hypoglobus Globe rupture Retinal detachment Optic nerve Injury
Inferior oblique muscle injury	Late – Asymmetry/ Supra, infraorbital nerve paresthesia

Management of Sequelae/Fibrotic Phase

Any further intervention (sequential surgery) for cosmesis, diplopia, or strabismus is done after 6 months of stable disease with normal thyroid function tests. (Figure no. 5)

Figure 5: Chart depicting the preferred sequential order of surgical intervention in an inactive thyroid eye disease

Lid retraction
Treatment	Non-surgical Botulinum injection Hyaluronic acid gel fillers Injection of triamcinolone acetate¹⁵ Surgical

Surgical correction of lid retraction
Upper lid retraction	Lateral tarsorrhaphy and mullerectomy- mild cases Recession of LPS Anterior blepharotomy¹⁶
Lower lid retraction	Spacer graft Lower lid recession

Blepharoplasty for orbital fat prolapse.
Correction of associated lacrimal gland prolapse and ptosis.

References

1. Li Z, Cestari DM, Fortin E. Thyroid eye disease: what is new to know? Curr Opin Ophthalmol. 2018 Nov;29(6):528–34.

2. Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc. 1994; 92:477–588.

3. Lazarus JH. Epidemiology of Graves’ orbitopathy (GO) and relationship with thyroid disease. Best Pract Res Clin Endocrinol Metab. 2012 Jun;26(3):273–9.

4. Liaboe CA, Clark TJ, Shriver EM, Carter KD.Thyroid Eye Disease: An Introductory Tutorial and Overview of Disease.EyeRounds.org. posted November 18, 2016; Available from http://www.EyeRounds.org/tutorials/thyroid-eye-disease/

5. Shan SJC, Douglas RS. The pathophysiology of thyroid eye disease. J Neuroophthalmol. 2014 Jun;34(2):177–85.

6. Krassas GE, Wiersinga W. Smoking and autoimmune thyroid disease: the plot thickens. Eur J Endocrinol. 2006 Jun;154(6):777–80.

7. Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velázquez-Villoria Á, Galofré JC. Graves’ Ophthalmopathy: VISA versus EUGOGO Classification, Assessment, and Management. Journal of Ophthalmology. 2015:1–16.

8. Haefliger I, von Arx G, Pimentel A-R. Pathophysiology of Intraocular Pressure Increase and Glaucoma Prevalence in Thyroid Eye Disease: A Mini-Review. Klin Monatsbl Augenheilkd. 2010 Apr;227(04):292–3.

9. Dolman PJ. Grading Severity and Activity in Thyroid Eye Disease: Ophthalmic Plastic and Reconstructive Surgery. 2018 Jul; 34-40.

10. Taylor PN, Zhang L, Lee RWJ, Muller I, Ezra DG, Dayan CM, et al. New insights into the pathogenesis and nonsurgical management of Graves orbitopathy. Nat Rev Endocrinol. 2020 Feb;16(2):104–16.

11. Gonçalves A, Gebrim E, Monteiro M. Imaging studies for diagnosing Graves’ orbitopathy and dysthyroid optic neuropathy. Clinics. 2012 Nov 7;67(11):1327–34.

12. Kizilca Ö, Öztek A, Kesimal U, Şenol U. Signs in Neuroradiology: A Pictorial Review. Korean J Radiol. 2017;18(6):992.

13. Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab. 2005 Sep;90(9):5234–40.

14. Ediriwickrema LS, Korn BS, Kikkawa DO. Orbital Decompression for Thyroid-Related Orbitopathy During the Quiescent Phase: Ophthalmic Plastic and Reconstructive Surgery. 2018 May;1.

15. Grisolia ABD, Couso RC, Matayoshi S, Douglas RS, Briceño CA. Non-surgical treatment for eyelid retraction in thyroid eye disease (TED). Br J Ophthalmol. 2017 Aug 9.

16. Ribeiro SFT, Shekhovtsova M, Duarte AF, Velasco Cruz AA. Graves Lower Eyelid Retraction: Ophthalmic Plastic and Reconstructive Surgery. 2016;32(3):161–9.

Articles Oculoplasty Oculoplasty Review

Dr. Amber Dubey

Postgraduate Trainee, Sankara Nethralya, Chennai

Dr. Amber Dubey is currently in his second year as a Primary DNB candidate at Sankara Nethralaya. He has completed his MBBS from Lokmanya Tilak Municipal Medical College, Mumbai with distinction.

Dr. Vazhipokkil Anju Chandran

Fellow, Department of Oculoplasty, Sankara Nethralaya

Dr. Vazhipokkil Anju Chandran is currently doing her fellowship in Orbit and Oculoplasty at Sankara Netralaya. She has completed her MBBS from Govt. Medical College, Kozhikode and DNB Ophthalmology from Dr. Agarwals Eye Hospital, Chennai. She has received Prof. Dr. V. Velayudham award for academic excellence and participated and won ophthalmology-based quizzes at various conferences.

Dr. Nisar Sonam Poonam

Associate Consultant, Department of Oculoplasty, Sankara Nethralaya

Dr. Sonam is currently an associate Consultant at Sankara Nethralaya. She completed her basic medical education from SDM College of Medical Sciences & Hospital, Dharwad, Karnataka. She finished her masters in Ophthalmology from Mamata Medical College, Khammam, Telangana. She did her research cum clinical fellowship in Orbit, Oculoplasty, Aesthetic and Reconstructive Services at Sankara Nethralaya, Chennai. Before joining Sankara Nethralaya she was incharge of the Department of Orbit and Oculoplasty at Nethradhama Super Speciality Eye Hospital, Bangalore. She has presented many papers at state, national and international level. She has special interest in ocular trauma, aesthetics and management of thyroid eye disease.