Thyroid Eye Disease : A Review for the Postgraduates

Dr. Amber Dubey
Dr. Vazhipokkil Anju Chandran
Dr. Nisar Sonam Poonam
Published Online: April 1st, 2021 | Read Time: 23 minutes, 15 seconds


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.


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


  • 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



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


Smoking1,6 (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


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.


Lasts for about 6 to 24 months


Episcleral injection (at the insertion of muscles)

Conjunctival injection and chemosis


Sight threatening complication secondary to corneal ulceration or compressive optic neuropathy


Progressive fibrosis

Stable proptosis

Eyelid retraction

Persistent restrictive strabismus

No signs of inflammation

Corrective Surgical management to be planned


  • 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


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


  • 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



  • 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*


  • 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


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


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

Proptosis (Exophthalmos)


  • 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]


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

Ocular Motility Restrictions


  • 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 1o position


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



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




Restrictive strabismus

Intraocular Pressure8


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.


  • 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


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


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


Eyelid signs

  1. Kocher’s – Staring Appearance
  2. Vigouroux – Fullness of eyelids
  3. Rosenbach’s – Tremors of the eyelids while closed
  4. Reisman’s – Bruit over the eyelids

Upper lid signs

  1. Von Graefe’s – Lid lag on downgaze
  2. Dalrymples’s – Lid retraction
  3. Stellwag’s – Incomplete and infrequent blinking
  4. Grove – Resistance to pulling the retracted upper lid
  5. Boston – Jerky movements of the lid on downward gaze

Lower lid signs

  1. Gellineck’s – Abnormal pigmentation of the upper lid
  2. Gifford’s – Difficulty in inverting the upper lid

Extraocular movements signs

  1. Moebius – the inability to converge eyes
  2. Ballet’s – Restriction of one or more EOM
  3. Sulker’s – Poor fixation on abduction
  4. Jendrassik’s – Paralysis of all EOM

Facial signs

  1. Joffroy’s sign – Absent creases on the forehead on upward gaze

Pupillary and conjunctival signs

  1. Knies – Uneven pupillary dilatation in dim light
  2. Cowen’s – Jerky contraction of the pupil to light
  3. Goldzeiher’s – conjunctival injection


A. No Specs/ Werners Classification 9


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)

  1. Spontaneous orbital pain in the last 4 weeks
  2. Gaze-evoked orbital pain in the last 4 weeks
  3. Eyelid swelling
  4. Eyelid erythema
  5. Conjunctival injection
  6. Chemosis
  7. Inflammation of caruncle or plica semilunaris

CAS ≥ 3 → "Active"

Follow-up Visit (1 point each)

Criteria 1-7

  1. Increase ≥ 2mm proptosis
  2. The decrease in uniocular motility in any one direction of ≥ 8°
  3. 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 features7,9

Management category



Eyelid retraction

Mild proptosis

Minimal muscle involvement

Moderate to severe

Greater proptosis (>25mm)


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


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 indexUsing 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 sign12The bellies of the extraocular muscles are enlarged sparing the tendons which give an appearance similar to the Coco- colaTM 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



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)


  • 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


  • 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




Inhibits insulin-like growth factor 1 receptor (IGF1R) signalling


a monoclonal antibody that targets CD20


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


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


  • External- transconjunctival
  • Endoscopic

Surgical Decompression

Reduction in Proptosis (mm)

Fat Removal Orbital decompression (FROD)


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.





Early – Infection


Retrobulbar haemorrhage

Diminution of vision



Lacrimal/supraorbital/infraorbital nerve injury


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


  • Non-surgical
    • Botulinum injection
    • Hyaluronic acid gel fillers
    • Injection of triamcinolone acetate15
  • Surgical

Surgical correction of lid retraction

Upper lid retraction

  1. Lateral tarsorrhaphy and mullerectomy- mild cases
  2. Recession of LPS
  3. Anterior blepharotomy16

Lower lid retraction

  • Spacer graft
  • Lower lid recession
  • Blepharoplasty for orbital fat prolapse.
  • Correction of associated lacrimal gland prolapse and ptosis.


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 posted November 18, 2016; Available from
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.
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.
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