THYROID EYE THYROID EYE DISEASEDISEASE

DR K HARIPRIYASSSIHMS

Also known as TRO / Graves’ orbitopathySelf-limiting auto-immune processMild to severe irreversible sight threatening

diseaseGraves' disease is the most common thyroid

abnormality Other associations include Hashimoto's

thyroiditis, thyroid carcinoma, primary hyperthyroidism, and neck irradiation

EPIDEMIOLOGY EPIDEMIOLOGY Most common disease affecting the orbitFemale to Male ratio 9.3:1 (mild cases) 1.4:1 (severe cases)Severe cases more frequent in >50 yr age

groupCigarette smoking is the strongest modifiable

risk factorMyasthenia gravis is 50 times more common in

patients with TAO

ETIOLOGYETIOLOGY80% are clinically hyperthyroid and 10% are

clinically euthyroid◦ Associated with normal to abnormal thyroid

function In patients who are hyperthyroid, eye signs

of TAO usually develop within 18 months

Smokers have a 5 time higher risk of developing TAO

Cawood and colleagues have established that orbital fibroblasts when exposed to cigarette extract showed an increased production of Glycosaminoglycans

There is evidence that cessation of smoking reduces the risk of progression of orbitopathy

A 6.4 times risk for development of orbitopathy in Europeans compared to Asians *

Genetic predisposition 20-60% - positive family history of thyroid

disease Concordance level is 50% in identical twins

* Tellez et al.Clin Endocrinol 1992

• Increased prevalence of HLA B8, DR-3 may increase susceptibility to TAO• Higher frequency of HLA-DRB1-16 allele in TRO patients with severe extra ocular muscle involvement ** **Akaishi et al. Thyroid

2008

PATHOGENESISPATHOGENESIS

PATHOGENESIS PATHOGENESIS Immune mediated inflammatory reaction Circulating auto antibodies like TRAb, TSI are

thought to be mediators of orbitopathy also IGF-IR ( Insulin like growth factor I receptor ) is

an auto antigen expressed by fibroblastsCOX-2 ( Cyclo oxygenase -2 )Expressed at

higher levels in fibro adipose tissue of TRO patients

PATHOPHYSIOLOGYPATHOPHYSIOLOGYFibroblasts are the target cells in TAOThey are extremely sensitive to stimulation

by cytokines and immunoglobulinsStimulated fibroblasts secrete Hyaluronic

acid which is hydrophilic and causes edema in extraocular muscles

Doubling of Hyaluronic acid content causes a 5 fold increase in tissue osmotic load

COURSE OF THE DISEASECOURSE OF THE DISEASETRO has an active inflammatory phase and

a stable post inflammatory phase Duration of active phase 6-18 monthsManagement of active phase is aimed at

modulating the immune response and reducing the inflammation

Reactivation of disease occurs in less than 5 percent of individuals

STAGINGSTAGINGWERNER´S CLASSIFICATION - NOSPECS

0 Nil (no symptoms or signs)

1 Only signs of: a) stare

b) lid lag

2 Soft tissue involvement: 0) absent

a) minimal

b) moderate

c) marked

3 Proptosis of 3mm or more: 0) absent

a) 3-4 mm

b) 5-7 mm

c) 8 or more mm

4 Extra ocular muscle involvement: 0) absent

a) limitation at extremes of gaze

b) evident restriction of motion

c) fixation of globe

5 Corneal involvement: 0) absent

a) SPE

b) corneal ulceration,

c) necrosis or perforation

6 Sight loss (due to optic neuropathy): 0) absent

a) 20/20-20/60

b) 20/70-20/200

c)Worse than 20/200.

MOURITS CLASSIFICATIONClinical Activity Score ( CAS ) to grade the

inflammatory phase of the diseaseThe CAS consists of two conjunctival,

eyelid and two orbital signsA score of 4 /> - active diseaseSubjective in nature with very large

interobserver variation

Clinical Activity ScoreFor initial CAS, only score items 1-71. Spontaneous orbital pain.2. Gaze evoked orbital pain.3. Eyelid swelling that is considered to

be due to active inflammatory phase.4. Eyelid erythema.5. Conjunctival redness that is

considered to be due to active inflammatory phase.

6. Chemosis.7. Inflammation of caruncle OR plica.Patients assessed after follow-up can

be scored out of 10 by including items 8-10.

8. Increase of > 2mm in proptosis.9. Decrease in uniocular ocular

excursion in any one direction of > 8º.10. Decrease of acuity equivalent to 1

Snellen line.

THE VISA CLASSIFICATIONTHE VISA CLASSIFICATIONDevised by Peter Dolman and Jack RootmanBased on four disease pointsBasic form consists of 4 sections recording

symptoms on the left and signs on the rightEach disease activity is gradedObjective and reproducibleAppropriate management for patients in a

logical sequence

VISA INFLAMMATORY SCOREVISA INFLAMMATORY SCORE

Clinical signs in TEDClinical signs in TEDFacial signs

joffroy’s sign-absent creases in the forehead on superior gaze.

Eyelid signsKocher’s sign-staring appearanceVigouroux sign-eyelid fullnessRosenbach’s sign-tremors of eyelidsRiesman’s sign-Bruit over the eyelids

Upper eye lid signsVon graefe’s sign-lid lag on downgazeDalrymple’s sign-lid retractionStellwag’s sign-incomplete & infrequent

blinkingGrove sign-resistance to pulling the

retracted upper lidBoston sign-jerky movements of lid on down

gazeGellineck’s sign-abnormal pigmentation of

upper lidGifford’s sign-difficulty in everting the upper

lidMeans sign-increase superior scleral show

on upgaze

Lower eye lid signs

Enroth ’s sign-edema of lower lidGriffith’s sign-lid lag on upgaze

Conjunctival signs

Goldzeiher’s sign-conjunctival injection

Extraocular movement signsMoebius sign-unable to converge eyes Ballet’s sign-restriction of one or more EOMSuker’s sign-poor fixation on abduction Jendrassik’s sign-paralysis of all EOM

Pupillary signs

Knies sign-uneven pupillary dilatation in dim lightCowen’s sign-jerky contraction of pupil to light

CLINICAL FEATURESCLINICAL FEATURES1. Eyelid Retraction2. Soft Tissue Involvement3. Proptosis4. Optic Neuropathy / Exposure

Keratopathy5. Strabismus

LID LID RETRACTIONRETRACTION

Eyelid RetractionEyelid Retraction Retraction of both upper and lower eyelids

occur in 50% of patients Normally, upper eyelid rests about 2mm

below limbus, with lower eyelid resting at the inferior limbus

When retraction occurs, the sclera (white) can be seen

Causes cosmetic problem May be due to contraction of the levator

muscle by fibrosis, or be chemically induced by high thyroid hormone levels

If persists when disease is inactive, can be helped by eye lid surgery

Eyelid Retraction – Clinical Eyelid Retraction – Clinical FeaturesFeaturesClinical signs:

◦Lid retraction in 1º (front) gaze

◦Lid lag i.e. delayed descent of upper lid in downgaze

◦Staring appearance of the eyes

SOFT TISSUE SOFT TISSUE INVOLVEMENTINVOLVEMENT

Soft Tissue Involvement - Soft Tissue Involvement - SymptomsSymptomsVariable grittinessPhotophobiaLacrimation - watery eyes

Soft Tissue Involvement - Soft Tissue Involvement - SignsSignsPeriorbital and lid swellingConjunctival hyperaemia

Sensitive sign of disease activityChemosis (edema of the

conjunctiva) Severe cases: conjunctiva prolapses over lower

eyelid

PROPTOSISPROPTOSIS

Proptosis(exophthalmos)Proptosis(exophthalmos) Proptosis is axial TED is the most common

cause of both bilateral and unilateral proptosis in adults

Proptosis is uninfluenced by Rx of hyperthyroidism and is permanent in 70% of cases

Severe proptosis prevents adequate lid closure, and may lead to severe exposure keratopathy and corneal ulceration

OPTIC NEUROPATHYOPTIC NEUROPATHY

Serious complication affecting about 5% of patients

Caused mainly through direct compression of the optic nerve or its blood supply by enlarged and congested rectus muscles at the orbital apex

May occur in the absence of proptosisCan cause severe but preventable visual

impairment

An early sign is decreased colour visionSlow progressive impairment of visual acuity

6/6 to 6/9 Va in 18% of cases Relative afferent pupillary defect -35%Visual defects, especially central scotomas –

66% Swollen or pale disc - 52%

CORNEAL CORNEAL INVOLVEMENTINVOLVEMENT

Exposure keratitis may result from proptosis, upper eyelid retraction, lower eyelid retraction, lagophthalmos, or a combination of these

OCULAR MOTILITY OCULAR MOTILITY PROBLEMSPROBLEMS

30% - 50% A defect in elevation

is most common due to fibrosis of inferior rectus muscle

IR>MR>SR>LR

CT SCAN

MRI SCAN

VISUAL FIELDVISUAL FIELD

Characteristically a central scotoma / an inferior altitudinal defect is seen in cases of compressive optic neuropathy

Other visual field defects include an enlarged blind spot, para central scotoma, nerve fibre bundle defect, or generalized constriction

TREATMENTTREATMENT

Compressive optic neuropathy Inflammation Motility disordersEyelid abnormalities

COMPRESSIVE OPTIC COMPRESSIVE OPTIC NEUROPATHYNEUROPATHYThe treatment possibilities include high doses

of corticosteroids, irradiation,immunosupressants and orbital decompression.

Some patients require only one of these modalities, while other patients need combined therapies.

CORTICOSTEROIDSCORTICOSTEROIDSIntra-venous Methyl Prednisolone 1 gm

alternate days for 3-6 cyclesCumulative dose not to exceed 6-8 gmEffective in 63-77% *No response in 48 hours - Steroids probably

will not work * Rajendran et. al, CIRTED trial

RADIATION THERAPYRADIATION THERAPYLymphocytes infiltrating the orbit are highly

sensitive to Radiation. The glycosaminoglycan production by fibroblasts is reduced

Dose =1500- 2000 cGy per eye fractioned over a period of 2 weeks

Co coverage with steroidsA relative contraindication in diabetics

Although congestive findings improve most consistently, significant improvement in proptosis and extra ocular muscle function has been reported.

Radiation therapy is most effective within the first year, when significant fibrotic changes have not yet occurred.

ORBITAL DECOMPRESSIONORBITAL DECOMPRESSION

Indicated for compressive optic neuropathy when there has been failure of or contraindication for corticosteroids or radiation therapy

Gross proptosis with exposure keratitis and corneal ulceration

Cosmesis for disfiguring exophthalmos.

ORBITAL DECOMPRESSIONORBITAL DECOMPRESSION

The swinging lower lid approach to inferior and medial wall decompression is the most common approach used by ophthalmologists.

Medial wall decompression to extend posteriorly for compressive optic neuropathy

Medial wall removal not to extend above the fronto ethmoidal suturePreservation of a strut of bone between ethmoid

and maxillary bonesLateral wall removal has little effect on apical

compressionFour wall decompression requires a neurosurgical

approachOrbital fat decompression for reducing proptosis

AFTER 3-WALL DECOMPRESSION & AFTER 3-WALL DECOMPRESSION & FAT EXCISIONFAT EXCISION

ACTIVE INFLAMMATIONACTIVE INFLAMMATION

Treatment depends on inflammatory scoreScore <4 - conservative managementScore > 5 – more aggressive therapy Oral/IV steroids Radiotherapy Immunosuppressive agents

Soft Tissue Involvement - Soft Tissue Involvement - RRxxFrequently unsatisfactory, may be of

some benefit Topical Rx – lubricants (artificial tears &

ointment) reduce irritation caused by conjunctival inflammation and mild corneal exposure

Elevating the head end of bed during sleep may decrease periorbital oedema. Diuretics given at night may also reduce the morning accumulation

Taping of eyelids at night may be useful for mild exposure keratopathy

MOTILITY DISORDERSMOTILITY DISORDERS A major source of morbidity in thyroid

orbitopathy, and the most frequent problem associated with orbital decompression surgery

Minimal degrees of ocular misalignment - compensatory head posture, Fresnel plastic press-on prisms, or temporary occlusion

If there is marked asymmetry in ocular deviation in different fields of gaze, prisms are less effective

Surgery is usually considered if there is diplopia in primary gaze or reading position

Diplopia must have been stable for about 6 months

Rx is by muscle surgery, with the aim of producing binocular vision when looking forward, and good cosmetic result

Botulinum toxin injection (Botox) to relax muscles may be useful in selected cases

EYELID ABNORMALITIESEYELID ABNORMALITIESMild eyelid retraction does not require Rx, in

50% of cases, there is spontaneous improvement

Rx of associated hyperthyroidism may also improve lid retraction

Main indications are exposure keratopathy and poor cosmesis

A graded Muller’s and levator aponeurosis weakening abnormalities(recession of lower lid retractors,mullertomy)

Blepharoplasty is the final surgical procedure in the rehabilitation of TRO patient

Orbital decompression is performed initially followed by strabismus surgery and then eyelid surgery

No effective means of preventing the disease or reliably altering it’s course

Current therapeutic options aimed at reducing the inflammation during active stage and correction of residual abnormalities secondary to fibrosis in the inactive stage

Intervention not targeting the cause because the precise pathogenesis is still elusive

TO CONCLUDE...

TRO is a self limiting diseasePatient educationStopping smoking

Newer medical therapies like anti CD 20 (Rituximab) to deplete B- cell lymphocytes, anti TNF drugs, Pentoxyfylline and nicotinamide which inhibit cytokine induced glycosaminoglycan synthesis ,intravenous immunoglobulin are being tried

More studies are required to determine the risk benefit ratio of these new modalities

Recent advances in molecular biology, identification of multiple genes and auto antigens with a possible role in thyroid orbitopathy may pave a way in preventing this common yet poorly understood disease