2. Also known as TRO / Graves’ orbitopathy
Self-limiting auto-immune process
Mild to severe irreversible sight threatening disease
Graves' disease is the most common thyroid
abnormality
Other associations include Hashimoto's thyroiditis,
thyroid carcinoma, primary hyperthyroidism, and
neck irradiation
3. EPIDEMIOLOGYEPIDEMIOLOGY
Most common disease affecting the orbit
Female to Male ratio 9.3:1 (mild cases)
1.4:1 (severe cases)
Severe cases more frequent in >50 yr age group
Cigarette smoking is the strongest modifiable risk
factor
Myasthenia gravis is 50 times more common in
patients with TAO
4. ETIOLOGYETIOLOGY
80% 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
5. 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
6. 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
7. • 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
10. PATHOGENESISPATHOGENESIS
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 fibroblasts
COX-2 ( Cyclo oxygenase -2 )Expressed at higher
levels in fibro adipose tissue of TRO patients
11. PATHOPHYSIOLOGYPATHOPHYSIOLOGY
Fibroblasts are the target cells in TAO
They are extremely sensitive to stimulation by
cytokines and immunoglobulins
Stimulated 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
12. COURSE OF THE DISEASECOURSE OF THE DISEASE
TRO has an active inflammatory phase and a stable
post inflammatory phase
Duration of active phase 6-18 months
Management 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
13. STAGINGSTAGING
WERNER´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
14. 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
15. 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.
16. MOURITS CLASSIFICATION
Clinical Activity Score ( CAS ) to grade the
inflammatory phase of the disease
The CAS consists of two conjunctival, eyelid and
two orbital signs
A score of 4 /> - active disease
Subjective in nature with very large interobserver
variation
17. Clinical Activity Score
For initial CAS, only score items 1-7
1. 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.
18. 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.
19. THE VISA CLASSIFICATIONTHE VISA CLASSIFICATION
Devised by Peter Dolman and Jack Rootman
Based on four disease points
Basic form consists of 4 sections recording symptoms
on the left and signs on the right
Each disease activity is graded
Objective and reproducible
Appropriate management for patients in a logical
sequence
22. Clinical signs in TEDClinical signs in TED
Facial signs
joffroy’s sign-absent creases in the
forehead on superior gaze.
Eyelid signs
Kocher’s sign-staring appearance
Vigouroux sign-eyelid fullness
Rosenbach’s sign-tremors of eyelids
Riesman’s sign-Bruit over the eyelids
23. Upper eye lid signs
Von graefe’s sign-lid lag on downgaze
Dalrymple’s sign-lid retraction
Stellwag’s sign-incomplete & infrequent
blinking
Grove sign-resistance to pulling the retracted
upper lid
Boston sign-jerky movements of lid on down
gaze
Gellineck’s sign-abnormal pigmentation of
upper lid
Gifford’s sign-difficulty in everting the upper
lid
24. Lower eye lid signs
Enroth ’s sign-edema of lower lid
Griffith’s sign-lid lag on upgaze
Conjunctival signs
Goldzeiher’s sign-conjunctival injection
25. Extraocular movement signs
Moebius sign-unable to converge eyes
Ballet’s sign-restriction of one or more EOM
Suker’s sign-poor fixation on abduction
Jendrassik’s sign-paralysis of all EOM
Pupillary signs
Knies sign-uneven pupillary dilatation in dim light
Cowen’s sign-jerky contraction of pupil to light
28. 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
29. Eyelid Retraction – Clinical FeaturesEyelid Retraction – Clinical Features
Clinical signs:
◦ Lid retraction in 1º
(front) gaze
◦ Lid lag i.e. delayed
descent of upper lid
in downgaze
◦ Staring appearance of
the eyes
32. Soft Tissue Involvement - SignsSoft Tissue Involvement - Signs
Periorbital and lid swelling
Conjunctival hyperaemia
Sensitive sign of disease activity
Chemosis (edema of the conjunctiva)
Severe cases: conjunctiva prolapses over lower eyelid
34. 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
35. 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 proptosis
Can cause severe but preventable visual impairment
36. An early sign is decreased colour vision
Slow 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%
41. 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
43. COMPRESSIVE OPTIC NEUROPATHYCOMPRESSIVE OPTIC NEUROPATHY
The 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.
45. RADIATION THERAPYRADIATION THERAPY
Lymphocytes 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 steroids
A relative contraindication in diabetics
46. 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.
47. 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.
48. 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
49. Medial wall removal not to extend above
the fronto ethmoidal suture
Preservation of a strut of bone between ethmoid and
maxillary bones
Lateral wall removal has little effect on apical compression
Four wall decompression requires a neurosurgical approach
Orbital fat decompression for reducing proptosis
52. ACTIVE INFLAMMATIONACTIVE INFLAMMATION
Treatment depends on inflammatory score
Score <4 - conservative management
Score > 5 – more aggressive therapy
Oral/IV steroids
Radiotherapy
Immunosuppressive agents
53. Soft Tissue Involvement - RSoft Tissue Involvement - Rxx
Frequently 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
54. 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
55. 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
56. EYELID ABNORMALITIESEYELID ABNORMALITIES
Mild 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
57. 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
58.
59. 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...
60. TRO is a self limiting disease
Patient education
Stopping 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
61. 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