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Thyroid Ophthalmopathy
Yash Shah

Introduction

hyroid ophthalmopathy often termed as Graves

ophthalmopathy, is a part of an autoimmune process that
can affect the orbital and periorbital tissue, the thyroid gland
and rarely the pretibial skin or digits.1 The condition primarily
effects women and has an incidence of approximately 4/10,000
per annum. During their lifetime approximately 1% of the
population is affected. The condition has disfiguring and sight
threatening complications and its the commonest cause of
unilateral and bilateral axial proptosis in young and middle aged
adults. Though the condition is associated with hyperthyroidism
in 90% of patients, 6% are euthyroid.2 Smoking is associated
with an increased risk of development and severity of thyroid
eye disease by seven to eight fold.3,4,5

Pathophysiology
The underlying pathophysiology is thought to be an
antibody-mediated reaction against the TSH receptor with
orbital fibroblast modulation of T- cell lymphocytes. The T-cell
lymphocytes are believed to react against thyroid follicular
cells with shared antigenic epitopes in the retrobulbar space.1
The lymphocytic infiltration leads to the activation of cytokine
networks and inflammation and interstitial oedema of the
extraocular muscles.5 Excess secretion of glycosaminoglycans
by orbital fibroblasts seems to be an important contributor. The
end result is expansion of the volume of extraocular muscles,
retrobulbar fat and connective tissue. Similar changes affect the
eyelids and anterior periorbital tissues.6

orbitopathy and thyroid induced sensitization of Mullers

muscle to circulating catecholamines resulting in a staring
look (Fig. 2).
2. Soft tissue signs: These are common in active eye disease
and include eyelid oedema (Fig. 3) and conjunctival
erythema and chemosis. Dilated episcleral veins over
insertion of recti can be seen in inactive disease.
3. Proptosis: Proptosis is commonly seen in thyroid eye
disease. Its extent is partly dependent on compliance of
orbital septum. Choroidal folds can occasionally be seen
and there is often an increased resistance to retropulsion.
Proptosis combined with lid retraction and inferior rectus
restriction may lead to corneal exposure and ulceration.
(Fig. 4 )
4. Restrictive extraocular myopathy: This is due to oedema,
inflammation and fibrosis due to lymphocytic infiltration of
the extraocular muscles. This causes tethering of the globe
by the tight recti muscles. The muscles (recti) involved in
decreasing order of severity and frequency are the inferior
rectus, superior rectus and lateral rectus.
5.

Anterior segment signs: They include superficial punctuate

keratitis, superior limbic keratoconjunctivitis, conjunctival
injection usually over the rectus muscle insertions, and
conjunctival chemosis.

6.

With severe proptosis, corneal exposure with frank corneal

ulceration may occur. A chronic, often recurrent condition
of ocular irritation, which may be attributable to mechanical
trauma transmitted from the upper eyelid to the superior
bulbar and tarsal conjunctiva and is purpoted to be a
prognostic marker for severe thyroid ophthalmopathy is
superior limbic keratoconjunctivitis.

7.

Strabismus is common and it often represents as hypotropia

or esotropia because the inferior rectus muscle and the
medial rectus muscle are the most commonly involved
extraocular muscles.

Since asymmetric proptosis and lid retraction may mask

the true relative positions of the globes, corneal light
reflexes should be examined closely.

Forced ductions or elevated intraocular pressure with

eye movement (e.g. upgaze in hypotropic patients) can
help confirm restrictive myopathy in cases in which the
diagnosis of thyroid ophthalmopathy is difficult.

Inferior rectus muscle restriction may mimic double

elevator palsy.

Pseudo-fourth nerve palsies have been described with

thyroid ophthalmopathy.

Although esotropia is a more common finding with

thyroid ophthalmopathy, convergence insufficiency
has been described.

In patients with thyroid ophthalmopathy and exotropia,

the possibility of concurrent myasthenia gravis should
be considered.

8.

Optic nerve compression may occur with seemingly mild

proptosis. Also, in most cases of compressive thyroid optic
neuropathy visible optic nerve oedema occurs. For this

Signs and Symptoms

The sign and symptoms may vary and depend on the stage
that the patient is experiencing. Initially, an acute or sub acute
stage of active inflammation occurs. A patient with thyroid
ophthalmopathy may progress from an acute or sub-acute stage
to a more quiescent stage, characterized by fibrosis.7 Patients may
complain of the ocular symptoms as shown in Table 1.

Signs
The clinical signs are characteristic and include a combination
of eye lid retraction, lid lag, globe lag, proptosis, restrictive
extraocular myopathy and optic neuropathy.2, 9
1. Lid signs: Lid lag and lid retraction (Fig. 1) result from
involvement of levator palpebrae superioris due to
Table 1 : Ocular symptoms of thyroid ophthalmopathy
Dry eyes
Puffy eyelids
Proptosis
Eyelid retraction
Diplopia, especially at extreme gaze5
Visual loss

Field loss
Dyschromatopsia
Photopsia on upgaze
Ocular pressure or pain
Lacrimation
Exposure keratitis8

Medical Director - Total Eye Care, E 1st Floor, Bhaveshwar Vihar, SVP
Road, Prarthna Samaj, Opp. Hurkisondas Hospital, Mumbai 400004,
India; Hon. Consultant, Bhatia Hospital, Conwest Jain Hospital,
Jagjivanram Western Railway Hospital,

 SUPPLEMENT TO JAPI JANUARY 2011 VOL. 59

61

Fig. 4 : Exophthalmos, proptosis

Fig 1 : Dalrymple sign Lid retraction

Fig 5 : Moebius sign- weakness of convergence

Fig 2 : Kochers sign - Staring look

Fig. 3 : Puffiness of eyes

reason, documenting visual acuity, colour vision, and the

presence or absence of a relatively afferent papillary defect
is important during each visit.
9. Glaucoma may result from decreased episcleral venous
outflow. Restrictive myopathy may cause an increase in
intraocular pressure of more than 8mm Hg on upgaze
(differential IOP).
10. Choroidal folds may be seen with thyroid ophthalmopathy.
11. Other eponymous signs are associated with thyroid
ophthalmopathy, including the following:

Vigouroux sign (eyelid fullness)

Stellwag sign (incomplete and infrequent blinking)

Grave sign (resistance to pulling down the retracted

upper lid)

Goffory sign (absent creases in the forehead on superior

gaze)

Mobius sign (poor convergence) (Fig. 5)

Ballet sign (restriction of one or more extraocular

muscles)

12. Deep glabellar rhytids has been found to be significantly

associated with thyroid ophthalmopathy, presumably
as a result of hypertrophy of brow depressor muscles
compensating for lid retraction.
13. Pretibial dermopathy and thyroid acropachy (which mimics
the appearance of clubbing) are less commonly encountered

Fig 6 : Exophthalmometry

dramatic, cutaneous signs of dysthyroidism.

Many a times, in cases of periorbital swelling and conjunctival
redness as the predominant features, thyroid eye disease is often
misdiagnosed as allergic conjunctivitis. Differentiating between
the thyroid eye disease and other causes of periorbital edema is
possible by (exophthalmometry Fig. 6) examining the presence
of eyelid retraction and restricted eye movements, which occurs
in thyroid eye disease.5

Differential Diagnosis

Allergic conjunctivitis

Myasthenia gravis

Orbital myositis

Chronic progressive external ophthalmoplegia

Orbital tumors (primary or secondary).

Carotid cavernous fistula

Any inflammatory orbitopathy

Sarcoidosis

Preseptal cellulitis

Orbital cellulitis

Classification for
Thyroid Ophthalmopathy
Simplest classification for thyroid ophthalmopathy is1:

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Table 2: NOSPECS classification (signs and symptoms).

Score
0
1
2

Grade

0
a
b
c
3
0
a
b
c
4
0
a
b
c
5
0
a
b
c
6
0
a
b
c

SUPPLEMENT TO JAPI JANUARY 2011 VOL. 59

Table 3: Point system used for Clinical Activity Score (CAS)

Pain

No signs or symptoms
Only signs
Soft tissue involvement, with symptoms and signs
Absent
Minimal
Moderate
Marked
Proptosis
<23mm
23-24mm
25-27mm
28mm
Extraocular muscle involvement
Absent
Limitation of motion in extremes of gaze
Evident restriction of movement
Fixed eyeball
Corneal involvement
Absent
Stippling of cornea
Ulceration
Clouding
Sight loss
Absent
20/20 20/60
20/70 20/200
<20/200

Type 1 is characterized by minimal inflammation and

restrictive myopathy.

Type 2 is characterized by significant orbital inflammation

and restrictive myopathy

NOSPECS classification (Table 2) for remembering clinical

features10
N - No signs or symptoms
O - Only signs (such as lid retraction), no symptoms
S - Soft tissue involvement
P - Proptosis
E - Extraocular muscle
C - Corneal involvement

Painful, oppressive feeling on or behind the globe

during the last 2 weeks.
Pain on attempted up, side or down gaze during
the last 4 weeks.
Redness
Redness of the eye lids.
Diffuse redness of the conjunctiva covering at
least one quadrant.
Swelling
Swelling of the eyelids.
Chemosis
Swollen caruncle
Increase of proptosis 2mm during a period of
1-3 months.
Impaired Function Decrease of eye movements in any direction 5
during a period of 1-3 months.
Decrease of visual acuity of 1 line on the Snellen
chart (using a pin hole) during a period of 1-3
months.

Diagnosis
Blood

In screening for thyroid disease, the combination of T4

(thyroxine) and TSH (thyroid-stimulating hormone) or
serum TSH (thyrotropin) are highly sensitive and specific.

Serum TSH is useful to establish a diagnosis of

hyperthyroidism and hypothyroidism. The TSH is low in
hyperthyroidism and high in hypothyroidism.

Other blood tests that may be useful include calculated free

T4 index, thyroid-stimulating immunoglobulin, antithyroid
antibodies and serum T3.

Thyroid peroxidase antibodies and antibodies to

thyroglobulin may be useful when trying to associate eye
findings with a thyroid abnormality, such as euthyroid
Graves disease.

Imaging Studies
Ultrasound
Orbital ultrasound can quickly confirm if the patient has
thickened muscles or an enlarged superior ophthalmic vein.
CT Scan and MRI
If the diagnosis of thyroid ophthalmopathy can be established
clinically, then it is not necessary to routinely order a CT scan
or an MRI.

If the above studies are required, obtain axial and coronal

views.12

Disease Activity

The assessment of disease activity is important as it is believed

that immunosuppression would be useful only in the early active
phase of disease. Disease activity can be assessed by using the
Clinical Activity Score (CAS) which was proposed by Mauritz in
1989.11 Clinical Activity Score (CAS) has been found to be of value
in predicting the outcome of immunosuppressive treatment and
immunotherapy because of its high specificity and high positive
predictive value. For each item in the Table 3, one point is given.
The sum of these points is the CAS. Studies have shown that
with CAS 4 were more responsive to treatment as compared
to patients with CAS<4.

Neuroimaging usually reveals thick muscles with tendon

sparing.

The inferior rectus muscles and the medial rectus

muscle usually are involved.

Isolated rectus muscle involvement may occur in

upto 6% of patients. In this sub group of patients, the
superior rectus muscle may be the most frequently
involved muscle.

Bilateral muscle enlargement is the norm; unilateral

cases usually represent asymmetric involvement rather
than normality of the less involved side

Neuroimaging may show a dilated superior ophthalmic

vein

Apical crowding of the optic nerve is well visualized on

S - Sight loss

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63

Fig 7 : CT scan (coronal section) showing thyroid associated

orbitopathy

neuroimaging

MRI is more sensitive for showing optic nerve.

CT scan is performed prior to bony decompression because

it shows better bony architecture.

Occasionally the proptosis results in straightening of the

optic nerve.

Monitor for visual loss from corneal exposure and optic

neuropathy and for strabismus development.

Visual field and colour vision testing may help in early

detection of visual loss.

If a patient has dry eye symptoms, consider using tears

during the day, lubricating ointment at night and punctual
plugs.

Morning lid edema may be reduced by sleeping on a bed

with its head slightly elevated.

Patients should be encouraged to stop smoking in order to

reduce the risk of congestive orbitopathy.

Atypical features requiring confirmation of the diagnosis of

thyroid eye disease by orbital imaging (CT or MRI) 5 :- (Fig. 7, 8)

Unilateral disease

Unilateral or bilateral disease in patients with no previous

or present evidence of thyroid dysfunction

Absence of upper eyelid retraction

Divergent strabismus

Diplopia sole manifestation

History of diplopia worsening towards the end of the day

Histologic findings

Lymphocytic cell infiltration

Enlargement of fibroblasts

Accumulation of mucopolysaccharides

Interstitial oedema

Increased collagen production

Fibrosis with degenerative changes in the eye muscles

Management
TEARS mnemonic for remembering initial management.5
T Tobacco abstinence is immensely important
E Euthyroidism must be achieved and maintained
A Artificial tears are helpful for the majority of the patients
and can afford rapid relief from symptoms of corneal exposure
R Referral to a specialist centre with experience and
expertise in treating thyroid eye disease is indicated in all but
the mildest of cases
S Self help groups can provide valuable additional support
Medical care

Inform patients that thyroid ophthalmopathy usually runs

a self limited but prolonged course over 1 or more years.
Patient should realize that no immediate care is available.13

Most patients with thyroid ophthalmopathy should be

observed and the follow up interval depends on disease
activity.

Fig 8 : CT scan (axial view) showing thyroid ophthalmopathy

Severe form of disease may need more aggressive management.

Whereas patients with active and progressive disease may
benefit from immunosuppression, patients with inactive burnt
out disease are only amenable to surgical intervention.14
Radiotherapy
This has a non specific anti- inflammatory effect and destroys
the radiosensitive lymphocytes and reduces glycosaminoglycans
production.15, 16, 17 Usually a cumulative dose of 20 Gy per eye
fractioned in 10 daily doses over a two week period is used.
Orbital radiotherapy may cause a transient exacerbation
of inflammation, but this can be prevented by concomitant
glucocorticoid administration.17
Glucocorticoids
These are highly effective in soft tissue changes and optic
neuropathy, whereas decrease in proptosis and ocular motility
is less impressive.16 Intravenous glucocorticoids seem to be
associated with higher success rate and better tolerability as
compared to oral glucocorticoids.18,19 Since recurrences are not
infrequent, treatment may prolong.9,19 Patients may be treated
with one gram of intravenous methyl prednisolone daily for
three days followed by oral steroids which may be tapered as
condition improves.
Antioxidants
Treatment with anti oxidants like nicotinamide and allopurinol,
has shown encouraging results in mild and moderately severe
newly diagnosed active disease.20 Nicotineamide and allopurinol
have been used in doses of 300mg daily. The effect was found
to be more pronounced in cigarette smokers. Though soft tissue
inflammation responds well to treatment, effect on proptosis is
not very impressive.16

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safe treatment modality, except possibly for patients

with diabetes mellitus.34

Somatostatin analogues
These receptors can be visualized in Vivo in orbital tissue of
Graves ophthalmopathy patients.21,22 Somatostatin analogues
are postulated to bind to certain somatostatin receptors on
surface of various orbital cells like lymphocytes, fibroblasts and
muscle cells, thereby altering their immunologic and metabolic
activities.20 Recent studies have shown successful therapy with
octreotide and lanreotide in patients with moderately severe
Graves ophthalmopathy and a positive Octreoscan, but the
number of treated patients is too small to draw conclusions.21,23,24
Monoclonal antibodies
Rituximab, a chimeric monoclonal antibody, is being
evaluated for its possible role in Graves ophthalmopathy.25,26
Rituximab causes an immediate depletion of circulating b cells
which usually lasts for 4-6 months but may last upto 4 years. T
cells and natural killer cells are usually not affected.27, 28
Immunosuppressive drugs
The autoimmune origin of Graves ophthalmopathy has
prompted the use of immunosuppressive drugs however
their efficacy is yet to be proven. Cyclosporine has a lower
effectiveness than glucocorticoids but a combination may be
more effective than either treatment alone.15 Low dose treatment
with Methotrexate is being used with apparent success, however
data to conclusively prove its efficacy is still lacking. 29,30
Other drugs that have been tried include Azathioprine and
cyclophosphamide.31, 32 However these drugs are yet to prove
their efficacy.

In patients with diplopia, prisms may be beneficial to those with

small angle and relatively comitant deviations.

Tape occlusion of one lens or segment of the glasses

may be helpful. An occluder or an eye patch can also
be tried, but with care not to compress the orbit.

Oral steroids usually are reserved for patients

with severe inflammation or compressive optic
neuropathy. Steroids may decrease the production
of mucopolysaccharides by the fibroblasts. Pulse
intravenous steroids may be considered.

Orbital radiation

This procedure sometimes is prescribed for moderate

to severe inflammatory symptoms, diplopia and visual
loss.

The radiation is administered via lateral fields with

posterior angulation. Radiation is believed to damage
orbital fibroblasts or perhaps lymphocytes.

- Radiation requires several weeks to take effect, and it

may transiently cause increased inflammation. Thus,
most patients are maintained on steroids during the
first few weeks of treatment.

Better response to radiation is observed in patients with

active inflammation who are treated within 7 months
of thyroid ophthalmopathy onset. Radiation may be
more effective if combined with steroid treatment.

Cataract, radiation retinopathy and radiation optic

neuropathy are possible risks. They are not common
if treatment is appropriately fractioned and the eyes
are shielded. In Marquezs study, 12% of patients
developed cataracts after irradiation with median
follow up of 11years.33

Wakelkamp also believed that orbital irradiation is a

Although improvement of motility disturbances can

occur with radiotherapy, radiation is limited when
used in isolation to treat diplopia.

Optic nerve compression

Compressive optic neuropathy may present with

blurry vision, visual loss, dyschromatopsia or field
loss. Patients may not have marked proptosis but they
usually show markedly decreased retropulsion.

If necessary, high-dose steroids and higher intravenous

doses are given. In case of non-response to high-dose
steroids and higher intravenous doses after 24 hours,
it must be borne in mind that steroids may not work.
Such patients should undergo surgical decompression
while being maintained on steroids.

If a good steroid response occurs, orbital radiation

may be considered. In severe cases, combined steroids,
radiation and surgery may be required.

Surgical care
Few patients may require surgical care. Patients must
be informed that surgical care will involve multiple staged
procedures.35
Orbital decompression
Patients undergoing surgical care should be explained
the probable complications that may occur with orbital
decompression prior to the procedure. These include blindness,
haemorrhage, diplopia, periorbital numbness, globe malposition,
sinusitis, and lid malposition. In patients with compressive optic
neuropathy, orbital decompression may be employed as initial
therapy or if medical treatment is found to be ineffective. A
medical and surgical treatment may be required in compressive
optic neuropathy.
Strabismus surgery
Although studies have described the practice of early
strabismus surgery during active thyroid ophthalmopathy,
this is not preferred. Strabismus surgery generally is delayed
until ophthalmopathy is inactive and the prism measurements
have been stable for a minimum of 6 months. Patients should
be informed of the expectations after strabismus surgery; the
goal of surgery is to minimize diplopia in primary and reading
positions and expecting binocular single vision in all positions
of gaze may be unrealistic. Strabismus surgery predominantly
involves recessions rather than resections because of the
presence of restrictive myopathy. Adjustable suture surgery is
recommended in all possible cases.
Lid-lengthening surgery
Lid-lengthening surgery should be considered if restoration
of the euthyroid state does not improve lid retraction. Corneal
exposure is reduced by this surgery which helps in camouflaging
mild-to-moderate proptosis. A muller muscle excision can be
used to ameliorate a 2 to 3 mm upper lid retraction. The temporal
flare may be reduced by employing lateral levator tenotomy. For
further lid recession, levator recession is a good option.
Blepharoplasty

This is the last phase of restorative surgery in thyroid

ophthalmopathy. Lower lid blepharoplasty can be
approached transconjunctivally if no excess lower lid skin
is present.

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Upper lid blepharoplasty is performed transcutaneously

with conservative skin excision. Brow fat resection may be
considered. Dacryopexy may be required if lacrimal gland
prolapsed occurs.

Consultations

Patients with thyroid ophthalmopathy benefit from

consultation and follow up care with an endocrinologist.

When endoscopic procedures are contemplated together with

orbital decompression, an otorhinolaryngologist should be part
of the surgical team.

Neurosurgical consultation is required when decompression

of the orbital roof is performed.

Conclusion

Thyroid ophthalmopathy (Graves ophthalmopathy),

is an autoimmune disorder with clinical signs which
are characteristic and include a combination of eye
lid retraction, lid lag, globe lag, proptosis, restrictive
extraocular myopathy and optic neuropathy.

Diagnosis is confirmed on various clinical signs and

investigative studies like ultrasonography, CT scan and
MRI.

The primary protocol of managing thyroid eye disease

is patient counseling emphasizing the self limited but
prolonged course of disease with not immediate care
available.

Various pharmacotherapy and surgical options are available

depending on the various stages of ophthalmopathy.

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