THYROID EYE DISEASE

Autoimmune disorder
characterised by infiltrative
orbitopathy

Graves' disease
Graves' disease is the most common thyroid
abnormality associated with thyroid
orbitopathy, but other disorders of the thyroid
can have similar ocular manifestations. These
include Hashimoto's thyroiditis, thyroid
carcinoma, primary hyperthyroidism, and
neck irradiation.
Approximately 40% of patients with Graves'
disease have or will develop thyroid
orbitopathy.

THYROID EYE DISEASE

Associated

with normal to abnormal

thyroid function which may coexist,
precede or follow the orbitopathy.
Related to but not the same as Graves
Ophthalmopathy (GO) The natural
history was described by Rundle and
Wilson in 1945

Thyroid statusOf those patients with thyroid orbitopathy,

approximately 80% are clinically hyperthyroid and
20% are clinically euthyroid.4 Most patients with
euthyroid Graves' orbitopathy, however, have
some detectable laboratory evidence of
subclinical hyperthyroidism.
Both hyperthyroid and euthyroid patients can
develop clinical signs and symptoms of thyroid
orbitopathy. In general, patients with euthyroid
Graves' disease tend to have less severe
orbitopathy

THYROID EYE DISEASE

The goal is to identify and treat patients who are at

particular risk of sight threatening complications. The
disease has a finite period of activity until it becomes
burnt out.The yellow region shows the early phase
where there is the best response to treatment.
Type 1 younger age group, whiter eyes with
proptosis. Inflammation is mostly in orbital fat not
muscles.
Type 11 older patient with red eyes, severe sight
threatening disease, tobacco addiction is frequent.

General Considerations
Severe exophthalmos and compressive optic
neuropathy are slightly more common in older
men.
There appears to be an increased prevalence of
thyroid disease in smokers, for whom the relative
risk of developing Graves' orbitopathy is twice as
high as it is for nonsmokers.
The reason for this difference is not known, but one
possibility is that the decreased
immunosuppression in smokers may allow greater
expression of autoimmune processes.

PATHOGENESIS

Type II reaction:- autoimmune antibodies target somatic tissues

such as extraocular muscles causing an antigen-antibody
reaction. A large number of lymphokines are implicated in the
inflammatory process.
Inflammation results in production of mucopolysaccharides by
fibroblasts leading to swelling followed by collagen production
resulting in restriction.
There is a high concentration of macrophages in the inferior
rectus muscle as well as CD4+ memory T cells and CD8 T cells.
This may account for the clinical observation of maximal
disease activity in this muscle.

ETIOLOGY

In 1956, Adams and Purves isolated a factor in the serum of

patients with Graves' hyperthyroidism that caused stimulation of
the animal thyroid gland. This factor was very similar to TSH but
had a longer half-life. It was therefore called long-acting thyroid
stimulator (LATS).

In 1964, Kriss and colleagues showed that LATS had the

structure of an IgG immunoglobulin and its action could be
neutralized by thyroid tissue, indicating that it was an antibody.

Further experiments showed that the antibody was directed

against the receptor for TSH on the follicular cell of the thyroid
gland.

Thyrotropin receptor
antibodies (TRAb).
antibodies

were originally classified into

those with stimulatory properties called
thyroid-stimulating immunoglobulin or
antibody (TSI, TSAb) and those with
inhibitory properties called TSH-binding
inhibiting immunoglobulin or antibody
(TBII, TBIA). Both of these groups are
now referred to as thyrotropin receptor
antibodies (TRAb).

PHYSIOLOGY
Hypothalamus

TRH pituitary TSH

thyroid T3 and T4
85% of T4 converted to T3 in tissues.
T3 has 5 times the activity of T4.

The predominant orbital pathology is

inflammation of the orbital soft tissues and
extraocular muscles. This immune-mediated
Pathology
inflammation consists mostly of lymphocytes
and plasma cells, with a scattering of mast
cells. These inflammatory changes differ from
the more exuberant lymphocytic infiltration of
the orbital fat and muscles, including their
tendinous insertions seen in orbital
pseudotumor

Pathology

The earliest change in extraocular muscles

appears to be inflammation of the endomysial
connective tissues, which stimulates
endomysial fibroblasts to produce first
hyaluronic acid and then collagen. In the
acute stage there is inflammation, edema,
and deposition of glycosaminoglycans.
Eventually there is tethering of orbital tissues
due to fibroblast proliferation.

CLINICAL

(orbitopathy in general is worst in the older age groups.)

LID RETRACTION1. sympathetic overactivity2. infiltration of levator / SR complex3. hypotropia (retraction

disappears on downgaze)
SIGNS:- Dalrymples (lid retraction), von Graefe (lid lag), Kochers (staring appearance)

INFILTRATION
1. soft tissue involvement :- chemosis, conjunctival injection over the recti insertions, puffy lids

Superior limbic keratoconjunctivitis (SLK) due to redundant conjunctiva

2. muscle involvement :- diplopia due to restriction.

Order of involvement IR, MR, SR (LR)
Braleys sign = increased IOP on upgaze (>4mmHg)

3. proptosis :- TED is the commonest cause of unilateral or bilateral proptosis

Sight Threatening
Complications

optic nerve compression :- <5% affected, due to

compression of orbital apex by enlarged EOM. Look
for decreased VA, colour vision defects, arcuate or
central scotomata, swollen optic disc. Confirmation
by orbital CT.
Treatment by medical or surgical decompression.
corneal exposure:- potentially serious:- treat with
lubricants, lid taping, tarsorrhaphy, decompression
less common causes of visual loss:- glaucoma,
vascular compression

Corneal involvement

Corneal involvement due to exposure keratitis

may result from proptosis, upper eyelid
retraction, lower eyelid retraction, lagophthalmos,
or a combination of these. A primary lacrimal
gland dysfunction may also be present in Graves'
orbitopathy. Although still speculative, there is
some evidence of a change in the protein
composition of tears in patients with thyroid
orbitopathy. This change might be caused by an
altered rate of tear production or by a general
change in tear composition

CLINICAL ASSESSMENT

MOURITS CLASSIFICATION Indicates position on Rundles curve (the

score reduces as inflammation decreases).Parameters of disease activity:
Integrated severity score of Graves ophthalmopathy (GO).Oppressive
feelingPain on deviation from primary positn, redness of lids (ie. recent
inflammation), diffuse redness of conjunctiva, chemosis, swollen caruncle,
oedema of eyelids, Proptosis (increase of 2mm or more)....

WERNERS CLASSIFICATION Indicates the damage level (so the score

may not reverse as activity diminishes).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 Diplopia: 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 nerve): 0) absent a) 20/20-20/60
b)20/70-20/200 c)Worse than 20/200.

THYROID EYE DISEASE

LID RETRACTION1.
sympathetic overactivity
infiltration of levator /
SR complex. hypotropia
(retraction disappears
on downgaze)
SIGNS:- Dalrymples
(lid retraction), von
Graefe (lid lag), Kocher
s (staring appearance)

THYROID EYE DISEASE

INFILTRATION
1. soft tissue
involvement :chemosis,
conjunctival injection
over the recti
insertions, puffy lids

THYROID EYE DISEASE

Superior limbic
keratoconjunctivitis
(SLK)

Optic neuropathy with visual

loss

The prevalence of optic neuropathy with visual loss in

patients with thyroid orbitopathy is less than 5%.
Optic neuropathy is, however, the most common
cause of blindness secondary to thyroid orbitopathy.
Its onset is often insidious and may be masked by
other symptoms. These patients are usually older
(age 50 to 70) are more frequently male, have a later
onset of thyroid disease, and more often have
diabetes.
Optic neuropathy is usually bilateral, but up to one
third of cases may be unilateral.

Optic neuropathy

Although a history of decreased vision should be carefully

sought, it is important to realize that optic neuropathy can occur
in a significant number (18%) of patients with visual acuities in
the range of 20/20 to 20/25 (6/6 to 6/7.5).*An afferent pupillary
defect is present in 35%. An abnormal disc (either swollen or
pale) is seen in only 52%. Visual field defects are present in
66%.Other tests that can be useful include color vision testing
and visual evoked potentials (VEPs). The Farnsworth-Munsell
100-hue test is a sensitive indicator of optic nerve dysfunction,
but pseudoisochromatic screening procedures (e.g.,Ishihara
plates) rarely identify an acquired color defect unless optic
neuropathy is severe.The pattern reversal VEP is very sensitive
at detecting early optic neuropathy and may be a useful means
of following patients after treatment.

Intraocular pressure

The increased intraocular pressure measured during

upgaze in patients with thyroid orbitopathy has been a
controversial finding. When restriction of the inferior rectus
muscle occurs, the intraocular pressure may increase by
6 mm Hg or more in upgaze as compared with primary
gaze. The increased intraocular pressure in upgaze is a
normal phenomenon exaggerated by thyroid orbitopathy
In patients with severe infiltrative disease there is an
increased pressure on upgaze as compared with normal
controls and patients with mild disease. It is often not an
indicator of early disease because it occurs infrequently in
patients with minimal eye findings

INVESTIGATION

SEROLOGICALT3 (hyperthyroid)T4 TSH

(hypothyroid)TSI (thyroid stimulating immunoglobulin).

RADIOLOGICAL TESTSOrbital CT (enlarged muscle

belly, tendon normal). Coca-Cola bottle sign = muscle
swelling deforming ethmoidal bones.MRI T2 showing
oedema of muscles; repeating the scan in different
positions of gaze can create a pseudo-video of eye
movements (for assessment of muscle restriction).
RADIOISOTOPE TESTS Octreoscan: quantitative
uptake of radio-labelled octreotide (which is a
somatostatin analogue).

VISUAL FIELD

A visual field should be performed in all patients

suspected to have optic neuropathy and is
useful when following patients after initiation of
treatment. Characteristically, a central scotoma
or an inferior altitudinal defect is seen in cases
of compressive optic neuropathy. Other visual
field defects include an enlarged blind spot,
paracentral scotoma, nerve fiber bundle defect,
or generalized constriction.

ULTRASONOGRAPHY

Ultrasonography can be useful to detect early thyroid disease in

patients with equivocal laboratory tests. Most patients with Graves'
disease, even those without overt eye findings, have
ultrasonographic evidence of extraocular muscle involvement.46
Ultrasonography is believed by some to be more accurate than CT
in detecting enlargement of the extraocular muscles. Also,
visualization of the tendinous insertions onto the globe may be more
accurately assessed using ultrasonography when differentiating
enlarged extraocular muscles secondary to myositis from
hyperthyroid orbitopathy. Ultrasonography is, however, less suited
than CT to assessing muscle thickness at the orbital apex.
This test may also be helpful in distinguishing between active and
inactive disease. Examination of the extraocular muscles shows
that there is a lower internal reflectivity in active as compared with
inactive disease.

CT findings in thyroid orbitopathy

The most characteristic CT finding in thyroid orbitopathy is

enlargement of the extraocular muscles with normal
tendinous insertions onto the globe. Other findings include
proptosis and anterior prolapse of the orbital septum due
to excessive orbital fat and muscle swelling (see Fig.
4).Patients at risk for developing optic neuropathy may
also have severe apical crowding, a dilated superior
ophthalmic vein, and anterior displacement of the lacrimal
gland. Of these, apical crowding is the most sensitive
indicator for the presence of optic neuropathy The CT scan
should be done in the coronal plane to assess the
enlargement of the extraocular muscles at the apex
because axial sections can sometimes be misleading.

THYROID EYE DISEASE

Orbital CT (enlarged muscle

belly, tendon
normal)

MAGNETIC RESONANCE
IMAGING

MRI using 1.5 tesla units and orbital surface coils

provides optimal spatial resolution of the orbit.34 MRI
may also be useful in distinguishing between active and
inactive disease. The changing intensities between T1and T2-weighted images may differentiate the active
edematous from the inactive fibrotic muscle changes.
Extraocular muscles that have acute inflammation
have longer T2 times owing to the higher water content.
Because acute inflammatory disease responds better to
radiation therapy than chronic fibrosis, the information
gained from MRI may theoretically be helpful in
choosing patients for radiation therapy.

SYSTEMIC THYROID DISEASE

There are no good recent studies of the natural

history of untreated hyperthyroidism, but based
on older reports, Wilson56 determined that about
one third of patients spontaneously improve, one
third remain chronically hyperthyroid, and one
third progress to thyroid storm and occasionally
death. Because it is not possible to predict which
patients will spontaneously improve, treatment of
thyroid dysfunction is recommended.

Treatment
acute

congestive ophthalmopathy,
compressive optic neuropathy,
motility disorders,
eyelid abnormalities.

TREATMENT
Acute Congestive Orbitopathy

1. SYMPTOMATIC:- elevate bedhead, lubricants, lid taping,

diuretics

2. SYSTEMIC:a) Normalise thyroid function with or without thyroxine.

Patients rendered euthyroid do improve their GO score

Tallstedt trial N Eng J Med 1992

antithyroid drugs cause a 10% chance of new or worsening GO
but radio-iodine causes a 30% chance of new or worsening GO.

Corticosteroids have been used successfully in

the treatment of acute congestive orbitopathy

Corticosteroids have been used successfully in the treatment of

acute congestive orbitopathy. They are believed to work by
altering cell-mediated immune response and diminishing the
production of mucopolysaccharides by the orbital
fibroblasts.Corticosteroids result in improvement of soft tissue
involvement and compressive optic neuropathy (but do not have
as much of an effect on diplopia Traditionally, a "short burst" of
high-dose corticosteroids has been given, usually in the range
of 60 to 120 mg/day of oral prednisone. Improvement in
subjective symptoms such as pain and tearing usually occurs
first, often as early as 24 to 48 hours, followed by improvement
in soft tissue congestion and muscle function over a period of
days to weeks.

Steroid Therapy
Prednisone or prednisolone

This is standard treatment but there are frequent side effects.

No response in 35% of patients and anyway the response is
only partial. High dose steroids given early in the disease when
muscle swelling occurs does not necessarily limit the long term
course of the disease. If there is no response to high dose
steroids in the first three weeks they should be rapidly reduced.
Prednisolone + orbital radiotherapy has slightly more effect
than either alone.Use high dose pulsed methylprednisolone if
urgent optic nerve decompression is required, This is more
effective than oral treatment but it is expensive and not justified
in most cases of TED.

Radiation therapy

During the past few years, radiation therapy has reemerged as a

useful form of treatment of severe orbitopathy. The rationale for
the use of radiation therapy is reduction or elimination of the
pathogenic orbital lymphocytes, which are markedly
radiosensitive. It is also thought that the glycosaminoglycan
production by fibroblasts is reduced, thereby reducing orbital
edema, orbital tension, and conjunctival injection. Although
congestive findings improve most consistently, significant
improvement in proptosis and extraocular muscle function has
been reported.Like corticosteroids, radiation therapy is most
effective within the first year, when significant fibrotic changes
have not yet occurred. Mourits and associates,135 however,
suggest that periods of active orbital inflammation within the long
natural history of thyroid orbitopathy would benefit from
corticosteroids or radiation therapy.

Radiotherapy

RETROBULBAR RADIOTHERAPY:- Trial of

prednisone versus radiotherapy showed no
difference in clinical improvement (about
50%).The patients all tolerated retrobulbar
radiotherapy better than steroids Consider if
steroid maintenance > 25mg/ day. Best effect
in acute disease.Do not irradiate patients with
diabetes mellitus as they are more susceptible
to radiation retinopathy.2000rads/ 10days,
effect starts at 4 weeks, maximal 4 months.

Compressive Optic Neuropathy

Compressive optic neuropathy can cause

permanent visual loss. The treatment
possibilities include high doses of
corticosteroids, irradiation, and orbital
decompression. Some patients require only
one of these modalities, while other patients
need combined therapies.

Compressive Optic Neuropathy

As in the treatment of acute congestive thyroid orbitopathy,

radiation therapy is becoming increasingly popular. A
retrospective series of 84 patients with compressive optic
neuropathy treated with either corticosteroids or radiation
therapy supports mounting evidence that radiation therapy
may be safer and more effective than corticosteroids.
Radiation therapy, however, must be administered in
fractionated doses, which delays its beneficial effect. For
this reason, if visual dysfunction progresses while the
patient is on corticosteroids, surgical decompression is
usually recommended if the patient is a surgical candidate.

Orbital decompression

Orbital decompression is indicated for compressive

optic neuropathy when there has been failure of or
contraindication for corticosteroids or radiation
therapy or if corticosteroid dependence has
developed with intolerable side effects. Other
indications include excessive proptosis with exposure
keratitis and corneal ulceration, pain relief, and
cosmesis for disfiguring exophthalmos. Orbital
decompression may also be indicated as a
preliminary procedure to extraocular muscle surgery
on a patient with sufficient proptosis to suggest that
decompression might ultimately be required.

Orbital decompression
A variety of approaches may be used, each with
its own advantages and associated complications.
The transorbital (via fornix or eyelid) approach to
inferior and medial wall decompression is the most
common approach used by ophthalmologists. The
addition of a lateral wall advancement has the
advantage of both further increasing the orbital
volume and simultaneously improving upper eyelid
retraction; this is the technique we prefer.

ORBITAL DECOMPRESSION
Subciliary approach.Inferior & medial wall
(6mm proptosis).Remove bone to posterior wall
maxillary sinus (5mm more posterior on medial
wall), Avoid IO neurovascular bundle, and the
anterior and posterior ethmoidal arteries.Incise
periosteum in A-P direction posteriorly and
circumferentially anteriorly.
Complications:
visual loss,
A pattern ET

Motility Disorders

A major source of morbidity in thyroid orbitopathy, and the most

frequent problem associated with orbital decompression
surgery, has been strabismus. In patients with relatively minimal
degrees of ocular misalignment, diplopia can be avoided with a
compensatory head posture, Fresnel plastic press-on prisms, or
temporary occlusion. Unfortunately there is significant image
degradation as larger prisms are used, limiting their efficacy. If
there is marked asymmetry in ocular deviation in different fields
of gaze, prisms are also less effective. In some cases during the
inflammatory period, use of intramuscular botulinum toxin has
shown some efficacy.
Extraocular muscle surgery should be postponed until the
muscles are no longer inflamed and the deviation has remained
stable for at least 6 months.

Surgery
STRABISMUS SURGERY:-Aim for maximal area of fusion without
abnormal head posture.IR recession on adjustable +/- contra SR
recession
iii) EYELID SURGERY:

Upper Lid retraction - Mullers tenotomy (<2mm), levator Z myotomy or

recession on hangback sutures, levator tenotomy +/- horns.
Lower Lid retraction - Usually needs a spacer from donor sclera (lid
retraction X 2 = amount of sclera required)

iv) BLEPHAROPLASTY for excess skin and fat

Ideally treatment combines a multidisciplinary coherent approach such
as
Combined radiotherapy and immunosuppression trial

Eyelid Abnormalities

As with other thyroid eye problems, eyelid retraction will often

improve with time, and only an estimated 50% of patients with
eyelid retraction have a significant eyelid abnormality 5 years
later.
Eyelid retraction can result from excessive autonomic discharge,
levator fibrosis, or contraction of the inferior rectus muscle.
Surgical correction of eyelid abnormalities should be performed
only after orbital or extraocular muscle surgery because these
operations may change eyelid position. For example, inferior
rectus muscle restriction may cause upper eyelid retraction
because of the superior rectus/levator palpebrae superioris
overaction against the restriction. Specific techniques for repair
of eyelid retraction are discussed in other chapters.