Evaluation of Proptosis: A

Evaluation of Proptosis: A Primer

Syed Shoeb Ahmad,1 Ramsha Anwar,2 Md Aleemullah Khan,2 Nazmi Usmani2 and Sadaf Jahan2
1. Ibn Sina Academy, Aligarh, India; 2. Ajmal Khan Tibbiya College, Aligarh, India

DOI:

P
roptosis is an abnormal prominence of the eyeball beyond the confines of the bony orbit. It can appear in various systemic, as well
as orbital or peri-orbital, disorders. Not only is proptosis potentially vision-threatening, but also it could be a manifestation of life-
threatening conditions, such as metastatic carcinomas. Therefore, management of proptosis is of vital importance. The objective of this
review is to present an overview of the systematic evaluation of a case of proptosis and simplify the overall management of this condition.
The article comprehensively deals with the causes and classification of proptosis, the problems encountered with the development of the
condition, evaluation of a case, and highlights the relevant investigations. The methods for investigating proptosis have been classified into
primary, secondary, pathological and laboratory techniques. The article extensively discusses thyroid eye disease, including the current
hypothesis of pathophysiology, mechanisms, stages, clinical features, classification and management of this disease. Literature for
this review was obtained from textbooks, online databases and search engines, as well as other educative materials available to the
authors
during the preparation of this review.

Keywords An abnormal protrusion of the eyeball, beyond the boundaries of the bony orbit, is termed
Exophthalmos, orbit, Graves’ disease, ‘proptosis’. A similar appearance, seen in endocrine dysfunction, especially thyroid disorders,
surgical decompression, diplopia
is called ‘exophthalmos’. These conditions are frequently encountered in clinical practice, and
Disclosures: Syed Shoeb Ahmad, Ramsha Anwar, for students, residents and trainees, the situation may prove rather challenging. This primer
Md Aleemullah Khan, Nazmi Usmani and Sadaf Jahan presents a concise blueprint to aid in the evaluation of a case of proptosis. The article also
have no financial or non-financial relationships or
activities to declare in relation to this article. provides an overview of thyroid eye disease (TED), the most common cause of proptosis in usual
Acknowledgements: The authors would like to clinical settings.1–4
acknowledge Prof. Dr. S. Zaheer-ul-Islam, for his
invaluable suggestions in the development of this
article. The bony orbit is virtually a closed socket for the eyeball. It is the cavity, or socket, of the skull
Review process: Double-blind peer review. in which the eye and its appendages are situated. It is enclosed from all sides except anteriorly.
Compliance with ethics: This study involves a review of Incidentally, the term ‘orbit’ can also imply the contents of the bony structure. Another term
the literature and did not involve any studies with human related to proptosis is ‘exorbitism’, a condition in which there is a decrease in the capacity of the
or animal subjects performed by any of the authors.
bony orbit, with the angle between the lateral orbital walls being more than 90 degrees. This
Authorship: The named authors meet the International
Committee of Medical Journal Editors (ICMJE) criteria leads to a shallow orbital depth but normal orbital content volume. Such a situation causes
for authorship of this manuscript, take responsibility proptosis in certain congenital disorders of the orbit.3,5
for the integrity of the work as a whole, and have
given final approval for the version to be published.
Access: This article is freely accessible at Because of the relatively small amount of space between the orbital walls and the eyeball,
touchOPHTHALMOLOGY.com © Touch Medical Media 2021. an expanding lesion within the orbit, or a shallow bony orbit, as often seen in congenital
Received: 9 August 2020
disorders, causes protrusion of the eyeball forwards. Due to inherent weaknesses in the walls of
Accepted: 19 January 2021
the orbit, diseases of surrounding structures may extend into the orbital cavity easily. Thus,
Published online: 21 May 2021
depending upon the location of the lesions impinging upon the orbit, the eyeball may get
Citation: touchREVIEWS in Ophthalmology. 2021;
15(1):26–32 displaced from its normal position. The term ‘dystopia’ indicates the displacement of the eyeball
Corresponding author: Syed Shoeb Ahmad. in the coronal plane. A number of conditions may lead to this situation, including extraconal
IbnSina Academy, Dodhpur, 202001, Aligarh, masses, craniofacial scoliosis complex, uncorrected unilateral or assymetric bilateral coronal
India. E: syedshoebahmad@yahoo.com
craniosynostosis, facial clefting
syndromes and trauma.6,7
Support: No funding was received for
the publication of this article.
Evaluation of a case of proptosis requires fine knowledge of the anatomy of the bony orbit
and eyeball, the surrounding structures, salient features of proptosis, causes, examination,
investigations, differential diagnosis and management. The objective of this review is to compile
the important steps in the evaluation of a case of proptosis. The article also incorporates an
overview on thyroid orbitopathy. The literature for this article was obtained from online searches
of articles related to proptosis, books and course material during the preparation for this article.

Applied anatomy
The orbits are bony cavities that enclose structures such as the eyeball, extraocular muscles,
nerves, blood vessels and a cushion of fat. The orbits are pear-shaped, tapering posteriorly to the
apex. The distance between the back of the globe and optic foramen is 18 mm. Conversely, the
length of the orbital segment of the optic nerve is comparatively longer, usually in the range of

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Table 1: Bones forming the walls of the orbit Table 2: Common causes of proptosis in adults

Wall Bones Category Specific conditions

Roof (upper wall) Frontal; lesser wing of sphenoid Endocrine Thyroid eye disease
Frontal bone separates the orbit from the anterior cranial
Trauma Facial fracture, soft tissue swelling, retrobulbar haemorrhage
fossa
Vascular Carotid-cavernous fistula, cavernous sinus thrombosis,
Floor (inferior wall) Maxilla; palatine; zygomatic
cavernous haemangioma
Maxillary bone separates the orbit from the underlying
Inflammatory Inflammatory orbital pseudotumor, dacryoadenitis, orbital
maxillary sinus
myositis, Tolosa–Hunt syndrome, Wegener’s granulomatosis,
Medial wall Ethmoid; maxilla; lacrimal; sphenoid
sinus mucocele, sarcoidosis, Churg–Strauss syndrome
Ethmoid bone separates orbit from ethmoid sinus
Infective Orbital cellulitis, mucormycosis
Lateral wall Zygomatic; greater wing of sphenoid
Tumours Lymphoma, schwannoma, sinonasal tumour, lacrimal gland
Apex Located at the opening of the superior orbital fissure
tumour, meningioma, neurofibroma, optic nerve glioma,
Base Forming the anterior part of the orbit metastasis, myeloid sarcoma, ossifying fibroma, orbital
osteoma, haemangioblastoma, neuroblastoma, neurofibroma,
acute leukaemia
25–30 mm. This extra length of the optic nerve and S-shaped
Other Paget’s disease, fibrous dysplasia, Langerhans cell
configuration allows proptosis to occur to some extent without
histiocytosis, Erdheim–Chester disease
compromising optic nerve function. The volume of each orbit is about
30 cc, approximately one-fifth of which is occupied by the eyeball.8,9,10
Table 3: Causes of proptosis in children
The bony orbit is enclosed by the medial and lateral walls, the roof and
the floor on four sides. The four walls converge at the apex of the orbit. 1. Thyroid eye disease
The medial is very thin, and is known as ‘lamina papyracea’. Therefore,
2. Rhabdomyosarcoma
infection from the ethmoidal sinuses can easily reach the orbit. The
3. Orbital cellulitis
lateral wall covers the posterior half of the eyeball, leaving the anterior
4. Optic nerve glioma
half exposed on this side. However, this wall is the strongest part of the
bony orbit. The roof of the orbit is thin and easily damaged by trauma 5. Orbital inflammatory disease

or iatrogenically during surgical procedures. Similarly, the floor of 6. Retrobulbar haemorrhage

the bony orbit is thin and easily damaged in blow-out fractures of the 7. Chloroma
orbit. Tumours from the maxillary antrum easily invade into the orbit 8. Neuroblastoma
through this pathway. The bones forming the walls of the orbit are 9. Histiocytosis
given in Table 1.11

Causes of proptosis Classification based on onset

The causes of proptosis are numerous and varied. Broadly, they can Depending upon the onset at which the disease appears, proptosis
be classified into vascular, inflammatory, traumatic, autoimmune, can be regarded as acute, subacute or chronic. Acute proptosis is
metabolic, iatrogenic, neoplastic, congenital and endocrine defined as one that develops over a few minutes or hours; subacute
(remembered by the mnemonic: VITAMIN CE).12 Vascular causes develops over a few days or weeks; and chronic develops over a few
include infantile haemangiomas, cavernous vascular malformations and months. Acute and subacute proptosis can occur in conditions like
direct or indirect carotid-cavernous fistulas. Orbital cellulitis is a type of non-specific orbital inflammation, orbital cellulitis, trauma, retrobulbar
inflammatory aetiology of proptosis. In at least two studies it was the haemorrhage, thrombophlebitis, and tumours such as
most common cause of proptosis.2,13 Trauma leads to retrobulbar rhabdomyosarcoma, neuroblastoma, granulocytic sarcoma and
haemorrhage and haematoma formation, which can cause rapid metastasis. Chronic proptosis occurs in diseases, such as fibrous
onset of proptosis and affect visual acuity from pressure on the optic dysplasia, and tumours, such as dermoid cysts, lymphomas, benign
nerve. Autoimmune disorders causing acute proptosis can range from mixed tumours, neurogenic and vascular tumours, and osteomas.5,21
idiopathic orbital inflammatory syndrome to immunoglobulin G
antibody-mediated inflammatory disease. Aggressive intravenous Direction of proptosis
rehydration therapy can cause orbital compartment syndrome, Proptosis can be axial, when it occurs in the anteroposterior direction or
regarded as a metabolic cause of proptosis. Less common causes include can be in the direction opposite to the causative lesion. Thus, a lesion in
iatrogenically induced proptosis through orbital implants and fillers. the upper-lateral aspect of the orbit, such as a lacrimal gland tumour,
Benign, malignant and metastatic neoplasms are also frequently will push the eyeball downwards and medially. Looking at the
reported in some studies.13,14,15 displacement of the eyeball the probable site and cause of the offending
lesion can be surmized. Further examination and investigations would
Congenital causes of proptosis include dermoid cysts and help in arriving at the correct diagnosis. Table 4 provides a list of causes
encephaloceles; the latter often show expansion on Valsalva manoeuver. and the direction in which they cause proptosis.
TED is the most common cause of endocrine and autoimmune proptosis
in adults and children.16,17 It leads to slowly progressive development Common problems due to proptosis
of eye signs, including proptosis. The common causes of proptosis in The displacement of the eyeball from its normal position causes a
adults are given in Table 2.12,13,15,16,18 The differential diagnosis for number of sequelae, which include the following:22
proptosis in the paediatric age group is given in Table 3.19,20

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Review Ocular Immunology and

Table 4: Direction and displacement of the eyeball due to haemorrhage, malignant tumours of the lacrimal gland or invasive
different causes
nasopharyngeal carcinoma, and metastatic lesions.5,16

Direction Aetiology Epistaxis/nasal obstruction should also be investigated. In cases of

Axial Thyroid eye disease; rhinological aetiology of proptosis, there can be symptoms like recurrent
Lesions in the muscle cone, e.g. optic nerve glioma, epistaxis or nasal obstruction. Furthermore, a history of trauma should
meningioma, haemangioma be elicited. Trauma is a common cause of proptosis in young adults. 15,16 It
Down and outward Lesion in the upper and inner quadrant of orbit, e.g. can be associated with haemorrhage, orbital emphysema or intra-orbital
dermoid, dermolipoma or invading lesions from foreign bodies.
ethmoid or frontal sinus
Down and inward Lacrimal gland tumour and dermoid in outer orbital History of systemic diseases, including family history, should be
margin taken. Several systemic diseases can cause proptosis. These include
Outward Lesions of anterior ethmoidal sinus and thyroid disorder, tuberculosis and blood-borne metastasis [Tables 2
nasopharyngeal carcinoma and 3]. Finally, any changes in proptosis should be noted. A history
Upward displacement Carcinoma of maxillary antrum of change in the severity of proptosis with posture is seen in
conditions such as orbital varix and carotid-cavernous fistulas. 16,24 The
change could also be associated with fractures of the roof of the orbit.
• Exposure keratopathy: Proptosis is associated with a poor blink However, in that situation, the proptosis may be too subtle to be noted
mechanism and the inability of the eyelids to completely cover by the patient or attendants.
the cornea (lagophthalmos). These mechanisms lead to dryness of
the eye and inability to wet the cornea properly, leading to Examination
exposure keratopathy. This may lead to an increased propensity An assessment of visual acuity should be conducted at the first visit
to develop corneal abrasions and ulcers. These ulcers have a high and on follow-up visits. If the patient is admitted to the ward, frequent
risk of perforation and the development of endophthalmitis. monitoring of visual acuity and colour vision may be required. The
• Diplopia: The displacement of the eyeball and enlargement of the mechanisms of visual loss in such scenarios include central retinal artery
extraocular muscles during the development of proptosis leads to occlusion, direct compressive optic neuropathy, compression of
restriction of ocular movements. These phenomena lead to diplopia small nutrient vessels of the optic nerve leading to ischemic optic
early during the course of the disease. In later stages, there is neuropathy. Stretching of the nerve and posterior globe tenting
fibrosis of the muscles, which causes various degrees of aggravate the situation.25 Vision may also be affected by exposure
dysfunction. The mechanical changes in the muscles affect their keratopathy as explained above.
function leading to diplopia.
• Optic nerve compression: The increase in the bulk of tissues A physical inspection should also be conducted; this should not be
behind the eyeball causes pressure on the optic nerve. This leads to limited to the eye. It should include the general appearance of the
a decrease in optic nerve function, characterized by signs such as patient, a cachexic build possibly implying a chronic disease; the
reduced visual acuity, relative afferent pupillary defect (RAPD), red- appearance of the skull, an abnormality suggesting craniosynostoses;
colour desaturation and visual field defects. and any swelling over the neck, which could relate to the thyroid gland.
Inspection should also be done to determine laterality of the proptosis,
Evaluation of a patient with proptosis whether it is unilateral or bilateral, and direction of the proptosis.
Patient history Additionally, the clinician should look for signs of acute inflammation,
The duration of the disease, concerning the onset and clinical course, is such as peri-orbital and conjunctival congestion and chemosis. A physical
a useful starting point in history taking. As mentioned previously, the examination can also reveal a squint, which may occur in both acute and
onset of proptosis can be acute, subacute or chronic. Acute proptosis is chronic stages of TED. The appearance of capillary haemangiomas of
usually seen in inflammatory and infective conditions, such as orbital the lids should be noted, as they produce skin lesions, known as
cellulitis. Such conditions normally have a short course, as the body’s strawberry nevi, which increase in size up to a year after birth. The
immune system or treatment usually resolves the cause of proptosis. presence of plexiform neurofibromas of the lids and orbits should also be
Conversely, chronic diseases, such as TED; tumours; and chronic established; they have a ‘bag of worms’ appearance and texture. They
infections, such as tuberculosis, may have a more prolonged course.23 may also produce an S-shaped curvature of the upper lids.5 In
asymmetrical proptosis, inspection can be done by looking from above
History of the patient’s vision should also be assessed. A history of and behind the patient. Examination can also be performed by
slowly worsening visual acuity can be attributed to either exposure extending the neck of the patient and observing from below.6
keratopathy or a slowly developing compressive lesion involving the
optic nerve. However, conditions such as orbital cellulitis and Many peri-orbital changes can provide clues to the possible
retrobulbar haemorrhage can cause an acute decrease in vision by diagnosis. Conditions such as mycosis fungoides, lymphangiomas and
affecting optic nerve or vascular integrity. Another vision-related orbital varices may produce non-specific changes including lid
clue is a history of diplopia, which can give a significant indication of oedema, erythema, ecchymosis and eczema. While appearing
the probable cause of proptosis. Slowly developing diplopia indicates a innocuous, they often point to deeper pathologies. Similarly, intra-
likely benign condition, such as TED, while a quick onset of diplopia can orbital haemangiomas are often associated with superficial lesions such
be seen in orbital cellulitis or haemorrhagic conditions. as strawberry nevi. Lymphomas are also associated with salmon patches
in the conjunctival fornix, while, corkscrew conjunctival vessels are
The patient should be assessed regarding pain; a painful proptosis seen in carotid-cavernous fistulas.16
occurs in inflammatory and infectious conditions. It also occurs in
orbital The orbital margin should be palpated for irregularities, swellings

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and foreign bodies. The little finger is insinuated between the orbital rim
and the eyeball to feel for any mass and for its consistency. Any area of

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tenderness should be recorded. A reducibility test can also be

his opposite eye to look at the distance of the apex of the cornea on
performed; this is done by placing the flat of the palm on the closed lids
the scale by excluding parallax. A millimetre-scale is provided on the
and applying light pressure for a short while and then releasing it. If
top of the instrument to measure the distance between the lateral
there is no change in the amount of proptosis, then reducibility is
orbital margins of the two eyes; this reading can be noted for future
excluded. Reducibility is seen in diffuse inflammation, such as early
reference. Errors in measurement are caused by thickness of
TED and vascular lesions, including haemangioma, lymphangioma and
subcutaneous tissue over the bone, facial asymmetry, parallax and
orbital varices. An increased resistance to reducibility is a non-
examiner skills.6,31 Apart from Hertel’s exophthalmometer, a simple
specific sign.5
plastic scale at the lateral orbital margin, or a Luedde
exophthalmometer, can be used. The latter is a thick plastic ruler with a
On inspection, pulsation can be observed, or a bruit felt on palpation of
notch to fit in the lateral orbital margin and markings in millimetres on
the proptosis. Pulsation, or thrill, occurs when a vascular pulse is
both sides of the scale to avoid parallax. In exophthalmometry,
transmitted to the orbit. It happens when an abnormal vascular flow
normal readings are taken as less than 21 mm between the lateral
creates an area of turbulence. The palm is put on the closed eyelids to feel
orbital rim and apex of the cornea, or a difference of less than 2 mm
for the thrill. Minor degrees of pulsation can be difficult to assess. In
between the two eyes.1,6
such cases, a Goldmann Applanation Tonometer can be applied to the
cornea and the movement of the mires with each arterial pulsation
A computed tomography (CT) scan is useful in determining the
observed. This would especially be useful in cases of orbital roof
shape, position, extent (including whether the lesion is within the
fractures.
orbit or has extension intra-cranially) and nature of lesions in the orbit.
Orbital scans are usually obtained in 3 mm slices, though ‘finer cuts’ of
Auscultation is performed by applying the bell of the stethoscope to
1.5 mm can be ordered for better vizualisation of orbital pathologies.
listen for sounds over the orbital and mastoid regions. A bruit can be
The CT scan appears to be the technique of choice to visualize bony
detected over the orbital bones or eyeball in vascular tumours, such as
lesions and erosions in most situations. CT also visualizes calcification
haemangioma, or in carotid-cavernous fistulas. Gentle pressure over
efficiently in cases of retinoblastoma. To better locate the lesions, 3D
the ipsilateral carotid artery in the neck would reduce the bruit and
images can be constructed with fine slices of the images.5 Axial scans,
thrill in case of carotid-cavernous fistulas. The patient may complain
which must include the lenses on both sides, are useful in identifying
of hearing an audible bruit or have tinnitus. 26 Several classical signs are
proptosis. The distance between the apex of the cornea and a line
seen in carotid-cavernous fistulas, such as pulsatile proptosis, chemosis,
joining the zygomatic processes (interzygomatic line) is measured. This
arterialized conjunctival and episcleral vessels, ptosis, ophthalmoplegia,
distance should not exceed 22 mm, or the difference between the two
increase in intraocular pressure due to rise in episcleral venous
sides should not be more than 2 mm.32 Measurements between the
pressure, orbital congestion, and occasionally, angle-closure
interzygomatic line and the posterior sclera can also be used; proptosis
mechanisms. Retinal changes, such as haemorrhages, disc swelling
is suggested when less than one-third of the eyeball lies behind this
and venous congestion, may also occur.6,27,28,29
line.33 In TED, imaging studies are not mandatory for diagnosis, but they
are utilized in cases where a diagnosis is difficult, such as uniocular
Another test is performed by asking the patient to bend forwards
cases. It is also required where visual obscuration is developing, to
and cough. This increases the intraorbital pressure. In case of orbital
assess the optic nerve. In TED, the muscle bellies are
varix, this action leads to an increase in the degree of proptosis, which
characteristically fusiform with sparing of the tendons.6,16,33-35
can also be demonstrated by performing the Valsalva manoeuvre.16,24

The wide range of orbital pathologies causing proptosis may prove to

Extraocular movements should also be assessed in all cardinal directions
be diagnostic and management challenges. Imaging techniques, such
of gaze. In lesions situated in the muscle cone and early/mild TED, the
as magnetic resonance imaging (MRI) provide high-resolution soft
movements are unaffected for a considerable period. However, in
tissue details leading to better lesion characterization. This may prove
traumatic, inflammatory or malignant conditions, a rapid restriction of
crucial where history and clinical evaluation are equivocal. 36 These
extraocular movements occurs. Haemorrhage in a benign tumour
techniques often use a common strategy of localizing the pathologies
may also cause a sudden onset of ophthalmoplegia.30
to one of the defined orbital compartments, namely, muscle cone,
extra-conal compartment, lacrimal gland and globe.37 MRI is invaluable
Finally, ophthalmoscopy should be performed. Fundus findings in cases
in determining the extent of disease, describing the exact location
of proptosis are varied, depend upon the cause and include disc swelling
of the lesion and detecting involvement of the orbital compartments
(in cases of raised intracranial pressure), optic atrophy (in cases of
and intracranial extension. It is also useful in identifying the size of the
primary/secondary optic atrophy), choroidal folds (due to retrobulbar
tumours, extraocular extension and ciliary body infiltration. In early
pressure), retinal haemorrhages (in central retinal vein occlusion,
TED, CT and MRI can reveal swelling of extraocular muscles and an
traumatic retrobulbar haemorrhage and carotid-cavernous fistulas) and
increase in the volume of orbital fat content. In active disease, the
optociliary collaterals (in optic nerve sheath meningioma and optic
muscles appear hyperintense in T2-weighted images.38 MRI can also
nerve glioma).6
reveal a stretched optic nerve, which is associated with an increased
risk for visual loss.34,39
Investigations
Primary investigations
Characteristics of orbital lesions can be studied by the formation of
The severity of proptosis can be measured by various methods. The
2D images on ultrasonography.40 The technique was found useful in
Hertel exophthalmometer uses a system of prisms to project a
assessment of disease activity in TED; however, it was less sensitive
lateral view of the eye forward. A millimetre-scale is superimposed on
compared to MRI.41 Other disadvantages of ultrasonography are the
this view and is read by the opposite eye of the examiner. The patient is
inability to image posterior structures, high intra- and inter-observer
made to sit at the eye level of the examiner. The two ends of the
variability, and the difficulty to image through bone or air.5 In TED,
instrument are placed at the lateral orbital margins of each eye.
individual muscles can be studied in a short time by this low-cost
Subsequently, the observer uses

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method, which also avoids dangers from radiation.

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Secondary investigations non-infectious, inflammatory autoimmune disorder, known as

Venography allows the visualization of blood flow in the veins. This Grave’s disease. However,
technique was more commonly used in the past to study vascular
lesions. Contrast is injected into the frontal, angular or superior
ophthalmic vein, and digital subtraction technologies have been
developed to better visualize vascular lesions. On the other hand,
arteriography (also called angiography) is useful to study arterial
lesions such as aneurysms and arteriovenous malformations.
However, since dye is injected directly into an artery there is an
inherent risk of neurological and vascular complications. With the
development of better technologies, such as CT and MR angiography, it
has become possible to digitally study vascular lesions without
resorting to the injection of dye into the arteries. However, these
techniques are still not superior to direct angiography.5,42

Finally, colour Doppler imaging produces ultrasonographic images along

with information regarding the direction and velocity of blood flow. This
method can be of some use in the evaluation of carotid-cavernous
fistulas, orbital varix, orbital tumours, orbital cellulitis and orbital
inflammatory conditions. In TED, reduction in superior ophthalmic vein
flow has been reported.43

Pathological studies
Biopsy specimens from orbital lesions or masses, causing proptosis,
can be sent for frozen section studies. The edge of tumours can be
analysed intra-operatively by micrographic techniques, making
excision of the lesion as complete as possible. Cell surface marker
studies on these specimens can be done to differentiate lymphoid
tissues, presence of oestrogen receptors, and in poorly differentiated
tumours. In certain cases, fine needle aspiration cytology can be
performed. However, in such cases, the risk of haematogenous spread of
the tumour should be kept in mind.5,44

Laboratory investigations
In cases of suspected TED, thyroid function tests such as the T3, T4
and thyroid-stimulating hormone (TSH) levels have to be performed.
Combined elevation of T4 and decreased TSH levels are sufficient to
diagnose hyperthyroidism. In cases of a high index of suspicion for TED
and if the above tests come back negative, then additional tests, such
as the thyroid-stimulating immunoglobulins or TSH-receptor antibody
test, thyroid-binding inhibitory immunoglobulins or anti-microsomal
antibody (also called thyroid peroxidase antibody), need to be
performed. Wegener’s granulomatosis has to be excluded by anti-
neutrophil cytoplasmic antibody serum assay. In suspected
sarcoidosis serum angiotensin-converting enzyme and lysozyme assays
are required.34

Pseudo-proptosis
A misleading impression of proptosis can occur either due to a false
appearance of proptosis, or a true asymmetry between the two eyes,
but excludes displacement of the globes by any extraocular lesions.
Conditions leading to pseudo-proptosis include facial asymmetry, lid
retraction (as in facial nerve palsy), asymmetric orbital size (seen in
congenital disorders such as Crouzon’s syndrome), enlargement of
the globe (myopia or buphthalmos), ipsilateral lid retraction, iatrogenic
pseudo-proptosis (following misuse of phenylephrine eyedrops) or
contralateral enophthalmos, ptosis or a small-sized eye.6,45

Thyroid eye disease

The commonest cause of proptosis in most age groups is TED, also called
thyroid-associated orbitopathy or Grave’s ophthalmopathy. The
condition is frequently associated with hyperthyroidism, where
excessive thyroid hormones are produced. This situation is regarded as a

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TED may also develop in euthyroid (ophthalmic Grave’s disease) or

hypothyroid individuals, or in hyperthyroid individuals at a later period after
being successfully treated. Grave’s disease reportedly occurs in 0.5–2.0% of
the Caucasian population.46

In Grave’s disease auto-antibodies develop against thyroid tissue leading to an

antigen–antibody reaction. This reaction then causes a cascade of events leading
to inflammation, and ultimately, two changes take place:
• There is increased binding of antibodies to TSH receptors present on the
epithelial surface of thyroid follicular cells, which leads to increased
production of thyroid hormones, known as thyrotoxicosis.34.46
• There is physical enlargement of the thyroid gland, known as goitre.

Several risk factors have been identified with the development of TED. These
include age above 50, smoking, microvascular disease, prior radioactive
iodine treatment, and possibly, a family history of Grave’s disease.47-49
Studies have reported that Grave’s disease occurs in 36% of first- or second-
degree relatives of individuals diagnosed with Grave’s disease or
autoimmunological thyroid disorders. 50 Others have reported concordance rates
of approximately 20–40% in monozygotic twins and >10% in siblings.46,51
TED is six times more common in females, as compared to men, and usually
develops in the third to fourth decade of life.52 However, the severity of the
disease is usually worse in males.34 The condition may occur prior to, during or
subsequent to the hyperthyroid phase. The severity of TED has no relation to the
level of thyrotoxicosis.

Thyrotoxicosis leads to inflammation of the extraocular muscles and

increased secretion of glycosaminoglycans. The formation of these
polysaccharides leads to a large osmotic gradient in the orbital tissues, with
increased fluid accumulation between the fibres of the extraocular muscles.
As a result, the muscles swell up by almost eight times, leading to restriction of
their activity. Another change brought about in thyrotoxicosis is the increased
inflammatory infiltrates, such as lymphocytes; plasma cells; macrophages;
and mast cells in the interstitial tissues, orbital fat and lacrimal glands. There
are three types of cells implicated in the development and progression of TED.
These include B cells, T cells and orbital fibroblasts. B cells occur in early
disease and produce antibodies against self-antigens. Orbital fibroblasts recruit
and activate T cells, which cause tissue remodelling characteristically seen in
TED. Some orbital fibroblasts differentiate into mature adipocytes causing
increased volume and expansion of the orbital contents. The extraocular
muscle swelling and waterlogging cause an increase in the intra-orbital
pressure, which compresses the optic nerve. These pathological changes
manifest clinically as exophthalmos, myopathy, soft tissue changes and
others.33,34,48

Stages of thyroid eye disease

TED is divided into two stages: congestive and fibrotic. The congestive or
inflammatory stage occurs early in the course of TED. In this stage, the eyes are
red and painful. Usually, this condition recedes within 3 years. After a few acute
attacks, the eye goes into the second stage known as the fibrotic or quiescent
stage. In this condition the eye is white and a painless motility defect is
present.34,49

A number of classifications have been developed to assess the stage of TED.

These include NOSPECS, developed by the American Thyroid Association; the
European Group on Graves’ Orbitopathy (EUGOGO); VISA (vision,
inflammation, strabismus, appearance); and the Clinical Activity Score (CAS).6,52
The CAS is given in Table 5. In this classification, each criterion is given 1 point
for a maximum of 10 points. A clinically significant active disease is regarded
as one with a score of more than 4.53

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Review Ocular Immunology and

Table 5: Clinical Activity Score classification • Dalrymple’s sign: upper lid retraction in primary position
• Griffith’s sign: lower lid lag on looking up
Item Parameters assessed • Joffrey’s sign: absence of folds on the forehead on looking up
Pain (over the last Pain on or behind the globe • Boston’s sign: jerky movements of the upper lid on looking down
4 weeks) Pain on attempted eye movements • Stellwag’s sign: infrequent blinking
• Kocher’s sign: staring and frightened appearance, especially on
Redness Redness of the eyelid(s)
attentive fixation
Diffuse redness of the conjunctiva, covering at least
• Moebius’ sign: convergence deficiency
one quadrant
• Gofford’s sign: difficulty in inversion of the upper lid
Swelling Swelling of the eyelid(s)
• Sainton’s sign: on looking up, the frontalis contracts after the levator
Chemosis
palpebrae superioris has ceased to act
Swollen caruncle • Rosenbach’s sign: a trembling of the lid evident on gentle closure of
Increase of >2 mm proptosis during a period the eyelids
of 1–3 months • Enroth’s sign: fullness of eyelids due to puffy, oedematous
Impaired function (over Decrease in eye movements in any direction swelling of the tissues
the past 1–3 months) Decrease in visual acuity (1 or more lines on Snellen • Jellinek’s sign: pigmentation of the upper lid
chart, using a pinhole) • Suker’s sign: inability to maintain fixation on extreme lateral fixation
of eyes
• Ballet’s sign: partial or complete immobility of one or all
Clinical features extrinsic ocular muscles without an internal ophthalmoplegia
The clinical features of TED include proptosis, eyelid retraction, soft
tissue signs, restrictive myopathy and optic neuropathy. Eyelid Treatment of thyroid eye disease
retraction (unilateral or bilateral in around 90% of individuals at The treatment of proptosis is directed at the cause. A few general
some point) and proptosis (unilateral or bilateral in up to 60% of principles can be applied depending upon the severity of the
individuals) are the most common features of TED.52 Eyelid retraction proptosis and the effects produced by it. There is often dry eye
occurs during the active stage due to sympathetic stimulation of produced by the inflammation, lagophthalmos and poor blink
Muller’s muscle by thyroid hormone overload. While in the fibrotic mechanisms. This can be managed by lubricants, cyclosporine and a
stage, eyelid retraction is attributed to a contracture of the levator short course of topical steroids, if required. In proptosis associated
palpebrae superioris and inferior rectus along with fibrotic adhesion to with exposure keratopathy, a moist chamber or tarsorrhaphy can be
surrounding structures. The levator palpebrae superioris may also have employed to tide over the condition. If the condition does not
compensatory overaction due to hypotropia, and conversely, the resolve, then later, decompressive surgery can be performed. In the
inferior rectus may attempt compensation for hypertropia. On case of retrobulbar haemorrhage, a small lateral canthotomy and
examination, lid retraction is presumed based on ‘scleral show’, a application of ice over the eyelids should be done urgently to stop the
situation in which the upper lid margin is at or above the superior bleeding and reduce the intra-orbital pressure that can compromise
limbus. The lower lid margin normally rests at the inferior limbus. In the optic nerve function. Since TED is the commonest cause of proptosis in
case of lid retraction, the margin lies below the limbus, allowing sclera adults, a brief discussion on its management is provided below.34,47,53
to become visible.6,54

The management of TED should be a multidisciplinary approach

Proptosis in TED is axial and frequently permanent. It can be involving not only the ophthalmologist, but also the endocrinologist,
symmetrical or asymmetrical in bilateral cases.6 Restrictive myopathy neuro-surgeon, optometrist and nursing staff to take care of the patient.
is seen in 30– 50% of patients.6 During the active stage, it occurs due to This disease is debilitating, vison-threatening, and affects quality of life.
inflammation and muscle enlargement, and in the quiescent stage, Smoking is four times more likely associated with the development
due to fibrosis. Diplopia occurs in about 17% of patients.12 The order and progression of TED.56 Therefore, cessation of smoking should be
of involvement of muscles is usually inferior rectus, followed by encouraged in all smokers. Low selenium levels are also found in
medial rectus, superior rectus, and finally lateral rectus.6 some individuals, and supplementation with this micro-nutrient can be
done in such patients. Radioactive iodine treatment tends to worsen
Although blurred vision has been reported in around 7% of patients TED, and patients undergoing such therapy should be covered with
with TED, optic neuropathy contributes to less than 2% of cases.12 The systemic steroids. Lubricants are useful in reducing the dry eye and
enlarged recti muscles and swollen orbital tissues cause compression grittiness associated with the condition. In mild cases, patients may only
of the optic nerve or its blood supply, and compromise its function. require this treatment. Patients with poor Bell’s phenomenon should
Such a compartment syndrome effect may occur even in the absence be supplemented with night-time use of lubricant ointment or gels.
of significant proptosis and is called ‘auto-decompression’.12 In these As TED has an inflammatory pathophysiology, soft-tissue involvement
patients it is imperative to regularly monitor optic nerve function can be treated with cyclosporine eye drops. In case there is
tests, such as visual acuity, red colour desaturation, RAPD, light increased intraocular pressure on ocular movements, the patients
brightness appreciation, visual fields and ophthalmoscopic examination should be treated with appropriate anti-glaucoma medications. Stable
of the optic disc. diplopia can be managed by the use of prisms or botulinum toxin.6,8,52

Eponymous signs in TED In moderate to severe cases of TED, active disease must be treated with
There are a few clinical signs that are classically associated with TED. 54,55 oral or intravenous corticosteroids. In case there is no sight-threatening
These signs are listed below: emergency, a low dose of oral steroid (10 mg/day) for 4–6 weeks
• von Graefe’s sign: characterized by lid lag. As the patient looks down followed by a slow taper can be attempted. Intra-orbital injection of
the upper lid does not follow the downward movement of the eye, as triamcinolone
is evident by the increasing exposure of the sclera superiorly

3 TOUCHREVIEWS IN
 Evaluation of Proptosis: A

or dexamethasone is also effective. The effect of such treatment starts

(including the floor), which can reduce proptosis by 6–10 mm. In
in 2–3 days and lasts a few weeks, when it can be repeated. In cases of
severe cases, the apex of the orbit is also resected. The greater the
sight-threatening optic neuropathy, intravenous methylprednisolone
number of walls that are removed, the higher the risk of diplopia
(500 mg–1 gm) is given weekly for 6–12 weeks. Steroid-sparing agents
and enophthalmos. Fat-only decompression is performed in milder
have also been reported. These include rituximab, etanercept,
cases where visual function is not affected. It can also be combined
intravenous immunoglobulin, colchicine and teprotumumab, a
when bony-wall decompression is performed to obtain better results,
human insulin-like growth factor I receptor inhibitory monoclonal
especially improvement in diplopia.6,12
antibody.12

Diplopia in primary or reading gaze requires surgical correction.

Radioactive iodine therapy has been utilized in selected cases, when
However, the angle of deviation should be stable for 6–12 months. The
vision is not threatened. It is also used as steroid-sparing or steroid-
commonest surgeries performed are inferior or medial rectus recession.
supplementing therapy. The effect of radiation therapy starts at
Lid retraction surgery should be reserved as a last resort, as the
around 4–6 weeks and reaches maximum improvement by 4 months.
recession of the inferior rectus can exacerbate lid retraction. In such
Complications of radiation therapy include retinopathy (reportedly up to
cases, the recession of the levator palpebrae superioris or lower lid
20% at 10 years), cataracts (10–30%), optic neuropathy, and
retractors is usually employed. Mullerotomy is also practiced for mild
increased risk of local cancers.12 Phosphorus-32 has been used as
cases. Other modalities to manage lid retraction include injection of
targeted brachytherapy and found to improve exophthalmos and to
hyaluronic acid, triamcinolone or botulin toxin. These injections are often
reduce tissue swelling and other associated symptoms. The procedure is
effective up to 6 months.53
cheaper and easier than radio-iodine therapy, and no side-effects have
been reported over 3–12 months of follow-up.6,8,53
Conclusion
Proptosis is often encountered in clinical practice, in situations ranging
Any vision-threatening situation should be aggressively managed. In
from the emergency room to the consultant’s chambers. Evaluating
instances where steroids are ineffective and there is documented
a case of proptosis has to follow a systemic algorithm in order to
evidence of RAPD, visual field loss or a CT scan showing a crowded
avoid missing the likely diagnosis. In certain situations, time is of
orbit, surgical decompression of the orbit is required. It can be done
vital importance to prevent optic nerve compression and permanent
by one-wall (lateral wall) decompression, which can reduce 4–5 mm
loss of vision. This review provides a simplified pathway to approach
of proptosis; two-wall (lateral and medial combined); or three-wall
proptosis and to improve patient care and outcomes.16 ❑

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