Hindawi Publishing Corporation

Journal of Ophthalmology
Volume 2015, Article ID 249125, 16 pages
http://dx.doi.org/10.1155/2015/249125

Review Article
Graves’ Ophthalmopathy: VISA versus EUGOGO Classification,
Assessment, and Management

Jesús Barrio-Barrio,1 Alfonso L. Sabater,1 Elvira Bonet-Farriol,1

Álvaro Velázquez-Villoria,1 and Juan C. Galofré2
1
Department of Ophthalmology, Clı́nica Universidad de Navarra, Navarra Institute for Health Research (IdiSNA),
31008 Pamplona, Spain
2
Department of Endocrinology and Nutrition, Clı́nica Universidad de Navarra, Navarra Institute for Health Research (IdiSNA),
31008 Pamplona, Spain

Correspondence should be addressed to Jesús Barrio-Barrio; [email protected]

Received 19 March 2015; Accepted 22 July 2015

Academic Editor: Kyoung Yul Seo

Copyright © 2015 Jesús Barrio-Barrio et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Graves’ ophthalmopathy (GO) is an autoimmune inflammatory disorder associated with thyroid disease which affects ocular
and orbital tissues. GO follows a biphasic course in which an initial active phase of progression is followed by a subsequent
partial regression and a static inactive phase. Although the majority of GO patients have a mild, self-limiting, and nonprogressive
ocular involvement, about 3–7% of GO patients exhibit a severe sight-threatening form of the disease due to corneal exposure
or compressive optic neuropathy. An appropriate assessment of both severity and activity of the disease warrants an adequate
treatment. The VISA (vision, inflammation, strabismus, and appearance), and the European Group of Graves’ Orbitopathy
(EUGOGO) classifications are the two widely used grading systems conceived to assess the activity and severity of GO and guide
the therapeutic decision making. A critical analysis of classification, assessment, and management systems is reported. A simplified
“GO activity assessment checklist” for routine clinical practice is proposed. Current treatments are reviewed and management
guidelines according to the severity and activity of the disease are provided. New treatment modalities such as specific monoclonal
antibodies, TSH-R antagonists, and other immunomodulatory agents show a promising outcome for GO patients.

1. Introduction autoimmune thyroiditis [1]. The estimated incidence of GO

is 16 women or 3 men per 100,000 person per year [4].
Graves’ ophthalmopathy (GO), thyroid eye disease (TED), GD is an autoimmune disorder where loss of immunolog-
or thyroid associated orbitopathy (TAO) is an immunome- ical tolerance to the thyroid-stimulating hormone receptor
diated inflammatory disorder that produces expansion of the (TSH-R) is pivotal to the appearance of the specific antibodies
extraocular muscles and fat in the orbit. Edema, accumula- [5, 6]. Several findings in patients with GO, including elevated
tion of glycosaminoglycans and collagen, and adipogenesis TSH-R expression in orbital tissues and elevated levels of
cause most patients to have enlargement of both extraocular TSH-R antibodies, support the concept that the TSH-R is the
muscle and orbital adipose tissue with a predominance of primary autoantigen in GO [1, 7]. This concept has recently
either one in some of the patients [1, 2]. GO is the most been reinforced with the development of the first complete
common and most important extrathyroidal manifestation animal model of GO achieved by immunization of female
of Graves’ disease (GD) [3]. This condition generally occurs BALB/c mice with human TSHR A subunit [8]. The serum
in patients with Graves’ hyperthyroidism but sometimes levels of TSH-R autoantibodies correlate positively with the
may take place in patients with euthyroid or hypothyroid clinical features of GO. These constitute an independent risk
2 Journal of Ophthalmology

factor and help predict the severity and progression of the are related to (1) ocular exposure (ocular dryness and gritti-
disease [1]. ness, photophobia, excessive tearing, and blurred vision), (2)
The aim of this review is to present a comprehensive and periorbital soft tissue inflammation and congestion (sensa-
concise overview of the current concepts needed to evaluate tion of retroocular pressure, conjunctival redness, and eyelid
GO patients and to provide guidelines to manage this dis- swelling), or (3) extraocular muscle involvement (aching with
ease. eye movement, restricted ocular motility, and double vision).
The two most common signs of GO are upper eyelid
2. Pathophysiology of retraction (90% of patients) and proptosis [1, 14]. Upper eyelid
Graves’ Ophthalmopathy retraction is produced by levator/Müller muscle inflamma-
tion and fibrosis or by levator complex overaction secondary
The pathogenesis of this illness is summarized in three main to inferior rectus restriction (pseudo-lid retraction). Propto-
phenomena: (1) inflammation of the periorbital soft tissues; sis is caused by expansion of the orbital fat and/or muscles.
(2) overproduction of glycosaminoglycans by orbital fibrob- Also, the lacrimal gland is frequently involved and enlarged
lasts; and (3) hyperplasia of adipose tissue [1]. Along with [15].
the orbital fibroblasts, the perimysium fibroblasts proliferate, About 3–7% of GO patients exhibit a severe sight-
producing collagen and glycosaminoglycans in the extra- threatening form of the disease due to corneal exposure or
cellular matrix. The polyanionic charge and the extremely compressive optic neuropathy [1, 2]. Dysthyroid optic neu-
high osmotic pressure of this matrix substance render it ropathy (DON) is commonly caused by enlarged extraocular
highly hydrophilic and increase its capacity to retain water. muscles at the orbital apex compressing the optic nerve.
As a consequence, the extraocular muscles swell dramatically Symptoms typically consist of desaturation of colors and
[9]. Several clinical manifestations of GO are caused by an blurring of central vision. Afferent pupil defect and optic
increase in the orbital soft tissue volume which leads to a disc edema are specific signs but are not always present. This
higher pressure within the inexpandable bone cavity. The optic neuropathy is potentially reversible with appropriate
periorbital edema is primarily congestive and it probably treatment. It is more frequently developed by males, elderly,
reflects a decrease in venous draining due to compression and diabetic patients [2].
in the orbital space [10]. Conversely, development of new If the clinical features are sufficient, orbital imaging
fat cells (adipogenesis) is also a cause of increased orbital may not be necessary for diagnosis of GO. In any case,
tissue volume. The orbit contains different subpopulations of computed tomographic scans show that most patients with
fibroblasts exhibiting phenotypic heterogeneity. This implies GO have enlargement of both the orbital fat compartments
important functional consequences from the cellular diver- and the extraocular muscles and that others appear to have
sity and provides evidence suggesting divergent biological involvement of only the adipose tissue or extraocular muscle.
roles for fibroblasts within the extraocular muscles and Type 1 orbitopathy (lipogenic variant) or type 2 orbitopathy
fibroblasts from the adipose tissue. The first ones, when (myogenic variant) is differentiated depending on which
exposed to cytokines, can differentiate into myofibroblasts component is predominant [16]. Calculation of orbital soft
and then participate in inflammation, repair, and fibrosis. tissue volumes may be helpful in understanding the etiology
On the other hand, half of the fibroblasts within the adipose and pathogenesis of the disease and permits an assessment of
tissue are preadipocytes that, under certain conditions, can be natural progression or response to therapy [17]. CT scans are
induced to differentiate. When prompted by the constellation also useful to demonstrate the enlarged extraocular muscles
of growth factors and cytokines that are expressed as a crowding the optic nerve at the orbital apex when optic
consequence of GO, these cells may undergo differentiation neuropathy is suspected and to plan an orbital bone decom-
into adipocytes and thus contribute to the increased tissue pression surgery when necessary. Comerci et al. [18] have
volume associated with the disease [11, 12]. developed an MRI-based computer-assisted segmentation
In most cases, GO develops with only one inflammatory method so that the volumes of fat, muscle, and vitreous bodies
onset (active phase), which is followed by a phase of stillness are automatically calculated for each orbital quadrant of each
(inactive phase). In the inactive phase, the long lasting eye accordingly. Regional automatic assessment of intraor-
muscular edema along with the increased production of bital fat by dividing the orbits into four quadrants could be
collagen leads ultimately to atrophy, fibrosis, and sclerosis of useful for more accurate surgical planning and for follow-
the extraocular musculature and subsequently to restrictive up studies. Magnetic resonance imaging with diffusion-
strabismus. weighted imaging (DWI) has recently been proven to be use-
ful in the objective assessment of activity in GO patients [19].
3. Clinical Features of As mentioned, typically GO follows a biphasic course.
Graves’ Ophthalmopathy Active phase generally lasts for 18–36 months, followed by a
stable or inactive phase. It is therefore essential to differentiate
The GO diagnosis is typically made clinically based on pre- between the concepts of activity (refers to the inflammatory
senting ocular symptoms and signs. Timely diagnosis permits process) and severity (refers to the quality of life or the risk of
appropriate evaluation and treatment and might prevent the vision loss) [20]. The currently assessment protocols of GO
progression to more severe disease manifestations. have, on one hand, specific scores to evaluate the activity and,
Nearly 50% of patients with GD report symptoms of on the other hand, items to evaluate the severity of the dis-
ophthalmopathy, which are generally mild [13]. Symptoms ease.
Journal of Ophthalmology 3

Table 1: NO SPECS modified classification [22].

Class Grade Suggestions for grading

0 No physical signs or symptoms
I Only signs
Soft tissue involvement
0 Absent
II a Minimal
b Moderate
c Marked
Proptosis (3 mm or more of normal upper limits with or without symptoms)
0 Absent
III a 3 or 4 mm over upper normal
b 5 to 7 mm increase
c 8 mm increase
Extraocular muscle involvement (usually with diplopia)
0 Absent
IV a Limitation of motion at extremes of gaze
b Evident restriction of motion
c Fixation of a globe or globes
Corneal involvement (primarily due to lagophthalmos)
0 Absent
V a Stippling of cornea
b Ulceration
c Clouding, necrosis, and perforation
Sight loss (due to optic nerve involvement)
0 Absent
VI a Disc pallor or choking, or visual field defect, vision 20/20–20/60
b The same, but vision 20/70–20/200
c Blidness, vision less than 20/200

4. Assessment Protocols of Graves’ strabismus, and appearance) [2, 25] and the European Group
Ophthalmopathy of Graves’ Orbitopathy (EUGOGO) Classification [3]. Both
systems are grounded in the NO SPECS and CAS classi-
Several classification systems have been conceived to assess fications and use indicators to assess the signs of activity
the clinical manifestations of GO. In 1969, Werner reported and the degree of severity. More importantly, they allow the
the NO SPECS Classification (No physical signs or symptoms, clinician to guide the treatment of the patient with GO. VISA
Only signs, Soft tissue involvement, Proptosis, Extraocular is more commonly used in North America and Canada while
muscle signs, Corneal involvement, and Sight loss) [21]. The EUGOGO is in Europe. Since the two protocols are not
modified NO SPECS was also published by Werner in 1977 interchangeable, only one of them should be employed as a
and has been broadly used since then [22]. This classifi- reference in a specific patient.
cation grades exclusively for clinical severity and does not
provide a means of distinguishing inflammatory progressive 4.1. VISA Classification. The VISA system was developed
from noninflammatory stationary Graves’ ophthalmopathy by Dolman and Rootman in 2006 [25] and adopted with
(Table 1). Therefore, the indication for treatments used to be modifications by the International Thyroid Eye Disease
based exclusively in the severity of symptoms instead of the Society (ITEDS). The current version is designed for office
rate of progression of the disease until 1989, when Mourits use and can be downloaded from the ITEDS website
et al. described the Clinical Activity Score (CAS) [23]. This (http://www.thyroideyedisease.org/). The VISA system is
score based on the classical signs of acute inflammation (pain, based on symptoms and signs inputs. The system assesses 4
redness, swelling, and impaired function) was proposed as a severity parameters: V (vision); I (inflammation/congestion);
clinical classification to discriminate easily between the active S (strabismus/motility restriction); and A (appearance/expo-
and quiescent stages of the disease and was modified in 1997 sure). Each feature is considered and graded independently.
[24] (Table 2). A global severity grade (maximum score is 20 points) is
The currently grading systems used for the assessment the sum of each of the involved systems graded indepen-
of GO are the VISA Classification (vision, inflammation, dently: vision: 1 point; inflammation/congestion: 10 points;
4 Journal of Ophthalmology

Table 2: Clinical Activity Score (CAS) (amended by EUGOGO Table 3: VISA Inflammatory Index (I) (Dolman and Rootman
after Mourits et al.). One point is given for the presence of each 2006 [25], ITEDS modified). Patients with moderate inflammatory
of the parameters assessed. The sum of all points defines clinical index (less than 4 of 10) are managed conservatively. Patients with
activity: active ophthalmopathy if the score is above 3/7 at the first high scores (above 5 of 10) or with evidence of progression in the
examination or above 4/10 in successive examinations. inflammation are offered a more aggressive therapy.
For initial CAS, only score items 1–7 Sign or symptom Score
1 Spontaneous orbital pain 0: absent
Caruncular edema
2 Gaze evoked orbital pain 1: present
3 Eyelid swelling that is considered to be due to active GO 0: absent
4 1: conjunctiva lies behind the
Eyelid erythema
Chemosis grey line of the lid
5 Conjunctival redness that is considered to be due to 2: conjunctiva extends anterior to
active GO the grey line of the lid
6 Chemosis 0: absent
7 Conjunctival redness
Inflammation of caruncle OR plica 1: present
Patients assessed after follow-up (1–3 months) can be 0: absent
Lid redness
scored out of 10 by including items 8–10 1: present
8 Increase of >2 mm in proptosis 0: absent
Decrease in uniocular ocular excursion in any one 1: present but without redundant
9
direction of >8∘ Lid edema
tissues
10 2: present and causing bulging in
Decrease of acuity equivalent to 1 Snellen line
the palpebral skin, including
lower lid festoon
Retrobulbar ache
strabismus: 6 points (diplopia: 3 points plus restriction: 3 At rest 0: absent; 1: present
points); appearance/exposure: 3 points. With Gaze 0: absent; 1: present
Vision (V) evaluates the visual repercussion particularly Diurnal variation 0: absent; 1: present
due to the development of dysthyroid optic neuropathy. This
is assessed through visual acuity, pupillary reflexes, color
vision, visual fields, optic nerve examination, and visual the nearest 5∘ in four directions using the corneal light reflex
evoked potentials. Most of these tests should be performed in technique. Accurate assessment of changes in ocular ductions
all patients, as optic neuropathy frequently occurs in patients in GO is vital to identify progressive disease, management,
with little or no proptosis. CT scans may be necessary in and response to therapy assessment. Any change of ≥12∘ in
selected cases to confirm the presence of an orbital apex any direction can be considered progression [26]. (3) Ocular
syndrome or before surgical decompression (Figure 1). restriction can be graded from 0 to 3 based on the range of
Soft tissue inflammation/congestion (I) evaluation is ductions (0 = duction >45∘ , 1 = 30–45∘ , 2 = 15–30∘ , and 3 <
graded according to the worst score for the eye or the eyelid 15∘ ). Strabismus can be quantified by prism cover testing in
with the Inflammatory Index (Table 3). Symptoms include order to plan surgical treatment.
orbital ache at rest or with ocular movement and diurnal In the assessment of the appearance/exposure (A) symp-
variation (inflammation worsening with the head dependent toms include appearance concerns (such as bulging eyes,
after sleep or worsening of diplopia at morning). Signs eyelid retraction, and fat pockets) and those derived from
include caruncular edema, chemosis, conjuntival redness, ocular exposure (such as gritting sensation, photophobia,
lid redness, and lid edema. Chemosis is graded as 1 if the dryness, and secondary tearing). Signs include measurements
conjunctiva lies behind the grey line of the lid (Figure 2) and of eyelid retraction (millimeters from the pupillary light
as 2 if it extends anterior to the grey line. Lid edema is graded reflex to the lid margin); scleral show (millimeters from
as 1 if it is present but not causing overhanging of the tissues the limbus to the lid margin); levator palpebrae superioris
and as 2 if it causes a roll in the lid skin including festoons function; lagophthalmos (incomplete eyelid closure); and
in the lower lid. Cases with moderate inflammatory index proptosis with the Hertel exophthalmometer. Signs of corneal
(less than 4 of 10) are managed conservatively. Patients with exposure are best assessed with the slit-lamp microscope and
high scores (above 5 of 10) or with subjective or objective may include punctate epithelial erosions, ulcerations, and, in
evidence of progression in the inflammation are offered a severe cases, corneal thinning and risk of perforation.
more aggressive therapy.
The presence of strabismus/motility restriction (S) is doc- 4.2. EUGOGO Classification. The EUGOGO was established
umented by three aspects. (1) Diplopia that is graded from in 1999 [20]. The Europeans developed an assessment proto-
0 to 3 (0 = no diplopia, 1 = diplopia with horizontal or col for the evaluation of patients with GO based upon activity
vertical gaze, 2 = intermittent diplopia in straight gaze, and 3 and severity parameters. The disease activity is evaluated
= constant diplopia in straight gaze). Fluctuation of diplopia based on the modified Clinical Activity Score (CAS) [24].
with worsening in the morning is frequent during the active Some severity parameters are evaluated by comparison with
phase of the disease. (2) Ocular ductions are measured to an image atlas developed by the group itself. New patient and
Journal of Ophthalmology 5

(a) (b)

Figure 1: (a) Sagittal CT scan showing severe exophthalmos. (b) Coronal CT scan: apical crowding causing bilateral DON.

Figure 2: Chemosis. Notice the conjunctiva separated from the

sclera and behind the grey line (arrows) and diffuse conjunctival
redness.

Figure 3: Inflammation of the plica (arrow) with diffuse conjuncti-

follow-up forms, together with the color atlas, may be down- val redness.
loaded from the EUGOGO website (http://www.eugogo.eu/).
A practical classification for the management of the ophthal- considered a sign of active inflammation of the orbital tissues
mopathy according to its severity was also developed [3]. [24]. “Equivocal” or “mild” conjunctival redness should not
be given a CAS score. Chemosis is assessed with slit-lamp
4.2.1. EUGOGO Activity Measures of Graves’ Ophthalmopathy:
at 60∘ midway between the limbus and the lateral canthus;
Clinical Activity Score. Disease activity is assessed through
true chemosis (separation of conjunctiva from sclera present
the rating of the 10 items of the modified CAS (Table 2). This
in >1/3 of the total height of the palpebral aperture or
Clinical Activity Score is based on four of the five well-known
conjunctiva prolapsing anterior to grey line of eyelid) should
classical signs of inflammation (pain, redness, (warmth),
be distinguished from the redundant folds of the conjunctiva
swelling, and impaired function). For each of the 10 items
(conjunctivochalasis, CAS negative). If plica is prolapsed
present, one point is given. Each item has the same weight.
through closed eyelids or caruncle and/or plica are inflamed
The sum of these points is the CAS which ranges from 0 to 10.
(Figure 3), CAS should be recorded as positive. Increasing
Soft tissue inflammatory signs and symptoms (pain,
proptosis ≥ 2 mm in the previous 1 to 3 months is the ultimate
redness, and swelling) are graded with the first 8 items.
item to evaluate swelling [27].
Orbital pain (spontaneous or gaze evoked) should only be
Impaired function is graded with the last 2 items: decreas-
scored if present for more than a few seconds and more
ing uniocular excursion in any one direction of ≥ 8∘ and
often than just occasionally. EUGOGO atlas is of great help
decrease in visual acuity equivalent to 1 Snellen line in the
in evaluating soft tissue inflammatory signs. Only eyelid
previous 1 to 3 months. During the first visit, the first 7 items
swelling and eyelid erythema thought to be due to active GO
are assessed, resulting in an active ophthalmopathy if the total
should be scored. When swelling or erythema varies between
score is higher than or equal to 3/7. In the follow-up visits, the
upper and lower eyelid of an eye the more severe lid should be
CAS is assessed on the 10 items, and the ophthalmopathy is
used to score that eye. Only “moderate” or “severe” and not
considered to be active if the score is higher than or equal to
“mild” eyelid swelling should be recorded as CAS positive.
4/10.
Some of the signs, such as redness of the conjunctiva, may be
difficult to recognize because of its nonspecificity. It should be 4.2.2. EUGOGO Severity Measures of Graves’ Ophthalmopa-
assessed without slit-lamp at 1 meter from the patient. Only thy. Severity assessment (Table 4) is based on the following:
redness due to active GO should be scored: diffuse redness,
covering at least one quadrant. Redness of the conjunctiva (1) Evaluation of CAS items for soft tissue inflamma-
as a result of corneal stippling or ulceration is not what is tion except pain that is not taken into account is
6 Journal of Ophthalmology

Table 4: Protocol to assess the severity of Graves’ ophthalmopathy (EUGOGO). Some of the signs may be assessed by comparison with the
image atlas provided by the EUGOGO (http://www.eugogo.eu/).

Eyelid swelling
(i) Absent
(ii) Mild: none of the features defining moderate or severe swelling are present
(iii) Moderate: definite swelling but no lower eyelid festoons and in the upper eyelid the skin fold
becomes angled on a 45∘ downgaze
(iv) Severe: lower eyelid festoons OR upper lid fold remains rounded on a 45∘ downgaze
Eyelid erythema
(i) Absent
(ii) Present
Conjunctival redness
(i) Absent
Soft tissues (ii) Mild: equivocal or minimal redness
(iii) Moderate: <50% of definite conjunctival redness
(iv) Severe: >50% of definite conjunctival redness
Conjunctival edema
(i) Absent
(ii) Present: separation of conjunctiva from sclera present in >1/3 of the total height of the
palpebral aperture or conjunctiva prolapsing anterior to grey line of eyelid
Inflammation of caruncle or plica semilunaris
(i) Absent
(ii) Present: plica is prolapsed through closed eyelids or caruncle and/or plica are inflamed
Palpebral aperture (mm)
Upper/lower lid retraction (mm)
Levator function (mm)
Lagophthalmos
Eyelid measurements (i) Absent
(ii) Present
Bell’s phenomenon
(i) Absent
(ii) Present
Proptosis Measurement with Hertel’s exophthalmometer. Recording of intercanthal distance.
Prism cover test
Monocular ductions
Ocular motility Head posture
Torsion
Field of binocular single vision
Corneal integrity
(i) Normal
Cornea (ii) Punctate keratopathy
(iii) Ulcer
(iv) Perforation
(i) Visual acuity (Logmar or Snellen)
Optic neuropathy (ii) Afferent pupil defect (present/absent)
(iii) Colour vision
(iv) Optic disc assessment: normal/atrophy/edema

done. Eyelid swelling is classified as mild, moderate corneal limbus to eyelid margin), and levator func-
(definite subcutaneous fluid or skin thickening), and tion.
severe (tense subcutaneous fluid or thickened skin
(3) Proptosis is measured with Hertel’s exophthalmome-
with lower eyelid festoons or upper lid fold remains
ter.
rounded on downgaze). Conjunctival redness is clas-
sified as mild/equivocal, moderate (definite redness (4) Ocular motility is assessed by prism cover test at
of < 50% bulbar conjunctiva excluding plica and distance, torsion, monocular ductions, and the field
caruncle), and severe (definite redness of ≥ 50%). of binocular single vision.
(2) Eyelid measurements are mid pupil palpebral aper- (5) Corneal integrity and the risk of corneal breakdown
ture, upper and lower lid retraction (distance from assessed by the evaluation of lagophthalmos (asking
Journal of Ophthalmology 7

patient to close their eyes as if asleep and using pen an assessment with practical implications for guiding the
torch to see whether sclera or cornea is still visible) management of patients, something valuable compared to the
and Bell’s phenomenon. NO SPECS classification.
(6) Optic neuropathy is judged on the basis of disc swell- The VISA classification follows a logical order from both
ing or atrophy thought to be due to GO, decreased an exploratory and management point of view (from vision
visual acuity, afferent pupil defect, and color vision, to appearance). Symptoms and signs are clearly assessed and
plus ancillary tests if necessary. Until further data collected for each of the involved systems. Apart from a global
is available, optic neuropathy may be assumed to severity grade every involved system is graded independently
be present if there is disc swelling or if two of the which adds an interesting value to assess the outcome
other clinical features are present. Impaired color of targeted treatments. Aside from this, the revised VISA
perception carries more weight than other features classification evaluates disease activity based on the disease
except disc swelling [27]. progression in any of the four parameters, either subjectively
(patient documentation) or objectively (by clinical measure-
ments). Therefore, an elevated inflammatory score provides
4.2.3. EUGOGO Classification of the Severity of the Oph- evidence that the disease may be active, but it is not the only
thalmopathy. The management of patients with GO depends parameter evaluated to study activity [2]. In a similar way, the
on the degree of severity of the ophthalmopathy, which is CAS assesses activity not only by the inflammation items but
established according to the impact of the disease on the also with the progression in the last 3 items (parallel to V-S-
patient’s quality of life and the risk of vision loss. The disease A in the VISA classification). A disadvantage of including the
is classified as mild, moderate, severe, or sight-threatening as “impaired function items” in the same score as the “soft tissue
follows [3]. inflammation items” is that equal weight is given, for exam-
(1) Mild: characteristics of GO have a minimum impact ple, to redness of the eyelids and visual function worsening.
on the patient’s life. They usually present one or more As explained by Mourits et al. in the first publication of the
of the following signs: modified CAS [24], they tried to adjust the CAS in such a way
that some items had a double or triple weight, but this did not
(i) Minor lid retraction (<2 mm). result in a more sensitive CAS. Therefore, they believed that
the CAS should be used in combination with other parame-
(ii) Mild soft tissue involvement.
ters of disease activity, such as laboratory determinations. It
(iii) Exophthalmos < 3 mm (above the normal range is also important to have in mind that severe complications
for the race and gender). as DON can appear with low CAS scores.
(iv) Transient or no diplopia. Otherwise, while CAS is binary (absent/present: 0/1)
(v) Corneal exposure responsive to lubricants. for every item, the Inflammatory Score of VISA assigns
a higher score for more severe forms of eyelid and con-
(2) Moderate to severe: patients without sight-threatening junctival edema (0–2). Sometimes, it could be difficult to
GO whose eye disease has sufficient impact on daily decide whether to score a patient to CAS 3 or 4 (and then
life to justify the risks of immunosuppression (if candidate or not of intravenous immunosuppression) only
active) or surgical intervention (if inactive). Patients for some subtle conjunctival or palpebral change. On the
usually present one or more of the following signs: other hand, conjunctival redness is better defined in the
CAS amended by EUGOGO than that in VISA, being scored
(i) Lid retraction (>2 mm). only if it is moderate or severe, but not equivocal or mild.
(ii) Moderate or severe soft tissue involvement. The Inflammatory Score of VISA also includes the diurnal
(iii) Exophthalmos ≥ 3 mm (above the normal range variation item, a relevant clinical symptom referred by many
for the race and gender). patients in the active phase of the disease, while the CAS
does not take it into account. The assessment of uniocular
(iv) Inconstant, or constant diplopia.
ocular excursion also has a different range in CAS and VISA-
(3) Sight-threatening GO: patients with dysthyroid optic S (strabismus). While CAS considers a decrease in ocular
neuropathy or corneal breakdown due to severe excursion of > 8∘ in any direction for the definition of motility
exposure. Other infrequent cases are ocular globe progression, VISA-S considers a decrease of >12∘ . Such figures
subluxation, severe forms of frozen eye, choroidal come from the coefficients of repeatability found in different
folds, and postural visual darkenings. This category studies using several methods of assessing ocular ductions in
warrants immediate intervention. patients with GO. The CAS definition of motility progression
is based on the perimetry method, whereas VISA is from the
As a rule of thumb, it is considered that all patients who do not light reflex technique. As demonstrated by Dolman et al. the
have a mild or a sight-threatening ophthalmopathy present a coefficient of repeatability is of 12.2∘ for ductions measured
moderate-to-severe disease. either by perimetry or by the light reflex technique [26].
As the perimetry method is time consuming and requires
4.3. VISA or EUGOGO Classification: Which One to Use a trained technician and an instrument that is increasingly
in Routine Clinical Practice? Both VISA and EUGOGO unavailable, it seems that decreased ocular motility of >12∘
systems provide not only a diagnostic classification, but also assessed by the light reflex technique is a better definition
8 Journal of Ophthalmology

of motility progression. There are also differences between a multidisciplinary team of ophthalmologists, endocrinol-
VISA and EUGOGO in grading the severity of ocular motility ogists, radiologists, and orbital surgeons [20]. It is vital to
problems. While in the global score of VISA ocular motility identify those patients who are likely to progress to serious
involvement is evaluated with 2 items out of 5 (diplopia and complications such as restrictive strabismus or dysthyroid
restriction), only the diplopia but not the restriction is consid- optic neuropathy before they develop.
ered in the classification of severity according to EUGOGO. Any patient with symptoms or signs of orbitopathy in the
EUGOGO classification of severity differentiates man- high-risk group (elderly, male, diabetic, or smoker), positive
agement categories which are very practical and of great family history of orbitopathy, a recent history of progression,
help in deciding a specific management plan for the patient. or any moderate inflammatory changes should be referred
However, there is no clear recording change in severity to the ophthalmologist within a few weeks. Cases with
in their forms. EUGOGO does not differentiate between reported color or central visual loss, progressive diplopia,
moderate and severe patients because they are all included rapid deterioration in symptoms, or significant inflammatory
in the same management plan. Likewise, VISA classification scores should be urgently evaluated within a few days. Any
does not specify what is considered a mild, moderate, or patient who is undergoing radioiodine therapy for hyperthy-
severe appearance. On the other hand, VISA takes more roidism suspected of having active disease should be previ-
into account the patient perception of her or his own illness ously referred for an ocular examination to decide on the
in terms of assessing the grading and progression than opportunity of prophylactic corticosteroid therapy [2].
does EUGOGO which is mainly a sign based classification. Management and treatment modalities are decided
Interestingly, whereas several GO specific quality of life according to the severity and activity of the disease. As men-
(QOL) questionnaires have been developed (GO quality of tioned, VISA management flow relies on the descending prio-
life questionnaire (GO-QOL); GO quality of life scale (GO- rity of treatment of the 4 affected functions in GO (impaired
QLS); and TED quality of life questionnaire (TED-QOL)) all vision, soft tissue inflammation, ocular motility involve-
of them have shown only moderate correlation with disease ment, and appearance changes). On the other hand, the
severity, emphasising the discrepancy between objective and management categories of the EUGOGO severity classifi-
subjective assessments and the importance of measuring both cation are indeed practical and sharp. Here, we describe
in order to offer the best management plan to the patient [28]. the management plan based on the Consensus Statement of
As said previously, the EUGOGO and VISA classifica- the EUGOGO on management of GO of 2008 [3]. It has
tions are not interchangeable. This is even more true when now been seven years from that consensus and numerous
using these systems to assess the response rate to different scientific evidences on GO treatment have been published
treatments because, then, even the EUGOGO outcome crite- since then. We summarize some of the current evidences on
ria and the CAS give incongruent and incomparable response GO treatment and provide an update in the management of
rates [29]. the disease (Table 6).
As both classifications have been devised to be used in
clinical trials apart from clinical practice, they have some 5.1. Measures for All Patients with Graves’ Ophthalmopathy
complexity in the extensive data to be collected. In any case,
both ITEDS and EUGOGO groups provide downloadable 5.1.1. Restore Euthyroidism. Management of GO patients
forms for the first and follow-up visits. The ITEDS group includes restoring and stabilizing thyroid function. Patients
might have developed a more elegant and user friendly with uncontrolled thyroid dysfunctions are more likely to
form to complete in only one page. On the other hand, the experience severe GO [30]. Furthermore, constant moni-
assessment of CAS is easy and quick to collect in routine toring (every 4–6 weeks) of thyroid function is particularly
clinical practice. important during the early stages of treatment.
As explained in the EUGOGO website, in July 2013 there Although controversial, the evolution of GO is likely not
was a meeting of members from the executive committees impacted by surgery or antithyroid [31–33]. Evidences exist
of both EUGOGO and ITEDS in Vancouver. The panel that radioiodine worsens the active ocular disease in 15%
of experts agreed to proceed jointly to work on improved of cases within the 6 months after the treatment. This risk
assessment systems. Until that work is developed, we propose may be reduced in patients with active GO by a short cycle
to merge the Inflammatory Index of VISA and the CAS (3 months) of orally delivered corticoids after the treatment
classification systems in a simplified “GO assessment activity (beginning with 0.3–0.5 mg of prednisone per kilogram daily
checklist” in order to use it in routine clinical practice and tapering the dose until withdrawal) and by avoiding
(Table 5). It joins the advantages of the more complete postradioiodine hypothyroidism, which is also important
assessment of the Inflammatory VISA items, the separation in patients with inactive GO [3]. Interestingly, Lai et al.
of the progression items from the inflammatory items, and suggested that a lower dose of steroids may be equally
the simplicity of the CAS assessment. effective in these cases [34].
It has not been until very recently that Stein et al. [35]
5. Management Protocols of have described that the risk of developing GO is substantially
Graves’ Ophthalmopathy reduced in patients who undergo thyroidectomy compared
with RAI ablation. They designed a retrospective longitudinal
Treatment plan should be individually designed for each cohort study to specifically analyze the influence of the man-
patient. An appropriate approach should be performed by agement of GD hyperthyroidism (treatment with antithyroid
Journal of Ophthalmology 9

Table 5: Proposed “GO activity assessment checklist” based on VISA and EUGOGO classifications. Any change in the progression symptoms
or inflammatory score higher than 5 would warrant more aggressive therapy.

(a)

Inflammatory signs and symptoms∗

0 1 2
(i) Inflammation worse with the
Diurnal variation head dependent after sleep or
Absent
(0)-(1) (ii) worsening of diplopia at
morning
Retrobulbar ache at
rest Absent Present
(0)-(1)
Retrobulbar ache with
gaze Absent Present
(0)-(1)
Present and causing bulging in
(i) Absent or the palpebral skin (tense
Lid edema
(ii) mild or Present but without redundant subcutaneous fluid):
(score worst eyelid)
(iii) not thought to be due to tissues (i) upper lid fold remains
(0)-(1)-(2)
active GO rounded on downgaze or
(ii) lower lid festoon
Lid redness (i) Absent or
(score worst eyelid) (ii) not thought to be due to Present
(0)-(1) active GO
(i) Absent or
Diffuse redness, covering at least
(ii) equivocal or
Conjunctival redness one quadrant assessed without
(iii) mild or
(0)-(1) slit-lamp at 1 meter from the
(iv) not thought to be due to
patient
active GO
Separation of conjunctiva from
sclera present in >1/3 of the total
Chemosis (i) Absent or Conjunctiva anterior to the grey
height of the palpebral aperture
(0)-(1)-(2) (ii) conjunctivochalasis line
Conjunctiva behind posterior to
the grey line
(i) Plica is prolapsed through
Inflammation of
closed eyelids or
caruncle OR plica Absent
(ii) caruncle and/or plica are
(0)-(1)
inflamed
Total inflammatory score: /10
∗
Score worst eye.
(b)

Progression symptoms (changes in the previous 1–3 months)

0 1
Disc swelling or atrophy thought to be due to GO, or 2
of the following:
Optic Neuropathy
Same or Better (i) Decreased visual acuity equivalent to 1 Snellen line
(0)-(1)
(ii) Afferent pupil defect
(iii) Impaired colour perception
Extraocular muscle
Decrease in uniocular ocular excursion in any one
ductions Same or Better
direction of ≥12∘
(0)-(1)
Proptosis
Same or Better Increase of ≥2 mm in proptosis
(0)-(1)
 10

Table 6: Orientative therapeutic protocol for Graves’ ophthalmopathy (see text for bibliographic references).
Restore euthyroidism
All patients Avoid smoking
Conservative local measures
Activity
Severity
Active Nonactive
(i) Artificial tears
(i) Artificial tears
(ii) Sunglasses
(ii) Prisms
(iii) Head of the bed slightly elevated
Mild (iii) Botulinum toxin in Müller muscle
(iv) Selenium (200 𝜇/g daily × 6 months)
(iv) Surgical Müllerectomy
(v) Fresnel-type prisms
(v) Blepharoplasty
(vi) Botulinum toxin in Müller muscle
(i) Intravenous methylprednisolone:
1st, 500 mg/week × 6 weeks
2nd, 250 mg/week × 6 weeks
3rd, if activity persists: consider prolongation of
treatment up to 8 g of maximum cumulative dosage 1st, orbital decompression (2 or 3 walls depending on
4th If non responsive after 6 weeks, change the the degree of exophthalmos)
treatment 2nd, surgery for strabismus (stability of 6-month
(ii) Patients resistant to glucocorticoids: deviation angle. Muscular recessions)
Moderate-severe (a) Association of cyclosporin A (5 mg/kg/day in 2 3rd, palpebral surgery
doses) plus oral glucocorticoids, methotrexate (i) Palpebral retraction: levator recession surgery,
(7,5–10 mg/week), tocilizumab (8 mg/kg/every 4 weeks), retractors for the lower eyelid.
and Rituximab (500 mg–1000 mg), (ii) Blepharoplasty of upper eyelids, lower eyelids, or
(b) If muscular involvement predominates: orbital both.
radiotherapy (20 Gy) (not in <35 years or diabetic
patients)
(iii) Consider botulinum toxin in extraocular muscles if
with diplopia (medial rectus or inferior rectus)
Threat to vision
Methylprednisolone 1 g intravenously × 3 days, repeat
after a week
Dysthyroid optic neuropathy If nonresponsive: urgent orbital decompression. (+/− Urgent deep orbital medial wall decompression
glucocorticoids intravenously if still active +/−
radiotherapy)
Intravenous methylprednisolone when relevant orbital
inflammation; palpebral closure, lubrication, Lateral tarsorrhaphy, orbital decompression, amniotic
Severe exposure keratopathy
tarsorrhaphy, botulinum toxin in Müller muscle, and membrane transplant, and corneal transplant
orbital decompression if other measures are inefficient
Journal of Ophthalmology
Journal of Ophthalmology 11

medications, exposure to RAI, or thyroidectomy) in the safe and well-tolerated preventive protocol as an alternative
risk of developing GO. The hazard of developing GO was to the “wait and see” strategy seems to be justified. A recent
determined by multivariable Cox regression analysis among study showed that a 6-month course with oral selenium
8404 patients with newly diagnosed GD. During the follow- (100 𝜇g twice daily) significantly improved quality of life,
up, 740 (8.8%) enrollees developed GO. After adjustment for reduced ocular involvement, and slowed progression of the
potential confounders, surgical thyroidectomy, alone or in disease in patients with mild GO [38]. The use of oral
combination with medical therapy, was associated with a 74% corticosteroids is usually not recommended in patients with
decreased risk for GO development (adjusted hazard ratio mild GO. Botulinum toxin injection may be considered to
(HR), 0.26 (95% CI, 0.12–0.51)) compared with radioactive reduce upper lid retraction and is a valuable therapeutic
iodine therapy alone. Those patients not requiring treatment option in active disease where definitive surgery remains
for hyperthyroidism exhibited a 73% decreased hazard of contraindicated. Rehabilitative surgery (Müllerectomy or
developing GO (adjusted HR, 0.27 (95% CI, 0.18–0.39)) rela- blepharoplasty) should be considered providing that the GO
tive to those treated with RAI alone. However, it is important remains stable and inactive [39].
to note that only 2 patients treated with RAI have been pre-
scribed with corticosteroids after the treatment. Prospective 5.3. Measures for Patients with Moderate to Severe Oph-
studies are necessary to confirm these findings. In addition, thalmopathy. In these patients, eye disease has sufficient
the same group also found that after adjustment for covari- impact on daily life to justify the risks of immunosuppressant
ates, enrollees with GD and statin use for more than 60 days treatment (if active) or surgical intervention (if inactive).
in the previous year were associated with a 40% decreased
hazard compared with those with less exposure to statins 5.3.1. Immunosuppressive Medical Treatment and Orbital
(adjusted HR, 0.60 (95% CI, 0.37–0.93)). This effect appears Radiotherapy. Only patients with active disease will respond
to be related to the anti-inflammatory actions of statins that to immunosuppressive treatments such as systemic corti-
are independent of their cholesterol-lowering properties. costeroids or orbital radiation. These treatments have no
benefit for patients in the quiescent phase in whom disease
5.1.2. Conservative Measures. Patients should be advised to manifestations are the consequence of fibrotic changes in the
adopt general measures such as the use of artificial tears, sun- orbital tissues [14].
glasses, and sleep with the head of the bed slightly elevated. A comparison of intravenous (IV) versus oral glucocor-
Nocturnal ointment is of great benefit for incomplete eyelid ticoid administration has been reviewed by Zang et al. [40].
closure provided that the cornea is protected. The overall response rate was 82% and 53.4% for intravenous
and oral steroids, respectively. Pulses of IV steroids were
5.1.3. Smoking Cessation. Smoking is the most important risk associated with fewer side effects, shorter treatment course,
factor amenable to modification in patients with GO and the and lower relapse risk compared with oral administration.
risk is proportional to daily cigarette intake. Smokers with GO The use of oral prednisone between IV pulses and its use
are more likely to develop a severe condition and have worse in the tapering after IV glucocorticoids did not increase the
response to the immunosuppressant therapies [1, 30]. Xing response rate [40]. Oral corticosteroids might be considered
et al. [36] have recently demonstrated that smoking, even when IV infusions are not logistically possible or if the patient
past smoking, was an independent risk factor associated with prefers the oral route [41]. Oral corticosteroids might be also
impaired response to intravenous corticosteroids in patients prescribed in some moderate to severe cases when the deter-
with GO. Never smokers with active moderate-to-severe GO, mination of activity is uncertain. A trial of therapy using a
who were treated with cumulative doses of 4.5 g intravenous three-day course of oral prednisolone (50 mg) can determine
methylprednisolone within 3 months, responded better than whether clinical features show improvement, and, therefore,
both active smokers and past smokers. Smoking patients did IV corticosteroids or radiotherapy may be indicated [2].
have more severe and active disease than never smokers. Although the optimum treatment protocol for patients
To exclude the interference of other factors, Xiang et al. with moderate to severe disease has yet to be defined in
performed a multivariable analysis and found a significant randomized controlled trials, a commonly used regimen is
Odds Ratio (OR) of 12.4 (𝑃 = 0.035) for smoking patients 500 mg methylprednisolone weekly for 6 weeks followed
to fail the treatment. This finding indicates that smoking by 250 mg weekly for another 6 weeks, for a cumulative
compromised therapeutic effects not only through disease dose of 4.5 g [41]. This weekly therapy protocol of 4.5 g IV
severity and activity but also through other independent methylprednisolone cumulative dose is not only safer but
mechanisms. is also more effective than a daily protocol (500 mg daily
for 3 consecutive days per week for 2 weeks, followed by
5.2. Measures for Patients with Mild Ophthalmopathy. Local 250 mg daily for 3 consecutive days per week for another
measures are the mainstay therapy for patients with mild 2 weeks, and by tapering oral prednisone) [42]. If there is
ophthalmopathy that generally have a self-limiting process. no clinical response, treatment with corticosteroids may be
In the majority of studies which have investigated the natural discontinued after the first 6 weeks [30, 40]. Prolongation of
history of GO in untreated patients, the orbitopathy improved treatment after 12 weeks in patients who are responsive to
in about a half of the patients, remained stable in about 35%, corticosteroids should be related to disease severity and its
and worsened in approximately 15% [37]. Since up to 15% of impact on the quality of life, providing that the cumulative
the patients with mild disease may experience progression, a dose does not exceed 8 g and consecutive day-dosing is
12 Journal of Ophthalmology

avoided. Fatalities with intravenous methylprednisolone in Thus, radiotherapy should be considered a second-line
GO have only been reported when higher than 8 g cumulative treatment, when the first course of steroids has produced only
dose was used. Severe adverse effects have occurred only in a partial response and the disease is still active. It should be
patients receiving daily and/or alternate single doses higher avoided in patients younger than 35 years of age or in patients
than 500 mg [40]. with diabetes or severe hypertension [45].
Assessment of liver morphology by sonography, liver Some patients seem to have a phase of activity which
function tests, detection of hepatitis viral markers, and lasts longer than usual. They may have a recurrence of
autoantibodies have to be performed prior to the administra- inflammatory signs of orbitopathy after withdrawal of cor-
tion of IV treatment. Patients with recent hepatitis, liver dys- ticosteroid treatment because of onset of steroid side effects
function, severe cardiovascular morbidity, or severe hyper- or intolerance. These patients can be candidates for a trial of
tension must be excluded [40]. Liver enzymes, glucose levels, treatment with methotrexate (weekly dose of 7.5 mg to 10 mg
and blood pressure should be monitored monthly during orally administered and fractionated) [46].
treatment. Assessment of adrenal function may be advisable Alternatively, patients who are nonresponsive to cor-
at the completion of the treatment with IV glucocorticoids. ticosteroids may be treated with combination therapy of
In patients who are not responsive to corticosteroids, cyclosporin A (5 mg/kg/day in 2 doses plus oral glucocorti-
other treatments may be attempted. Though the efficacy coids), azathioprine, or specific monoclonal antibody agents.
of orbital radiotherapy alone for treatment of GO remains In preliminary clinical trials, rituximab significantly reduced
controversial, its combination with glucocorticoids is effec- the inflammatory activity and severity of the ophthalmopathy
tive in early and active thyroid eye disease and has an in patients with active eye disease. However, two recent
acceptable safety profile [43]. Orbital radiotherapy (10–20 Gy randomized trials on the efficacy of rituximab in moderate to
in 10 sessions, over 2 weeks) is particularly effective in ocular severe GO reported conflicting results [47, 48]. The reasons
motility involvement and, in some cases, in dysthyroid optic for this disagreement are unclear but may be related to
neuropathy. The group of Rootman and Dolman in Van- the differences in the study designs. The rationale is also
couver [44] has recently conducted a retrospective study to strong for the study of other immunomodulatory agents
compare the risk of developing compressive optic neuropathy in GO, including those targeting receptors for IL-1, IL-6,
in 351 patients with active thyroid eye disease treated only and TNF, modulating costimulatory pathways or decreasing
with corticosteroids (144 patients) or with corticosteroids leukocyte recruitment into the orbit [49]. There are some
and orbital radiotherapy (105 patients). The main indications evidences in short series reports of the efficacy of other
for offering orbital radiotherapy to patients already being molecules such as tocilizumab, adalimumab, or etanercept
treated with corticosteroids were development of significant [50, 51]. Other promising treatments such as the production
restriction in ocular motility (88%); total cumulative dose of TSH-R antagonists, either as monoclonal TSH-R-blocking
of corticosteroids reaching unsafe levels over 8 g (17%); antibodies or as small-molecule-ligand antagonists of TSH-
intolerance to corticosteroids (8.6%); and inadequate control R, are being developed [52].
of disease activity with corticosteroids (6.5%). At an average
of 3.2 years follow-up, 17% of corticosteroids-only-treated 5.3.2. Surgical Treatment. Once the disease has become
group progressed to develop compressive optic neuropathy inactive, several rehabilitative surgical procedures for patients
while 0% of corticosteroids-plus-radiotherapy-treated group with moderate to severe ophthalmopathy may be used. Before
(𝑃 < 0.0001) did. There were no known adverse effects offering surgery, patients should show evidence of disease
secondary to orbital radiotherapy in this series. Although quiescence over a period of at least 6 months.
both groups experienced a significant reduction in periocular Available procedures include orbital decompression for
inflammation, the radiotherapy-treated group demonstrated disfiguring proptosis [53]; strabismus surgery for symp-
a significantly greater improvement in diplopia and restric- tomatic ocular motility restriction; eyelid recession for eyelid
tion in motility, supporting the idea that orbital radiotherapy retraction causing lagophthalmos, exposure keratitis, and
combined with corticosteroids has an effective and sustained disfigurement; and blepharoplasty for excessive soft tissue
response and is protective against disease progression to prominence of the eyelids [14, 39, 54]. If necessary, orbital
restrictive myopathy and compressive optic neuropathy. Cor- decompression must be first addressed because of its influ-
ticosteroids are effective at suppressing acute inflammation, ence on ocular motility and lid width followed by strabismus
but the response to corticosteroids is brief and may be poor surgery and, finally, eyelid surgery.
or incomplete. Orbital radiotherapy may not show benefit Many different techniques and approaches have been
for several days to weeks, but its effects last longer. Orbital described for orbital decompression surgery, including 1-, 2-,
radiotherapy is supposed to work through its nonspecific and 3-wall decompression with orbital fat removal depending
anti-inflammatory effects and the high radiosensitivity of on the degree of exophthalmos. Different combinations of
lymphocytes infiltrating the orbital space and, hence, by medial, inferior, and lateral wall decompression have been
reducing the secretion of proinflammatory cytokines from used as areas of bone removal. Proptosis regression after
activated lymphocytes. Moreover, orbital radiotherapy may surgery varied from 5.6 to 6.5 mm after 3-wall decompression
target orbital fibroblasts inducing terminal differentiation in and from 3.2 to 4.8 mm after 2-wall decompression [54, 55].
progenitor fibroblasts, suppressing the downstream conse- Surgically induced diplopia is the most common complica-
quences of fibroblast activation by reducing their capability tion of orbital decompression, with the highest rates of 38%–
to synthesize and secrete glycosaminoglycans [44]. 60% reported with inferomedial decompression, possibly as
Journal of Ophthalmology 13

a result of inferomedial shift of the globe after removing

the inferomedial strut. Balanced orbital decompression may
reduce the incidence of postoperative diplopia by producing
a more equivalent displacement of the medial and lateral
soft tissues into the surrounding space. New techniques such
as deep lateral wall orbital decompression [53] or modified
endoscopic medial orbital fat decompression [56] carry a
lower risk of morbidity associated to ocular motility problems (a)
while providing a significant proptosis reduction.
The goal of extraocular muscle surgery in patients with
GO is to restore binocular single vision in the primary posi-
tion at distance and near (reading position). Residual double
vision may persist in peripheral positions of gaze. The basic
concept of most operations is to recess the fibrotic muscles
in order to correct ocular ductions. Muscle resections should
(b)
be avoided since any restriction is likely to be aggravated
if a muscle is shortened. Most vertical deviations can be
corrected by single inferior rectus recessions due to high-
dose effect. Dose effects for medial rectus recessions are lower
and bilateral medial rectus muscle is often required to treat
horizontal strabismus [54].
Lid retraction of both upper and lower eyelids is probably
the most common feature of GO. Surgery is recommended
for significant upper lid retraction of >1 mm, asymmetry of (c)
palpebral apertures, or lateral (temporal) flare. Surgery for
Figure 4: Threatening-to-vision GO. (a) Initial presentation of
upper lid retraction is divided into the anterior approach a patient with threatening-to-vision GO. LE: corneal breakdown,
through an eyelid crease incision where the levator aponeuro- chemosis, conjunctival redness, eyelid swelling, swollen caruncle,
sis and Müller’s muscle are disinserted from the tarsus until retrobulbar ache at rest and with gaze, diurnal variation (inflamma-
appropriate height of the eyelid is achieved and a posterior tory score: 9/10), proptosis > 2 mm, optic neuropathy, and extraoc-
approach through the conjunctiva and Müller’s muscle. In ular muscle restriction (3/3 progression score). (b) Appearance after
most cases, the use of implants is not necessary [54]. methylprednosolone IV treatment, amniotic membrane transplant,
Lower lid lengthening is indicated in lower lid retraction. and lateral tarsorrhaphy in LE. (c) Appearance after bilateral orbital
It mainly occurs in cases in which the ligamentum capsu- decompression and levator recession surgery (Dr. Barrio-Barrio and
lopalpebrale to the lower lid retractors has not been disin- Dr. Fernandez-Hermida performed the surgical procedures).
serted when an inferior rectus recession has been performed.
In lower lid retraction repair, the conjunctiva and lower lid
retractors are detached from the edge of the tarsus through of intravenous steroids followed by decompression in those
a posterior approach and a spacer (auricular cartilage, hard patients with no response [58].
palate mucosa, expanded polyethylene microplates, auto- Depending on the severity of the exophthalmos, cases of
genous tarsus transplants, porcine acellular dermal matrix, corneal exposure keratopathy could be treated with aggres-
donor sclera, or pericardium) is placed between the retractors sive topical lubrication, moisture chamber, botulinum toxin,
and tarsus [54]. levator recession surgery, tarsorrhaphy, or even orbital
Upper and/or lower eyelid blepharoplasty is frequently decompression in very severe cases of exophthalmos which
needed as the last step in the functional and cosmetic impede lid closing. Intravenous methylprednisolone should
rehabilitation of GO patients. be administered prior surgery if the disease is active (Figure
4).
5.4. Measures for Patients with Sight-Threatening Oph-
thalmopathy. Patients with sight-threatening ophthalmopa- 6. Conclusions
thy due to dysthyroid optic neuropathy must be treated
urgently. High-dose intravenous glucocorticoids are the rec- GO is a complex inflammatory disorder that is better man-
ommended first-line treatment for DON (3 × 500 mg–1 g on aged by a multidisciplinary team. Early detection of sight-
consecutive days within one week; if necessary, repeated the threatening ophthalmopathy and identification of risk factors
following week). If the response is insufficient after 1-2 weeks, for severe outcomes are critical. An appropriate assessment of
or the dose/duration of steroid treatment required induces both severity and activity of the disease warrants an adequate
significant side effects, orbital decompression (deep medial treatment. The VISA and EUGOGO grading systems have
orbital wall decompression including posterior ethmoidal been demonstrated as invaluable tools in the assessment
cells near the orbital apex) should be carried out promptly and management of GO patients. A simplified “GO activity
[54, 57]. Immediate surgical decompression as first-line assessment checklist” would help the physicians involved in
therapy has not resulted in a better outcome than the use the management of these patients in routine clinical practice.
14 Journal of Ophthalmology

Intravenous glucocorticoids remain the treatment of choice [10] M. Pérez-López, M. Sales-Sanz, G. Rebolleda et al., “Retrobul-
for active moderate to severe disease. Orbital radiotherapy bar ocular blood flow changes after orbital decompression in
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line treatment which is particularly effective when ocular Investigative Ophthalmology & Visual Science, vol. 52, no. 8, pp.
motility is involved. Immediate surgical decompression may 5612–5617, 2011.
be needed in cases of dysthyroid optic neuropathy. Several [11] T. J. Smith, L. Koumas, A. Gagnon et al., “Orbital fibroblast het-
rehabilitative surgical procedures may be necessary once the erogeneity may determine the clinical presentation of thyroid-
disease has become inactive. New treatment modalities such associated ophthalmopathy,” Journal of Clinical Endocrinology
as specific monoclonal antibodies, TSH-R antagonists, and and Metabolism, vol. 87, no. 1, pp. 385–392, 2002.
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Conflict of Interests
[13] A. P. Weetman, “Graves’ disease,” The New England Journal of
The authors declare that they have no conflict of interests. Medicine, vol. 343, no. 17, pp. 1236–1248, 2000.
[14] K. Eichhorn, A. R. Harrison, E. D. Bothun, L. K. McLoon, and
Authors’ Contribution M. S. Lee, “Ocular treatment of thyroid eye disease,” Expert
Review of Ophthalmology, vol. 5, no. 3, pp. 313–325, 2010.
Jesús Barrio-Barrio researched and cowrote the paper. [15] C. M. Bingham, M. A. Harris, T. Realini, J. Nguyen, J. P. Hogg,
Alfonso L. Sabater, coauthor, researched and cowrote the and J. A. Sivak-Callcott, “Calculated computed tomography
paper. Elvira Bonet-Farriol, ophthalmologist, undertook volumes of lacrimal glands and comparison to clinical findings
overall review. Álvaro Velázquez-Villoria, ophthalmologist, in patients with thyroid eye disease,” Ophthalmic Plastic &
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aspects of the paper. and Y. Inoue, “Cytokine profiles in eye muscle tissue and orbital
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