Thyroid Eye Disease

Yao Wang and Raymond S. Douglas

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Thyroid Dysfunction in Graves’ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Thyroid Eye Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Molecular Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Clinical Course of TED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Abstract autoimmune thyroid disease. Clinical manifes-

Thyroid eye disease (TED) can be a debilitat- tations commonly include eyelid retraction,
ing disorder that occurs in the setting of exposure keratitis, exophthalmos, and restric-
tive strabismus. Patients frequently complain
of dry eyes, photophobia, and excessive lacri-
mation. While the exact relationship between
the thyroid and orbit is not fully understood,
Y. Wang
Department of Surgery, Division of Ophthalmology, recent research has shown that orbital tissues
Cedars Sinai Medical Center, Los Angeles, CA, USA are infiltrated by immunocompetent cells
Beverly Hills Ophthalmic Plastic and Reconstructive which subsequently causes orbital extraocular
Surgery, Beverly Hills, CA, USA muscle and connective tissue expansion.
e-mail: wangx699@umn.edu Numerous cell types and molecular mediators
R. S. Douglas (*) have been found to be involved in its patho-
Department of Surgery, Division of Ophthalmology, genesis, and early trials targeting various
Cedars Sinai Medical Center, Los Angeles, CA, USA
immunomodulators as disease-modifying ther-
Beverly Hills Ophthalmic Plastic and Reconstructive apy have shown promising results.
Surgery, Beverly Hills, CA, USA
State Key Laboratory of Ophthalmology, Zhongshan
Ophthalmic Center, Sun Yat-sen University, Guangzhou,
China

© Springer Nature Switzerland AG 2020 1

D. M. Albert et al. (eds.), Albert and Jakobiec's Principles and Practice of Ophthalmology,
https://doi.org/10.1007/978-3-319-90495-5_61-1
2 Y. Wang and R. S. Douglas

Keywords chapter, we describe the thyroid dysfunction in

GD, and the pathogenesis, diagnosis, and clinical
Thyroid eye disease · Graves’
course of TED.
ophthalmopathy · Graves’ disease

Thyroid Dysfunction in Graves’

Introduction
Disease
Graves’ disease (GD) is an autoimmune condition
Thyroid hormone overproduction in GD results
characterized by dysregulated thyroid gland activ-
from the imbalanced actions of activating (most
ity. In North America, its incidence of GD is
common) and blocking antibodies directed
~0.4% [1]. An age-adjusted incidence rate is 16
against the thyrotropin receptor (TSHR) [28–30].
cases and 2.9 cases per 100,000 population per
This G-protein-coupled receptor is displayed on
year, respectively, for women and men [1]. Esti-
the surface of thyroid epithelial cells where it
mates of the female-to-male ratio have ranged
ordinarily binds to and becomes activated by
from 2.5:1 to 7:1, with a ratio of 4:1 cited in
TSH from the anterior pituitary. In GD, anti-
most studies [2–7]. Individuals with GD are also
TSHR antibodies are detectable in nearly all
more likely than the general population to develop
patients with hyperthyroidism [28, 31, 32].
other autoimmune diseases including insulin-
Clinical presentation of hyperthyroidism might
dependent diabetes mellitus [8–11], rheumatoid
include weight loss (despite normal or increased
arthritis [12–14], pernicious anemia [15], and vit-
appetite), heat intolerance, menstrual irregulari-
iligo [16, 17].
ties, infertility, palpitations, emotional lability,
The pathogenesis of GD involves stimulatory
hyperdefecation, and tremor. Increased incidence
autoantibodies directed against thyrotropin recep-
of atrial fibrillation and accelerated bone loss are
tor (TSHR), resulting in glandular enlargement
among the consequences of elevated circulating
and overproduction of thyroid hormones [18].
thyroid hormone levels, especially in older
GD consists of both systemic and anatomically
patients. The most sensitive laboratory assess-
localized immune responses. Manifestations
ment of thyrotoxicosis remains a depressed
include hyperthyroid goiter, dermopathy, and thy-
serum TSH concentration coupled with elevated
roid eye disease (TED) [19]. While TED is typi-
thyroxine and triiodothyronine levels and
cally associated with GD, it can manifest in
increased radioactive iodine (RAI) uptake in the
primary hypothyroidism, Hashimoto thyroiditis,
thyroid [33]. The presence of high titers of anti-
or euthyroidism [19]. While the clinical course
TSHR antibodies usually confirms the diagnosis
of glandular GD is usually predictable and can
of GD.
be easily treated, TED is not. Specific and safe
With regard to therapy, RAI is a definitive
therapies are limited, in large part because of poor
treatment in the United States for most patients
insight into disease pathogenesis. Moreover, the
over 21 years. Following administration, the vol-
relationship between thyroid gland dysfunction
ume of the thyroid gland is often reduced [34].
and TED remains unclear.
The most common outcome of RAI therapy is
Clinically important TED occurs in approxi-
irreversible hypothyroidism, which develops in
mately 10–45% of patients with GD, with clinical
the majority of adequately treated patients [35,
presentations ranging from mild ocular irritation
36]. Another approach involves the surgical
to severe proptosis, strabismus, and optic nerve
removal of thyroid tissue, which, in the hands of
compression [19–21]. The proximate causes of
a skilled surgeon, can be performed safely and
TED are probably unrelated to thyrotoxicosis
effectively.
[22–27]. Rather, it is driven by an underlying
autoimmune process. The complex pathogenesis
makes the management of TED difficult. In this
Thyroid Eye Disease
Thyroid Eye Disease
Epidemiology
The prevalence of TED is more evenly distributed
among men and women than is GD [3, 37]. TED
most commonly presents during the fourth and
fifth decades of life, which suggests that as yet
unidentified acquired factors might contribute to
susceptibility (Fig. 1). In one large series, the age
range was 15–86 years, with a median of 52 years;
however, TED may occur at any age and, albeit
extremely rarely, even in neonates [20, 38–40].
The most common cause of bilateral exoph-
thalmos is TED, as it accounts for approximately
85% of cases [41]. TED also presents as unilateral
exophthalmos, accounting for 15–28% of cases
[42, 43]. Although many patients are thought to
have unilateral disease on the basis of clinical
findings, the majority of patients actually show
bilateral disease radiographically [44].
Risk Factors
Cigarette smoking has been considered the stron-
gest risk factor for developing TED [45–49]. The
odds ratio relative to controls is as high as 20.2 for
active smokers and 8.9 for former smokers,
suggesting both direct and secondary effects of
smoking [50, 51]. Patients with TED who are
smokers also have more severe eye disease [48,
52]. Additionally, the risk of developing TED is
associated with the number of cigarettes smoked
following the diagnosis of GD, rather than the
cumulative pack-years [51]. Smokers also had
less therapeutic response to orbital radiation or
corticosteroids [48]. Smoking can worsen several
other autoimmune diseases including rheumatoid
arthritis [53, 54] and Crohn’s disease [55], but the
mechanisms remain unclear. Serum cytokine
levels do not differ substantially in smokers and
nonsmokers with TED [56–59].
As previously mentioned, RAI is a common
modality used to treat hyperthyroidism in GD.
There is a transient increase of TSHR antibodies
(TRAb) and thyroid stimulating immunoglobulin
(TSI) following RAI treatment [60]. Numerous
3
studies have shown that RAI worsened TED coin-
ciding appearance of TSI [61, 62]. There is a
relative risk of 4.23 (95% CI 2.04–8.77) for devel-
oping TED following RAI compared to anti-thy-
roid medication [63]. The resultant damage from
RAI could potentiate further release of thyroid
antigens, which in turn, increases production of
antibodies toward TSH-R [64]. Concomitant cor-
ticosteroid use (oral prednisone of 0.3–0.5 mg/kg/
day with a 3-month total course) was found to be
an effective prophylaxis [62]. Later studies con-
firmed that a 6-week course of 0.2 mg/kg per day
was equally sufficient [65–67].
Molecular Pathogenesis
The pathogenesis of TED results from infiltration
of tissues by immunocompetent cells early in the
disease process and subsequent orbital volume
expansion. The infiltrate consists of predomi-
nantly CD4+ T lymphocytes exhibiting an acti-
vated memory phenotype and numerous
granulated mast cells in the extraocular muscle
(EOM) interstitial tissue, orbital fat, and connec-
tive tissue (Fig. 2) [30, 68, 69]. Interferon (IFN)-g,
tumor necrosis factor (TNF)-a, and interleukin
(IL)-1 have been detected adjacent to mononu-
clear cell infiltrates, suggesting cytokine produc-
tion by these cells [70]. Local production of both
Th1 and Th2 cytokines appears likely, and the
balance between cytokine class predominance
may change at different disease stages [71–74].
Th1 responses appear to predominate in patients
with early disease while the Th2 pattern might
become more abundant later [75].
The basis for many of the clinical symptoms
and signs of TED can be reconciled with increased
volume of EOM and orbital fatty connective tis-
sue (Fig. 3) [20, 76]. Increased orbital volume
eventually displaces the globe forward, decreases
venous drainage, restricts extraocular movement,
and can cause compressive optic neuropathy [77].
Some patients demonstrate predominant enlarge-
ment of the EOM (Fig. 4), while others exhibit
increased orbital adipose volume with little EOM
abnormality (Fig. 5) [78–80]. Intact muscle fibers
are widely separated by edematous connective
4 Y. Wang and R. S. Douglas

Fig. 1 Age distribution of

500 patients with
hyperthyroidism (a)
compared with that of 194
patients who underwent
orbital decompression for
severe orbitopathy (b).
(From Jacobson and
Gorman [140], 5:200–220.)

Fig. 2 Pathologic changes early in the course of thyroid
eye disease. In the acute phase, a lymphocytic inflamma-
tory infiltrate predominates. This may be focal and
involves the endomysial connective tissue. Lower (a) and
higher (b) magnification H & E staining. Note the dense
lymphoid infiltrate and increased intracellular volume.
(From Jakobiec FA, Font RL: Orbit. In: Spencer WH, ed.
Ophthalmic pathology. 3rd edn. Philadelphia: WB
Saunders; 1986.)

tissue in early disease [81]. The perimysial tissue Orbital Fibroblasts

contains excessive glycosaminoglycans (GAGs)
composed of hyaluronan and chondroitin sulfate
[82]. It is only late in the disease that the fibers
become damaged, in large part from extensive
fibrosis that often follows aggressive inflamma-
tion (Fig. 6). The GAGs also accumulates in fatty
connective tissue [83–85]. The fibroblast is an
important source of hyaluronan [86–89]. The
extraordinary water binding capacity of
hyaluronan attracts water and accounts, at least
in part, for the expansion of tissues.
Fibroblasts both respond to and produce numerous
molecular mediators that serve to activate and mod-
ulate the behavior of bone marrow-derived cells and
provoke their migration to sites of inflammation
(Fig. 7) [90, 91]. The unique phenotype of orbital
fibroblasts may underlie the isolated involvement of
the orbit in TED [92]. Orbital fibroblasts exhibit a
distinct morphology in vitro, display receptors and
gangliosides, and generate macromolecular compo-
nents of the extracellular matrix differently from
other fibroblasts [89, 93–96].
Thyroid Eye Disease 5

Fig. 3 Enlarged
extraocular muscles. These
are the exenterated orbital
contents from a recently
diagnosed patient. Orbital
fat has been dissected away
to demonstrate the
extraocular muscles. (From
Hufnagel et al. [84],
91:1411–1419.)

Fig. 4 Axial CT image of a

patient with enlarged
nontendinous portion of
extraocular muscles. The
equator of the globe is
anterior to the lateral orbital
rim, indicating proptosis

There are two subpopulations of orbital fibro- Fibrocytes

blasts [97]. A subset of orbital fibroblasts from the
adipose/connective tissue (~50%) express Thy-1,
a surface glycoprotein marker [98]. In contrast,
those associated with EOM uniformly display
Thy-1 [97]. Thy1-expressing orbital fibroblasts
can differentiate into myofibroblasts [93]. Thy1-
deficient orbital fibroblasts can differentiate into
adipocytes [97]. The demonstration of adipogenic
potential in Thy-1 deficient orbital fibroblasts has
substantial implications for the pathogenesis of
TED, since expansion of orbital fat is a prominent
feature of the disease.
Orbital fibroblasts appear to be derived to
fibrocytes from the bone marrow [99]. These pro-
genitor cells are from monocyte and B cell line-
ages [99]. They express hematopoietic stem cell
marker CD34, CD45, and alpha-smooth muscle
actin, collagen I and III, fibronectin, and vimentin
[100]. Fibrocytes comprise of only 0.5% of circu-
lating peripheral blood mononuclear cells. They
are more abundant in patients with GD compared
to controls [99]. They can traffic to sites of inflam-
mation and are responsible for tissue remodeling
[101]. When activated, they produce cytokines
and chemokines similar to that of activated orbital
6 Y. Wang and R. S. Douglas

Fig. 5 Occasionally, patients with thyroid eye disease Increased orbital fat volume with minimal enlargement of
(TED) exhibit exophthalmos reflecting increased orbital extraocular muscles. The equator of the proptotic left globe
fat volume. (a) Euthyroid patient with TED with 4-mm is anterior to the lateral orbital rim
proptosis of the left eye and left lower eyelid retraction. (b)

Fig. 6 Pathologic changes

late in the course of thyroid
eye disease. H & E staining
demonstrating progressive
fibrosis of extraocular
muscle occurring late in the
disease. Note that the entire
muscle has been replaced
by fibrous connective tissue
with a scattering of
mononuclear inflammatory
cells

fibroblasts [102] and can differentiate into
myofibroblasts and adipocytes [101].
Thyrotropin Receptor (TSHR)
A feature common to nearly all individuals with
GD is the presence of activating anti-TSHR anti-
bodies [103, 104]. This appears true for individ-
uals with and without clinically important TED.
When TSHR was initially cloned and character-
ized, several investigators attempted to insinuate
this receptor in the pathogenesis of TED. Several
studies have examined the relationship between
TSHR antibodies and TED [105–108]. Gerding et
al. reported that TSI levels are positively corre-
lated with clinical activity score (CAS), while
weaker but significant correlation was established
between antibody levels and proptosis [184].
In addition to its expression on the thyroid
epithelium, TSHR has been found to be present
on many different cell types throughout the body.
Further, TSHR mRNA has been found in orbital
tissues of patients with GD as well as healthy
controls. Fibroblasts from all anatomic regions
appear to express similar relatively low levels of
TSHR [109–112]. Moreover, treatment of orbital
fibroblasts with extremely high concentrations of
TSH has failed to elicit convincing and biologi-
cally meaningful responses [113]. On the other
hand, although fibrocytes from both patients
with TED and healthy controls, the fraction of
Thyroid Eye Disease
Fig. 7 Schematic of the
complex interaction
between bone marrow-
derived cells and orbital
fibroblasts. These
fibroblasts exhibit
exaggerated responses to
and production of
proinflammatory mediators.
When activated by
cytokines, they mediate
immune infiltration,
inflammation, fibrosis,
hyaluronan accumulation,
and tissue remodeling
fibrocytes expressing TSHR is increased in
patients with TED [102]. When orbital fibroblasts
expressing Thy1 were treated with TSH or M22
(stimulatory TSHR antibody) or were subjected to
adipocyte differentiating factors, there was
enhanced adipocyte differentiation [114]. To
date, the exact role of this autoantigen in TED
remains uncertain.
Cytokines
Orbital tissue remodeling in TED appear to be due
to cytokine-depending cytokine activation [115].
Evidence of numerous cytokines, including IFNγ,
TNFα, IL-1α, IL-1β, IL-4, IL-6, IL-10, and IL-2R,
have been detected in orbital fat and extraocular
muscle in patients with TED [70, 72, 116]. Fur-
ther, serum IL-6 and IL-6R was found to be ele-
vated in patients with GD and even higher in
patients with TED [57].
Tocilizumab, a recombinant humanized mono-
clonal antibody directed against the IL-6 receptor,
has been used to successfully treat patients with
rheumatologic conditions, such as rheumatoid
arthritis and giant cell arteritis [117]. Early studies
have shown improvement in TED severity and
activity in patients on tocilizumab [118–120].
7
Insulin-Like Growth Factor-I (IGF-I)
Fibroblasts from patients with GD respond to
disease-specific IgGs (GD-IgG). Rotella et al.
reported that GD-IgG from several patients with
TED could enhance collagen synthesis in normal
human dermal (arm) fibroblasts [121]. Sera and
GD-IgG from these patients induced the expres-
sion of IL-16 and in disease-derived fibroblasts
but not in those from control donors [122]. IL-16,
a CD4-specific chemoattractant cytokine, has
been implicated in a number of human autoim-
mune diseases, including rheumatoid arthritis
[123–126], inflammatory bowel disease [127,
128], and lupus erythematosus [129, 130].
RANTES is a potent chemokine with pro-
inflammatory properties. It has also been impli-
cated in autoimmunity and can be detected in the
thyroid gland of patients with GD [131–133].
The GD-IgG provoking IL-16 and RANTES
expression in fibroblasts is directed against the
insulin-like growth factor-1 receptor (IGF-IR)
[91, 122]. IGF-IR is a membrane-spanning tyro-
sine kinase protein, which can be activated by
insulin or insulin like growth factor-I (IGF-I)
[134]. A disproportionate fraction of fibroblasts
derived from patients with GD display IGF-1R
which appears to mediate the response [91]. This
same GD-IgG enhances the production of
hyaluronan by GD orbital fibroblasts [135].
8 Y. Wang and R. S. Douglas
Blocking fibroblast signaling through the mTOR/
FRAP/Akt/p70S6K pathway with rapamycin can
attenuate the induction of IL-16 and hyaluronan
production [122, 135]. Thus, strong evidence has
been generated for IGF-1R and activating anti-
bodies directed against the receptor playing
potentially important roles in the pathogenesis of
TED.
IGF-IR and TSHR may also work together in
the pathogenesis of TED. The relationship
between IGF-IR and TSHR was first described
by Tramontano et al. in 1986 [136]. Since then,
Tsui and colleagues have shown that TSHR and
IGF-IR form a protein complex that is found on
orbital fibroblasts [137]. Antibodies directed
against either IGF-IR or TSHR can immunopre-
cipitate both proteins [137]. Similarly, in orbital
fibroblasts, IGF-IR blocking antibodies can also
block TSH, TSHR-stimulating antibody, and GD-
IgGs [137]. Therefore, interruption of IGF-IR
activity seemed to be a possible therapeutic target
for TED.
Teprotumumab, a fully human, inhibitory
monoclonal antibody against IGF-IR, was
recently evaluated in both a Phase 2 and Phase 3
multicenter, placebo-controlled, double-masked
clinical trials and demonstrated efficacy in
patients with active, moderate-to-severe TED
[138, 139]. The studies enrolled patients 18–
75 years old, who exhibited signs of TED within
9 months, CAS  4 points with moderate-to-
severe disease. Patients were randomized to
receive either placebo or teprotumumab adminis-
trated intravenously once every 3 weeks for a total
of eight infusions. Pooled data of 171 patients in
the intent-to-treat analysis (84 patients receiving
teprotumumab and 87 receiving placebo) demon-
strated that a greater proportion of patients receiv-
ing teprotumumab had at least 2 mm reduction in
proptosis (65/84 [73.8%] vs. 13/87 [14.9%],
p < 0.001) at week 24. Additionally, patients
who received teprotumumab had greater reduc-
tion of proptosis than placebo ( 2.63 mm vs.
0.31 mm, p < 0.001), greater percentage of
achieving low CAS scores (0 or 1) compared to
placebo (52/84 [61.9%] vs. 19/87 [21.8%],
p < 0.001), and greater diplopia responder rate
compared to placebo (69.7% vs. 30.5%,
p < 0.001) at 24 weeks. TED quality-of-life
score also improved in a greater proportion of
patients receiving teprotumumab compared to
placebo at 24 weeks (overall 15.55 vs. 5.92,
p < 0.001).
Teprotumumab was well tolerated in both the
Phase 2 and Phase 3 trials [138, 139]. The most
common side effects were muscle spasms, nausea,
and alopecia. Mild cases of hyperglycemia were
detected in several patients with preexisting glu-
cose intolerance or diabetes and did not result in
discontinuation of teprotumumab. There were no
cases of diabetic ketoacidosis. There were no sig-
nificant abnormalities in electrolytes. A single
infusion reaction occurred in one patient in
Phase 3 trial that resulted in discontinuation of
the drug [139]. Another patient developed ele-
vated blood pressure which was treated with med-
ications prior to scheduled infusions.
Clinical Course of TED
Clinical Manifestations of TED
Patients with TED often complain of excessive
lacrimation, a gritty sensation, discomfort, and
photophobia. These symptoms might prompt
them to seek medical attention or might only be
elicited through the physician’s careful
questioning. Similarly, the physical signs of
TED might prove subtle, despite substantial dis-
comfort. The most common clinical finding is
eyelid retraction [19] and occurs commonly in
37–92% of patients and gives a characteristic star-
ing appearance (Figures 8 and 9) [140]. It may
present as an isolated finding or in association
with exophthalmos [141]. Upper eyelid retraction
may result from increased sympathomimetic tone
but may also be the consequence of eyelid fibrosis
[142–145]. Retraction of the lower lid usually
correlates with the severity of proptosis [146].
Periorbital inflammation often predominates
early in the disease course. The most characteristic
signs are eyelid erythema/edema and caruncular
and conjunctival injection/edema [67, 147]. Con-
junctival and caruncle signs usually suggest active
disease [148, 149]. Conjunctival signs include
deep temporal injection (Fig. 10). Enlarged
Thyroid Eye Disease
Fig. 8 Upper eyelid
retraction (Dalrymple’s
sign) and soft tissue
changes in thyroid eye
disease. The retraction can
be asymmetric. Patients
characteristically exhibit a
staring gaze
Fig. 9 (a) Left upper eyelid retraction. (b) Upper eyelid lag on downward gaze (von Graefe’s sign)
vessels may be visible over the insertion of the
medial and lateral rectus muscles. Fluctuating
upper or lower eyelid swelling indicates active
disease, while chronic swelling in the absence of
erythema suggests congestive ophthalmopathy.
Exposure keratitis occurs in patients with TED
for several reasons. Proptosis and eyelid dysfunc-
tion can cause inadequate eyelid closure, which in
turn causes excessive moisture loss. Loss of Bell’s
phenomenon from inferior rectus infiltration can
also exacerbate exposure. Additionally, lacrimal
gland infiltration causes diminished tear produc-
tion. A careful slit-lamp examination using rose
bengal and fluorescein stains allows identification
of exposure. Many patients benefit from artificial
tear supplementation, punctal occlusion, and
occlusive dressing at night. Rarely, severe expo-
sure keratitis can result in cornea thinning, ulcer-
ation, and even perforation (Fig. 11).
Exophthalmos occurs in 25–60% of patients
(Fig. 12) [19]. As quantified with an exo-
phthalmometer, any measurement of 21 mm or
differences greater than 2 mm between eyes sug-
gests orbital disease. Racial differences can
9
confound these measurements. Readings as high
as 23 and 25 mm, respectively, can prove normal
in black women and men. This is due to shallower
bony orbits [42, 150]. The onset of exophthalmos
is usually gradual and insidious, although in some
cases it can be stormy or “malignant” (Fig. 13).
Most patients exhibit mild to moderate proptosis
[19, 150–152]. Although sometimes markedly
asymmetric, TED usually presents as a clearly
bilateral process [42, 43, 153–155]. The usual
presentation includes evidence of both EOM and
fatty/connective tissue depot involvement,
although a predominance of one of these manifes-
tations can occur [78, 80]. Individuals younger
than 40 years of age are considerably more likely
to exhibit proptosis related to fat expansion in the
apparent absence of muscle infiltration [156]. On
the other hand, older patients, especially those in
their eighth decade or beyond, can develop severe,
isolated muscle enlargement associated with com-
pressive optic neuropathy, usually as a conse-
quence of fusiform enlargement of the EOMs
[157].
10 Y. Wang and R. S. Douglas

Fig. 10 Deep injection of

temporal conjunctival
vessels (Goldzieher’s sign)

Fig. 11 (a) Exposure keratitis manifested by a superficial epithelial defect. (b) Less commonly, chronic exposure
keratopathy resulting in visual loss from changes including corneal vascularization and scarring

Fig. 12 (a) Marked proptosis in thyroid eye disease associated with upper and lower eyelid retraction. (b) Measurement
of exophthalmos with exophthalmometer

Clinically severe TED can present as the corresponding fields of gaze. Range of motion
dysfunctional eye motility (Fig. 14). Limited eye should be documented in the six cardinal posi-
movements are usually associated with diplopia in tions. The range of fusion can be tested with the
Thyroid Eye Disease
Fig. 13 (a) Patient with characteristic findings of severe,
acute (malignant) thyroid eye disease, including soft tissue
inflammation, congestion, exophthalmos, and dysthyroid
optic neuropathy. The majority of patients present with
Fig. 14 (a) Limitation of upward gaze of the left eye caused by restrictive myopathy of the inferior rectus muscle. (b) Left
esotropia caused by a tethered (and restricted) left medial rectus muscle
red glass test or Maddox rod and prisms. Signifi-
cant changes in the exam signal evolving disease
[158]. Involvement of the inferior, medial, supe-
rior, and lateral rectus muscle is encountered in
decreasing frequency [19, 159–161]. Certainly,
patients with involvement of all muscles may be
encountered. Motility dysfunction from involve-
ment of the oblique muscles is generally over-
whelmed by those of the rectus muscles [162,
163]. It should also be noted that most patients
with TED, including those with no evidence of
ocular motility abnormalities, exhibit some
degree of EOM involvement demonstrable by
radiographic techniques [76, 164–166].
11
more subtle findings. (b) Patient with fulminant thyroid
eye disease, lid swelling, and secondary ptosis. (Courtesy
of G. H. Daniels, Massachusetts General Hospital,
Boston.)
Elevated intraocular pressure in the primary
position or on upgaze can accompany TED,
often related to either restrictive myopathy or
orbital congestion [167–169]. This results from
the pull of an inelastic inferior rectus muscle on
the eye. It can be demonstrated on attempted
upgaze [170]. Although this finding is not specific
to TED, it has been observed in a large fraction of
these patients, regardless of whether they manifest
exophthalmos or not.
The most feared complication of TED is
dysthyroid optic neuropathy, typically caused by
compression. This occurs in ~5% of individuals
with TED, and affected individuals usually do not
exhibit marked proptosis or optic nerve changes
12
Fig. 15 Optic nerve
swelling can be seen in
thyroid eye disease
under ophthalmoscopic examination [20, 171,
172]. European Group on Graves’ Orbitopathy
(EUGOGO) found that 25% of patients with
dysthyroid optic neuropathy had CAS or three or
less, suggesting that these patients may not have
significant visible inflammation [173]. Risk fac-
tors for optic neuropathy include older age,
smoking, male gender, and significant strabismus
with mild proptosis [174]. Because of its often
insidious onset and subtlety, visual loss may pro-
gress undetected or its cause may be mis-
diagnosed [175, 176]. Typically, acuity and color
perception are slightly decreased with a question-
able afferent pupillary defect and vague visual-
field defects, while the optic disk appears entirely
normal to clinical examination [177]. Less com-
monly, optic nerve edema and peripapillary hem-
orrhages occur (Fig. 15). These represent ominous
findings necessitating aggressive treatment.
Direct orbital manometry has elegantly demon-
strated an increase in orbital pressure in TED
[178]. Increased pressure results from reduced
orbital compliance and can compromise the optic
nerve [179–181]. Patients developing optic neu-
ropathy may develop late nerve atrophy and irre-
versible visual loss. Suspected optic neuropathy
necessitates careful assessment of visual acuity,
color vision, visual fields, afferent pupillary
responses, and funduscopy [182]. Arcuate or alti-
tudinal defects, paracentral scotomas, and
Y. Wang and R. S. Douglas
generalized constriction represent the most com-
mon visual field defects in TED [183].
Natural History of TED
TED typically pursues a self-limited course,
becoming quiescent within 3–5 years of its onset
[20, 184, 185]. In a landmark study, Rundle and
Wilson followed the natural history of 226
patients with TED and described orbital changes
in the three phases of disease [184, 185]. The
active inflammatory phase is associated with
orbital and periorbital signs including proptosis
and eyelid retraction. Subsequently, the static
phase heralds little clinical improvement despite
reduced inflammation. Finally, gradual improve-
ment in lid retraction and ocular motility may
occur in the chronic quiescent phase. Upper eyelid
retraction improves in a majority of patients. Ocu-
lar motility follows a more variable course, and
unless vision is threatened, patients should be
followed regularly to document stability prior to
therapeutic intervention [158, 186]. Proptosis
usually improves only slightly, even after long
periods of time, and the increased orbital content
often proves irreversible [21]. Occasional cases of
spontaneously improved proptosis have been
reported [187].
Clinical manifestations during the chronic
phase are typically stable. However, a small per-
centage of patients do experience reactivation, in
which patients reenter the active inflammatory
Thyroid Eye Disease
phase with fluctuating and often worsening clini-
cal signs and symptoms [188–191]. In a retrospec-
tive study, 5% of patients developed late
reactivation. At the time of reactivation, there
was an average of 12 years from initial TED
presentation. Further, all the patients were euthy-
roid at that time [188]. The most common wors-
ening symptom was proptosis. Recurrent active
phase lasted for mean of 14 months. Potential risk
factors for reactivation included history of
smoking during initial TED presentation, peri-
ocular surgery, fluctuating thyroid levels, preg-
nancy, and significant life stressors [191].
Clinical Classification System
Useful classification of TED has proven difficult,
a consequence of the complex and variable course
of the disease. Lack of consensus regarding its
pathogenesis and descriptors has severely ham-
pered progress in evaluating therapeutic interven-
tion. NOSPECS, developed by Werner et al. and
adopted by the American Thyroid Association
categorizes the disease based upon clinical pre-
sentation [192, 193]. This classification has been
criticized because it relies on subjective evalua-
tion, fails to take into account the severity of
manifestations, and is relatively insensitive to
subtle changes. Thus, it has been abandoned.
Other systems have been proposed, but none is
well-standardized [148, 149]. The most widely
utilized of these is the CAS system, first described
by Mourits and colleagues [148, 149]. It attempts
to identify patients with active disease who are
likely to respond to medical therapy. Each symp-
tom or sign (retrobulbar pain, eyelid erythema,
conjunctival injection, chemosis, swelling of the
caruncle, eyelid edema or fullness) is assigned
equal weight, and the score is a simple summa-
tion. Unfortunately, the CAS score is limited to
the subjectivity of both patient and practitioner. In
addition, the manner in which the score is gener-
ated fails to account for active improvement or
worsening of the disease. In practice, the charac-
terization of TED remains imperfect and based on
vague and largely subjective clinical parameters
[67, 158, 194].
13
Imaging Techniques
Computed tomography (CT) without contrast
remains the most widely utilized imaging tool in
the diagnosis of TED [195]. Enlargement of the
EOM bellies, with tendon sparing, is the classic
finding but has proven far from universal [76,
196–198]. Both direct axial and coronal cuts in
addition to small (2–3 mm) cuts through the
orbital apex are utilized for evaluation. CT is
particularly helpful in assessing the relationship
between the EOM and optic nerve at the orbital
apex and can aid in surgical planning [176, 199].
B-mode ultrasonography represents a useful
imaging technique for the diagnosis of TED
[166, 200]. Enlarged EOM can be identified but
the approach yields images confined to the ante-
rior one-third of the orbit with a standard 10 MHz
probe. Increased EOM reflectivity, a potential
marker for TED activity, can be measured by A-
mode ultrasound. This technique, however, is
extremely operator-dependent [201].
A number of small studies have explored the
potential utility of magnetic resonance imaging
(MRI) in the diagnosis of active TED [202–204].
The ability of MRI to identify the typical fusiform
rectus muscle enlargement and orbital fat expan-
sion has been established (Fig. 16) [164, 165]. Its
utility in the assessment of disease activity has
been explored by assessing water content in mus-
cles, which may correlate with active inflamma-
tion [205–208]. Strategies for enhancing its
sensitivity and specificity as an effective tool
include fat suppression, short-term inversion
recovery, and T2 relaxation time. None of these,
however, has proven consistently valuable [209,
210].
Conclusion
TED remains a challenging disease to treat, in part
due to its complex pathophysiology. Historically,
medical therapies have not been able to modify
the disease course and primarily aimed at symp-
tomatic relief only. Recently on January 21, 2020,
the US Food and Drug Administration approved
teprotumumab to treat TED. The clinical usage of
14
Fig. 16 Magnetic resonance imaging of a patient with
thyroid eye disease. (a) Parasagittal image demonstrates
enlargement of the nontendinous portion of the right
teprotumumab likely extends beyond the drug’s
use in the clinical trials and can be used as first-
line therapy in patients with clinically significant
TED.
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