Eur Radiol

DOI 10.1007/s00330-014-3103-3

HEAD AND NECK

Magnetic resonance imaging with diffusion-weighted imaging

in the evaluation of thyroid-associated orbitopathy: getting
below the tip of the iceberg
Letterio Salvatore Politi & Claudia Godi & Gabriella Cammarata & Alessandro Ambrosi &
Antonella Iadanza & Roberto Lanzi & Andrea Falini & Stefania Bianchi Marzoli

Received: 8 October 2013 / Revised: 21 December 2013 / Accepted: 21 January 2014

# European Society of Radiology 2014

Abstract with muscle dysfunction and CAS. EOMs of active

Objectives To compare extraocular muscles (EOMs) T2, patients showed higher T2 and T1Gad SIRs than those
post-contrast T1 (T1Gad) signal intensity ratios (SIRs) with inactive disease. The T2 SIR and n-ADC of nor-
and normalized-apparent diffusion coefficient (n-ADC) mally functioning TAO EOMs were higher than those of
values in patients with thyroid-associated orbitopathy healthy controls. SIRs decreased in clinically improved
(TAO) at different phases of activity and severity and and clinically stable EOMs after therapy.
correlate MRI modifications to clinical evolution during Conclusions T2 SIR, T1Gad SIR and n-ADC are objective
follow-up. measures of activity and severity of EOMs in TAO patients.
Methods A total of 74 TAO patients were classified as MRI shows clinically silent muscle involvement and
active or inactive on the basis of the clinical activity modifications.
score (CAS). Severity of EOM impairment was evalu- Key Points
ated by assigning a functional score to each rectus. T2, • MRI and DWI measures are objective, quantitative param-
T1Gad SIRs and n-ADC of EOMs were compared in eters of TAO activity and severity
patients with active inflammation, those with inactive • MRI and DWI measures significantly correlate with clinical
disease and 26 healthy controls, and correlated with scores in TAO patients
clinical scores. MRI parameter variation was correlated • MRI and DWI can identify clinically silent inflammation of
with clinical modifications during follow-up. deep orbital structures
Results All MRI parameters in TAO EOMs were signif- • MRI and DWI can depict subclinical modifications during
icantly higher than in healthy subjects and correlated follow-up
• MRI and DWI may aid clinicians in choosing the most
appropriate treatment
Electronic supplementary material The online version of this article
(doi:10.1007/s00330-014-3103-3) contains supplementary material,
which is available to authorized users. Keywords Thyroid-associated ophthalmopathy . Orbit .
L. S. Politi (*) : C. Godi : A. Iadanza : A. Falini ADC . Extraocular muscle inflammation
Neuroradiology Department and Neuroradiology Research Unit, San
Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
e-mail: politi.letterio@hsr.it
Abbreviations and acronyms
L. S. Politi : C. Godi : A. Ambrosi : A. Falini ADC apparent diffusion coefficient
Università Vita-Salute San Raffaele, Milan, Italy
CAS clinical activity score
G. Cammarata : S. Bianchi Marzoli CT computed tomography
Neurophthalmology Service, Ophthalmology Department, IRCCS DWI diffusion-weighted imaging
Istituto Auxologico Italiano, Milan, Italy EOM extraocular muscle
R. Lanzi
MRI magnetic resonance imaging
Endocrinology Unit, Department of Internal Medicine, San Raffaele n-ADC normalized apparent diffusion coefficient
Scientific Institute, Milan, Italy ROI region of interest

SIR signal–intensity ratio
TAO thyroid-associated orbitopathy
T1Gad post-contrast T1
Introduction
Thyroid-associated orbitopathy (TAO) is the most common
inflammatory disease of the orbit occurring in a very large
proportion of patients (25–80 %) affected by autoimmune
thyroidopathy [1–6].
Prompt recognition of the “active” inflammatory disease
phase is critical for beginning immediate treatment in order to
prevent extraocular muscle (EOM) fibrosis and compressive
optic neuropathy that may require surgery [7–9]. So far, the
universally accepted criterion to define the “active” phase of
the disease is the clinical activity score (CAS) reported by
Mourits et al. [10], which is based on the clinical evaluation of
the anterior visible part of the orbit. However, the acute
inflammatory involvement of deep orbital structures, such as
the EOMs, may escape clinical assessment if diplopia or
motility impairment is not present. Moreover, diplopia and
strabismus, occurring in more than 70 % of subjects and
representing a major complaint for patients and a serious
concern for ophthalmologists, can be produced either by
inflammatory changes in the “active” disease or by fatty
degeneration and fibrosis in the “inactive” phase. Therefore,
a precise assessment of EOM inflammation is required, be-
cause acute EOM involvement could benefit from early anti-
inflammatory treatment, whereas diplopia due to “chronic”
EOM fibrosis requires rehabilitative surgical correction. Since
each EOM can be involved at different phases of the disease, a
precise assessment of individual EOM disease stage (inflam-
matory versus fibrotic) may not be differentiated with CAS
alone.
Overall, the clinical evaluation of inflammatory activity is
limited to the visible anterior part of the orbit, and more
information on inflammatory involvement of deep orbital
structures might be obtained by imaging investigation.
Given the high contrast resolution for soft tissues, magnetic
resonance imaging (MRI) may be the ideal technique for
studying EOMs and deep structures in the orbit. Quantitative
and semi-quantitative MRI studies have demonstrated that
EOM involvement in patients with clinically active TAO
shows increased T2 relaxation times, owing to the presence
of oedema [11–13]. Conversely, there is no agreement on T1
signal intensity after gadolinium-based contrast administra-
tion, and contradictory results have been reported [14–16].
MRI with diffusion-weighted imaging (DWI) has recently
been proven to be useful in the non-invasive diagnosis of
orbital lymphoma, pseudotumour and other orbital mass-like
lesions [17–20]. Yet, a systematic evaluation of the apparent
Eur Radiol
diffusion coefficient (ADC) modifications in EOMs of TAO
patients has never been performed.
The purposes of this study were (i) to assess whether T2,
T1 with gadolinium (T1Gad) signal intensity ratios (SIRs) and
normalized ADC values (n-ADC) of the EOMs are signifi-
cantly different in patients with active inflammatory TAO, in
those with inactive disease and in healthy controls; (ii) to
determine whether these MRI parameters correlate with
CAS and the severity of ocular movement impairment; (iii)
to correlate SIRs and n-ADC variations with clinical disease
changes during follow-up.
Materials and methods
Population
This study was conducted upon the local ethics com-
mittee’s approval. Written informed consent was obtain-
ed from each participant. Seventy-four consecutive pa-
tients with the clinical diagnosis of TAO (25 men, 49
women; mean age 52±13 years) during different phases
of disease were prospectively enrolled to receive a com-
bined ophthalmological and MRI evaluation of the orbit
(mean interval 7.6 days). A clinical and radiological
follow-up was available for 34 out of 74 patients with
a mean interval of 7.7±3.1 (SD)months. Twenty-six out
of these 34 patients received intravenous corticosteroids
as anti-inflammatory treatment following clinical indica-
tions, with the same treatment protocol.
Twenty-six healthy controls (8 men, 18 women; mean age
44±17 years) were enrolled and underwent the same clinical
and MRI protocol. Healthy subjects showed no significant
difference in gender distribution or in age compared to the
TAO patient group.
Overall, a total of 134 orbital MRI studies were performed.
Clinical evaluation
All subjects were enrolled upon informed consent collection
after evaluation by two trained neurophthalmologists (S.B.M.
and G.C., with 24 and 12 years of clinical experience,
respectively).
Clinical activity was determined for each subject according
to CAS, and TAO was considered active when CAS was ≥3
[10]. In each patient the severity of EOM dysfunction was
estimated by evaluating duction for each of the four rectus
muscles in both eyes. A functional score ranging from 1 to 4
(1=normal, 2=mild, 3=moderate, 4=severe) was assigned to
each muscle on the basis of the degree of duction limitation of
the ipsilateral antagonist muscle.
Eur Radiol
MRI technique
All the 134 MRI studies were performed on a 1.5-T system
(Achieva, Philips Medical Systems, the Netherlands)
equipped with 66 mT/m gradients using an 8-channel head
coil permitting parallel imaging acquisition. The imaging
protocol included the following: (1) axial and coronal T2-
weighted turbo spin-echo (TSE) spectral pre-saturation with
inversion recovery (SPIR) sequences (for coronal images:
repetition time ms/echo time ms=3,000/120, turbo factor
[TF]=17, voxel size mm [VS]=0.7×0.8×3, number of sam-
ple acquisition [NA]=6, acquisition matrix [AM]=204×156;
for axial images: 3,000/120, TF=17, VS=0.7×0.8×3, NSA=
6, AM=256×204); (2)axial and coronal T1-weighted spin-
echo (SE) sequences (coronal: 550/15, VS =0.9× 1.1×3,
NSA=3, AM=224×179; axial: 416/15, VS=0.7×0.8×3,
NSA=3, AM=256×204).
After intravenous administration of 0.2 ml/kg of
gadobenate dimeglumine 0.5 M (Multihance®, Bracco, Italy),
axial and coronal T1-weighted SE SPIR were acquired (550/
15, VS=0.9×1.1×3, NSA=2, AM=200×160). All the im-
ages had a 3-mm slice thickness, a 0.3-mm slice gap and a
180×180-mm field of view (FOV) that included all the orbital
structures, lids and optic chiasm. In 112 out of 135 examina-
tions, a post-contrast axial 3D T1-weighted fast field echo
SPIR sequence (39/4.6, flip Angle=30, FOV=180×180×49,
thickness=0.7 mm, AM=256×256, NSA=1) was also ob-
tained, and multiple plane reconstructions were subsequently
performed.
All examinations also included axial and coronal single-
shot echo planar DWI sequences with b values of 0 and 700 s/
mm2 (axial: 3,863/46, SENSE-factor=3.0, thickness=3 mm,
AM=96×79, FOV=200×200, NSA=10; coronal: 4453/46,
SENSE-factor=3.8, AM=96×78, thickness=3 mm, FOV=
200×200, NSA=8), obtained before contrast administration.
Diffusion gradients were applied on three orthogonal direc-
tions and trace images were obtained using the manufacturer’s
software. ADC maps were calculated using no masks.
In 28/134 cases (12 healthy controls, 16 patients)
DWI results were not of diagnostic quality and were
excluded from further analyses; contrast agent adminis-
tration was avoided owing to high individual allergic
risk in 17/134 examinations.
Identification of regions of interest and data processing
Regions of interest (ROIs) were positioned on all subjects’
recti muscles by a single operator (L.S.P., with 13 years of
experience in neuroradiology) blinded to diagnosis. A manual
segmentation of the entire muscle section in the coronal slice
with the most prominent signal alteration was performed on
T2 SPIR and SE T1-weighted post-contrast images, and then
signal intensities were measured. The ROIs were transposed
on the ADC maps using the manufacturer’s software, and
corresponding ADC values from recti muscles were obtained.
The values were then normalized to the signal intensity of
each patient’s anterior right thalamus, resulting in SIRs and n-
ADC. Distortion artefacts were carefully excluded from ROI
delimitation. T2 SIRs, T1Gad SIRs and n-ADC were then
compared with clinical scores. A total of 2,856 ROIs were
measured.
Statistical analyses
Statistical analyses were performed using SPSS 18.0.
Since T2 and T1Gad SIRs turned out to be non-
normally distributed (Kolmogorov–Smirnov significant,
p<0.001), the nonparametric Mann–Whitney test with
Bonferroni–Holm correction for multiple comparisons was
applied to compare mean group values. Fisher’s exact test
was used to rule out differences in gender distribution
between TAO patients and the healthy group. Paired-
group analysis was performed through Wilcoxon signed
ranks test. Spearman rank correlation coefficients between
MRI and clinical values were calculated. P values less
than 0.05 were considered significant.
Results
Baseline evaluation
Clinical findings
Healthy subjects All healthy subjects had normal thyroid
hormone levels, were negative for anti-thyroid antibodies
and had a CAS of 0. None of them showed EOM dysfunction.
TAO patients Of the 74 clinically diagnosed TAO patients, 16/
74 had normal thyroid function, 20/74 were undergoing med-
ical treatment for hypofunctioning thyroid and 38/74 were
receiving methimazole for Basedow disease.
At baseline, 55.4 % of patients (41/74) had clinically active
disease and 44.6 % of patients (33/74) had inactive disease
according to CAS.
In TAO patients the majority of EOMs (394/592, 66.6 %)
showed clinically normal function. Among 198/592 clinically
abnormal muscles, 19.8 % (117/592) showed mild duction
limitation, 6.8 % (40/592) showed moderate and 6.9 % (41/
592) showed severe. The inferior and medial recti of both eyes
were the most frequently involved muscles (impairment of the
right inferior rectus in 37/198, 18.7 %; left inferior rectus in
43/198, 21.7 %; right medial rectus in 33/198, 16.7 %; left
medial rectus in 42/198, 21.2 %).

MRI findings
MRI parameters in healthy subjects and in TAO
patients Mean T2 SIRs, T1Gad SIRs and mean n-ADC
from EOMs of healthy controls were respectively 57.25
±2.26, 148.28±4.56 and 176.52±6.8 (±CI, confidence
interval). At baseline examination, mean T2 SIRs,
T1Gad SIRs and mean n-ADC in EOMs of TAO pa-
tients were 82.95±2.72, 165.37±3.82 and 195.74±2.50,
respectively. Statistically significant differences in T2
SIRs, T1Gad SIRs and in n-ADC were observed be-
tween the TAO and healthy groups (p<0.001; Table 1,
Suppl. Fig. 1).
Mean T2 SIR and T1Gad SIR were significantly
increased in patients with active TAO versus those with
inactive disease (p=0.004 and p=0.003, respectively).
Conversely, no significant differences in n-ADC were
observed between the two groups (p>0.05). Mean n-
ADC and T2 SIR in patients with inactive TAO were,
however, higher than those in healthy controls (p =
0.003; Table 1, Figs. 1 and 2, Suppl. Fig. 2).
MRI parameters in impaired muscles Mean T2 SIR and
T1Gad SIR were significantly higher in TAO EOMs with
clinical dysfunction compared to EOMs without clinical dys-
function (p<0.01). In TAO EOMs with normal clinical func-
tion, mean T2 SIR and n-ADC were significantly higher
(p<0.01) than those in healthy control muscles (Table 2). No
significant differences (p>0.05) in mean T2 SIR, T1Gad SIR
or n-ADC were observed when comparing TAO EOM groups
with different scores of dysfunction, apart from the values of
T1Gad SIR between mild and severe muscle dysfunction
groups (p<0.05, Fig. 3a–c).
Correlation of MRI parameters and clinical scores In TAO
patients, T2 SIRs, T1Gad SIRs and n-ADC significantly
correlated with CAS and muscle dysfunction score
(p<0.001, Spearman rank correlation); the highest cor-
relation coefficient was found between T2 SIR and
clinical scores (muscle dysfunction severity ρ, 0.44;
CAS ρ, 0.37; Fig. 3d–f).
Table 1 Mean T2 SIR, T1Gad SIR and n-ADC in healthy controls and in TAO patients (considered altogether or divided into those with inactive/active
disease). Notice the progressive increase of mean SIRs and n-ADC from healthy controls to active TAO patients
Mean T2 SIR (± CI)
Healthy controls 57.25±2.26
Inactive (CAS<3) TAO 78.91±4.06
Active (CAS≥3) TAO 86.07±3.63
TAO patients (inactive+active) 82.95±2.72
CI confidence interval
Eur Radiol
Follow-up evaluation
Clinical findings at follow-up
Thirty-four out of the 74 TAO patients (46 %) underwent a
follow-up evaluation after a mean interval of 7.7±3.1 (SD)
months. During this period, 26 out of 34 (76 %) received anti-
inflammatory treatment following clinical indications (intra-
venous steroid in 24 patients, rituximab in 1 patient, steroid
and radiotherapy in 1 patient).
Of these patients, active TAO disease (CAS≥3) was de-
fined in 24/34 (70 %) at baseline; only 35 % (12/34) of them
showed active disease at follow-up, whereas 65 % (22/34) had
inactive disease (CAS<3). Overall, CAS reduction over time
was shown in 19/34 (56 %), stability in 14/34 (41 %) and
increase in only 1/34 (3 %).
In these treated TAO patients, EOM function remained
stable over time in 217/272 (80 %) muscles; it improved in
41/272 (15 %) and worsened in 14/272 (5 %).
MRI findings at the follow-up
MRI parameters in TAO patients with reduced or stable CA-
S A significant decrease in mean T2 SIR, T1Gad SIR and n-
ADC was observed in TAO patients who experienced a CAS
reduction over time (p<0.001, p=0.02, p=0.002 respectively;
Suppl. Fig. 3a–c, Table 3). A reduction in mean T2 SIR,
T1Gad SIR and n-ADC was also noticed in TAO patients
with stable CAS (p=0.05, p=0.004, p<0.001; Table 3, Suppl.
Fig. 3g–i).
MRI parameters and EOM dysfunction modification A sig-
nificant decrease in mean T2 SIR, T1Gad SIR and n-ADC
was observed in those EOMs that showed partial or complete
functional recovery (p<0.001, p=0.004 and p=0.025 respec-
tively; Table 4, Suppl. Fig. 3d–f) and in EOMs with stable
motility dysfunction over time (p = 0.001, p = 0.008 and
p<0.001; Suppl Fig. 3j–l).
No significant T2 SIR, T1Gad SIR or n-ADC differences
between baseline and follow-up were observed in 14 TAO
Mean n-ADC (± CI) Mean T1Gad SIR (± CI)
176.52±6.82 148.28±4.56
192.58±3.32 154.27±5.34
198.12±3.58 172.92±5.13
195.74±2.5 165.37±3.82
Eur Radiol
Fig. 1 Box plots comparing T2 SIR (a), T1Gad SIR (b) and n-ADC (c)
values of healthy controls’ EOMs with those of TAO patients with
inactive (CAS<3) or active (CAS≥3) disease based on CAS. EOMs of
patients affected by clinically active TAO showed significantly higher T2
EOMs with worsened clinical dysfunction (p=0.87, p=0.18
and p=0.59, respectively).
Clinical applications
At baseline examination, MRI showed clearly detectable
EOMs hyperintensity on T2 and T1Gad sequences in 16
patients who presented CAS<3. The follow-up evaluation
was available in 7 of these 16 patients. Four of them who
had not been treated according to clinical indications were
stable or worsened at clinical follow-up; on the other hand, the
three who had received steroid treatment according to MRI
results had a clinical improvement at follow-up.
Fig. 2 MRI features of a representative healthy control (a, d, g), clini-
cally inactive TAO patient (b, e, h) and clinically active TAO patient (c, f,
i) with coronal turbo spin echo T2 SPIR images (a, b, c), spin echo post-
gadolinium T1 SPIR images (T1Gad, d, e, f) and ADC maps from single-
shot echo planar (SSh-EPI) diffusion-weighted imaging (obtained with
SIR, T1Gad SIR and n-ADC than those of healthy controls. EOMs T2
SIR and T1Gad SIR, but not n-ADC, were significantly increased in
clinically active TAO patients compared to inactive TAO patients (Mann–
Whitney test, **p<0.01, n.s. p>0.05)
Here we report two examples of the potential usefulness of
MRI studies in the clinical management of TAO patients.
A 41-year-old woman with the clinical diagnosis of inac-
tive TAO (CAS=0) had moderate impairment of the left
medial rectus (score=3). Despite baseline T2 SPIR and T1
post-contrast SPIR images showed clearly detectable
hyperintensity of the clinically impaired muscle, suggesting
active inflammation (Fig. 4a, b), based on CAS, the patient
received no anti-inflammatory treatment. At the 6-month
follow-up, she experienced clinical worsening (CAS=2) with
the onset of severe dysfunction to the left inferior muscle
(score=4), which in fact was accompanied by easily recog-
nizable T2 hyperintensity and intense contrast enhancement
on MR images (Fig. 4c, d). After steroid bolus administration,
b=0–700, g, h, i). The patient with active TAO (right column) had more
prominent T2 SPIR and T1Gad hyperintensity of EOMs (medial, superior
and inferior recti muscles) than the patient with inactive TAO (middle
column), whereas in ADC maps no differences could be appreciated
between the two
 Eur Radiol

Table 2 Mean T2 SIR, T1Gad SIR and n-ADC in healthy controls’ controls to TAO EOMs with severe dysfunction, and mean T2 SIR and n-
EOMs and in TAO patients’ EOMs with different severity of motility ADC difference between TAO EOMs with normal function and healthy
dysfunction. Notice the increasing mean SIRs and n-ADC from healthy controls

Healthy controls TAO EOMs TAO EOMs TAO EOMs TAO EOMs
Normal function Mild dysfunction Moderate dysfunction Severe dysfunction

Mean T2 SIR (± CI) 57.25±2.26 74.52±2.71 98.70±6.73 96.55±12.16 103.17±12.49

Mean n-ADC (± CI) 176.52±6.8 195.52±3.04 197.21±5.50 191.63±11.03 197.55±9.40
Mean T1 Gad SIR (± CI) 148.28±4.56 156.08±4.23 178.67±8.05 182.68±16.86 204.75±17.32

CI confidence interval

both CAS and EOM dysfunction improved. This was a case of
clinically misdiagnosed active TAO, confirmed by the clinical
evolution, which could have been correctly classified as active
disease using MRI findings.
Conversely, a 49-year-old woman had inactive TAO
(CAS=1), with severe dysfunction of medial rectus in both
eyes (score=4) and mild functional impairment of the remain-
ing EOMs (score=2). These were enlarged and clearly hyper-
intense on baseline T2 SPIR and post-contrast T1 SPIR im-
ages (Fig. 5a, b), suggesting active disease. As a result of the
MR findings, the patient was treated with i.v. steroid admin-
istration despite inactive CAS. At follow-up, muscle dysfunc-
tion had improved in all EOMs bilaterally and MRI showed
reduced T2 SPIR and post-contrast T1 SPIR signal intensities
(Fig. 5c, d). This was another example of a clinically
misdiagnosed active disease, correctly identified by MRI
and then treated, thus preventing the clinical worsening of
the disease.
Discussion
TAO is the most common disease of the orbit, with 16.1–27.5
new cases per 100,000 every year [6, 21]. Patients affected by
TAO often experience highly incapacitating symptoms such
as severe ocular pain and diplopia. The natural history of TAO

Fig. 3 Box plots showing (upper row) mean T2 SIR (a), T1Gad SIR (b)
and n-ADC (c) of EOMs with different muscle dysfunction [from 1
(normal) to 4 (severe dysfunction); H.C. healthy controls]. TAO EOMs
without clinical dysfunction had significantly higher T2 SIR and n-ADC
than healthy controls’ EOMs, although they were clinically indistinguish-
able (Mann–Whitney test with Bonferroni–Holm correction for multiple
comparison, *p<0.05, **p<0.01, ns p>0.05); (lower row) mean T2 SIR
(d), T1Gad SIR (e) and n-ADC (f) of patients with different CAS. All
MRI parameters (T2 SIR, T1Gad SIR and n-ADC) showed significant
correlation with clinical scores (Spearman correlation, ***p<0.001)
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Table 3 Baseline and follow-up mean T2 SIR, T1Gad SIR and n-ADC in patients with reduced or stable CAS over time. Notice the significant decrease
of mean SIRs and n-ADC occurring not only in patients with CAS improvement, but also in patients with stable CAS

CAS reduction Stable CAS

Baseline Follow-Up p Baseline Follow-Up p

Mean T2 SIR (± CI) 82.43±5.38 71.26±4.38 <0.001 88.15±6.58 78.48±7.55 0.05

Mean n-ADC (± CI) 193.54±4.52 187.69±5.37 0.002 199.88±6.91 186.82±6.41 <0.001
Mean T1 Gad SIR (± CI) 172.13±7.96 164.47±5.80 0.02 175.71±7.46 160.11±9.82 0.004

CI confidence interval

is that of a progressive disease, but involvement of each EOM
can occur in different phases and therefore it may be difficult
to identify which EOM is in the inflammatory phase by
clinical assessment alone. Improving the diagnosis of inflam-
matory activity in TAO patients is fundamental to turning off
inflammation with early immunosuppressive treatment [22]
and thus preventing EOM fibrosis and compressive optic
neuropathy, which may require surgery, and avoiding unnec-
essary rehabilitative surgery when inflammation is still present
[10].
Since clinical evaluation of inflammatory activity is limited
to the visible anterior part of the orbit, MRI depiction of deep
orbital structure inflammation may help clinicians to direct
TAO patients toward the most appropriate treatment.
Computed tomography (CT) of the orbit can provide infor-
mation on fat and muscle enlargement [3], which can be useful
for diagnosing TAO. Although the increase in EOM dimen-
sions as measured by CT are predictive of the development of
compressive optic neuropathy [23], EOM dimension mea-
surements do not correlate with the inflammatory activity of
the disease, because muscle enlargement can also be found in
chronic stages [16, 22, 24]. Further, correct quantification of
EOM volume or diameter can be challenging. As a matter of
fact, a normal range for EOM dimensions has not been re-
ported, and dimensions may vary with orbit size and patient
sex and age. Moreover, the cross-sectional diameters of EOMs
are influenced by duction and thus the measure may be
influenced by the position of the eye during the examination.
In addition, different diameters can be obtained according to
MRI sequences and plane of acquisition used [25].
Conversely, MRI signal alterations of EOMs may correlate
with inflammatory activity in TAO patients [5, 11, 22]. In
agreement with previous studies [11–13, 22], we have dem-
onstrated that EOM T2 SIRs obtained from SPIR sequences
are significantly higher in TAO patients with active disease
than in patients in the chronic phase, probably owing to
intramuscular inflammatory oedema. Furthermore, in this
study T2 SIR correlated with CAS and with muscle dysfunc-
tion, thus suggesting that the increased T2 signal intensity
might predict the severity of inflammatory status and motility
impairment. Importantly, and not previously shown, the T2
SIRs of normally functioning TAO patient EOMs were sig-
nificantly higher than those of healthy control EOMs (p=
0.01), although they were clinically undistinguishable. Simi-
larly, n-ADC was significantly higher in normally functioning
TAO EOMs in comparison to those of healthy subjects. These
findings suggest that MRI might be more sensitive than clin-
ical examinations in identifying muscular involvement in
TAO and that both T2 and ADC could be biomarkers of early
asymptomatic inflammatory involvement of EOMs.
Differently from T2 signal intensities, little information is
available on T1 signal intensity changes after gadolinium-
based contrast administration in TAO patients, and contradic-
tory results have been reported by different authors [14–16,
22]. Interestingly, the present study shows that T1Gad SIRs
were consistent with other semi-quantitative findings of

Table 4 Baseline and follow-up mean T2 SIR, T1Gad SIR and n-ADC in EOMs with clinical functional improvement, but also in EOMs with
TAO EOMs with improved or stable function over time. Notice the clinically stable dysfunction
significant decrease of mean SIRs and n-ADC occurring not only in

Improved function EOMs Stable function EOMs

Baseline Follow-up p Baseline Follow-up p

Mean T2 SIR (± CI) 95.69±11.65 72.34±11.41 <0.001 79.34±4.43 70.68±4.19 0.001

Mean n-ADC (± CI) 195.41±9.48 184.55±12.73 0.025 194.68±4.50 185.77±4.26 <0.001
Mean T1 Gad SIR (± CI) 190.93±12.34 169.06±9.97 0.004 166.86±6.30 157.44±6.03 0.008

CI confidence interval

Fig. 4 Representative case of a 41-year-old woman with inactive TAO
(CAS=0), moderate impairment of left medial rectus (dysfunction score=
3) and no impairment of the remaining EOMs (dysfunction score=1).
Baseline coronal TSE T2 SPIR (a) and post-contrast SE T1 SPIR (b)
images showed hyperintensity of the clinically involved muscle. Ignoring
increased enhancement in TAO EOMs compared to normal
subjects [16], suggesting the presence of permeability changes
within inflamed muscles. Moreover, mean T1Gad SIR was
significantly higher in clinically active TAO patients than in
inactive ones, and functionally impaired EOMs had signifi-
cantly higher T1 Gad SIRs than those without clinical dys-
function. However, mean T1Gad SIR of inactive TAO patient
EOMs was not significantly different from that of healthy
subjects. Therefore, different to T2 SIR which is increased
in EOMs of both “inactive” and “active” TAO patients when
compared to healthy subjects, even at a significantly different
level, depiction of an increased T1Gad signal may immedi-
ately identify clinically active EOMs [12].
Although the driving hypothesis that active inflamed
EOMs should have shown increased n-ADC values in
Fig. 5 Another representative case of a 49-year-old woman with inactive
CAS (=1), severe dysfunction of both medial recti muscles (dysfunction
score=4) and mild impairment of the remaining muscles (dysfunction
score=2). Baseline coronal T2 SPIR (a) and post-contrast SE T1 SPIR
images (b) showed enlargement and hyperintensity of all EOMs,
Eur Radiol
MRI findings, the patient went untreated based on CAS. At follow-up
evaluation after 6 months, CAS had increased and she developed severe
impairment of the left inferior rectus muscle (dysfunction score=4) which
was depicted as hyperintensity on coronal TSE T2 SPIR (c) and post-
contrast SE T1 SPIR images (d)
opposition to fibrotic EOMs that were expected to present
decreased values, no significant differences were found in n-
ADC values between “active” versus “inactive” TAO patients,
even if TAO patient EOMs were observed to have significant-
ly higher mean n-ADC values than healthy subjects. Many
factors might influence ADC values within EOMs in TAO,
including oedema, fibrosis, infiltration of inflammatory cells
and deposition of glycosaminglycans; thus, it might be diffi-
cult to define which biological phenomenon underlies n-ADC
modifications in this clinical setting. In any case, the increase
in n-ADC in TAO patients indicates the presence of relevant
structural modifications within affected muscle fibres that can
be measured objectively and non-invasively with MRI.
At the follow-up evaluation, a significant reduction over
time in T2 SIR, T1 Gad SIR and n-ADC was observed in
suggesting a clinically misdiagnosed active disease. Despite inactive
CAS, the patient underwent i.v. steroid administration; at follow-up
evaluation, muscle dysfunction had improved bilaterally while MRI
showed normalization of T2 SPIR (c) and post-contrast T1 SPIR signal
intensities (d). CAS remained stable (=1) over time
Eur Radiol
patients with clinical improvement. This finding strengthens
the positive correlation among MRI parameters and clinical
evaluation. Further, a significant reduction in these MRI pa-
rameters was also found in patients with stable CAS and in
EOMs with stable dysfunction. These data suggest that MRI
could depict even subclinical modifications of each single
EOM during follow-up, despite stable clinical scores.
The results of the follow-up in patients with discordant
clinical and MRI results at baseline evaluation may suggest
that MRI might play an important role in the clinical manage-
ment of TAO; however, more extensive studies are required to
confirm these preliminary encouraging data.
Overall, T2 SIR, T1Gad SIR and n-ADC are objective
MRI parameters that correlate well with the CAS and muscle
dysfunction in TAO patients, and may depict for each single
EOM clinically silent involvement and modifications during
follow-up. These quantitative MRI parameters may be of
fundamental importance for treatment choices and for moni-
toring the orbital part of the disease. Furthermore, they are less
influenced by the operator than clinical scores are and should
be included in future clinical trials to objectively evaluate the
efficacy of new therapies.
Acknowledgments The scientific guarantor of this publication is
Letterio Salvatore Politi. The authors of this manuscript declare no
relationships with any companies whose products or services may be
related to the subject matter of the article. The authors state that this work
has not received any funding. One of the authors (A.A.) has significant
statistical expertise. Institutional review board approval was obtained.
Written informed consent was obtained from all subjects (patients) in this
study. Methodology: prospective, observational, performed at one
institution.
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