Dysthyroid Optic Neuropathy
Peerooz Saeed, M.D., Ph.D., Shahzad Tavakoli Rad, M.D., Peter H. L. T. Bisschop, M.D., Ph.D.
Departments of Ophthalmology and Endocrinology, Orbital Center, Academic Medical Center, University of
Amsterdam, Amsterdam, The Netherlands
Purpose: Dysthyroid optic neuropathy (DON) is a
serious complication of Graves orbitopathy that can result
in irreversible and profound visual loss. Controversy exists
regarding the pathogenesis and management of the disease. The
authors provide an overview of the current understanding of
DON and present a therapeutic guideline.
Downloaded from http://journals.lww.com/op-rs by BhDMf5ePHKbH4TTImqenVCbF2BRbWAbdB7roytyzXgCVq9nssdZSf/+JnPBiB/7QpZMGkTL861E= on 08/18/2018
Methods: A review of the literature.
Results: The mechanism of DON appears to be multifactorial:
direct compression of the optic nerve by enlarged extraocular
muscles, stretching of the optic nerve by proptosis, orbital
pressure, vascular insufficiency, and inflammation. Some or
all of these factors may be involved in an individual patient.
There has only been one controlled trial comparing high-dose
intravenous methylprednisolone to bony orbital decompression
for DON. Both 2-wall and 3-wall decompression techniques
successfully improve visual functions of patients with DON.
There are few case reports/case series that suggest biologic
agents may improve visual function in DON.
Conclusions: DON is a serious complication of Graves
orbitopathy, the diagnosis and management of which is complex
and requires a multidisciplinary approach. There is little
evidence regarding the optimum management strategy. Based
on the current literature, the first line of treatment is intravenous
methylprednisolone, with the exact timing and indication of
bony orbital decompression still to be determined. In addition,
there may be a role for the use of biologic agents that will
require a systematic program to determine efficacy.
(Ophthal Plast Reconstr Surg 2018;34:S60–S67)
D ysthyroid optic neuropathy (DON) is a relatively uncom-
mon but a serious complication of Graves orbitopathy
(GO). It has an estimated incidence of 5% to 8.6%.1–3 Without
timely diagnosis and intervention, there is a risk of sight loss.
This makes accurate and prompt recognition and management
essential to reduce morbidity and improve prognosis.
Controversy still exists regarding the diagnostic features
of DON and recognition of DON might be delayed, especially if
the presentation is atypical. In newly presenting patients, it can
be particularly difficult to determine whether DON has devel-
oped recently and thus warrants urgent management. Alternative
causes of visual impairment can be present in patients with GO,
highlighting the fact that serious efforts should be undertaken to
improve diagnostics and management of DON.1,3–8
This review provides an overview of the current under-
standing of DON and the controversies related to its diagnosis
and management.
Accepted for publication April 5, 2018.
The authors have no financial or conflicts of interest to disclose.
Address correspondence and reprint requests to Peerooz Saeed, Academic
Medical Center, Department of Ophthalmology, University of Amsterdam,
Meibergdreef 9, Amsterdam, The Netherlands. E-mail: p.saeed@amc.uva.nl
DOI: 10.1097/IOP.0000000000001146
S60 Ophthal Plast Reconstr Surg, Vol. 34, No. 4S, 2018
Copyright © 2018 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Clinical Presentation. DON is primarily a clinical diagnosis
based on a constellation of findings including decreased visual
acuity, a relative afferent pupillary defect, disturbed color vision,
optic disc abnormalities, visual field (VF) defects, and evidence
of apical crowding on radiographic imaging. The signs and
symptoms of DON are not always obvious, and the lack of a
gold standard or diagnostic criteria has led to some controversies
regarding the relative significance of clinical signs, imaging, and
functional testing. For instance, good visual acuity and lack of
a relative afferent pupillary defect do not exclude the diagnosis
of DON as 50% to 70% of cases of confirmed DON have best-
corrected visual acuity of 20/40 or better, and 76% of DONs are
bilateral. Evidence of optic nerve swelling on examination is also
thought to be present in only 20% to 50% of cases of DON.9–11
The large survey by the European Group on Graves’
Orbitopathy did not establish a “gold standard” for the diagnosis
of DON. There was a high prevalence of impaired color vision,
changes in visual acuity, and crowding of the orbital apex. Fat
prolapse through the superior orbital fissure had a specificity
of 100% but a sensitivity of only 20%. Median clinical activity
score (CAS) in these series was 4/7, and in 25% of patients with
DON and visual acuity of 20/40 or less, the CAS was 3 or less.10
It has often been noted that marked proptosis is often absent
in patients with optic neuropathy. Furthermore, the degree of pro-
ptosis may not correlate with the severity of neuropathy. Lack of
proptosis could increase the orbital pressure, precipitating DON.
European Group on Graves’ Orbitopathy cohorts
observed slightly higher degrees of proptosis in males with
DON, but these were not significant (mean 22.8 mm males,
mean 21.8 mm females). Proptosis measurements alone were
not associated with the presence of DON. Twenty eyes with
DON had exophthalmometry values of 20 mm or less com-
pared with 13 eyes with values more than 25 mm. The absence
of severe proptosis in many DON patients has been previously
reported. Lack of proptosis could increase the orbital pressure,
precipitating DON in some cases10 (Fig. 1).
Weis reported that total ductions, marginal reflex dis-
tance, and apical crowding are able to predict the presence of
DON with high sensitivity and specificity. Eyelid ptosis might
be a novel predictor of DON.12
Optic disc appearance is normal in 55% of DON cases,
while the proportion of normal discs in eyes without DON is
95%, indicating that optic disc swelling, if present, is a very
specific indicator of DON.10
VF testing accurately detects DON. Nearly all eyes with
DON develop a central or paracentral scotoma, and many develop
other peripheral breakout patterns as well, including inferior arcu-
ate defects, inferior altitudinal, increased blind spot/nerve bundle
defect generalized field constriction, and inferolateral defects.1,4
Visual evoked potential may also help detect and monitor DON
and is possibly more sensitive than kinetic perimetry.9,10
Computer Tomography. The overwhelming majority of
computed tomography (CT) imaging studies in cases of DON
 Ophthal Plast Reconstr Surg, Vol. 34, No. 4S, 2018 Dysthyroid Optic Neuropathy
FIG. 1.  Flow diagram of the clinical criteria for dysthyroid optic
neuropathy (DON).
demonstrate moderate-to-severe muscle enlargement. To show
an example of different causes of proptosis, CT scans from
2 patients with GO are included. One patient with bilateral
proptosis due to enlargement of the medial and lateral recti
(Fig. 2A) and another patient with severe proptosis bilateral
due to increase of fat volume and no extraocular muscle (EOM)
involvement (Fig. 2B).
The muscle index represents a way to approximate
the relative EOM volume within the orbit and is significantly
greater in orbits with DON than in orbits with GO alone. A mus-
cle index of greater than 70% is seen in about 2/3 of cases of
DON, and DON almost never occurs in the setting of a muscle
index <50%.13,14
The assessment of apical crowding based on single coro-
nal images, as described by Nugent et al., has been shown to be a
good predictor of DON.13–17 A coronal image at the apex is sub-
jectively graded according to the severity of the muscle crowding.
According to this method, the effacement of the perineural fat
is graded 0 (none), 1 (up to 25%), 2 (25%–50%), or 3 (greater
than 50%).16 Nugent et al.16 found severe apical orbital crowding
(grade 3) in 12 of 18 orbits with DON but in only 16 of 124 orbits
without DON. Nugent et al.16 graded 79.2% of the orbits with
DON and 12.9% of the orbits without DON as having moderate
or severe crowding. Birchall et al.17 found severe apical crowding
to be a good predictor of DON, with a sensitivity of 62% and
specificity of 91%. A European Group on Graves’ Orbitopathy
multicenter study found apical muscle crowding in 49 of 56
orbits with DON.10 Although it is evident that the Nugent’s apical
crowding score is useful for raising suspicion of DON, the score
does not provide a clear definition of the position along the orbit
where the coronal plan should be taken to determine the score.
Although linear or square measurements of apical crowding have
proven helpful in diagnosing DON, the estimation of the orbital
apex crowding based on volumetric estimates of structures could
potentially improve the ability to detect DON.
Chan et al.15 highlighted the importance not only of EOM
enlargement but also the role of the bony orbit and its usefulness
as a predictor of DON. The bony orbit capacity was quantified
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Copyright © 2018 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
FIG. 2.  Axial computed tomography (CT) scans from 2
patients with Graves orbitopathy (GO). A, Patient with pro-
ptosis bilateral due to enlargement of the medial and lateral
recti. B, Patient with severe proptosis bilateral due to increase
of fat volume and no enlarged extraocular muscle (EOM)
involvement.
using standardized orbital angles on axial scans. The study
showed that these measurements were independent predictors of
DON and that narrower orbits were more susceptible to develop
DON. The authors also calculated an index of orbital muscular
crowding in combination with lateral and medial orbital wall
angles that had 73.3% sensitivity and 90% specificity.
Orbital fat prolapse through the superior orbital fissure
may predict DON, with up to 94% sensitivity and 91% speci-
ficity and a positive and negative predictive value of 69% and
98%, respectively.10,13,14
Magnetic Resonance Imaging. Magnetic resonance imaging
(MRI) may reveal findings similar to CT imaging but allows for
superior soft-tissue imaging. T2-weighted and fat-suppressed
images using turbo-inversion-recovery-magnitude and short-
tau inversion recovery sequences enable detection of EOM and
orbital fat, interstitial edema, and therefore disease activity.
This makes MRI ideal for distinguishing active inflammatory
GO from fibrotic end-stage disease, which is essential for
determining the type and timing of treatment. Figure 3A shows
prominent enlargement of medial recti and lateral recti on the
CT scan and MRI, and apical crowding is seen on the MRI
short-tau inversion recovery sequences (Fig. 3B).
MRI changes of the optic nerve may correlate with CASs,
suggesting that future MRI studies of the optic nerve itself may
help detect DON. Although MRI is superior at imaging soft tis-
sue, CT is better at evaluating bony orbital anatomy, which is
critical for surgical planning.10,18
Dodds et al. assessed DON in a high-resolution MRI study
in which they compared the diameter of the optic nerve at 7 dif-
ferent positions from the eyeball to the pre-chiasmal region in 3
groups (control, GO with DON, and GO without DON). The optic
nerve diameter was significantly smaller in the group with DON.
However, the overall reduction was not substantial, and there was
considerable overlap between the control subjects and patients
with DON. The authors indicated that despite the observed reduc-
tion in the optic nerve size in the DON group, neural compression
could not be shown to be the pathogenic mechanism underlying
the nerve dysfunction, but they found mechanical compression of
the optic nerve to be the most plausible explanation. Alternatively,
DON might be caused by vascular compression or some other
unidentified mechanism. The authors also observed reductions in
the optic nerve diameter in the absence of enlarged EOM, sug-
gesting that the compression results from increases in the intraor-
bital pressure due to the increased fat volume.13,19
Epidemiology and Risk Factors. A recent epidemiologic study
shows that the incidence of Graves disease is 210 per million per
year, with a peak in the fifth decade of life, in Sweden.20 It more
 P. Saeed et al. Ophthal Plast Reconstr Surg, Vol. 34, No. 4S, 2018
FIG. 3.  Clinical presentation of a 55-years-old female with dysthyroid optic neuropathy (DON) and nonresponsive to methylpredniso-
lone. A, Axial computed tomography (CT) scan (left) and magnetic resonance imaging (MRI; right) of the same patient with prominent
enlargement of medial recti and lateral recti. B, MRI STIR (short-tau inversion recovery) of the same patient with apical crowding.
frequently affects women than men, with a female to male ratio
of 4:1. GO is an autoimmune disorder with an incidence of 42 per
million per year.20–22 In GO, the orbit is affected due to the expression
of thyroid-stimulating hormone receptors in orbital fibroblasts,
which serve as an autoantigen for circulating thyrotropin binding
inhibiting immunoglobulins. The insulin-like growth factor receptor
is another autoantigen that is involved in the pathophysiology of
GO.23 Moderate-to-severe and very severe GO will develop in 5%
to 6% of cases.8,20–23 Increased age correlates with greater severity of
GO, and age may represent one of the biggest risk factors for DON.
Patients with DON are significantly older than those with GO alone,
with an average age of 61 years.8,9,23 In a large retrospective study,
8.6% of patients with GO developed DON, and patients with DON
were older (54 vs. 46 years) compared with those without DON. For
every decade increase in age of onset of GO, the odds of developing
DON may increase by 58%. Male gender is strongly associated with
the development of DON, especially with advancing age.3,9
While the prevalence of diabetes mellitus in GO patients is
similar to the normal population (0.22%–0.26%), the prevalence
of patients using insulin is significantly higher (1.7%). Among
these patients, the disease course is generally more severe and
more often refractory to therapy.9,24 The vasculopathy associated
with diabetes mellitus leads to reduced oxygenation of the optic
nerve, leaving it more susceptible to damage due to EOM expan-
sion and optic nerve compression. In one study, while only 3.1%
of patients with GO had diabetes and 3.9% developed DON,
33.3% of patients with diabetes eventually developed DON.
Medical and surgical treatment may be less effective in improv-
ing visual outcome for patients with diabetes.9,24
Tobacco use is associated with a 7- to 8-fold increase in
the risk of developing GO, increased disease severity, and an
unfavorable response to treatment.8,9,25 Smoking may represent a
risk factor for DON as well, although the evidence is not as over-
whelming. Khong et al.’s2 review of 604 patients with GO found
an odds ratio of 1.5 for current smokers developing DON, but
this was not statistically significant. Another retrospective study
identified smoking to be the strongest predictive factor in the
development of severe GO (odds ratio 6.6) and DON (odds ratio
10.0).26 In Korean patients, current smoking status is the stron-
gest risk factor for the development of severe GO and DON.26
Thyroid Function. Thyroid dysfunction is closely related to the
development and severity of GO. Dysthyroidism has long been
observed to contribute to the development and progression of GO.
Potential risk factors include hypothyroidism as well as the severity,
duration, and recent onset of hyperthyroidism. Establishment and
maintenance of euthyroidism are essential. Specific treatments of
Graves hyperthyroidism may impact the course of GO. Radio-
iodine therapy increases the risk of GO progression by 15% to
39%, in comparison to antithyroid medication. Radio-iodine may
also increase the risk of developing DON, although no meaningful
data exist to validate this extrapolation.9,23,27
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Copyright © 2018 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ponto et al. reported that high serum thyroid-stimulating
immunoglobulins concentrations are associated with the pres-
ence of DON, of recent onset. Despite the strong association
between clinical activity and the level of thyroid-stimulating
immunoglobulin, the vast majority of patients with inactive
GO and DON of recent onset were thyroid-stimulating immu-
noglobulin positive. This study further indicated that serum
thyroid-stimulating immunoglobulin levels might be a useful
diagnostic tool to identify patients with early onset DON, who
require urgent therapy even if signs of activity are absent.28
Pathogenesis and Mechanism. Compression of the optic nerve
or restriction of its blood supply by enlarged EOMs is currently
the most widely accepted mechanism of DON.3,5–7
EOM swelling can cause optic nerve ischemia or inhibit
axonal flow. The medial rectus volume, which can be estimated by
the medial rectus axial diameter, appears to be the strongest pre-
dictor of DON.12 Orbital CT shows significant optic nerve crowd-
ing at the orbital apex in the vast majority of patients with DON.
Histopathological examination has revealed axonal loss, which
was more pronounced in the apical sections of the optic nerve.9
Clinical evidence for an important role of mechanical com-
pression is derived from the dramatic improvement in visual acu-
ity that can occur within hours after bony decompression, which
relieves the pressure from the crowded orbital apex. Furthermore,
the VF defects in patients with DON are similar to those produced
by other orbital mass lesions that compress the optic nerve.
Optic Nerve Stretching. In some cases, radiographic findings
do not fit in the mechanism of compression of the apical part
of the optic nerve by enlarged EOMs. Three-dimensional
volumetric analysis using high-resolution orbital CT images has
shown that there may be subpopulations of patients with GO.29
Regensburg et al.29 described 4 subtypes of GO in 95
orbits of GO patients. Twenty-five orbits showed no increase of
fat or muscle volume (Group 1), 5 orbits only showed fat vol-
ume increase (Group 2), 58 orbits only showed muscle volume
increase (Group 3), and 8 orbits showed both fat and muscle
volume increase (Group 4).29
Most GO patients have increased volume of EOM and
orbital fat. A small proportion of GO patients have increased
orbital fat with normal EOM volume.29,30 It is reasonable to
expect that increased soft-tissue volume from any source within
the confines of the bony orbit will increase orbital pressure. With
an increase in intraorbital volume and pressure, there is a gradual
but sustained strain on the optic nerve leading to stretching of
the optic nerve and subsequentially resulting in optic neuropa-
thy. Radial stretching of the optic nerve can lead to indirect cir-
cumferential compression of the optic nerve by circumferential
tension on the optic nerve sheath.31–33 The threshold for nerve
dysfunction secondary to stretch, and distribution of strain,
varies in different nerves.33 Peripheral nerves have a Schwann
 Ophthal Plast Reconstr Surg, Vol. 34, No. 4S, 2018 Dysthyroid Optic Neuropathy
cell–derived myelin sheath and are heterogeneously organized
with differing sizes of nerve fibers. In contrast, the optic nerve is
a direct extension of the central nervous system with oligoden-
drocyte-derived myelin, and the nerve has a fairly homogeneous
organization with nearly uniform nerve fiber size. It is possible
that these differences help to distribute stretch-related forces,
accounting for the greater ability of peripheral nerves to with-
stand greater strain as compared with the optic nerve.31
Bain et al. used guinea pig optic nerves to demonstrate
that stretching of these homogeneously organized fibers causes
a uniform distribution of strain. They documented that stretching
the optic nerve by 18% from its baseline length resulted in neuro-
praxia, exhibited by a conduction block on visual evoked poten-
tials. When the optic nerve was stretched by 21% of its baseline
length, immunohistochemical evidence of injury was observed.32,33
Jou et al.34 demonstrated significant blood flow reduction in rat
sciatic nerves stretched by 8% of baseline and histologic changes
at 24% stretch. We suspect that vascular insufficiency in the short
posterior ciliary and peripapillary retinal arteries of the optic nerve
head may occur with continued optic nerve stretching.34
Anderson et al.35 reported 3 atypical cases of DON with
progressive VF loss and normal-sized or minimally enlarged
EOMs. Other atypical findings included optic nerves that
appeared to be linearly on stretch with only moderate proptosis,
good ocular motility, and mildly reduced central visual acuity
and color vision in the presence of severe field loss. These cases
responded rapidly to decompressive surgery after failing high-
dose corticosteroid therapy. Another etiology such as short optic
nerves on stretch appeared to be involved in these atypical cases.35
Retrobulbar Pressure. A relation between intraorbital volume
increase and retrobulbar pressure has been described both
in clinical and experimental settings. Increased retrobulbar
pressure can also damage the o­ ptic nerve and other intraorbital
nerve branches by direct pressure.36,37
Otto et al. measured retrobulbar pressure in 9 patients
with GO before and during surgical decompression using an
intraorbitally ­applied pressure transducer.
Assuming a normal retrobulbar pressure of 3.0 to 4.5 mm
Hg, the experiments performed in the study described here show
that all investigated patients with bilateral Graves ophthalmopa-
thy had a significantly increased tissue pressure in the orbit.
In the orbits operated for DON, the mean retrobulbar pres-
sure measured before surgery was 28.7 (range 17 and 40) mm
Hg and decreased at the end of decompression to 18.7 mm Hg.37
Inflammation. It should be noted that no histopathologic study
of an optic nerve with acute DON has appeared in the literature.
Therefore, the role of inflammatory infiltration of the optic
nerve during the acute phase of DON remains an open question.
An early theory on the pathophysiology of DON pro-
posed that an inflammatory neuritis was produced by the gen-
eralized orbital inflammation present in the acute phase of the
disease. This theory fell out of favor when the study of necropsy
specimens in prolonged thyroid eye disease failed to demon-
strate an inflammatory infiltrate in the optic nerve.
Doppler sonography shows the superior ophthalmic vein
as the most susceptible to changes, exhibiting decreased flow
in the active stage and reversed or absent flow in the setting of
severe orbitopathy. These vascular changes may contribute to
DON.38–40 Color Doppler imaging has been used to study the
ocular blood flow in patients with GO. Decreased superior oph-
thalmic vein blood flow velocity has been widely documented.
Doppler ultrasound parameters of the retrobulbar arterial
vascular structures have been related to the CAS, suggesting
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Copyright © 2018 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
increased arterial flow velocity in patients with active GO due
to inflammation of the retro-orbital tissue.18,41
Yanik et al.18 tried to correlate disease activity, deter-
mined by the CAS, with Color Doppler imaging blood flow
parameters and found higher arterial flow velocities and lower
resistance in the ophthalmic artery of patients with a high CAS.
Orbital inflammatory activity was considered to be responsible
for the blood flow alterations.18
Treatment. Pulsed intravenous methylprednisolone is more
effective than oral glucocorticoids to treat active GO and has
less side effects.4,42–44 However, methylprednisolone can have
severe, but fortunately rare, side effects like acute liver failure and
cardiovascular and cerebrovascular events.45 The majority of severe
complications are associated with doses exceeding 8 g and daily or
alternate day administration.45 A recent European Group on Graves’
Orbitopathy consensus statement advocates methylprednisolone
as a first-line treatment for moderate–severe GO.4 A generally
accepted dosing regimen for these patients is a once per week dose
of 500 mg intravenous methylprednisolone per week for 6 weeks,
followed by 250 mg per week for another 6 weeks. The cumulative
dose should remain under approximately 6–8  g, and patients
should be monitored for side effects during treatment.4 DON may
necessitate more intensive dosing regiments, such as 500–1000 mg
methylprednisolone daily for 3 consecutive days and repeated if
necessary after 1 week. An urgent orbital decompression should be
performed if response is absent or poor within 2 weeks.4
Regimens such as this may lead to a complete visual recov-
ery in approximately 43% of cases.42 Other methylprednisolone
regimens have shown similarly successful outcomes. Because
systemic glucocorticoids can effectively treat DON, they should
be considered as a first-line treatment in most cases.4,42
Methylprednisolone is successful in restoring the visual
function of the eyes treated, particularly in those in which therapy
induces inactivation of the orbital inflammation within 2 weeks.
Deterioration of visual parameters after 2 weeks of treatment
seems to be indicative of poor long-term visual recovery if surgi-
cal decompression is delayed. In the authors’ experience, surgical
decompression, particularly when delayed, may not allow com-
plete restoration of normal visual function. The presence of optic
disc swelling at diagnosis and persistent active disease at 2 weeks
are good predictors of unresponsiveness to steroids.42 Table shows
the study characteristics of treatment trials for DON.
Orbital Decompression in DON. Decompression surgery for
rehabilitation of GO is best performed after the disease has
become inactive, but decompression may also be required in
the active phase of GO for cases of DON that are refractory
to medical treatment. DON has been managed with orbital
decompression by various techniques. Early studies suggest that
medial wall decompression is the most effective approach for
DON. These results have been described via transcaruncular,
medial transcutaneous transorbital, transantral, and endonasal
approaches. Despite the focus on medial wall decompression
for DON, reports of other effective methods are available.54
Orbital fat decompression for DON was reported by Kazim
et al.30 and resulted in improvement or complete resolution
of DON. Intraconal fat removal, alone or in combination
with other techniques, may effectively alleviate optic nerve
compression. Olivary reported an average proptosis reduction
of 5.9 mm by a mean fat removal of 6.0 ml. Other studies
report contradictory results with more fat excision required per
millimeter of proptosis reduction (mean 7.3 ml of fat for a 4.7-
mm reduction) with the technique, producing significantly less
reduction of exophthalmos. The literature reports suggest that
 P. Saeed et al. Ophthal Plast Reconstr Surg, Vol. 34, No. 4S, 2018

Study characteristics of treatment trials for DON

Study Publication Design DON patients Intervention Outcome: visual function

Henderson et al. 7
1958 Review 16 Combination of several surgical and 10 improved
nonsurgical treatments
Trobe et al.5 1978 Restrospective 21 21 Oral corticosteroids 10 improved
4 unimproved
7 progressive visual loss
Ogura et al.46 1978 Retrospective 220 Surgery (transantral) All remained stable or
improved
Anderson et al.35 1989 Restrospective 3 Surgery All improved
McNab et al.47 1998 Retrospective 21 (33 orbits) Surgery All improved
Kazim et al.30 2000 Restrospective 5 (8 orbits) Fat decompression All improved
Perry et al.48 2003 Retrospective 16 (26 orbits) Surgery All remained stable or
improved
Wakelkamp et al.49 2005 RCT 15 6 surgery 1/6 (18%) improved
9 IVMP 5/9 (55%) improved
Soni et al.31 2010 Observational 3 Surgery 2 improved
Khanna et al.50 2010 Retrospective 4 Rituximab All improved
Choe et al.51 2011 Retrospective 17 (28 orbits) 10 orbits lateral decompression All improved
18 orbits medial decompression More proptosis reduction
with lateral decompression
Jeon et al.11 2012 Retrospective 40 (65 orbits) 16 (26 orbits) Surgery More vision improvement
24 (39 orbits) nonsurgical (IVMP and with surgery
orbital radiation therapy)
Currò et al.42 2014 Retrospective 24 (40 orbits) IVMP 17 orbits (42.5%) improved
Baril et al.52 2014 Retrospective 34 (59 orbits) Combined endoscopic medial and All improved
external lateral decompression
Korkmaz et al.53 2016 Retrospective 42 (68 orbits) 41 orbits 2-wall surgery All improved
27 orbits 3-wall surgery More proptosis reduction
with 3-wall surgery
DON, dysthyroid optic neuropathy; IVMP, intravenous methylprednisolone.

fat decompression may be comparable to bony decompression
for the management of DON in selected cases.30,51,52,54
Removal of the deep lateral wall may sufficiently decom-
press the orbital content and is becoming the procedure of
choice either alone or in combination with other techniques.
The published degree of proptosis reduction varies from
2.3 mm in the early reports to a range of 3 to 7 mm with tech-
nological advancements. Total removal of the lateral orbital rim
offers maximum globe retro-displacement of up to 9 mm and
augments the efficacy of the procedure. Removal of the deep
lateral wall is the safest decompressive procedure, associated
with minimal if any complications. It has no significant effect
on horizontal and vertical deviations with a low rate (2.6%) of
new-onset diplopia, whereas in some cases, preoperative diplo-
pia was corrected after surgery.51,52,54 Many studies have shown
lateral and floor decompression to be effective in cases of DON.
A study by Choe compared lateral and medial decompression.
Eighteen and 10 orbits were decompressed medially and later-
ally, respectively, for DON. In this retrospective, comparative
compressive optic neuropathy was not different between the 2
groups, suggesting that both approaches are equally effective.51
Endoscopic Orbital Decompression for DON. The endonasal
inferomedial orbital decompression might effectively treat DON
but may induce new diplopia in 60% to 80% of cases. This may
be due to the difficulty in maintaining an inferomedial bony strut
via the endoscopic approach.54,55 More recent attempts at selective
posterior endoscopic decompression for DON may result in less
postoperative diplopia.55 Fat can also be removed during this
approach to improve visual acuity with a low rate of consecutive
diplopia.54,55 The endoscopic medial decompression might be the
best approach for deep medial decompression and in the cases of
inadequate earlier medial decompression.
In general, 3-wall decompression provides better
improvement in the parameters of VF analysis and Hertel mea-
sures; however, new-onset diplopia, orbital and adnexal compli-
cations are more common with this surgical technique.54
Wakelkamp et al. compared the surgical bony wall removal
via a coronal approach with the intravenous administration of meth-
ylprednisolone for DON. Both groups had improvements in visual
acuity, severity, and CASs at 52 weeks posttreatment. Additional
interventions were recorded in a mean follow-up of 64 months for
the surgery group where 5 out of 6 participants needed immuno-
suppression. Similarly, within 78 months in the steroids group, 4
out of 9 had decompression. From the total number of 15 random-
ized participants, 5 participants in the same group did not undergo
surgical decompression. Treatment side effects were more frequent
in the steroids group and included weight gain and a cushingoid
appearance in 12 out of 15 patients, hypertension and reversible
hyperglycemia in one case, and visual deterioration in one eye due
to retinal vein occlusion. Side effects of surgery were transient
infraorbital hypoesthesia in 4 out of 14 participants and strabismus
in one participant. Based on these results, the authors propose that
methylprednisolone is a good first-line agent as it can prevent the
need for urgent orbital decompression in many patients.49
Radiotherapy. Theoretically, radiotherapy may be effective in
GO due to the anti-inflammatory effects of radiation and the high
radiosensitivity of lymphocytes, which infiltrate the orbit in GO.
One study comparing radiotherapy (administered in 10 fractions
of 2 Gy) to sham radiation showed a decrease in symptoms
from 63% to 31%. Another study compared prednisolone and

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Copyright © 2018 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
 Ophthal Plast Reconstr Surg, Vol. 34, No. 4S, 2018 Dysthyroid Optic Neuropathy

radiotherapy and showed equal efficacy but more rapid recovery

and more effect on soft tissue after prednisolone as opposed to
a better recovery in terms of extraocular motility after radiation.
Orbital radiotherapy has been shown in randomized clini-
cal trials to synergistically potentiate the effects of oral predni-
sone. It is possible that orbital radiotherapy may also potentiate
the effects of intravenous methylprednisolone, but evidence on
this specific issue is currently missing.56–58
Shams et al.58 reported in her retrospective study an
improvement of ocular motility and reduced DON in patients
with severe and active GO who received radiotherapy in combi-
nation with corticosteroids.
The radiation scheme most commonly used is a total dose
of 20 Gy per eye administered in 10 fractions of 2 Gy over a
2-week period. Radiation can sometimes exacerbate orbital
inflammation, and therefore corticosteroids are often given
around the time of radiation treatment.59 The side-effect profile of
radiation therapy has considerably decreased with current radia-
tion techniques, with no increased risk of cataract or secondary
malignancies and a small increased risk of radiation retinopathy
(1% to 2% risk over 10 years). Patients with diabetes mellitus and
hypertension have a higher risk of developing retinopathy.59

Inadequate Response to Treatment. Although intravenous

methylprednisolone is the first-line and generally effective
treatment for DON, partial or inadequate responses or recurrences
are not uncommon. Management of patients experiencing
medical treatment failure to intravenous methylprednisolone is
a major challenge due to the limited evidence on the efficacy of
alternative treatment regimens in this clinical setting. In general,
the second course of intravenous methylprednisolone can be
administered if tolerated and if the cumulative dose does not
exceed 8 g. Intravenous methylprednisolone can be combined
with radiotherapy, although the effect of the latter may be
delayed.4 In general, decompression surgery within 2 weeks
is advised in cases of glucocorticoid refractory DON. Recent-
onset choroidal folds and eyeball subluxation should undergo
orbital decompression as soon as possible.4 Insufficient orbital
decompression might also be the cause of absent or poor visual
recovery or even visual deterioration and requires additional
decompression. A further lateral decompression and endoscopic
complete medial wall decompression should be considered.
Second-line Medical Treatment. Other immunosuppressive
and biologic agents, such as methotrexate, rapamycin,
adalimumab, and rituximab, have been investigated but are
generally second-line therapies. Surgery is best performed after
cessation of active disease but may be required earlier for cases
of DON refractory to medical treatment.4
Two randomized controlled studies have demonstrated
that the combination of cyclosporine with oral GCs was more
effective than either treatment alone in patients with moderate-
to-severe and active GO.60,61 Combined treatment was associ-
ated with a better ocular outcome and a significantly lower rate
of recurrences of GO.60,61 In the second study, patients who did
not respond adequately to single-drug therapy, either prednisone
(starting dose, 60 mg per day) or cyclosporine (starting dose,
7.5 mg/kg body weight), received also the second drug: about
60% of nonresponders to single-drug therapy had a response
to combined-drug therapy. The most common adverse events
related to cyclosporine are dose-dependent liver and renal tox-
icities and gingival hyperplasia.60,61
One retrospective case series demonstrated that rituximab
was associated with significant improvement of the clinical mani-
festations of severe GO that were refractory to steroids therapy
FIG. 4.  Flow diagram for treatment of dysthyroid optic neu-
ropathy (DON).
or orbital decompression. In 4 of the 6 patients, DON developed
before rituximab treatment. Orbital inflammation (elevated CAS
scores) and DON improved without recurrence in all patients, but
proptosis and strabismus were unimproved by rituximab, but the
available evidence from one of the randomized studies, as well as
a case report of a patient with GC-resistant GO, suggests that pro-
gression of DON may also occur after rituximab.61,62 In the second
study, rituximab (1,000 mg twice over 2 weeks) was given to 13
patients and compared with placebo (n = 12). This study failed
to demonstrate a difference in outcomes between rituximab and
placebo. Two patients, who had no overt or impending DON prior
to treatment, developed DON after rituximab.50
Infusion-related reactions are the most frequently
reported short-term side effects of rituximab, may occur in
about 10% to 30% of patients at first infusion, and can be
minimized by premedication with antihistamine and 100 mg of
hydrocortisone prior to infusion. Rarely, transient, but signifi-
cant periorbital edema and inflammation may occur. A recent
review of over 3,000 patients with rheumatoid arthritis showed
comparable serious infection rates in those treated with ritux-
imab versus placebo plus methotrexate over 9.5 years of obser-
vation. Based on the above, rituximab should not be used in
patients with impending DON or long duration of disease.50,61,62
There are few case series that suggest biologic agents
may improve visual function. The antitumor necrosis factor
agent, Tocilizumab, a humanized monoclonal antibody against
the interleukin-6 receptor agents, might be effective in severe,
active GO.63–65
Recently, Smith et al. reported on the use of an insulin-
like growth factor-1 receptor-blocking monoclonal antibody,
teprotumumab. The most striking and unexpected effect of
teprotumumab was the treatment-related decrease in exophthal-
mos. It is well known that immunosuppressive treatments for
GO cause a limited reduction in exophthalmos. This important

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Copyright © 2018 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
 P. Saeed et al. Ophthal Plast Reconstr Surg, Vol. 34, No. 4S, 2018
study provided that, compared with placebo, teprotumumab
appears to be a disease-modifying drug. However, results must
be confirmed in a repeat study and second randomized con-
trolled trial comparing teprotumumab to the gold standard treat-
ment for moderate-to-severe and active GO with steroids.66
SUMMARY OF THERAPEUTIC GUIDELINE
The first-line treatment after diagnosis of DON is high doses of
intravenous methylprednisolone (e.g., 500–1000 mg of methyl-
prednisolone for 3 consecutive days or on alternate days during
the first week). If the response is absent or poor, or when there
is rapid deterioration in visual function (acuity/VF), urgent
decompression surgery should be performed.4 In the case of
optic nerve compression, decompression can be better achieved
by means of medial orbital wall removal, combined with lat-
eral wall and when necessary the orbital floor. Severe corneal
exposure is treated medically or by means of progressively more
invasive surgeries as soon as possible to avoid progression to
corneal breakdown.
In the cases of inadequate response within 2 weeks or
recurrence, a second course of intravenous methylprednisolone
can be administered if the patient tolerates it and a cumulative
dose of 8 g of methylprednisolone is not exceeded. Intravenous
methylprednisolone can be combined with radiotherapy,
although latter can have a delayed effect. Also, an additional
orbital decompression might be necessary. In the cases of re-
decompression, additional medial decompression through an
endonasal endoscopic approach gives the easiest access to the
posterior region of the medial wall (Fig. 4).
CONCLUSIVE SUMMARY OF REVIEW
DON is a serious complication of GO that can cause permanent
blindness. The mechanism of DON has been described as hav-
ing direct compression of the optic nerve by enlarged EOMs,
stretching of the optic nerve by proptosis, orbital pressure, vas-
cular, and inflammation. The first-line treatment after diagnosis
of DON is high-dose intravenous methylprednisolone followed
by bony orbital decompression.
Both 2-wall and 3-wall decompression techniques suc-
cessfully improve visual functions of patients with DON, but
close postoperative monitoring of patients for additional treat-
ment regimens is of particular importance to maximize favor-
able visual outcomes as patients may need additional treatment
for continuing features of DON after surgery.
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