REVIEW ARTICLE
Steroid Treatment of Optic Neuropathies
Leanne Stunkel, MD,* and Gregory P. Van Stavern, MD†
Abstract: The etiologies of optic neuropathy include inflammation,
ischemia, toxic and metabolic injury, genetic disease, and trauma. There
is little controversy over the practice of using steroids in the treatment of
optic neuritis—it is well established that intravenous steroid treatment
can speed visual recovery but does not alter final visual function. How-
ever, there is controversy surrounding the acceptable routes of adminis-
tration, dosage, and course of treatment. Additionally, the typical patient
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with optic neuritis is young and otherwise healthy, and thus is likely to
tolerate steroids well. In ischemic and traumatic causes of optic neurop-
athies, the initial injury is not inflammatory, but damage may be com-
pounded by secondary injury due to resultant inflammation and swelling
in the confined space of the optic canal. Steroids have been considered as
a means of minimizing inflammation and swelling, and thus minimizing
the secondary injury that results. However, the use of steroids in traumat-
ic and ischemic optic neuropathies is highly controversial—the evidence
for the efficacy of treatment with steroids is insufficient to show that
there is significant benefit. Additionally, patients with these conditions
are more likely to have comorbidities that make them vulnerable to sig-
nificant adverse events with the use of steroids. In this article, we attempt
to analyze the current state of the literature regarding the use of steroids
in the treatment of optic neuropathies, specifically optic neuritis, nonarte-
ritic anterior ischemic optic neuropathy, and traumatic optic neuropathy.
Key Words: steroids; optic neuropathies
(Asia-Pac J Ophthalmology 2018;7:218–228)
T he optic nerve is part of the central nervous system. It is a
large structure, heavily myelinated along its entire course by
oligodendrocytes. The nerve travels through a narrow, bony canal
that physically encases it at some places along its course.
The term “optic neuropathy” indicates impaired optic nerve
function, which can be due to damage to the myelin of the ax-
ons, the axons themselves, or due to dysfunction or death of the
neuron cell body. Clinically apparent visual loss requires loss of
a threshold level of axons, which may be up to 30–50%,1–3 and
retinal nerve fiber layer thinning to around 70 μm.4,5 Etiologies
of optic neuropathy include inflammation, ischemia, toxic and
metabolic injuries, hereditary disease, and trauma. Prognosis is
dependent upon the etiology of injury, duration, residual axonal
and neuronal integrity, and potential response to treatment.
Steroids are cholesterol-based hormone molecules that dif-
fuse across the cell membrane to enter the cytoplasm, bind to
From the *Department of Neurology; and †Department of Ophthalmology and
Visual Sciences, Washington University School of Medicine, St. Louis,
Missouri.
Received for publication April 9, 2018; accepted May 24, 2018.
The authors have no funding or conflicts of interest to declare.
Reprints: Gregory P. Van Stavern, MD, Washington University School of Medicine,
660 S. Euclid Ave., St. Louis, Missouri 63110. E‑mail: vanstaverng@wustl.
edu.
Copyright © 2018 by Asia Pacific Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.22608/APO.2018127
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intracellular receptors, enter the cell nucleus, and affect gene
transcription.6 Corticosteroids, which have both mineralocorti-
coid and glucocorticoid activity, are relevant to the treatment of
optic neuropathies due to their glucocorticoid activity. Glucocor-
ticoids exert an anti-inflammatory effect by both inhibiting the
transcription of proinflammatory genes and by upregulating the
transcription of anti-inflammatory genes.6–9 For optic neuropathy,
steroids are typically administered systemically, either orally or
intravenously. Prednisone and methylprednisolone are common
choices, but systemic dexamethasone and intravitreal triamcino-
lone have also been explored.
Potential benefits of steroids must be weighed against the
risk of possible complications. Side effects are common, with up
to 90% of patients who use steroids reporting adverse reactions.10
Adverse events range from mild to life-threatening, including re-
current infection due to immunosuppression, hyperglycemia and
drug-induced diabetes mellitus, weight gain, osteoporosis, gastro-
esophageal reflux disease, hypertension, hyperlipidemia, avascu-
lar necrosis of the hip, myopathies, friable skin (dermal atrophy)
and acne and skin bruising, slow wound repair, ophthalmolog-
ic side effects such as glaucoma and cataracts, and neurologic/
psychiatric side effects such as poor concentration, agitation,
insomnia, and behavioral changes.8–10 Side effects are dose- and
duration-dependent.8 Life-threatening adverse effects have been
reported, including pancreatitis, adrenal insufficiency, metabolic
derangements,8,9 and susceptibility to serious infections.
The rationale for the use of steroids in optic neuropathies
varies among the different etiologies. Optic neuritis (both demy-
elinating and nondemyelinating), in which inflammation is the
etiology of the injury, is treated with steroids on the basis of their
anti-inflammatory properties. There is little controversy over the
practice of using steroids in the treatment of optic neuritis. How-
ever, there is controversy surrounding the acceptable routes of ad-
ministration, dosage, and course of treatment.11 In other forms of
optic neuropathy, the use of steroids at all is more controversial.
In ischemic and traumatic causes of optic neuropathies, the initial
injury is not inflammatory, but it may be compounded by second-
ary injury due to resultant inflammation and swelling within the
confined space of the optic canal. Steroids are intended to mini-
mize the inflammation and swelling associated with the original
injury, and thus prevent the secondary injury.
Reports of improvement with treatment may be confounded
by a variety of factors, including placebo effect, response bias
(the tendency for patients to report more favorable outcomes and
fail to report unfavorable outcomes), spontaneous improvement
as part of the natural history of the condition, and regression to the
mean (the latter is particularly important for conditions in which
spontaneous improvement occurs). Even large case series can be
prone to bias due to factors such as lack of randomization, lack
of control group, and lack of masked observers.12,13 These factors
are particularly important when some of the outcomes are psy-
chophysical tests that are dependent upon patient response and
cooperation with the test (eg, visual acuity, visual field testing,
and so on). Thus, the necessity of critical analysis of the literature.
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Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018
Humans are prone to mistake correlation for causation—the “post
hoc, ergo proptor hoc” fallacy (“after this, therefore because of
this”). Major medical organizations have developed a “hierarchy
of evidence” as a tool to assess the quality of the extant litera-
ture and help physicians make treatment decisions (Table 1).14,15
Randomized, placebo-controlled, double-blind masked studies
are the gold standard at the top of the hierarchy but may not be
feasible with rare diseases. In such cases, the physician must use
the best available evidence in the medical literature and apply it
to the individual patient. This does not mean that studies with
lower levels of evidence are worthless—they retain value, but the
results must be interpreted with a degree of caution until better
and confirmative evidence emerges.
In this article, we attempt to analyze the current state of the
literature regarding the use of steroids in the treatment of optic
neuropathies including optic neuritis, nonarteritic anterior isch-
emic optic neuropathy (NAION), and traumatic optic neuropathy.
STEROIDS FOR OPTIC NEURITIS
Optic neuritis is an acute to subacute, inflammatory, demy-
elinating optic neuropathy that presents with visual changes and
pain with eye movements.16,17 The incidence of optic neuritis has
been reported to be as high as 6.4 per 100,000.18 Optic neuritis is
most common in women and more common in the young; it may
present in patients ranging from the teenage years to the 50s, but
it is most common in the 20s and 30s.16,19 The most common as-
sociation is with multiple sclerosis (MS),16,17,20,21 but optic neuritis
can also be associated with other disorders, such as neuromyelitis
optica (NMO), myelin oligodendrocyte glycoprotein antibodies,
sarcoidosis, lupus, and others. For the purposes of this review,
“optic neuritis” will refer to primary demyelination, either idio-
pathic or related to MS. Optic neuritis is characterized by changes
in visual acuity, visual fields, and color vision.16,17,19,22,23 In unilat-
eral cases, the examination will almost always show a relative
afferent pupillary defect—in fact, presence of a relative afferent
pupillary defect was an inclusion criterion for the Optic Neuritis
Treatment Trial (ONTT).16 In about 30% of cases, the examina-
tion will show swelling of the optic disc, but most are retrobul-
bar, with no visible disc swelling.16 Magnetic resonance imaging
(MRI) may show supportive features such as T2 hyperintensity
and enhancement of the optic nerve, but is not required to make
the diagnosis.
The natural history of optic neuritis is to improve sponta-
neously over the course of weeks, as the inflammatory process
resolves.19,24 After a single occurrence of optic neuritis, final vi-
sual acuity will usually recover to normal or very mild residual
deficits—in the ONTT, 74% of patients had visual acuity of 20/20
or better in the affected eye 10 years after the optic neuritis ep-
isode. Residual deficits are more likely in severe cases, or after
subsequent attacks of optic neuritis in the same eye.25
TABLE 1. Categories of Evidence
Category of Evidence Data Source
I Well-designed randomized controlled trials, meta-analyses of randomized controlled trials
II Randomized controlled trials with flaws and controlled studies without randomization
III Descriptive studies, including comparative, cohort, and case-control studies
IV Case series, case studies, expert opinion
© 2018 Asia-Pacific Academy of Ophthalmology
Copyright © 2018 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Steroid Treatment of Optic Neuropathies
Steroids have long been an important treatment
consideration for this inflammatory condition. An American
Academy of Neurology practice parameter published in 2000
by Kaufman et al26 provides an extensive summary of the re-
search done on steroids since the 1950s.
The ONTT is the largest and most influential trial. The
ONTT randomized 448 patients within 8 days of symptom onset
into 3 arms: 1) intravenous (IV) methylprednisolone 1 g daily
(divided into 4250 mg doses) for 3 days (followed by an 11-day
oral prednisone taper), 2) oral prednisone 1 mg/kg daily for 14
days, or 3) oral placebo. Participants were masked to oral pred-
nisone versus placebo but unmasked to IV methylprednisolone.
Examiners were masked to treatment. The group that received IV
methylprednisolone recovered faster, with better visual function
at 2–3 weeks, and slightly better visual function still detectable
at 6 months (P = 0.001). However, long-term recovery was the
same for all groups. At 1-year and at 10-year follow-up there
was no difference.24,25,27,28 The ONTT also found a higher rate of
subsequent optic neuritis attacks in the group treated with oral
prednisone.25,27
This well-designed, large, randomized study collected data
over an impressive 15-year follow-up period. It significantly im-
proved understanding of steroids as a treatment for optic neuritis,
and its results had an appreciable effect on practice patterns.29
Further supporting the validity of the ONTT results, subsequent
studies have consistently replicated its results: steroid treatment
speeds recovery but does not alter long-term visual outcome.26,30–34
In keeping with these results, Kapoor et al35 also showed that ste-
roids hasten recovery without changing the final visual outcome,
regardless of the length of the optic neuritis lesion. Longer lesions
did not exhibit greater benefit from steroids than shorter ones,
suggesting that secondary injury from compression is not a sig-
nificant mechanism of injury in optic neuritis.35
After the ONTT showed a higher rate of subsequent optic
neuritis attacks in the group treated with oral prednisone, guide-
lines and expert opinions recommended intravenous steroids
only.26,36 However, the ONTT examined mega dose (1 g daily)
intravenous steroids versus regular high-dose (1 mg/kg daily)
oral steroids. In 1999, Sellebjerg et al37 showed that in a place-
bo-controlled trial of 60 patients, oral methylprednisone 500 mg
daily for 5 days followed by a taper increased the speed of visual
recovery (P = 0.008), and that after 1 year of follow-up, there
was no increase in disease activity in the oral steroid group.37 A
recent, single-blind trial of 55 patients randomized to receive in-
travenous methylprednisolone (1 g daily) versus a bioequivalent
dose of oral prednisone (1250 mg daily) showed no difference in
visual outcome after 6 months.38
Although many optic neuritis patients return to normal or
near-normal levels of visual function and are able to resume visu-
al tasks of daily living, some continue to complain of mild resid-
ual symptoms.39 Self-reported visual impairment continues even
www.apjo.org | 219
Stunkel and Van Stavern
5–8 years after an episode of optic neuritis.40 Although standard
office tests of visual function may be normal, low contrast visu-
al acuity changes may be detectable using Sloan charts, and the
changes correlate to poorer self-reported quality of life scores.41
Optic neuritis associated with other disorders, such as NMO,
myelin oligodendrocyte glycoprotein antibodies, sarcoidosis, sys-
temic lupus erythematosus, Behcet syndrome, Sjogren syndrome,
and others, is described as atypical optic neuritis. Chronic re-
lapsing intermittent optic neuritis (CRION) resembles idiopathic
optic neuritis but recurs when steroids are weaned. Concerning
features for atypical optic neuritis include very old or very young
age, bilateral onset, lack of pain, severe disc edema, hemorrhages,
exudates, uveitis, macular star, severe visual loss, atypical disease
course (progression for more than 2 weeks, failure to recover af-
ter 3 weeks, relapsing after improvement, or relapsing after ste-
roids are stopped), and history of cancer or stigmata of systemic
disease.42–44 Features on MRI that suggest an alternate diagnosis
include posterior or chiasmal optic nerve involvement, or longi-
tudinally extensive optic nerve involvement.45 Data on the natural
history and treatments for atypical optic neuritis are more lim-
ited.42 Treatment varies depending on the underlying condition.
Neuromyelitis optica–optic neuritis may improve with steroids,
but with a limited response compared with typical optic neuritis,46
and may require plasma exchange treatments.44 Sarcoidosis-relat-
ed optic neuritis and CRION are both exquisitely responsive to
steroids and may be dependent on steroids—relapses are common
when attempts to wean steroids are made.44
Some commentators have suggested that, in light of the high
rate of spontaneous recovery, patients should not be exposed to
the risks of steroid treatment. However, the typical population—
young, healthy women—has a favorable side effect profile for
short-term steroid treatment. Side effects reported in studies of
steroids for optic neuritis include weight gain, transient mood
disturbances (euphoria), insomnia, gastrointestinal upset, facial
flushing, and acne. The only severe adverse effects reported in
the published studies were acute pancreatitis and psychosis, each
reported once out of the 457 patients in the ONTT, and both re-
covered fully.17,34,47–49 For some patients with profound visual loss
and specific occupational needs, early recovery of visual function
and binocularity is enough to warrant the relatively low risk of
short-term corticosteroids.
Overall, there is sufficient data to show that mega dose (1 g)
intravenous steroid treatment for optic neuritis is a safe treatment
to speed recovery of visual function in optic neuritis that does not
affect long-term visual recovery, and there is new evidence that
bioequivalent doses of mega dose oral steroids can also speed
visual recovery in this condition, without increasing the risk of
recurrent optic neuritis.
STEROIDS FOR NAION
The incidence of NAION is estimated at around 2–10 per
100,000.50,51 Risk factors include a small, crowded disc, along
with systemic risk factors such as hypertension, diabetes melli-
tus, and cerebrovascular disease.52–55 Typically, NAION presents
with painless, acute-onset, unilateral visual loss, although it can
rarely present bilaterally and simultaneously. The visual acuity at
onset is variable, ranging from 20/20 to no light perception.19,52–55
Visual field defects are very common19,52,55 and the most common
type of visual field defect is altitudinal,19,51,52 particularly inferior
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Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018
altitudinal.19,54 Fundus examination by definition shows optic disc
edema.19,52
The mechanism of NAION is thought to be impaired per-
fusion of the optic nerve head, leading to optic disc edema, re-
sulting in compression of the optic nerve within the canal and
further ischemic injury.56–58 About 40% of patients with NAION
may have spontaneous improvement of 3 or more lines of visual
acuity.53,55 However, visual fields are less likely to improve spon-
taneously.55 There is evidence that optic disc swelling can persist
for 6–11 weeks.59 After the edema resolves, the disc develops
pallor.
Despite being studied for decades, there is no high-quality
evidence supporting any treatment for NAION. Myriad treat-
ments have been attempted, including hyperbaric oxygen, al-
lowing the nerve to swell safely (surgical techniques including
optic nerve decompression and transvitreal optic neurotomy), de-
creasing optic nerve swelling (anti–vascular endothelial growth
factor agents), decreasing intraocular pressure to improve perfu-
sion (topical brimonidine), preventing platelet aggregation (ie,
aspirin), preventing blood clotting (anticoagulants), increasing
blood pressure to improve perfusion (norepinephrine), vasodi-
lation (systemic or subtenon administration of vasodilators or
stellate ganglion block), neuroprotection (ie, antiepileptic drugs),
and promotion of nerve regeneration (transcortical electric stim-
ulation).53,60–64 Currently, there is an ongoing prospective phase
2/3, placebo-controlled, double-masked trial of an siRNA against
caspase 2, which is intended to treat NAION by preventing
apoptosis.65
Steroids as a treatment for NAION were first considered
in the 1960s.66 The mechanism of NAION provides a plausible
mechanistic reason to explore steroids as a potential therapy: as
optic disc edema may contribute to the optic nerve damage, re-
ducing disc edema with steroids might potentially minimize the
damage that follows the initial ischemic insult and limit the sec-
ondary injury resulting from inflammation, swelling, and further
compression of the capillaries in the optic nerve head.56,67 Oral
steroids, and more recently both intravenous and intravitreal ste-
roids, have been considered (Table 2). However, more than 50
years after they were first considered for treatment of NAION,
steroids remain controversial at best.
In 1970, Foulds67 reported a case-control study of 60 mg
prednisolone daily in 13 patients compared with 11 controls,
which showed improvement of visual acuity in 85% of those
treated with steroids compared with only 45% of the controls.
A 1974 study of oral prednisone 40–80 mg daily in 8 patients
compared with 6 controls showed that 75% of the treated patients
had improvement in visual acuity compared with 17% of the
controls.56
The largest study of steroids in NAION to date was a series
of 236 patients collected from 1973 to 2000, comparing patients
who chose to receive a steroid taper starting with prednisone 80
mg daily for 2 weeks with 301 patients who chose to be con-
trols and not receive steroid therapy. The results of the study were
promising—visual acuity improved more than 3 Snellen lines in
70% of the steroid-treated group compared with improvement of
40% in the control group (P = 0.001) and visual fields improved
in 40% compared with improvement in 24.5% of the controls
(P = 0.005). Optic disc swelling resolved more quickly in the ste-
roid-treated group—6.8 weeks versus 8.2 weeks (P < 0.0001).68
The main strength of this study is the large number of
© 2018 Asia-Pacific Academy of Ophthalmology
 TABLE 2. Studies Examining Steroid Treatment in NAION

Time From Class of

Author (Year) Intervention Onset N Study Type Edvience Results
Intravitreal
Alten et al (2014)72 Intravitreal dexamethasone implant x1; 3–7 d 3 cases, 0 controls Case series IV Improvement in optic disc edema but not visual function. 1 developed
also 3 d IV systemic steroids IOP increase.
Radoi et al (2014)76 Intravitreal triamcinolone 4 mg x1 0–31 d (1 mo) 21 cases, 15 controls Retrospective case control III VA improvement at 6 mo was statistically better in treated compared
with controls. A significant improvement of VF was noted in
treated group compared with controls (P < 0.0028).
Sohn et al (2009)90 Intravitreal triamcinolone 4 mg x1 4d 1 case, 0 controls Case report IV VA improved more than 7 lines.
Yaman et al (2008)74 Intravitreal triamcinolone 4 mg x1 4–10 d 4 cases, 0 controls Case series IV All experienced some visual gain. 2 of 4 gained 3 or more lines.
Kaderli et al (2007)75 Intravitreal triamcinolone 4 mg x1 1–22 d 4 cases, 6 controls Case control III VA improved.

© 2018 Asia-Pacific Academy of Ophthalmology

Jonas et al (2006)73 Intravitreal triamcinolone 20 mg x1 0–7 d 3 cases, 0 controls Case series IV VA improved 3 lines in 1 patient, improved 1 line in 1 patient, and
worsened in the 3rd. 1 developed IOP increase.
Patel and Lee (2006)91 Intravitreal triamcinolone 4 mg x1 0–14 d 20 cases, 0 controls Case series IV VA improved at least 1 line in 55%.
Systemic: Oral
Vidović et al (2015)92 Methylprednisolone 80 mg daily for Variable (not 38 cases, 0 controls Case series IV Improvement in both VA and VF in 65%, no change in 30%,
5 d, then taper reported) worsening in 5%.
Prokosch and Thanos Fluocortolone taper starting at 1 mg/kg 0–3 d 30 cases, 30 controls (both Prospective, II Improved VA but not VF.
(2014)62 for 5 d, then taper; all were taking cases and controls quasirandomized*
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018

pentoxifylline were also treated with intervention trial,

pentoxifylline) unblinded
Rebolleda et al (2013)70 Prednisone taper starting at 80 mg 0–14 d 10 cases, 27 controls Case control (with III No visual improvement. 3 of the 10 treated had complications due to
comparison to steroids.
noncontemporary
controls)
Hayreh and Zimmerman Prednisone 80 mg for 14 d, then taper 0–14 d 236 cases, 301 controls Prospective, nonrandomized, III VA improved in 69.8% of treated compared with 40.5% of controls;
(2008)68 controlled VF improved in 40.1% of treated compared with 24.5% of
controls.
Hayreh (1974)56 Steroids 40–80 mg daily Variable 8 cases, 6 controls Case control III VA improved in 75% of treated compared with 17% of controls.
Foulds (1970)67 Steroids 60 mg daily 13 cases, 11 controls Case control III VA improved in 85% treated compared with 45% of controls.
Systemic: Intravenous
Pakravan et al (2016)63 IV MP 500 mg BID for 3 d, then PO 0–14 d 30 cases, 30 controls, Randomized controlled trial, II No statistically significant differences.
prednisone 1 mg/kg/d for 14 d 30 treated with nonblinded
alternative treatment
(hyperbaric oxygen)

Copyright © 2018 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Kinori et al (2014)71 IV MP 250 mg q6hr for 3 d, then PO 0–14 d 23 cases, 23 controls Retrospective case III No statistically significant differences.
prednisone taper

*Unclear from paper why they call it “quasirandomized”.

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BID indicates 2 times per day; IOP, intraocular pressure; MP, methylprednisolone; PO, taken orally; q6hr, every 6 hours; VA, visual acuity; VF, visual field.

221
Steroid Treatment of Optic Neuropathies
Stunkel and Van Stavern
patients. However, there are important limitations. The lack of
randomization and the lack of blinding raise concerns about bias.
The 2 groups were not equivalent at baseline. The control group
was older (the mean age was 59.2 in the steroid-treated group
and 62 in the control group, P = 0.006) and had more vascular
risk factors. Different rates of hypertension—34% versus 43%
(P = 0.036)—reached statistical significance. Ischemic heart dis-
ease, transient ischemic attack/stroke, and diabetes mellitus were
also seen at a higher rate in the control group (but did not reach
statistical significance).68 Hayreh has defended the validity of his
results despite the lack of randomization by arguing that the 2
groups are similar enough that the data is useful, pointing spe-
cifically to the demographic results as reported above.69 Further-
more, the data were analyzed using those factors as covariates to
minimize their effect on the results.68,69 However, it is important
to note that even if the 2 groups seem similar in every important
way, the aim of randomization is also to produce groups that are
the same regarding variables that could never be predicted to have
an impact on the results. The lack of placebo control, blinding, or
masking in the study is arguably an even more important source
of bias. It is unknown to what extent the placebo effect, along
with other factors mentioned above (response bias, regression to
the mean, and so on), might have influenced patients’ recovery as
well as their experience of their recovery, especially in a disease
that has a natural history of some spontaneous improvement.
Since the Hayreh and Zimmerman study in 2008,68 there have
been a few additional studies of oral steroids in NAION. In 2013,
a retrospective study of 10 patients who received prednisolone
80 mg daily for 14 days followed by a taper showed no improve-
ment with steroid treatment and showed steroid-related compli-
cations in 3 out of the 10 patients.70 The only randomized study
of oral steroids, done in 2013, compared 30 patients randomized
to receive fluocortolone therapy as adjuvant to pentoxifylline
versus 30 controls who received pentoxifylline alone. Patients
treated with steroids had improvement in visual acuity but not
visual fields.62 Visual acuity improvement without corresponding
improvement in visual fields has often been called into question
due to the fact that the visual acuity improvement may be due to
eccentric fixation and not due to structural improvement.55,59
There have been only 2 studies of intravenous steroid treat-
ment for NAION. In 2014, a retrospective study found no statis-
tically significant difference comparing 23 patients who received
IV methylprednisolone for 3 days followed by a prednisone taper
with 23 controls.71 In 2016, a randomized, placebo-controlled,
unmasked trial comparing 30 patients who received IV methyl-
prednisolone for 3 days then prednisone taper against 30 controls
also found no statistically significant difference.63
Despite its flaws, the data collected by the large Hayreh and
Zimmerman68 study cannot be discarded. However, it must be
interpreted in light of its limitations and in the context of other
available data. If steroids have a positive effect on recovery in
NAION, then this effect should be reproducible in other studies.
However, other studies have been unable to replicate these results.
More recently, intravitreal steroid injections have been eval-
uated as a possible route of administration that would allow the
patient to have maximal benefit without exposure to the adverse
effects of systemic steroids. Small case series showed mixed re-
sults and found that ocular hypertension is a potential adverse
effect.72–74 Two case-control studies have shown improvement.
In 2007, Kaderli et al75 showed improvement in visual acuity
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Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018
but not visual fields in 4 patients who received intravitreal tri-
amcinolone compared with 6 controls. However, the study was
criticized because the visual acuity change may have been due to
eccentric fixation. In 2014, Radoi et al76 showed both visual acui-
ty improvement and visual field improvement in 21 patients who
received intravitreal triamcinolone compared with 15 controls.76
The debate over steroids for NAION has been limited by
small studies, lack of randomization, and difficulty in determining
what improvements are truly due to treatment effect in a disease
with wide variation in its natural history. The allure of steroids as
a treatment is in part due to plausibility and in part due to the fact
that there is no proven treatment for patients with NAION. How-
ever, the evidence to date would argue against the routine use of
corticosteroids for patients with NAION.
STEROIDS FOR TRAUMATIC OPTIC NEUROPATHY
Traumatic optic neuropathy (TON) refers to damage to the
optic nerve that occurs due to trauma to the head or the face. The
incidence is around 1 per million.77,78 Presenting visual acuity is
6/60 or worse in 70% of patients, and 36% of patients may have
no light perception.77 However, the rate of spontaneous recovery
may be as high as 40–60%.79 Worse visual acuity at the time of
injury corresponds to worse visual outcomes.77
There are 2 mechanisms of trauma-related injury to the optic
nerve—direct and indirect. Direct trauma to the optic nerve refers
to an injury that causes mechanical disruption of the nerve, which
can be due to a penetrating injury or due to orbital fractures with
bone shards lacerating or impinging directly upon the nerve. Indi-
rect trauma to the optic nerve refers to cases in which the nerve is
not directly or mechanically injured, but optic neuropathy devel-
ops after trauma to the head or face. Indirect trauma is thought to
damage the optic nerve due to shearing of the retinal ganglion cell
axons in the optic canal.80 Primary injury is immediate damage
due to either direct laceration or compression of the optic nerve
or due to shear forces. Secondary injury is delayed-onset damage,
thought to be at least in part due to inflammation and subsequent
edema within the confined space of the bony canal leading to
compression of capillaries and thus ischemic damage.80–83
There has been longstanding controversy regarding the best
course of treatment for TON. Steroid treatment, the focus of this
article, aims to minimize secondary injury due to inflammation
and edema. Another common treatment option is surgical decom-
pression of the optic canal, also intended to minimize secondary
damage due to swelling. A third option, watchful waiting, is in-
tended to minimize potential harm from those controversial treat-
ments, especially in light of the fact that spontaneous recovery is
not uncommon.79
The idea that steroids may decrease inflammation in
TON came from the National Acute Spinal Cord Injury Study
(NASCIS). The spinal cord, like the optic nerve, is heavily my-
elinated and encased in a bony structure that physically limits its
ability to swell safely. Steroids for spinal cord injury are intend-
ed to prevent or decrease inflammation and swelling and thereby
minimize further damage to the spinal cord. The NASCIS was
a study of acute spinal cord patients that showed benefit for IV
steroids given within 8 hours. It showed that patients who were
treated with intravenous steroids within 8 hours of spinal cord
injury had better motor and sensory outcomes 6 months later.84,85
However, clinical studies have remained inconclusive about the
© 2018 Asia-Pacific Academy of Ophthalmology
 TABLE 3. Studies Examining Steroid Treatment in TON
Author (Year) Intervention
Lai et al (2016)93 IV MP 30 mg/kg x1, then 15 mg/kg q6hr
for 3 d
Ropposch et al (2013)94 Variable: 10 received >500 mg IV MP
initial dose, 11 received low-dose
regimen
Miliaris et al (2013)95 IV MP 1 g per 24 hr for 3 d
Soldevila et al (2013)96 IV MP 250 mg q6hr for 3 d, then
© 2018 Asia-Pacific Academy of Ophthalmology
prednisone 80 mg PO daily for 1
week, then alternating for 3 more d
Ford et al (2012)78 Variable: Included oral prednisolone,
oral dexamethasone, and IV MP
Samardzic et al (2012)82 IV MP 30 mg/kg IV x1, 2 hr later IM
VP 15 mg/kg q6hr for 24–48 hr; also
received steroid eye drops
Lee et al (2010)77 Variable: Included IV dexamethasone,
IV MP, and oral prednisolone
Tandon and Dorrepaal IV MP for 2 d
(2009)97
Dojcinovic and Richter IV MP 1 g/d for 2 d; later developed
(2008)98 retrobulbar hematoma and received
additional IV MP 1 g/d for 14 d
Entezari et al (2007)88 IV MP 250 mg q6hr for 3 d, then
prednisolone PO 1 mg/kg for 14 d
Copyright © 2018 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Das et al (2007)99 IV MP 30 mg/kg x1, then 5.4 mg/kg/hr
for 48 hr, then 2 wk PO prednisone
taper
www.apjo.org |
223
Time From Class of
Onset N Study Type Edvience Results
Variable. Comparing steroid 20 treated, 0 controls; 0 underwent Case series IV Receiving steroids within 0–24 hours of injury
treatment: 0–8 hr, surgical decompression. was correlated with improvement.
8–24 hr, >24 hr
Variable 21 treated, 21 controls; 42 underwent Case control III Steroids had no beneficial effect on visual
surgical decompression. outcome (P = 0.97).
Unclear 5 treated, 0 controls; 0 underwent Case series IV Vision returned in 1 patient.
surgical decompression.
Unclear 1 treated, 1 control; 0 underwent Case series IV No significant difference in outcome.
surgical decompression.
0–48 hr Pediatric; 9 treated, 14 controls; Prospective case III No significant improvement with steroids.
0 underwent surgical control
decompression.
30 min 1 treated, 0 controls; 0 underwent Case report IV Vision returned to baseline.
surgical decompression.
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018
Variable 35 treated with steroids and/or Prospective case III The proportion of patients with VA that
surgical decompression, 58 control improved 3 lines or more was similar in the
controls treated (24%) and untreated (20%) group
(P = 0.61). However, patients with worse
VA were more likely to be treated.
24 hr Pediatric; 1 treated, 0 controls; Case report IV Final VA counting fingers at 0.6 m.
Underwent surgical
decompression.
0d 1 treated, 0 controls; Underwent Case report IV After 1 round of steroids, OD recovered
surgical decompression. completely, OS recovered to LP. After 2
Patient with bilateral TON and rounds of steroids, OD recovered 20%,
contaminated cheek wound. then developed mucormycosis.
0–7 d 16 treated, 15 controls; 0 underwent Double-masked, I VA improved in 68.8% of the treatment group
surgical decompression. placebo- and 53.3% of the placebo group (P = 0.38).
controlled,
randomized
3 hr to 11 d 9 treated, 0 controls; 0 underwent Case series IV 2 patients improved, these 2 improved were
surgical decompression. treated at a shorter time since onset. No
complications due to steroids.
Continued on next page
Steroid Treatment of Optic Neuropathies
 TABLE 3. (Continued)
Author (Year)
100
Acaturk et al (2004)
224 | www.apjo.org
Hsieh et al (2004)87
Rajiniganth et al (2003)101
Levin et al (1999) (The
International Optic
Nerve Trauma
Study)86
Mahapatra and Tandon
(1993)102
Joseph et al (1990)103
LP indicates light perception; NLP, no light perception; OD, right eye; OS, left eye.
Copyright © 2018 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
© 2018 Asia-Pacific Academy of Ophthalmology
Time From Class of
Intervention Onset N Study Type Edvience Results
11 treated, 0 controls; 8 underwent Case series IV All patients had complete improvement; none
IV MP 30 mg/kg x1, then 5.4 mg/kg/hr 0–1 d
for 48 hr, then prednisone taper surgical decompression. had complications due to steroids.
Stunkel and Van Stavern
IV MP 1–2 g (~30 mg/kg) then 500 mg Unclear 33 treated, 15 controls; 22 Retrospective case III No significantly improved vision was found
q6hr for 72 hr, then taper eyes underwent surgical control after treatment with mega dose steroids.
decompression. In patients who did improve, steroids
correlated with greater improvement.
IV MP 30 mg/kg/d for 72 hr, then PO Variable; 11 patients within 44 treated, 0 controls; 30 underwent Prospective, IV Combined therapy (both steroids and surgery)
prednisolone 1 mg/kg/d for 11 d, 3 d; 12 patients within surgical decompression. nonrandomized was more successful when initiated within
then taper 4–7 d; 21 patients >7 d case series 7 d of injury.
Variable, ranging from 100 mg daily 0–7 d 85 treated, 9 controls; 33 additional Prospective II VA increased by ≥3 lines in 32% of the surgery
to ≥5400 mg daily patients underwent surgical comparative group, 57% of the untreated group, and
decompression. nonrandomized 52% of the steroid group (P = 0.22).
interventional
study
Dexamethasone 4–8 mg (1 mg/kg) Unclear Pediatric; 50 treated, 0 controls; Prospective case IV 50% improved on steroid therapy.
IV q6hr for 48 hr, then oral or 7 underwent surgical series
nasogastric prednisolone for 3 wk decompression.
Dexamethasone 8–10 mg IV for 1–2 d 0–7 d 14 treated, 0 controls; 14 Case series IV 11 of the 14 patients improved, including 3 of
underwent surgical the 5 who were NLP at time of injury. No
decompression. adverse effects.
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018
efficacy of steroids in TON (Table 3). There are few data on the
natural history of TON, which makes it difficult to evaluate the
effect of treatment and much of the available literature consists of
case reports or case series without controls.
The International Optic Nerve Trauma Study in 1999 was
the earliest controlled study of steroids for TON and showed no
improvement due to steroid treatment. However, the study was
not randomized, only had 9 patients in the control group, and the
steroid doses patients received were quite variable.86 In 2004, a
retrospective study of patients with TON treated with mega dose
steroids (the regimen tested in the NASCIS) compared with un-
treated controls did not show a higher rate of improvement with
steroid treatment. However, in patients who did improve, steroid
treatment correlated with a greater degree of improvement. This
study did not control for whether patients received surgical de-
compression as well.87 The only randomized, placebo-controlled
trial was unable to show a statistically significant benefit of ste-
roids. In 2007, a randomized, placebo-controlled, double-blind-
ed study of 31 patients showed improvement in visual acuity in
68.8% of the treatment group and 53.3% of the placebo group,
but the difference was not statistically significant (P = 0.38).88
Subsequent literature has been limited to case reports and case
series. However, despite the lack of strong evidence that steroids
are efficacious for TON, steroids continue to be used, often due
to individual and institutional preferences. This limits the data
available on the natural history of TON.
The urgency of determining whether steroids are efficacious
for TON increased with the results of the Corticosteroid Rando-
misation After Significant Head Injury study, which showed that
steroid treatment may increase mortality in patients with traumat-
ic brain injury.89 All patients with TON by definition have a head
injury, and many of them have traumatic brain injuries. There-
fore, given the lack of robust evidence of benefit for steroids in
TON, the potential risk may outweigh any potential benefit.
Evaluation of steroids as a treatment for TON has also been
limited by poor recruitment, variable steroid regimens, recruit-
ment of patients at variable time limits after injury, the broad
range of severity seen in TON, and variable comorbidities of pa-
tients. Furthermore, surgical decompression may also confound
analysis of the effects of steroids. Traumatic optic neuropathy is
a complicated disorder and there are not yet sufficient data on
whether steroids improve visual outcomes. It is important to im-
prove understanding of the possible benefits of steroids for optic
neuropathy in light of the risks of steroid treatment in patients
with head injuries.
CONCLUSIONS
The optic neuropathies described above all have a natural
history of (varying degrees of) acute to subacute onset of visual
disturbance, often followed by slow improvement, even without
treatment. This makes it particularly difficult to analyze the effi-
cacy of treatments for these disorders. When studying conditions
that may improve spontaneously, it is particularly important to
have a matched control group to avoid confounding, as discussed
above. These conditions may manifest with a variety of severities
at initial presentation, complicating analysis of treatment efficacy.
Traumatic optic neuropathies and NAION are particularly com-
plicated in that a single optic nerve injury may have more than 1
mechanism of injury contributing to the manifested visual loss.
© 2018 Asia-Pacific Academy of Ophthalmology
Copyright © 2018 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Steroid Treatment of Optic Neuropathies
The complicated mechanism of these optic neuropathies
makes it less surprising that large clinical trials have found un-
expected results—for example, the ONTT finding that treatment
does not impact final visual outcome and that treatment with oral
steroids is associated with an increased incidence of recurrence
of optic neuritis. This demonstrates the value of doing large, ran-
domized clinical trials to evaluate for unexpected outcomes and
control for unforeseeable variables.
For optic neuritis, it is well established that intravenous ste-
roid treatment can speed visual recovery but does not alter final
visual function. Oral steroids, which have long been avoided in
optic neuritis out of concern that they may increase the risk of
recurrence, have recently been shown to speed visual recovery
when given at doses bioequivalent to intravenous treatment doses
without increasing recurrence rates over a 6-month follow-up pe-
riod. Additionally, the typical patient with optic neuritis is young
and otherwise healthy, and thus likely to tolerate steroids well.
For traumatic and ischemic optic neuropathies, the evidence for
the efficacy of treatment with steroids is insufficient to show that
there is significant benefit. Additionally, patients with these con-
ditions are more likely to have comorbidities—head injury in the
case of TON and metabolic and vascular disease in the case of
NAION—that make them more likely to have significant adverse
events with the use of steroids. The use of corticosteroids for
TON and NAION remains unproven and the individual physician
must decide whether to use these treatments on a case-by-case
basis, weighing the risk against any potential benefit.
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