Editorial

Erythropoietin for Optic Neuritis

Rod Foroozan, MD

Division of Neuro-Ophthalmology, Baylor College of Medicine, Houston, TX, USA

ORCID:
Rod Foroozan: https://orcid.org/0000-0002-7937-830X

J Ophthalmic Vis Res 2019; 14 (3): 240–242

Inflammatory optic neuropathy remains the most
common acute optic neuropathy in patients under
the age of 50 years. The most common cause
for inflammatory optic neuropathy is sterile inflam-
mation from demyelination, with multiple sclerosis
(MS) as the most common associated condition.
This is the type of optic neuropathy most commonly
referred to as “optic neuritis.” The inflammation
more commonly occurs posteriorly, does not cause
optic disc edema, and is termed retrobulbar optic
neuritis.

For the last 25 years or so, and primarily based
on information from the optic neuritis treatment
trial (ONTT),[1] the standard treatment for acute
inflammatory optic neuritis has been high dose
corticosteroids, typically given intravenously for 3–
5 days, followed by oral steroids. The expectation is
that corticosteroids will hasten visual improvement
without altering the degree of recovery of visual
function. There has been a relative paucity of
adjunctive agents that have been used in con-
junction with corticosteroids. Given the persistent
deficits that remain after a bout of optic neuritis,
there remains an unmet need for neuroprotective
therapy.

Erythropoietin, best recognized as a regulator
of erythropoiesis, has shown potential neuropro-
tective properties in animal models of brain injury,
including that from ischemia, trauma,[2, 3] epilepsy,
and optic neuropathy.[4, 5] A rat model using immu-
nization with myelin oligodendrocyte glycopro-
tein (MOG) showed functional and histopatholog-
ical improvement of retinal ganglion cells and
optic nerves when erythropoietin treatment was
combined with high dose methylprednisolone
therapy.[6]

The use of erythropoietin in humans with
optic neuropathy has been reported in multiple
studies from Iran. The treated conditions included

traumatic optic neuropathy,[7, 8] nonarteritic
anterior ischemic optic neuropathy,[9, 10] multiple
sclerosis,[11] and methanol optic neuropathy.[12–14]
With some exceptions (particularly methanol optic
neuropathy), the proof of benefit has been rather
underwhelming thus far; however, the balance of
evidence suggests that there has been no harm to
visual function (although one patient was reported
to develop cerebral venous sinus thrombosis[11]).

One confounding issue with prior studies
assessing the effect of erythropoietin on optic
neuropathy is that the method of administration
of the agent varied and included intravenous
injection, intravitreal injection, and the use of
microspheres. In addition, the dose of erythropoi-
etin was inconsistent between the studies.

In this issue, Soltan Sanjari and coworkers
assessed the addition of intravenous recombinant
human erythropoietin (IVE) to intravenous methyl-
prednisolone (IVMP) in patients with retrobulbar
optic neuritis. Thirty-five patients were treated with
IVMP alone and twenty-seven with the combination
of IVMP and IVE (20,000 international units). Both
groups were treated with intravenous agents for
3 days and were then given 11 days of oral
prednisolone at 1 mg/kg. The primary outcome
measure was the change in best corrected visual
acuity, which was assessed up to 120 days. Other
measures of visual function included contrast sen-
sitivity (Yang vision tester), color vision (Ishihara
pseudoisochromatic color plates), and automated
perimetry (Humphrey 24-2 SITA Standard).[15]

While the cited inclusion criteria were described
as those from the ONTT, it was not clear what
ancillary laboratory studies were performed, and
specifically whether blood was sent for aquaporin-
4 and anti-MOG antibodies.[15]

By three months, there was no difference in
the visual acuity between the two groups. In

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Editorial; Foroozan

addition, there was no suggestion that the rate
of visual recovery was different between the two
groups. The mean deviation on automated perime-
try showed no difference between the two groups
at three months. There was also no difference in
the contrast sensitivity and color vision between
the two groups after treatment.[15]

The authors should be commended for enrolling
a relatively large number of patients with inflam-
matory optic neuropathy within a short (10 day)
window of symptoms. It was slightly disappointing
that there were no structural, objective measures
such as optical coherence tomography (OCT) of
the retinal nerve fiber layer (RNFL), ganglion cell
layer, or macula, particularly given the citation of
work from another group which showed less RNFL
thinning in patients with optic neuritis treated with
IVE (33,000 international units) and IVMP for three
days.[16]

While this was a negative study in terms of
primary visual outcome, the authors point out
that there was no evidence of clinically relevant
side effects of IVE treatment. This is consistent
with the prior literature. Regardless of the route
of administration (including intravitreal injection),
the use of erythropoietin appears to be safe,
which is encouraging given the approval of a ran-
domized, placebo-controlled trial [clinicaltrials.gov
(NCT01962571)] from a group of investigators in
Germany.[17]

So far, IVE for optic neuritis and demyelination[18]
has not proven to be a game changer. If additional
studies are performed, I would encourage the
authors to include additional measures of structure
and function of the visual pathways to ensure
that the focus is not solely on central visual
function.

REFERENCES

1. Beck RW, Cleary PA, Anderson MM, Jr., Keltner JL, Shults
WT, Kaufman DI, et al. A randomized, controlled trial of
corticosteroids in the treatment of acute optic neuritis. The
Optic Neuritis Study Group. N Engl J Med 1992;326:581–
588.

2. King CE, Rodger J, Bartlett C, Esmaili T, Dunlop SA,
Beazley LD. Erythropoietin is both neuroprotective and
neuroregenerative following optic nerve transection. Exp
Neurol 2007;205:48–55.

3. Tan H, Zhong Y, Shen X, Cheng Y, Jiao Q, Deng L.
Erythropoietin promotes axonal regeneration after optic
nerve crush in vivo by inhibition of RhoA/ROCK signaling
pathway. Neuropharmacology 2012;63:1182–1190.

4. Weishaupt JH, Rohde G, Polking E, Siren AL, Ehrenreich H,
Bahr M. Effect of erythropoietin axotomy-induced apopto-
sis in rat retinal ganglion cells. Invest Ophthalmol Vis Sci
2004;45:1514–1522.

5. Zhong L, Bradley J, Schubert W, Ahmed E, Adamis
AP, Shima DT, et al. Erythropoietin promotes survival of
retinal ganglion cells in DBA/2J glaucoma mice. Invest
Ophthalmol Vis Sci 2007;48:1212–1218.

6. Diem R, Sattler MB, Merkler D, Demmer I, Maier K, Stadel-
mann C, et al. Combined therapy with methylprednisolone
and erythropoietin in a model of multiple sclerosis. Brain
2005;128:375–385.

7. Kashkouli MB, Pakdel F, Sanjari MS, Haghighi A, Nojomi
M, Homaee MH, et al. Erythropoietin: a novel treatment for
traumatic optic neuropathy-a pilot study. Graefes Arch Clin
Exp Ophthalmol 2011;249:731–736.

8. Entezari M, Esmaeili M, Yaseri M. A pilot study of the
effect of intravenous erythropoetin on improvement of
visual function in patients with recent indirect traumatic
optic neuropathy. Graefes Arch Clin Exp Ophthalmol
2014;252:1309–1313.

9. Modarres M, Falavarjani KG, Nazari H, Soltan Sanjari
M, Aghamohammadi F, Homaii M, et al. Intravitreal ery-
thropoietin injection for the treatment of non-arteritic
anterior ischaemic optic neuropathy. Br J Ophthalmol
2011;95:992–995.

10. Pakravan M, Esfandiari H, Hassanpour K, Razavi S, Pakra-
van P. The effect of combined systemic erythropoietin and
steroid on non-arteritic anterior ischemic optic neuropathy:
a prospective study. Curr Eye Res 2017;42:1079–1084.

11. Borhani-Haghighi A, Ghodsi M, Razeghinejad MR, Mardani
S, Mardani M, Nikseresht AR, et al. Erythropoietin for acute
multiple sclerosis in patients with optic neuritis as a first
demyelination event. Neurosciences (Riyadh) 2012;17:151–
155.

12. Pakravan M, Sanjari N. Erythropoietin treatment for
methanol optic neuropathy. J Neuroophthalmol 2012;32:
325–328.

13. Pakravan M, Esfandiari H, Sanjari N, Ghahari E. Erythropoi-
etin as an adjunctive treatment for methanol-induced toxic
optic neuropathy. Am J Drug Alcohol Abuse 2016;42:633–
639.

14. Pakdel F, Sanjari MS, Naderi A, Pirmarzdashti N, Haghighi
A, Kashkouli MB. Erythropoietin in treatment of methanol
optic neuropathy. J Neuroophthalmol 2018;38:167–171.

15. Soltan Sanjari M, Pakdel F, Moosavi F, Pirmarzdashti N,
Nojomi M, Haghighi A, et al. Visual outcomes of adding
erythropoietin to methylprednisolone for treatment of
retrobulbar optic neuritis. J Ophthalmic Vis Res 2019;299–
305.

16. Suhs KW, Hein K, Sattler MB, Gorlitz A, Ciupka C, Scholz
K, et al. A randomized, double-blind, phase 2 study of
erythropoietin in optic neuritis. Ann Neurol 2012;72:199–
210.

17. Diem R, Molnar F, Beisse F, Gross N, Drüschler K, Heinrich
SP, et al. Treatment of optic neuritis with erythropoietin
(TONE): a randomised, double-blind, placebo-controlled
trial-study protocol. BMJ Open 2016;6:e010956.

18. Suhs KW, Papanagiotou P, Hein K, Pul R, Scholz K, Heesen
C, et al. Disease activity and conversion into multiple
sclerosis after optic neuritis is treated with erythropoietin.
Int J Mol Sci 2016;17:1666.

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How to cite this article: Foroozan R. Erythropoietin for optic neuritis. J
Ophthalmic Vis Res 2019;14:240–242.

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