2011 by the Iranian Society of Ophthalmology

Published by Otagh-e-Chap Inc.

11

Memantine Treatment in Acute Nonarteritic Anterior
Ischemic Optic Neuropathy: A Randomized Clinical Trial
Mohammad Riazi Esfahani, MD
1,2
Zahra Aalami Harandi, MD
1
Saman Kiumehr, MD
3

Afsaneh Gholmi, MD
3
Abdolreza Tabasi, MD
4
Niloofar Piri, MD
5
Ahmad Mirshahi, MD
1

Mehdi Nili Ahmadabadi, MD
6
Morteza Movassat, MD
1
Ghasem Fakhraee, MD
7


Abstract

Purpose: To evaluate the effects of memantine on improving visual function in patients with acute nonarteritic
anterior ischemic optic neuropathy (NAION)
Methods: This was a prospective, double masked, randomized, clinical trial. The study involved 47 subjects
with unilateral NAION of less than 8 weeks duration. Eligible patients were randomly allocated to take either
memantine tablets (5 mg daily during the first week and then 10 mg daily for the next two weeks, 25
subjects) or placebo tablets (22 subjects). Baseline visual acuity (VA) tests, pattern visual evoked potential
(VEP) and automated perimetry (SITA-standard 24-2) were performed. VA tests were repeated 3 weeks, 3
months and 6 months after initial visit. VEP and automated perimetry were repeated 3 months after initial
visit.
Results: At baseline there was no significant difference between the two groups in terms of clinical and
laboratory characteristics. After 3 weeks, 3 months and 6 months of treatment, best corrected visual acuity
(BCVA) improved by -0.310.39, -0.490.47 and -0.530.48 logMAR in the memantine group respectively
and -0.020.41, -0.090.60 and -0.050.67 logMAR in the placebo group respectively (P=0.024, P=0.025
and P=0.017). VEP results demonstrated a reduction of implicit time of -8.3217.18 ms in the memantine
group after 3 months, whereas in the placebo group it increased +5.721.60 ms (P=0.043). The change in
VEP amplitude was not significantly different between the memantine and placebo groups (P=0.083). The
effect of the memantine on mean deviation (MD) and pattern standard deviation (PSD) changes was not
significantly different from that of the placebo (P=0.428 and 0.863 respectively).
Conclusion: Treatment of patients who experience acute NAION with memantine may result in significant
improvement in BCVA compared with no treatment. The VEP changes seen at 3 months may indicate
improved transmission of impulses through the optic nerve.

Keywords: Automated Perimetry, Memantine, Nonarteritic Anterior Ischemic Optic Neuropathy, Visual Evoked
Potential

Iranian Journal of Ophthalmology 2011;23(1):11-20 2011 by the Iranian Society of Ophthalmology

1. Associate Professor of Ophthalmology, Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences
2. Noor Ophthalmology Research Center, Noor Eye Hospital
3. Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences
4. Associate Professor of Neurology, Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences
5. Fellowship in Vitreoretinal, Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences
6. Professor of Ophthalmology, Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences
7. Assistant Professor of Ophthalmology, Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences

Received: May 27, 2010
Accepted: January 20, 2011

Correspondence to: Zahra Aalami Harandi, MD
Associate Professor of Ophthalmology, Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran,
Iran, Tel:+98 21 55414941-6, Email: aalami_harandi@yahoo.com

No authors have any financial/conflicting interests to disclose.
This study was supported by a grant from the Research Section of Tehran University of Medical Sciences.
Presented in part as a poster at the Eighth European VitreoRetinal Society Congress - Prague - Czech Republic- September 6-9, 2008.
Iranian Journal of Ophthalmology Volume 23 Number 1 2011

12
Introduction
Nonarteritic anterior ischemic optic
neuropathy (NAION) is the most common
cause of visual loss from optic nerve diseases
among individuals older than 50 years, with an
annual incidence rate of 2.3 to 10.2 per
100,000 persons for this population group.
1

Patients with NAION typically present with
painless monocular visual loss developing
over hours to days. Visual field loss is always
present and includes altitudinal defect, central
scotoma and generalized depression. A
relative afferent pupillary defect (RAPD) is
present unless the optic neuropathy is
bilateral. The affected optic disk is by
definition always swollen.
2
There is no widely
accepted treatment for NAION. Although
surgical decompression and various medical
therapies have been proposed, none has
been consistently shown to be effective.
2

NAION is caused by disruption in arterial
blood supply to the optic nerve head.
3,4
This
disruption leads to permanent visual loss from
ischemic injury to optic nerve axons, ultimately
resulting in death of retinal ganglion cells from
necrosis and apoptosis.
5
Glutamate is the
principal excitatory neurotransmitter in the
retina. Retinal ischemia is associated with an
increase in the level of extracellular glutamate
and excessive activation of N-methyl-d-
asparate (NMDA) type glutamatergic
receptors.
6
NMDA-type glutamatergic
excitotoxicity has been implicated as a
mechanism for ischemic injury to retinal
ganglion cells and neurons in many regions of
the CNS and drugs that directly antagonize
the actions of glutamate have been shown to
be neuroprotective.
7

Memantine is a relatively new drug
especially developed for use in moderate to
severe dementia and approved by the FDA in
2003 because of its significant efficacy.
8
It is a
noncompetitive NMDA receptor antagonist
and reduces glutamatergic excitotoxicity.
8

Memantine has also been used for the
treatment of Parkinson disease in Europe for
the last 2 decades.
9
In fact, the pathogenesis
of both dementia and Parkinson disease has
been linked to excitotoxic injury induced by
excessive glutamate levels in the synaptic
cleft and over-stimulation of the NMDA
receptor.
8,9
Memantine has been shown to
ameliorate glutamate NMDA-receptor
mediated toxicity in both retinal ganglion cells
and cortical neurons.
10-12
There are several
studies indicating that memantine is
neuroprotective in various in vitro and in vivo
animal models of neural cell/brain
ischemia
13-21
as well as glaucoma.
22-25

Memantine has been shown to reduce the
retinal injury in rat ischemia/reperfusion
models.
26,27
In addition, memantine has been
shown to be relatively safe and is well
tolerated in patients.
28
We have recently
shown that memantine significantly improved
visual acuity (VA) in a nonrandomized small
group of patients with acute NAION.
29

The aim of the current randomized clinical
trial was to compare the effects of memantine
on VA, visual field and visual evoked potential
(VEP) findings with placebo in patients with
acute NAION.

Methods
This prospective randomized double-masked
clinical trial was registered at
http://www.anzctr.org.au as
ACTRN12607000181404. Subjects with acute
visual loss from unilateral NAION of less than
8 weeks duration were enrolled. Inclusion
criteria were as follows: acute onset of
painless loss of vision, localized or
generalized swelling with or without pallor of
the optic nerve head, flame-shaped
hemorrhages, arterial narrowing without
venous congestion, a RAPD, and a visual field
defect.
This study was performed with informed
consent and following all the guidelines for
experimental investigations required by the
investigational review board and ethics
committee of Tehran University of Medical
Sciences.
The main exclusion criteria were: age<40
years, elevated sedimentation rate as well as
presence of systemic signs and symptoms
consistent with arteritic AION, diabetic
retinopathy, uncontrolled glaucoma, or
conditions other than NAION that could
contribute to the visual loss, drug history such
as anti-convulsants, barbiturates,
neuroleptics, amantadine, hydrochlorthiazide
and history of renal insufficiency.
At baseline, eligible subjects were
randomly assigned to receive either
memantine or placebo, in a masked fashion.
All patients underwent a complete ophthalmic
Riazi Esfahani et al Memantine in Acute Nonarteritic Anterior Ischemic Optic Neuropathy

13
examination including manifest refraction to
determine best corrected visual acuity (BCVA)
by ETDRS chart and expressing acuity in
logMAR scale, visual field testing using a
Humphrey automated perimeter (24-2 SITA-
standard program), slit-lamp examination,
tonometry, evaluation of pupillary responses
to light stimulation, and funduscopic
examination with a fully dilated pupil using an
indirect ophthalmoscope and/or a 78-diopter
biconvex indirect lens with the slit-lamp
biomicroscope. All patients were referred to a
cardiologist for assessment of cardiovascular
status, including measurement of blood
pressure. Laboratory evaluation including
complete blood count (CBC), erythrocyte
sedimentation rate (ESR), C-Reactive Protein
(CRP), fasting blood sugar (FBS), cholesterol,
triglyceride, blood urea nitrogen (BUN) and
creatinine measurements were done for all
subjects at baseline. VEP (pattern VEP if
possible), and color fundus photography were
performed at baseline. Fluorescein
angiography was done if necessary.
For suspicion of an intracranial mass
lesion, demyelinating disease, or other
neurologic conditions, a neurologic consult
was obtained and neuroimaging performed.
Each subject received either memantine
(Ebixa) tablets (5 mg daily for first week and
10 mg daily for the next 2 weeks) or placebo
taken in the same manner. Both placebo and
memantine tablets were made similar in
appearance by putting memantine tablets into
a capsular shell containing lactose
monohydrate/microcrystal cellulose. Placebo
capsules contained only lactose
monohydrate/microcrystal cellulose. Both the
patient and the treating physician were
masked to the drug being dispensed. Medical
and ophthalmologic data, including BCVA and
fundoscopy were collected at baseline and at
3 weeks, 3 months and 6 months after
initiation of treatment. Perimetry was
performed at the 3-month follow-up as was
VEP.
Improvement in BCVA was defined as a
difference of -0.3 logMAR or less between the
follow-up and the initial visit VAs. This change
corresponds to an improvement of three lines
on a Snellen VA chart and represents a
doubling of the visual angle. The main
outcome of pattern VEP were changes of
implicit time [P100 millisecond (ms) or P2
(flash VEP)] and amplitude (v) and the two
main measurements of automated perimetry
(SITA-standard C24-2) were mean deviation
(MD) and pattern standard deviation (PSD).

Statistical analysis
Sample size was calculated from the result of
previous studies which showed 42.7%
spontaneous improvement of VA in NAION.


N=
2[ z(1-
/2
) + z(1- )
2
] P(1-p)
(P
0
- P
1
)
2


P
0
= 40% improvement of visual acuity in the
placebo group
P
1
= 80% improvement of visual acuity in the
Memantine group
=5%
=20%
Attrition rate =20%

Thus, the minimum number of subjects
necessary to detect a clinically meaningful
difference to a power of 80% and risk of 5%
and a loss to follow up of 20% was 44.
Statistical analysis was performed by the
T-test and the
2
test with SPSS software
version 11.5. The level of significant for all
analyses was set at P<0.05.

Results
A total of 47 patients with NAION were
enrolled. 25 subjects were in the memantine
group and 22 subjects were in the placebo
group. Tables 1 and 2 summarize the
demographic data and results of the study.
The meanone standard deviation is provided.
The demographic and ocular characteristics of
the subjects at baseline were similar between
the two groups.
The mean duration of symptoms from the
onset of NAION to the initiation of treatment
was 19.811.6 days (ranging from 4 to 42
days) in the memantine group and 17.811.6
days (ranging from 5 to 50 days) in the
placebo group (P=0.548). Distribution of risk
factors between the two groups was similar
(Table 1). Over all, systemic hypertension was
found in 25 subjects (53.2%), diabetes in the
18 subjects (38.3%) and hyperlipidemia in 11
subjects (23.4%).



Iranian Journal of Ophthalmology Volume 23 Number 1 2011

14


Table 1. Comparison of baseline characteristics in memantine group with control group
Memantine group Control group P-value
Mean age SD 57.28.4 yrs 59.88.2 yrs 0.298
Number (gender) 25 (17 M : 8 F) 22 (14 M : 8 F) 0.753
Diabetes mellitus 9 (36.0%) 9 (40.9%) 0.730
Hypertension 13 (52.0%) 12 (54.5%) 0.861
Hyperlipidemia 5 (20%) 6 (27.3%) 0.557
Visual loss duration 19.811.6 days 17.811.6 days 0.548
Initial logMAR acuity 1.270.80 1.280.75 0.966
Initial VEP implicit time 129.4314.80 ms 129.2919.66 ms 0.979
Initial VEP amplitude 6.554.58 v 8.827.44 v 0.236
Initial mean deviation -18.107.07 db -21.496.90 db 0.140
Initial pattern standard deviation 9.395.22 db 9.653.39 db 0.856

SD: Standard deviation
VEP: Visual evoked potential



Table 2. Comparison of endpoint values in different timepoints in memantine group with
control group
Memantine group Control group P-value
3-Week logMAR acuity 0.940.64 1.250.74 0.150
3-Month logMAR acuity 0.780.54 1.160.76 0.071
6-Month logMAR acuity 0.730.53 1.110.75 0.090
3-Month VEP implicit time 118.9620.35 135.8311.83 0.008
3-Month VEP amplitude 5.724.39 7.115.99 0.441
3-Month mean deviation -15.177.64 db -21.536.68 db 0.019
3-Month pattern standard deviation 10.444.31 db 9.993.51 db 0.752
Change in logMAR acuity at 3-weeks -0.310.39 -0.020.41 0.024
Change in logMAR acuity at 3-months -0.490.47 -0.090.60 0.025
Change in logMAR acuity at 6-months -0.530.48 -0.050.67 0.017
Change in VEP implicit time at 3-months -9.2917.30 ms 5.7021.60 ms 0.031
Change in VEP amplitude at 3-months -0.402.95 v -2.674.04 v 0.067
Change in mean deviation at 3-months 2.375.27 db 0.855.42 db 0.428
Change in pattern standard deviation at 3-months 0.965.60 db 0.673.17 db 0.863

VEP: Visual evoked potential





Riazi Esfahani et al Memantine in Acute Nonarteritic Anterior Ischemic Optic Neuropathy

15
Visual acuity
Mean baseline BCVA was 1.270.80 logMAR
(ranging from 0.24 to 2.60 logMAR) in the
memantine group and 1.280.75 logMAR
(raging from 0.04 to 0.60 logMAR) in the
placebo group (P=0.966).
Three subjects (1 subject in the memantine
group and 2 subjects in the placebo group)
discontinued drug before completion of
treatment and were excluded from further
analysis. Side effects were seen in 4 subjects
in the memantine group. Dizziness appeared
in 2 subjects and there was a crisis of
systemic hypertension in 2 subjects which
was controlled with medication. No other
serious side effect was seen.
Forty-four subjects completed 3 weeks of
follow-up. After 3 weeks, mean BCVA
improved -0.310.39 logMAR in the
memantine group (24 subjects) and -
0.020.41 logMAR in the placebo group (20
subjects). The difference of VA between the
two groups was statistically significant
(P=0.024, Figure 1). At 3 weeks of follow-up
10 subjects (41.7%) had a VA improvement of
0.3 logMAR in the memantine group
compared to 3 (15%) subjects in the control
group (P=0.054).
At 3 months of follow-up, the difference of
mean BCVA from baseline was -0.490.47
logMAR in the memantine group (22 subjects)
and -0.090.60 logMAR in the placebo group
(18 subjects). The difference of VA between
the two groups was statistically significant
(P=0.025). At 3 months of follow-up 13
subjects (51.9%) had a VA improvement in
the memantine group compared to 7 (38.9%)
subjects in the control group (P=0.204).
Thirty-six subjects completed 6 months of
follow-up. In memantine group (21 subjects),
mean difference of BCVA from baseline was
-0.530.48 logMAR and in the placebo group
(15 subjects) was -0.050.67 logMAR. The
difference of VA between the two groups was
statistically significant (P=0.017). At 6 months
of follow up 13 subjects (61.9%) had a VA
improvement in the memantine group
compared to 5 (33.3%) subjects in the control
group (P=0.091).



Figure 1. Comparison of best corrected visual acuity between the memantine and control
groups at baseline, 3 weeks, 3 months, and 6 months of follow-up



Iranian Journal of Ophthalmology Volume 23 Number 1 2011

16
Pattern visual evoked potential
VEP was performed for 42 subjects
(5 subjects were not cooperative) at baseline
and implicit time [P100 millisecond or P2
(flash VEP)] and amplitude (v) were
evaluated.
It was not possible to perform pattern VEP
in 15 subjects (6 in the memantine group and
9 in the placebo group) because of low vision,
therefore flash VEP was done in this group
and implicit time (P2) and amplitude were
evaluated.
Mean baseline implicit time was
129.4314.80 ms in the memantine group (22
subjects) and 129.2919.66 ms in the placebo
group (20 subjects). Mean baseline amplitude
was 6.554.58 v in the memantine group (22
subjects) and 8.827.44 v in the placebo
group (20 subjects). The difference of implicit
time and amplitude between the two groups
was not statistically significant
(Table 1).
At 3 months of follow-up VEP was done in
34 subjects. Difference of mean baseline
implicit time from follow up was
-9.2917.30 ms in the memantine group
(19 subjects) and 5.7021.60 ms in the
placebo group (15 subjects). At 3 months of
follow-up, the implicit time decreased in the
memantine group, however, it increased in the
control group (Table 2). The change in VEP
implicit time at 3 months of follow-up was
statistically significant between the two groups
(P=0.031).
There was a decrease of VEP amplitude in
both groups. However, the reduction of
amplitude in the memantine group was less
than that of placebo group (P=0.067).

Automated perimetry
Perimetry program of SITA-standard C2-24 for
all subjects (47 subjects) at base line were
done, however, only in 39 subjects perimetries
were reliable. In this study reliability indices
were defined as follows: False negative <12%,
False positive <4% and Fixation loss <20%.
Common visual filed defect patterns were
inferior altitudinal pattern in 12 subjects
(27.3%), general depression in 8 subjects
(18.2%), double arcuate pattern in 6 subjects
(13.6%), superior altitudinal pattern in 3
subjects (6.8%), and nasal altitudinal pattern
in 3 subjects (6.8%).
In the memantine group (21 subjects) the
mean of the initial MD and mean of the initial
PSD were -18.107.07 db and 9.395.22 db
respectively. In the control group (18
subjects), the mean of initial MD and mean of
initial PSD were -21.496.90 db and
9.653.39 db respectively. There was no
significant difference in the magnitude of the
initial MD PSD between the two groups
(Table 1).
At 3 months of follow-up perimetry results
were not reliable in 7 subjects; thus only in 32
subjects perimetry was evaluated. In
memantine group (17 subjects) the mean of
the 3 months MD and mean of the 3 months
PSD were -15.177.64 db and 10.444.31 db
respectively. In control group (15 subjects),
the mean of 3 months MD and mean of PSD
were -21.536.68 db and 9.993.51 db
respectively.
The difference between baseline and
3-months follow-up MD was 2.375.27 db in
the memantine group and 0.855.42 db in the
control group which was not significant
between the two groups (P=0.428)(Table 2).
The difference between baseline and
3-months follow-up PSD was 0.965.60 db in
the memantine group and 0.673.17db in the
control group which was not significant
between the two groups (P=0.863).

Discussion
We performed this randomized clinical trial
because of the lack of widely accepted
treatment for NAION and the strong clinical
and histological evidence of the
neuroprotective effects of memantine in
animal models of neuronal and retinal
ischemia.
13-27
Neuroprotection is an important
issue in the field of ischemic/hypoxic damage
and several clinical trials are currently
underway, investigating neurological as well
as ophthalmologic disorders.
30,31
Therefore,
memantine seemed an appropriate treatment
in patients with NAION. One of the main
challenges with neuroprotective agents is the
time of administration. Experimental studies
suggest that they are most effective when
given shortly after ischemic onset, or even in
advanced cases.
31,32
Therefore, the clinical
reality of delayed presentation and diagnosis
of patients with AION represents a major
problem to the application of neuroprotective
Riazi Esfahani et al Memantine in Acute Nonarteritic Anterior Ischemic Optic Neuropathy

17
agents. The initial ischemic injury in the
NAION, however, is often followed by further
progression of damage due to cascade of
apoptotic processes.
31
In addition, some 25%
of affected eyes show stepwise progression of
optic nerve ischemia and visual deterioration
in the coming next 6 months.
33,34
This provides
the unique opportunity to administer a
therapeutic agent before additional ischemic
events occur. Interestingly, it has been
speculated that the neuroprotective effects of
memantine are more likely to be related to the
modulation of slow apoptotic cell death
processes rather than to the limitation of acute
necrosis.
21

Our study was a double blind randomized
clinical trial and there was no significant
difference in the clinical characteristics of
subjects between the two groups. Also, there
was no significant difference between the
initial VA and visual field indices. Our data
indicate that memantine tablets with the dose
of 5 mg daily for the first week and 10 mg
daily for the next 2 weeks in the subjects with
NAION causes significant improvement of VA
-0.530.48 logMAR versus
-0.050.67 logMAR in the placebo group at 6
months of follow-up (Figure 1). In memantine
group, VA at the final examination improved
by 0.3 log units (i.e. 3 lines) or more in 61.9%
of subjects. In contrast, only 33.3% of subjects
in the placebo group had spontaneous VA
improvement (P=0.091). Although the
difference between the two groups was not
significant and it had a borderline P-value but
increasing the number of subjects may prove
our claim.
The VEP is a particularly useful tool which
reflects the bioelectrical activity of the visual
pathways in response to visual stimuli.
35

Consistent with the course of NAION, we
found an increase in the implicit time of
placebo subjects.
35,36
Interestingly, there was
a significant reduction of implicit time in the
memantine group. Although memantine did
not improve the amplitude and both groups
had reduction of amplitude, the degree of
amplitude reduction in the memantine group
was less than placebo group. Our findings are
consistent with those of Hare et al who have
shown that daily oral administration of
memantine in the monkey model of
experimental glaucoma results in less VEP
amplitude reduction and treatment with
memantine is without significant effect on the
normal function of the retina and central visual
pathways.
24

Memantine did not show a significant
improvement in the automated perimetry
parameters such as MD or PSD compared
with placebo. One of the shortcomings of our
study was its low sample size. It is possible
that a significant difference could have existed
in the proportion of improved visual fields
between treated and control subjects but this
fact was not identified because our sample
size was small. The other limitation was that
memantine was prescribed for only 3 weeks
with maximum dosage of 10 mg. It is possible
that more promising results could be obtained
with longer durations of treatment as it has
been elicited in studies in patients with
dementia.
Loss of retinal ganglion cells is a hallmark
of many ophthalmic diseases including
anterior ischemic optic neuropathy.
5

Neurotoxicity is caused by excessive
stimulation of receptors for excitatory amino
acids. In particular, the amino acid glutamate
has been shown to act as a neurotoxin which
exerts its toxic effect on retinal ganglion cells
predominantly through the NMDA subtype of
glutamate receptor.
6
Over-activation of NMDA
receptors causes excessive Ca
2+
influx into
the cell, mitochondrial dysfunction and
production of free radicals leading to necrotic
and apoptotic cell death.
6
In addition
increased NMDA receptor mediated Ca
2+

influx can elevate energy demand further,
enhance depolarization, trigger further Ca
2+

increase and favor release of endogenous
glutamate.
19
The systemic administration of
memantine may act on NMDA receptors
located in the retina. Memantine produces
reversible open-channel block of NMDA
receptor associated channels. The kinetics of
memantine action in the channel results in
block of excessive NMDA receptor activity but
sparing of physiological receptor activity.
14,16

Moreover, it has been reported that
memantine inhibits ATP-dependent K+
conductances in dopamine neurons of the
substantia nigra pars compacta.
37
This latter
effect ultimately results in an increase of
dopamine release in the striatum. Dopamine
may promote visual recovery by enhancing
neuronal function in retina, lateral geniculate
nucleus, or visual cortex.
38
Dopamine also
Iranian Journal of Ophthalmology Volume 23 Number 1 2011

18
may alter the metabolic milieu of the retina
and vitreous, thereby preventing ischemic
neuronal injury mediated by excessive levels
of the excitatory amino acid glutamate.
10,38-40
It
has been reported that administration of
levodopa may improve vision loss in
recent-onset of NAION.
38

Recently Hayreh and Zimmerman have
reported that treatment of NAION patients with
systemic corticosteroids during the acute
phase, results in a significantly higher
probability of improvement in VA and visual
field compared with untreated patients.
41
It has
been postulated that the faster resolution of
optic disk edema with corticosteroid results in
progressive decrease of compression of the
capillaries in the optic nerve head, better
blood flow in the capillaries, improved
circulation in the optic nerve head and finally
improved function of the surviving but not
functioning hypoxic axons.
41

The neuroprotective effects of memantine
suggested by our study and other
experimental studies, implies memantine as a
promising adjunctive treatment to
corticosteroids in patients with NAION.
However further larger clinical trials with
prolonged and maximum tolerable dosages of
memantine are needed to confirm the efficacy
of memantine on NAION.

Conclusion
Three weeks course of treatment with
memantine in patients with NAION causes
significant improvement of VA and implicit
time of VEP when administered within 8
weeks of onset of NAION. Further
investigations are needed to prove the
efficacy of memantine in NAION patients.


References

1. Hattenhauer MG, Leavitt JA, Hodge DO, et al. Incidence of nonarteritic anterior ischemic optic
neuropathy. Am J Ophthalmol 1997;123(1):103-7.
2. Fontal MR, Kerrison JB, Garcia R, Oria V. Ischemic optic neuropathy. Semin Neurol
2007;27(3):221-32.
3. Hayreh SS. Blood supply of the optic nerve head. Ophthalmologica 1996;210(5):285-95.
4. Hayreh SS. Role of nocturnal arterial hypotension in the development of ocular manifestations
of systemic arterial hypertension. Curr Opin Ophthalmol 1999;10(6):474-82.
5. Osborne NN, Chidlow G, Layton CJ, et al. Optic nerve and neuroprotection strategies. Eye
(Lond) 2004;18(11):1075-84.
6. Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion
cells. Vision Res 1997;37(24):3483-93.
7. Muir KW, Lees KR. Excitatory amino acid antagonists for acute stroke. Cochrane Database
Syst Rev 2003;(3):CD001244.
8. Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer's disease. Drugs
2006;66(11):1515-34.
9. Lange KW, Kornhuber J, Riederer P. Dopamine/glutamate interactions in Parkinson's disease.
Neurosci Biobehav Rev 1997;21(4):393-400.
10. Vorwerk CK, Lipton SA, Zurakowski D, et al. Chronic low-dose glutamate is toxic to retinal
ganglion cells. Toxicity blocked by memantine. Invest Ophthalmol Vis Sci 1996;37(8):1618-24.
11. Erd SL, Schfer M. Memantine is highly potent in protecting cortical cultures against
excitotoxic cell death evoked by glutamate and N-methyl-D-aspartate. Eur J Pharmacol
1991;198(2-3):215-7.
12. Chen HS, Pellegrini JW, Aggarwal SK, et al. Open-channel block of N-methyl-D-aspartate
(NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated
neurotoxicity. J Neurosci 1992;12(11):4427-36.
13. Seif el Nasr M, Peruche B, Rossberg C, et al. Neuroprotective effect of memantine
demonstrated in vivo and in vitro. Eur J Pharmacol 1990;185(1):19-24.


Riazi Esfahani et al Memantine in Acute Nonarteritic Anterior Ischemic Optic Neuropathy

19
14. Chen HS, Wang YF, Rayudu PV, et al. Neuroprotective concentrations of the N-methyl-D-
aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation
following post-ischemic administration and do not block maze learning or long-term
potentiation. Neuroscience 1998;86(4):1121-32.
15. Dogan A, Eras MA, Rao VL, Dempsey RJ. Protective effects of memantine against ischemia-
reperfusion injury in spontaneously hypertensive rats. Acta Neurochir (Wien)
1999;141(10):1107-13.
16. Stieg PE, Sathi S, Warach S, et al. Neuroprotection by the NMDA receptor-associated open-
channel blocker memantine in a photothrombotic model of cerebral focal ischemia in neonatal
rat. Eur J Pharmacol 1999;375(1-3):115-20.
17. Grgl A, Kin T, Cobanoglu S, et al. Reduction of edema and infarction by Memantine and
MK-801 after focal cerebral ischaemia and reperfusion in rat. Acta Neurochir (Wien)
2000;142(11):1287-92.
18. Culmsee C, Junker V, Kremers W, et al. Combination therapy in ischemic stroke: synergistic
neuroprotective effects of memantine and clenbuterol. Stroke 2004;35(5):1197-202.
19. Volbracht C, van Beek J, Zhu C, et al. Neuroprotective properties of memantine in different in
vitro and in vivo models of excitotoxicity. Eur J Neurosci 2006;23(10):2611-22.
20. Lapchak PA. Memantine, an uncompetitive low affinity NMDA open-channel antagonist
improves clinical rating scores in a multiple infarct embolic stroke model in rabbits. Brain Res
2006;1088(1):141-7.
21. Tozzi A, Costa C, Di Filippo M, et al. Memantine reduces neuronal dysfunctions triggered by in
vitro ischemia and 3-nitropropionic acid. Exp Neurol 2007;207(2):218-26.
22. Gu Z, Yamamoto T, Kawase C, et al. Neuroprotective effect of N-methyl-D-aspartate receptor
antagonists in an experimental glaucoma model in the rat. Nippon Ganka Gakkai Zasshi
2000;104(1):11-6.
23. WoldeMussie E, Yoles E, Schwartz M, et al. Neuroprotective effect of memantine in different
retinal injury models in rats. J Glaucoma 2002;11(6):474-80.
24. Hare WA, WoldeMussie E, Lai RK, et al. Efficacy and safety of memantine treatment for
reduction of changes associated with experimental glaucoma in monkey, I: Functional
measures. Invest Ophthalmol Vis Sci 2004;45(8):2625-39.
25. Ycel YH, Gupta N, Zhang Q, et al. Memantine protects neurons from shrinkage in the lateral
geniculate nucleus in experimental glaucoma. Arch Ophthalmol 2006;124(2):217-25.
26. Lagrze WA, Knrle R, Bach M, Feuerstein TJ. Memantine is neuroprotective in a rat model of
pressure-induced retinal ischemia. Invest Ophthalmol Vis Sci 1998;39(6):1063-6.
27. Osborne NN. Memantine reduces alterations to the mammalian retina, in situ, induced by
ischemia. Vis Neurosci 1999;16(1):45-52.
28. Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the
treatment of Alzheimer's disease. CNS Drug Rev 2003;9(3):275-308.
29. Aalami-Harandi Z, Gholami A, Riazi-Esfahani M, et al. Efficacy of memantine in acute non-
arteritic ischemic optic neuropathy. Iranian Journal of Ophthalmology 2008;20(3):39-44.
30. Levin LA, Peeples P. History of neuroprotection and rationale as a therapy for glaucoma. Am J
Manag Care 2008;14(1 Suppl):S11-4.
31. Wilhelm B, Ldtke H, Wilhelm H; BRAION Study Group. Efficacy and tolerability of 0.2%
brimonidine tartrate for the treatment of acute non-arteritic anterior ischemic optic neuropathy
(NAION): a 3-month, double-masked, randomised, placebo-controlled trial. Graefes Arch Clin
Exp Ophthalmol 2006;244(5):551-8.
32. Riazi-Esfahani M, Kiumehr S, Asadi-Amoli F, Dehpour AR. Effects of intravitreal morphine
administered at different time points after reperfusion in a rabbit model of ischemic retinopathy.
Retina 2009;29(2):262-8.
33. Kline LB. Progression of visual field defects in ischemic optic neuropathy. Am J Ophthalmol
1988;106(2):199-203.
34. Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic optic neuropathy: natural history of
visual outcome. Ophthalmology 2008;115(2):298-305.
Iranian Journal of Ophthalmology Volume 23 Number 1 2011

20
35. Holder GE. Electrophysiological assessment of optic nerve disease. Eye (Lond)
2004;18(11):1133-43.
36. Thompson PD, Mastaglia FL, Carroll WM. Anterior ischaemic optic neuropathy. A correlative
clinical and visual evoked potential study of 18 patients. J Neurol Neurosurg Psychiatry
1986;49(2):128-35.
37. Giustizieri M, Cucchiaroni ML, Guatteo E, et al. Memantine inhibits ATP-dependent K+
conductances in dopamine neurons of the rat substantia nigra pars compacta. J Pharmacol
Exp Ther 2007;322(2):721-9.
38. Johnson LN, Guy ME, Krohel GB, Madsen RW. Levodopa may improve vision loss in recent-
onset, nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2000;107(3):521-6.
39. Kashii S, Takahashi M, Mandai M, et al. Protective action of dopamine against glutamate
neurotoxicity in the retina. Invest Ophthalmol Vis Sci 1994;35(2):685-95.
40. Dreyer EB, Zurakowski D, Schumer RA, et al. Elevated glutamate levels in the vitreous body
of humans and monkeys with glaucoma. Arch Ophthalmol 1996;114(3):299-305.
41. Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role of systemic
corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol 2008;246(7):1029-46.