Seminars in Ophthalmology

ISSN: 0882-0538 (Print) 1744-5205 (Online) Journal homepage: http://www.tandfonline.com/loi/isio20

Medical Therapies of Amblyopia: Translational

Research to Expand Our Treatment
Armamentarium
Charlotte Gore & Carolyn Wu
To cite this article: Charlotte Gore & Carolyn Wu (2016) Medical Therapies of Amblyopia:
Translational Research to Expand Our Treatment Armamentarium, Seminars in
Ophthalmology, 31:1-2, 155-158, DOI: 10.3109/08820538.2015.1114851
To link to this article: http://dx.doi.org/10.3109/08820538.2015.1114851

Published online: 09 Mar 2016.

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Date: 29 March 2016, At: 07:34

Seminars in Ophthalmology, 2016; 31(12): 155158

! Taylor & Francis
ISSN: 0882-0538 print / 1744-5205 online
DOI: 10.3109/08820538.2015.1114851

REVIEW

Medical Therapies of Amblyopia: Translational

Research to Expand Our Treatment Armamentarium
Charlotte Gore and Carolyn Wu

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Boston Childrens Hospital, Boston, Massachusetts, USA

ABSTRACT
Amblyopia is a developmental brain disorder in which vision is lost due to asymmetric or inadequate visual
stimulation early in life. Although amblyopia is responsive to treatment if therapy is initiated early, treatment of
older children and adults is usually unsuccessful due to closure of a window of cortical brain plasticity.
Extensive basic research has been devoted to understanding modulators in shaping the visual cortex during the
critical period of plasticity, and to providing potential clinical applications of neurotransmitters in the treatment
of amblyopia. Current pharmacological treatments are reviewed from basic science research extending into
clinical use, focusing on the acetylcholinesterase inhibitor donezepil, serotonin receptor inhibitor fluoxetine,
dopamine precursors carbidopa-levodopa, and catecholamine modulator citicoline.
Keywords: Carbidopa-levodopa, critical period, donezepil, fluoxetine, plasticity

INTRODUCTION

Amblyopia is most responsive to treatment if

therapy is initiated early, during the critical period
of visual development. If left untreated past this
critical period of cortical brain plasticity, amblyopia
can result in permanently impaired vision.
However, new studies in animal models have
shown that amblyopia may be repaired even past
the critical phase. Clinical trials are underway to
unmask the potential for promoting recovery after the
end of the critical period for visual cortex plasticity.
These studies point toward the intracortical inhibitory
transmission as a crucial brake for therapeutic
rehabilitation and recovery from amblyopia in postcritical period brain.

Amblyopia is defined as a reduction of visual acuity

that cannot be attributed to any structural abnormality of the eye or visual system. It can be caused by
strabismus, anisometropia, or occlusion of the visual
axis early in life, for example, from congenital cataract
or ptosis. The asymmetry of visual inputs from the
two eyes forms the basis for binocular competition,
resulting in loss of vision in the nondominant eye and
disruption of ocular dominance columns that are
responsible for binocular organization.
The current treatment regimen for amblyopia starts
with eliminating the competitive advantage of the
dominant eye. This is usually done by prescribing the
cyclopegic refraction in spectacles for the child to
wear in cases of strabismic or anisometropic amblyopia, and removal of the offending cause in occlusive
amblyopia. For those with residual amblyopia, the
next step is optic penalization for the dominant eye.
There are a number of methods for optical penalization, which include patching therapy, pharmacologic
blurring with atropine, and defocus with neutral
density filter.

STUDIES IN THE GABA-PATHWAY

AND THE MOLECULAR BASIS OF
AMBLYOPIA
The pathological changes from amblyopia occur
primarily in the primary visual cortex and the lateral
geniculate nucleus. Experiments by Hubel and
Wiesel1 were the first to demonstrate neuronal loss

Accepted 2 April 2015; published online 1 March 2016

Correspondence: Charlotte Gore, MD, Boston Childrens Hospital, 300 Longwood Ave, Fegan 4, Boston, MA 02115, USA. E_mail:
charlotte.gore@childrens.harvard.edu

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156 C. Gore and C. Wu

in the primary cortex (V1) using experimental deprivation amblyopia in cats. Subsequent amblyopia
studies in animals have shown neurological changes
in layer IVc of V1 and the lateral geniculate nucleus.
During a critical period, cortical plasticity consolidates neural circuits, and discordant vision through
the two eyes results in aberrant circuit remodeling
within the primary visual cortex. Beyond the
critical period, neural plasticity is significantly
limited.
During the pre-critical period early in development, excitation dominates cortical circuitry.
Transition to the critical period is characterized by
a change in the excitatoryinhibitory balance when
specific inhibitory circuits develop. In the post-critical period, development prevents brain plasticity as
new structures, or brakes, emerge and curtail
neurite outgrowth in the adult brain. Changes in the
excitatoryinhibitory balance regulate the plasticity of
established neural networks. Strategies aimed to
modulate brain plasticity in adulthood include
removing structural brakes, or resettinh the excitatoryinhibitory balance to a juvenile state.
Inhibitional mechanisms in amblyopia are speculated to involve the synaptic neurotransmitters. In 1976,
Duffy and colleagues2 evaluated the effect of bicuculline, a GABA receptor blocker that causes catecholamine depletion, on reversing visual deprivation in
cats. If injected intracisternally in animals, substances
involved in the maturation of the central nervous
system delayed the maturation time and therefore
eliminated the occurrence of amblyopia. This suggests
that a reduction of GABA may be a crucial step for the
restoration of plasticity in adulthood.
GABA neurons express parvalbumin and become
enwrapped by perineuronal nets, and maturation of
these parvalbumin cells corresponds to the closing of
the critical period. Promoting parvalbumin cell function or delaying perineuronal net formation can push
plasticity onset into adulthood and prevent absence of
vision. The involvement of perineuronal nets was
demonstrated by Pizzorusso and colleagues3 in 2006,
when an injection of the enzyme chondroitinase into
the visual cortex of adult rats with amblyopia restored
the critical period. Chondroitinase dissolved the
extracellular matrix and destroyed perineuronal nets
to reactive ocular plasticity. After patching a rats
good eye, the researchers witnessed the recovery of
normal vision: Cortical circuitries for both the left and
right eyes were nudged into firing together, just as
they are during the early phase of childhood
development.
The Hensch4 lab discovered that Otx2 (orthodenticle homeobox protein 2) coordinates the maturation of
the parvalbumin cells. This protein becomes prominent after birth and may serve as the start signal of
the critical period. Otx2 is found to travel from the
retina to the visual cortex and signals the onset of

visual maturation. Otx2 binds with high affinity to

the perineuronal nets, and a competitive blocker of
Otx2 to its binding site restores visual cortical plasticity in mature mice and rescues cortical acuity in
amblyopic mice.
McGee et al.5 presented work that showed that
myelination and the extracellular matrix play a role in
closing of the critical period as well. Nogo, a
growth-inhibiting protein that originates in the myelin
insulation, is required for visual maturation. In NgR1
(Nogo receptor) knockout mice, monocular deprivation did not cause loss of vision, in fact, these mice
did not have the molecular brake of the NgR1 and are
able to spontaneously regain vision.

STUDIES IN THE
NEUROMODULATORS AND THE
CHOLINERGIC PATHWAYS IN
AMBLYOPIA
In addition to direct anti-inhibitory agents, neuromodulators, such as those containing noradrenaline,
serotonin, and acetylcholine, that project to the
cortex targeting GABAergic interneurons have also
been shown to specifically affect the output of this
system. In 1982, Kasamatsu6 showed that an increase
in the local availability of noradrenalin enhances
neuronal plasticity, accelerating cortical recovery from
deprivational amblyopia in cats.
The Hensch7 lab in 2010 demonstrated that brain
plasticity is modulated by cholinergic transmission,
and that it may be possible to reactivate plasticity by
manipulating cholinergic pathways, potentially
reopening the window for effective amblyopia therapy after the critical period has passed. In adult
mice with amblyopia, vision was restored to normal
acuity levels by administration of acetylcholinesterase
inhibitors. Lynx1 is an endogenous prototoxin that
binds to nicotinic acetylcholine receptors, reducing
their sensitivity to acetylcholine. Lynx1 levels increase
only after the critical period for visual development. While there was typically little effect of shortterm monocular deprivation on adult wild-type mice,
adult mice lacking the Lynx1 gene exhibited heightened plasticity and susceptibility. Treatment of Lynx1
knockout mice with an acetylcholine receptor
antagonist was sufficient to prevent their adult
plasticity.
The clinical relevance of these findings was extrapolated to amblyopia recovery after long-term monocular occlusion during the critical period. Once the
deprivation was reversed, Lynx1 knockout mice
recovered visual acuity but mature wild-type
mice did not. However by analogy, in wild-type
mice initially rendered amblyopic, systemic injection of an acetylcholinesterase inhibitor restored
vision.
Seminars in Ophthalmology

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TRANSLATION OF BASIC SCIENCE

RESEARCH INTO CLINICAL USE
Translating this research to humans with amblyopia,
strategies aimed at the Lynx1 and nicotinic acetylcholine receptors interaction may extend the effective
period for amblyopia treatment. Donepezil is a centrally acting reversible acetylcholinesterase inhibitor
that has been postulated to exert its treatment effect by
enhancing cholinergic function, and increasing the
level of acetylcholine in the brain. Donepezil is
currently indicated for the treatment of Alzheimers
disease. It has also been used for the control of
behavioral symptoms and cognitive impairment associated with vascular dementia, multiple sclerosis,
schizophrenia, fragile X syndrome, autism spectrum
disorder, Down syndrome, and attention-deficit hyperactivity disorder (ADHD) in varying age groups from
2 years and older. Clinical studies are underway
to assess the benefit of donepezil in amblyopia
recovery.8
Other anti-GABAnergic neurotransmitters have
been used in the laboratory to demonstrate reversal
of the critical period. In 2008, Maya Vetencourt et al.9
showed that fluoxetine, a selective serotonin reuptake
inhibitor, which enhances extracellular serotonin and
noradrenalin levels, reactivates cortical plasticity in
amblyopic rats, promoting full recovery of visual
function. There is a reduced intracortical inhibition
and increased expression of brain-derived neurotrophic factors in the visual cortex. This result
suggests a potential therapeutic application of fluoxetine in amblyopia; however, there have not been any
clinical studies involving fluoxetine and amblyopia to
date.
Dopamine is another neurotransmitter that has
been focused on for its ability to enhance cortical
plasticity. Dopamine is a neurotransmitter that is
active in the retina and the cortex but does not cross
the bloodbrain barrier. A catecholamine precursor to
dopamine, known as levodopa, does cross the blood
brain barrier and is converted to dopamine in the
brain. Levodopa is currently used to treat patients
with Parkinson disease and children with dystonia. In
1993, carbidopa-levodopa was described as a possible
drug to treat amblyopia, and various human studies
tried different dosages and durations and showed
transient improvement of vision in amblyopic
eyes.10,11 Furthermore, the efficacy of dopamine has
been demonstrated by functional magnetic resonance
imaging (MRI), which measures the neuronal activity
within the visual cortex in amblyopic patients. Yang
and colleagues12 showed that older amblyopic children treated with carbidopa-levodopa had visual
cortical activation. In 2010, a PEDIG (Pediatric Eye
Disease Investigator Group) pilot study was initiated
to evaluate for the use for levodopa as treatment for
residual amblyopia. However, an observation was
!

2016 Taylor & Francis

made that there may be evidence of regression of the

improvement after cessation of treatment, and hence
no conclusions can be made without a randomized
controlled trial.13
Citicoline is a molecule hypothesized to prevent
nerve cell damage by acting directly on cell membrane and maintaining its anatomical and functional
integrity. It has been used as supportive treatment in
traumatic and ischemic neurological pathologies, and
has been used as an adjunct to levopoda in Parkinson
disease. Animal experimental studies for citicoline are
still insufficient. It appears that citicoline improves
membrane ATPase activity and modulates the turnover of catecholamine and acetylcholine. Oral
administration of citicoline combined with patching
therapy seems to show that there are more stable
effects of this medication on the results of patching
therapy compare to patching therapy alone. And in
patients beyond the critical period of visual plasticity,
citicoline showed visual acuity improvement,
although the improvement was not sustained after
discontinuation of the medication.14,15

CONCLUSION
Experiments on animal models have underscored a
pivotal role of cortical GABAergic inhibition in limiting plasticity and amblyopia recovery in adulthood.
The balance between excitation and inhibition has
been suggested to be impaired during development of
amblyopia.
A
reduction
of
inhibitory
transmission may open a previously closed critical
period.
Clinical studies based on these laboratory findings
are beginning to show the possibility of extending
amblyopia treatment beyond the critical period.
Currently, there are four promising substances that
show potential for clinical use in amblyopia: acetylcholinesterase inhibitor donezepil, serotonin receptor
inhibitor fluoxetine, dopamine precursors carbidopalevodopa, and catecholamine modulator citicoline.
The most convincing evidence from laboratory
research to clinical use includes that of donezepil
and possibly fluoxetine; however, it is still not quite
clear at this point to what effect each neurotransmitter
has on reversing amblyopia. Whether pharmacologic
treatment of amblyopia will one day have a firm place
in our therapeutic armamentarium remains to be
established.

DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of
this article.

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