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  • Amblyopia Emerging Treatments

    Amblyopia
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    Binocular Treatment

    Amblyopia is classically taught as a monocular problem that results from a disruption in binocularity. Patching therapy is therefore aimed at improving vision in the amblyopic eye with hopes that an improvement in binocularity will follow.  Recent studies have shown, however, that amblyopia is caused by active suppression that renders a structurally intact binocular system into a functionally monocular system, and that amblyopia is in fact a binocular problem.1  Evidence suggests that focusing on binocular treatments for amblyopia may prove to be beneficial in both improving vision as well as possibly improving binocularity.

    Perceptual learning training, with dichoptic glasses and an iPad-based video game, is currently being studied and has shown promising results for the treatment of amblyopia. This approach differs from currently used “binocular” treatments such as atropine penalization and Bangerter filters. For a treatment to be dichoptic, a stimulus is presented exclusively to each eye, and the brain is forced to integrate the images into a single perception. Under binocular conditions, the signal strength coming into the subject’s good eye is reduced enough so that it cannot suppress the amblyopic eye.  The result is binocular perception in a patient with otherwise deep suppression of the amblyopic eye. Over time, the viewing conditions are changed and the image seen by the good eye is suppressed less until both eyes see approximately the same image. 

    This video game treatment has been studied in both adults and children and has demonstrated variable but positive results in the improvement of amblyopia.2,3 Vision improved with as little as 4 hours of treatment a week in the children studied, but the authors noted a plateau in improvement beyond 4 weeks.3,4 Some studies have demonstrated improved stereopsis,2 while others have shown no significant improvement.3,4

    Because this is a fairly new area of research, the Pediatric Eye Disease Investigator Group (PEDIG) has initiated a prospective, randomized, controlled study comparing binocular therapy with patching in children aged 5–17 years. Future outcomes may indicate that diochoptic therapy is a viable option and a possible first-line therapy. 

    Treatment in Adults

    Many clinicians believe that poor visual acuity as a result of amblyopia can be reversed only if treatment is initiated before the end of the critical period for visual development, around 10 years of age. There is some anecdotal evidence that visual acuity may improve beyond the critical period in patients who have never before been treated, though there is no data on the efficacy of patching for adults.  Recently, studies have demonstrated improvement in both visual acuity and stereopsis in amblyopic adults through dichoptic binocular training.5,6

    In the most recent study by Vedamurthy and colleagues, dichoptic video-game play was compared to patching in adults with both strabismic and anisometropic amblyopia.6  Interestingly, there were significant improvements in visual acuity, stereopsis, contrast sensitivity, and reading speed in the dichoptic video-game group.  In the patching group, there was improvement in visual acuity but only in anisometropic amblyopes, with strabismic amblyopes showing no change. Across all studies of adult amblyopes, improvement in visual acuity seems to plateau around 1-2 lines, which may represent a ceiling that can be achieved with current treatments. 

    Medical Therapy

    Over the last century, several pharmacologic therapies have been studied as a treatment for amblyopia.7 In the 1870s, strychnine was studied for its vasodilation properties. In the 1950s, nicotinic acid and oxygen were suggested to reduce amblyopic suppression scotomas. As clinicians learned about the role of neurotransmitters on visual maturation, more targeted therapies were studied including bicuculline (a GABA receptor blocker) and exogenous nerve growth factor.  Unfortunately, none of these therapies demonstrated significant or enduring effects.

    Upon discovering that dopamine plays an important role in both retinal neurotransmission and central visual processing, investigators began studying oral levodopa, a precursor of dopamine, as an adjunctive treatment to patching for amblyopia.  The effect of levodopa on visual acuity and visual evoked potentials in amblyopic children has been studied by many groups with varying results.8-13  Many studies have shown the treatment leads to improvement in visual acuity, size of suppression scotoma, and visual-evoked potential.8-12  Some have found that improvement in vision seems to regress after discontinuation of the drug,11,14  though similar amounts of regression after patching monotherapy have also been noted.12  Most recently, PEDIG performed a randomized, placebo-controlled study of levodopa that included 139 children aged 7–12 years with residual strabismic and/or anisometropic amblyopia. This study did not show a clinically or statistically meaningful improvement in vision compared with placebo administered 3 times daily while patching the fellow eye 2 hours daily.13 

    Citicoline (also known as cytidine diphosphate choline or CDP-choline) is a nucleotide that plays a role in cellular metabolism and is in current use as a neuroprotectant in traumatic, ischemic, and degenerative diseases.  By acting directly on cell membranes, citicoline may oppose or prevent nerve cell damage.  It also increases the levels of neurotransmitters such as dopamine, serotonin, noradrenaline, and acetylchoine.  As a result, citricoline has been studied as an adjunctive treatment in patients with amblyopia.  When compared with patching alone in amblyopic children, oral citricoline has been shown to stabilize the effects of patching and reduce recurrent amblyopia.15,16

    Although the effectiveness of medical therapy for amblyopia is debatable, it remains an active area of current and future research.  Further studies are needed to define whether medical agents may be beneficial as adjuvant therapies for amblyopia.

    References

    1. Mansouri B, Thompson B, Hess RF. Measurement of suprathreshold binocular interactions in amblyopia. Vision Res. 2008;48:2775-84.
    2. Hess RF, Mansouri B, Thompson B. A new binocular approach to the treatment of amblyopia in adults well beyond the critical period of visual development. Restor Neurol Neurosci. 2010;28:793-802.
    3. Birch EE, Li AL, Jost RM, Morale SE, DeLaCruz A, Stager Jr, D, Dao L, Stager Sr DR. Binocular iPad treatment for amblyopia in preschool children.  J AAPOS.  2015;19:6-11.
    4. Li SL, Jost RM, Morale SE, Stager DR, Dao L, Stager D, Birch EE. A binocular iPad treatment for amblyopic children. Eye. 2014;28:1246-53.
    5. Hess RF, Mansouri B, Thompson B. A new binocular approach to the treatment of amblyopia in adults well beyond the critical period of visual development. Restor Neurol Neurosci. 2010;28:793-802.
    6. Vedamurthy I, Nahum M, Huang SJ, et al. A dichoptic custom-made action video game as a treatment for adult amblyopia. Vision Research. 2015. In Press.
    7. Campos EC, Fresina M. Medical treatment of amblyopia: present states and perspectives. Strabismus. 2006;14:71-3.
    8. Gottlob I, Charlier J, Reinecke RD. Visual acuities and scotomas after one week levodopa administration in human amblyopia. Invest Ophthalmol Vis Sci. 1992;33:2722-8.
    9. Leguire LE, Rogers GL, Bremer DL, et al. Levodopa/carbidopa for childhood amblyopia. Invest Ophthalmol Vis Sci. 1993;34:3090-5.
    10. Leguire LE, Walson PD, Rogers GL, et al. Levodopa/carbidopa treatment for amblyopia in older children. J Pediatr Ophthalmol Strabismus.1995;32:143-51.
    11. Mohan K, Dhankar V, Sharma A. Visual acuities after levodopa administration in amblyopia. J Pediatr Ophthalmol Strabismus. 2001;38:62-7.
    12. Leguire LE, Komaromy KL, Nairus TM, Rogers GL. Long-term follow-up of L-dopa treatment in children with amblyopia. J Pediatr Ophthalmol Strabismus. 2002;39:326-30.
    13. Repka MX, Kraker RT, Dean TW, et al. Pediatric Eye Disease Investigator Group. A randomized trial of levodopa as treatment for residual amblyopia in older children. Ophthalmology. 2015;122:874-881.
    14. Repka MX, Kraker RT, Beck RW, et al. Pilot study of levodopa dose as treatment for residual amblyopia in children aged 8 years to younger than 18 years. Arch Ophthalmol. 2010;128:1215-7.
    15. Fresina M, Dickmann A, Salerni A, et al. Effect of oral CDP-choline on visual function in young amblyopic patients. Graefes Arch Clin Exp Ophthalmol. 2008;246:143-50.
    16. Pawar PV, Mumbare SS, Patil MS, et al. Effectivemenss of the addition of citicoline to patching in the treatment of amblyopia around visual maturity: a randomized controlled trial. Indian J Ophthalmol. 2014;62:124-9.