Review
New concepts concerning the neural mechanisms of amblyopia and their clinical implications

https://doi.org/10.1016/j.jcjo.2012.05.002Get rights and content

Abstract

Amblyopia is a visual impairment secondary to abnormal visual experience (e.g., strabismus, anisometropia, form deprivation) during early childhood that cannot be corrected immediately by glasses alone. It is the most common cause of monocular blindness globally. Patching remains the mainstay of treatment, but it is not always successful and there are also compliance and recurrence issues. Because amblyopia is a neural disorder that results from abnormal stimulation of the brain during the critical periods of visual development, it is essential to understand the neural mechanisms of amblyopia in order to devise better treatment strategies. In this review, I examine our current understanding of the neural mechanisms that underlie the characteristic deficits associated with amblyopia. I then examine modern neuroimaging findings that show how amblyopia affects various brain regions and how it disrupts the interactions among these brain regions. Following this, I review current concepts of brain plasticity and their implications for novel therapeutic strategies, including perceptual learning and binocular therapy, that may be beneficial for both children and adults with amblyopia.

Résumé

L'amblyopie est une déficience visuelle résultant d'une expérience visuelle anormale (par exemple, le strabisme, l'anisométropie, la privation de vision des formes) dans la première enfance, qui ne peut être corrigée immédiatement par des lunettes seulement. C'est la cause la plus commune de cécité monoculaire à l'échelle planétaire. L'occlusion demeure la base du traitement, mais il ne réussit pas toujours et il y a des problèmes d'observance et de récurrence. Comme l'amblyopie est un trouble résultant d'une stimulation anormale du cerveau pendant la période critique du développement de la vue, il est essentiel d'en comprendre les mécanismes neuraux pour mettre au point de meilleures stratégies de traitement. La présente revue examine notre compréhension actuelle des mécanismes neuraux qui sous-tendent les déficiences caractéristiques associées à l'amblyopie. Nous examinons ensuite les données modernes de la neuroimagerie, qui montrent comment l'amblyopie affecte les différentes régions du cerveau et comment elles perturbent les interactions entre ces régions. Par la suite, nous revoyons les notions courantes concernant la plasticité du cerveau et leurs implications dans les nouvelles stratégies thérapeutiques, y compris l'apprentissage perceptuel et la thérapie binoculaire, qui peuvent être bénéfiques pour les enfants et les adultes atteints d'amblyopie.

Introduction

Amblyopia is a unilateral (or less commonly, bilateral) reduction of best-corrected visual acuity that cannot be attributed only and directly to the effect of a structural abnormality of the eye.1 It is caused by abnormal visual experience early in life and cannot be remedied immediately by spectacle glasses alone.1 It is defined clinically as a 2-line difference in best-corrected acuity between the eyes.1 Amblyopia is the most common cause of monocular blindness, affecting about 3% to 5% of the population worldwide.2, 3, 4, 5, 6, 7, 8 Because of its prevalence, amblyopia has a huge financial impact. It has been estimated that untreated amblyopia is associated with a loss of US$7.4 billion in gross domestic product and an additional cost of US$341 million for its prevention and treatment annually in the United States alone.9 In addition to the financial cost, the personal cost of amblyopia is also considerable. People with amblyopia (including those treated successfully and those whose treatment has failed) often have restricted career options and reduced quality of life,10 including decreased social contact, cosmetic issues when amblyopia is associated with strabismus, distance and depth estimation deficits, visual disorientation, and anxiety about losing vision in the fellow eye.11

Amblyopia is associated most commonly with early childhood strabismus, anisometropia, or both (mixed-mechanism) and, more rarely, with visual deprivation, including congenital cataract or ptosis. A large study of 427 adults has shown that these subtypes of amblyopia are associated with distinctive patterns of loss of acuity and contrast sensitivity.12 This study used a variety of tests for acuity (Vernier, grating, and Snellen), for contrast sensitivity (Pelli-Robson and edge test), and for binocular function (motion integration and stereo-optical circles). It was found that strabismic amblyopia is associated with moderate acuity loss and better-than-normal contrast sensitivity at low spatial frequencies.12 Anisometropic amblyopia is associated with moderate acuity loss and worse-than-normal contrast sensitivity.12 Mixed-mechanism amblyopia is associated with very poor acuity and normal or subnormal contrast sensitivity.12 The status of residual binocular function is also a major determinant of the pattern of visual deficits. People with no residual binocular function tend to have poorer acuity but better contrast sensitivity, whereas those with residual binocular function tend to have better acuity but poorer contrast sensitivity.12

The mainstay of treatment for amblyopia has been occlusion therapy (patching or pharmacologic penalization), with the rationale that the visual acuity in the amblyopic eye will improve when vision in the fellow eye is blocked. Depending on how treatment success is defined,13 the success rate of patching ranges from 60% to 80%,14, 15, 16 and it is critically dependent on patients' compliance.15 Recurrence may occur after treatment is discontinued,17 requiring continued monitoring of visual acuity and initiation of further treatment if necessary. Furthermore, because occlusion therapy does not promote binocular cooperation, many patients with histories of amblyopia continue to have abnormal binocular vision despite improved acuity. A better therapeutic approach is thus needed.

Although amblyopia has been treated traditionally by eye care professionals, it is a neural disorder that results from abnormal stimulation of the brain during the critical periods of visual development. In order to devise a more effective treatment strategy, it is crucial to understand the neural underpinnings of amblyopia. In this review, I examine our current understanding of the neural mechanisms that underlie the deficits typically seen in amblyopia, based on existing neuroanatomic, neurophysiologic, electrophysiologic, and psychophysical evidence. I then examine modern neuroimaging findings that shed light on the level of neural dysfunctions in amblyopia. Following this, I review the concept of brain plasticity and its implications for new therapeutic strategies, including perceptual learning and binocular therapy.

Section snippets

Neural Mechanisms of Amblyopia

In the past few decades, significant inroads have been made into our understanding of the neural mechanisms of amblyopia. Extensive studies have shown no significant anatomic or physiologic abnormalities in the retina.18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 Similarly, no significant abnormality has been found in the response properties of cells in the lateral geniculate nucleus (LGN).31, 32, 33, 34, 35, 36, 37 There is evidence, however, of changes in cell morphology in the LGN38, 39

Neuroimaging in Amblyopia

A number of neuroimaging studies114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 have investigated the loci and extent of cortical deficits in humans with amblyopia using such techniques as positron emission tomography,114, 115, 116, 117, 118, 119 anatomic121, 122, 123, 124 and fMRI,123, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140,

Plasticity And Its Clinical Implications

Although modern neuroimaging has opened an unprecedented window for us to investigate brain activity in humans in vivo in health and disease, tremendous scientific advances have also been made in our understanding of brain development, in particular, the fundamental concept of brain plasticity. The term plasticity refers to the dynamic ability of the brain to reorganize its connections functionally and structurally in response to changes in the environment. The existence of critical periods in

Interocular Suppression And Its Clinical Implications

In addition to perceptual learning, reducing interocular suppression has also received considerable attention as a therapeutic strategy for amblyopia. Classic studies of visual deprivation using animal models have shown a loss of binocularly driven neurons and those driven by the amblyopic eye in V1.36, 48, 49, 58 Newer emerging evidence (primarily from humans233, 234, 235, 236, 237, 238, 239 and also from a feline model240), however, suggests that binocularly driven neurons are actually

Conclusions

Although amblyopia has traditionally been treated by eye care professionals, it is a neural disorder that results from abnormal stimulation of the brain during critical periods of development. At first glance, amblyopia appears to result in subtle neural dysfunction, which upon closer examination produces far-reaching consequences. Although tremendous resources are spent on preventing or treating amblyopia, many patients with amblyopia continue to have abnormal vision throughout their lives. To

Disclosure

Supported by grant MOP 106663 from the Canadian Institutes of Health Research, Leaders Opportunity Fund from the Canadian Foundation for Innovation, and the Department of Ophthalmology and Vision Sciences.

References (249)

  • A.J. Zele et al.

    Magnocellular and parvocellular pathway mediated luminance contrast discrimination in amblyopia

    Vision Res

    (2010)
  • J.J. Sloper et al.

    A comparison of cell size changes in central and pericentral representations within the primate lateral geniculate nucleus following early monocular deprivation

    Brain Res

    (1988)
  • J.J. Sloper et al.

    Changes in the size of cells in the monocular segment of the primate lateral geniculate nucleus during normal development and following visual deprivation

    Brain Res

    (1987)
  • M.P. Headon et al.

    Effects of monocular closure at different ages on deprived and undeprived cells in the primate lateral geniculate nucleus

    Brain Res

    (1985)
  • M.P. Headon et al.

    Initial hypertrophy of cells in undeprived laminae of the lateral geniculate nucleus of the monkey following early monocular visual deprivation

    Brain Res

    (1982)
  • M.P. Headon et al.

    Shrinkage of cells in undeprived laminae of the monkey lateral geniculate nucleus following late closure of one eye

    Brain Res

    (1981)
  • L. Kiorpes et al.

    Neural mechanisms underlying amblyopia

    Curr Opin Neurobiol

    (1999)
  • M.A. Goodale et al.

    Separate visual pathways for perception and action

    Trends Neurosci

    (1992)
  • D.M. Levi et al.

    Spatial scale shifts in amblyopia

    Vision Res

    (1994)
  • D.M. Levi et al.

    Position jitter and undersampling in pattern perception

    Vision Res

    (1999)
  • R. Dallala et al.

    The global shape detection deficit in strabismic amblyopia: Contribution of local orientation and position

    Vision Res

    (2010)
  • U. Polat et al.

    Abnormal long-range spatial interactions in amblyopia

    Vision Res

    (1997)
  • D.M. Levi et al.

    Global contour processing in amblyopia

    Vision Res

    (2007)
  • D.M. Levi et al.

    Vernier acuity, crowding and amblyopia

    Vision Res

    (1985)
  • D.M. Levi

    Crowding—An essential bottleneck for object recognition: A mini-review

    Vision Res

    (2008)
  • R.F. Hess et al.

    The threshold contrast sensitivity function in strabismic amblyopia: evidence for a two type classification

    Vision Res

    (1977)
  • A.J. Simmers et al.

    The representation of global spatial structure in amblyopia

    Vision Res

    (2004)
  • A.J. Simmers et al.

    The influences of visibility and anomalous integration processes on the perception of global spatial form versus motion in human amblyopia

    Vision Res

    (2005)
  • A.J. Simmers et al.

    Deficits to global motion processing in human amblyopia

    Vision Res

    (2003)
  • B. Mansouri et al.

    Detection, discrimination and integration of second-order orientation information in strabismic and anisometropic amblyopia

    Vision Res

    (2005)
  • E.H. Wong et al.

    Second-order spatial summation in amblyopia

    Vision Res

    (2005)
  • E.H. Wong et al.

    Is second-order spatial loss in amblyopia explained by the loss of first-order spatial input?

    Vision Res

    (2001)
  • J. Hayward et al.

    Effects of speed, age, and amblyopia on the perception of motion-defined form

    Vision Res

    (2011)
  • C.S. Ho et al.

    Abnormal spatial selection and tracking in children with amblyopia

    Vision Res

    (2006)
  • H.M. Mohr et al.

    Altered mental number line in amblyopia: Reduced pseudoneglect corresponds to a decreased bias in number estimation

    Neuropsychologia

    (2010)
  • A.J. Simmers et al.

    Visual deficits in amblyopia constrain normal models of second-order motion processing

    Vision Res

    (2011)
  • A.J. Simmers et al.

    The extent of the dorsal extra-striate deficit in amblyopia

    Vision Res

    (2006)
  • Preferred Practice Pattern GuidelinesAmblyopia

    (2007)
  • S.A. Brown et al.

    Prevalence of amblyopia and associated refractive errors in an adult population in Victoria, Australia

    Ophthalmic Epidemiol

    (2000)
  • A. Hillis

    Amblyopia: Prevalent, curable, neglected

    Public Health Rev

    (1986)
  • D.E. Krueger et al.

    Report on the National Eye Institute's Visual Acuity Impairment Survey Pilot Study

    (1984)
  • T. Vinding et al.

    Prevalence of amblyopia in old people without previous screening and treatmentAn evaluation of the present prophylactic procedures among children in Denmark

    Acta Ophthalmol (Copenh)

    (1991)
  • H. Buch et al.

    The prevalence and causes of bilateral and unilateral blindness in an elderly urban Danish populationThe Copenhagen City Eye Study

    Acta Ophthalmol Scand

    (2001)
  • J. Carlton et al.

    Amblyopia and quality of life: A systematic review

    Eye

    (2011)
  • E.S. van de Graaf et al.

    Amblyopia & Strabismus Questionnaire: Design and initial validation

    Strabismus

    (2004)
  • S.P. McKee et al.

    The pattern of visual deficits in amblyopia

    J Vis

    (2003)
  • C.E. Stewart et al.

    Defining and measuring treatment outcome in unilateral amblyopia

    Br J Ophthalmol

    (2003)
  • A randomized trial of atropine vs. patching for treatment of moderate amblyopia in children

    Arch Ophthalmol

    (2002)
  • S.E. Loudon et al.

    Electronically measured compliance with occlusion therapy for amblyopia is related to visual acuity increase

    Graefes Arch Clin Exp Ophthalmol

    (2003)
  • C.E. Stewart et al.

    Treatment of unilateral amblyopia: Factors influencing visual outcome

    Invest Ophthalmol Vis Sci

    (2005)
  • Cited by (0)

    View full text