ReviewNew concepts concerning the neural mechanisms of amblyopia and their clinical implications
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.
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