Clinical manifestations

Presentation and course

A period of abnormal visual input to the brain from one or both eyes during development causes amblyopia. The impaired visual experience during the critical period of visual cortex plasticity results in abnormal central processing of visual input. The degree of vision loss may vary from a minimal decrease of acuity to light-perception only vision. Total loss of vision (no light perception) does not occur in amblyopia without the presence of other ocular disease. Unless treated during childhood, the visual deficit will nearly always persist into adulthood and throughout life (44; 24).

Amblyopia is categorized as (A) refractive, (B) strabismic, and (C) deprivational. More than one category of amblyopia is frequently found in a single individual. In refractive amblyopia, optical defocus degrades the image that is sent to the brain causing impaired visual cortex development. Refractive amblyopia is distinct and more challenging to treat than refractive error. In refractive error, appropriate optical correction of blur by glasses or contact lenses will result in immediate normal “best-corrected” visual acuity. In refractive amblyopia, the acuity will remain suboptimal even after eliminating image blur with appropriate glasses or contact lenses, demonstrating abnormalities in central visual processing. Anisometropia, in which the refractive error differs between the two eyes, is much more likely to cause amblyopia than isometropia, in which the refractive error is equal in the two eyes (13; 31). Full-time correction of the refractive error alone may improve vision and resolve refractive amblyopia with time, but in some cases, penalization therapy such as patching may be needed to improve the vision of the amblyopic eye (06).

The second category of amblyopia is strabismic. In strabismus, the two eyes point in different directions. If the images from the two eyes are so disparate that they cannot be fused by the brain, diplopia or suppression of one image occurs. Older children and adults frequently experience diplopia in this scenario. The young child does not experience diplopia; instead, the visual cortex suppresses the image from the nondominant eye. Over time, the suppression impairs the ability to interpret the image from the nondominant eye causing unilateral amblyopia and reduced binocularity. The severity of the suppression is directly correlated to the degree of impairment in visual acuity and binocularity (26). Isolated strabismic amblyopia is unilateral, but not all patients with strabismus develop amblyopia. Strabismic amblyopia is more commonly associated with esotropia (convergent eye deviation or crossed eyes) than with exotropia (divergent eye deviation or “walleyed”) (49).

The last category of amblyopia is deprivation or occlusion amblyopia. This is the least common form of amblyopia and the most difficult to treat. It may be unilateral or bilateral. As indicated by its name, it is caused by a structural abnormality that obstructs the visual axis of the eye(s). Examples of these occlusions include congenital or acquired cataracts, corneal opacities from trauma or infection, ptosis occluding the pupil, or vitreous or retinal hemorrhage as is observed in nonaccidental infantile trauma, for example. An infant is exquisitely sensitive to deprivation amblyopia, so concern for congenital cataracts or other ophthalmic disorders in an infant should be referred to pediatric ophthalmology for evaluation on an urgent basis. Even with optimal surgical care as well as aggressive treatment of amblyopia, removal of a cataract in an infant is unlikely to return visual acuity to normal.

In general, amblyopia may occur at any time during visual immaturity, even if there are new circumstances that did not exist at birth. For example, if a child develops a visually significant cataract at 5 years of age, irreversible vision loss from amblyopia may develop if the cataract is not addressed during the critical period of visual development. The critical period of visual development in humans is from birth to approximately 9 years of age. The risk of developing amblyopia, as well as the speed of its onset, is inversely proportional to the age of the patient. Earlier initiation of amblyopia management results in better visual outcomes, although there is some improvement in teenagers who have not been previously treated (42). Therefore, the American Academy of Ophthalmology Preferred Practice Patterns recommends offering treatment to children of any age, even those in their adolescent years (52).

The diagnosis of unilateral amblyopia is more common than bilateral amblyopia. Unilateral amblyopia presents as a difference in best-corrected vision between the eyes. Although this differential may in fact be very small, it is clinically accepted that a verbal child must have a 2-line or greater difference in optotype identification, which is usually tested with letters or pictures, to be classified as amblyopic. This minimum differential is meant to decrease the significant potential for false positives that may occur when testing the vision of young verbal children. Observation of comparative monocular fixation attention or behavior is used to assess infants and preverbal children.

Prognosis and complications

The age at risk for the development of amblyopia is from birth to approximately 9 years of age. Unless treated before 9 years of age, amblyopia will almost always persist unchanged for life into adulthood (44; 24).

Clinical vignette

A 10-month-old healthy male was referred for examination and treatment of an esotropia. The ocular misalignment was first noted at 3 months of age. He had received no previous treatment for the problem. Medical and family histories were noncontributory.

Examination. In order to evaluate the vision in this preverbal infant, he was placed on the parent’s lap, and his attention was drawn to a small toy that was held approximately 2 feet from his face. With the left eye covered, the right eye was central and steady, and it maintained fixation. When the occluder was then switched to the right (normal vision) eye, the child objected and moved the examiner’s hand away to see around the occlusion. When the right eye was covered, the left eye was central and steady, but it did not maintain fixation when the right eye was uncovered. This objection to occlusion of the right eye indicated that the vision of the left eye was significantly less than that of the right eye and that amblyopia was present.

The esotropia measured 50 prism diopters using the Krimsky method. This involves shining a penlight at the infant’s eyes and placing prisms of increasing strength in front of the left eye in a step-wise approach until the light reflexes are aligned. Careful observation of the extraocular movements showed features consistent with infantile esotropia. Extraocular movements with both eyes open initially suggested a possible limitation of abduction in the left eye (version movement). However, a closer look using the Doll’s head maneuver while simultaneously covering the right eye demonstrated full abduction of the left eye (duction movement). There was also subtle elevation of each eye in adduction, consistent with inferior oblique overaction, another feature common in infantile esotropia. Otherwise, the comprehensive examination was normal. Observation of the ocular adnexa, the pupils, and anterior segment were performed and were within normal limits. The patient had a dilated fundus examination, which showed normal optic nerves and retinae as well as a cycloplegic refraction that showed low, age-appropriate hyperopia.

For this infant, the severity of his esotropia and his young age puts him at high risk for profound strabismic amblyopia and loss of binocular vision. Given this, it was discussed with the family to consider this as a lifelong condition that can be managed, but not necessarily cured. The amblyopia was treated with patching of the normal-vision right eye two hours daily. The family was concerned that the patching itself could produce a deprivation amblyopia in the better-seeing right eye. There is indeed a risk of overpenalization causing a reverse/occlusion amblyopia, and this risk is inversely proportional to the patient’s age or and level of visual immaturity. Therefore, close serial monitoring of the patient during amblyopia treatment was performed. If an occlusion/reverse amblyopia is induced by patching, it is almost always correctable. In addition to the amblyopia therapy, strabismus surgery was also promptly performed before age 1 year to correct the esotropia. Prior to the surgery, the family was cautioned that patching would still be required after the strabismus surgery, that the development of binocular vision does not always occur despite an excellent post-op ocular alignment, and that individuals with infantile esotropia frequently require more than one strabismus surgery over their lifetime.

The patient was followed throughout childhood with decreasing frequency as he became less sensitive to amblyopia with age. By his teenage years, he achieved an excellent result with a best-corrected visual acuity of 20/40 in his weaker left eye, and 20/15 in his right eye. He had a small angle residual esotropia that was observed in the eye clinic, but he reported that the eye misalignment was not observed by his peers or even his family. He denied any psychosocial stress from the residual strabismus.

This clinical vignette is a composite and does not describe a specific individual.

Biological basis

Etiology and pathogenesis

The pathogenesis of amblyopia, especially the similarities and differences underlying the various forms of the disorder, is unsettled. It is believed that because strabismus prevents stimulation of corresponding retinal points in each eye, binocularity is disrupted as a result of the reduction in the proportion of cortical binocular neurons (23). Refractive amblyopia appears to be due to a decrease of the spatial resolution of neurons with preferred spatial frequency in the higher range or the actual loss of these neurons (23). Occlusion of the visual axis/deprivational amblyopia has been shown to produce physiologic and anatomic changes of the visual pathways in animal models (53; 54). Deprivational amblyopia has been demonstrated experimentally to produce a loss of binocularly driven cortical neurons, as well as those neurons responding to the amblyopic eye (01; 08). In addition to these abnormalities in the visual cortex, histologic changes have also been detected in the lateral geniculate bodies in deprivational and strabismic amblyopia (51; 50).

Epidemiology

Amblyopia is a common visual disorder. Its estimated global prevalence is approximately 1.4% (36; 13; 32; 31; 15). The accuracy of epidemiological amblyopia data is poor due to the lack of data from certain regions and the differences in study methodologies (15).

Prevention

Early detection and treatment of the major risk factors for amblyopia, namely strabismus, refractive error, and visual deprivation, prevents or mitigates amblyopia.

Preventive monitoring is especially important for postsurgical patients, as these families sometimes mistakenly consider surgery as curative treatment for not only strabismus but also amblyopia. After strabismus surgery, children must be followed at least until age 9 to monitor for amblyopia. Similarly, postsurgical ptosis, cataract, or eye trauma patients require monitoring to identify early amblyopia and prevent its progression. As a child ages, the risk of developing amblyopia diminishes.

There is growing awareness of the prevalence and treatment options for childhood myopia (47; 18; 38; 03). However, refractive error is distinct from refractive amblyopia, and if the vision is correctable to a normal level with glasses, only refractive error is present, not refractive amblyopia. The presence of anisometropia (difference in refractive error between the two eyes) greatly increases the likelihood that refractive amblyopia will develop (13; 31). In all cases of refractive error, and especially in cases of anisometropia, the early use of appropriate glasses in young children is sometimes sufficient to prevent refractive amblyopia.

Although low outdoor light exposure and near work among children are established risk factors for myopia progression, there has also been growing concern in the general public concerning screen time as a risk factor for refractive error/refractive amblyopia. There is presently no scientific evidence that the use of near screen time is a risk factor for refractive amblyopia, although the American Academy of Pediatrics recommends limiting screen time to promote overall child development (07). As far as the effect of near screen time on myopic progression, in a study of Dutch teenagers who spent an average of about 4 hours on their smartphones a day, smartphone use was only minimally associated with myopia (11). Distance from the eyes to the phone screen was not correlated with myopic progression. The effect of screen time may be more pronounced on preteen children, however.

Differential diagnosis

Confusing conditions

Amblyopia must be distinguished from other causes of visual impairment, particularly cerebral visual impairment. Cerebral visual impairment (CVI) is defined as decreased vision from postgeniculate visual pathway brain damage and is most commonly seen in children with a history of perinatal hypoxic-ischemic damage. It is more common in children born prematurely, and as many as 93% of cerebral visual impairment patients have seizures (04). The key distinguishing factor is that amblyopia is secondary to abnormal visual input to the brain, whereas cerebral visual impairment is caused by abnormalities in the brain itself.

Associated or underlying disorders

Amblyopia is often confused with its associated risk factors namely strabismus, refractive error, or causes of visual deprivation such as cataracts or trauma. Although closely related, amblyopia and its associated ophthalmic diseases are distinct. Amblyopia refers only to abnormal central processing of visual input secondary to impaired visual experience during the critical period of early childhood. In turn, this impaired brain development is caused by abnormal visual experience from an ophthalmic disease such as cataracts or strabismus. The distinction is important because if the ophthalmic disease is acquired after the critical period of early childhood, it will not cause amblyopia. For example, a traumatic cataract acquired in a teenager will not cause deprivational amblyopia. If the cataract is removed surgically, even years later, normal visual acuity may be achieved, as the brain visual processing developed normally prior to the injury. In contrast, a traumatic cataract before age 9 has a high risk of causing deprivational amblyopia as central visual processing is still developing.

Diagnostic workup

The basic diagnostic test for amblyopia is an age-appropriate determination of the vision of each eye with identification of the source causing the amblyopia. A qualitative assessment of monocular and binocular fixation behavior is used for preverbal children. Guidelines have been published for pediatric vision screening and referral criteria (27). In preverbal children, a qualitative assessment of fixation and following objects with each eye is performed. Failure to maintain fixation on an object, an asymmetric response to occlusion of one eye, or tracking warrants further investigation. Verbal children should be asked to identify a series of letters or pictures on each acuity line. If single objects are used, they should be surrounded by crowding bars because of the “crowding phenomenon.” This is because the use of single letters or figures in children with amblyopia would overestimate the visual acuity compared to a linear, or crowded, presentation of several optotypes. Amblyopia is defined as vision below age-normal or a difference of 2 lines or more on the visual acuity chart. The work-up of a patient suspected to be amblyopic also requires a complete eye examination to identify the cause, including evaluation of pupils, external, motility, anterior segment, and fundus exam, as well as determination of their refractive error. As the conditions associated with amblyopia may be hereditary, a family history is also indicated. If a patient is determined to be amblyopic, ophthalmologic examination of young siblings is recommended.

Management

Refractive error. Treatment of refractive error alone improves vision in refractive amblyopia and to a lesser degree strabismic amblyopia (06; 05; 55). Glasses are the most common modality and are often well tolerated by children if they are properly fitted by an optician familiar with children. It is important to choose a pair of spectacles that the child can wear for all waking hours and that does not allow them to look over the frames. Although ordering glasses on the internet without evaluation by an in-person optician is more affordable in the U.S., this is not recommended due to the difficulty of fitting glasses in children. Contact lenses are indicated in specific clinical scenarios (eg, in postsurgical cataract patients or for myopia control). The risks of contact lens use and proper care must be explained. Elective use of contact lenses for refractive error alone in young children may be considered on a case-by-case basis depending on the parents’ and physician’s evaluation of the child’s ability to comply with hygiene requirements.

Occlusion. The most widely accepted and time-proven treatment of an amblyopic eye is occlusion of the better-seeing fellow eye. Patching is performed on a part-time basis, with studies demonstrating equivalent results between 2 and 6 hours of daily patching for moderate amblyopia (39). For severe amblyopia, 6 hours of patching a day is recommended (19). Patching earlier in life results in better visual outcomes with children under age 7 years having superior improvement compared to older children undergoing similar patching times (14). Teenagers who have not previously been treated for amblyopia may still benefit from occlusion therapy (42).

Covering the better-seeing eye prevents the child from seeing well during occlusion therapy. As a result, compliance is often be a serious problem limiting the effectiveness of patching (45). If well explained by the physician to understanding parents, occlusion therapy is effective (09; 28).

During occlusion therapy for amblyopia, some practitioners have suggested near visual activities for their patients (19; 39). The presumption is that these activities performed at near viewing stimulate the visual system of the brain and help alleviate the amblyopia. However, a controlled, randomized study comparing 2 hours of patching combined with either 2 hours of near activities (eg, reading, writing, playing computer games) or 2 hours of distance activities (eg, outdoor play, television viewing at a distance of at least 6 feet) demonstrated no difference in visual acuity improvement between the 2 groups (36).

Pharmacologic treatment. Chronic cycloplegia of the unaffected eye with 1 drop daily of atropine sulfate 1% solution is comparable in effect to occlusion therapy in children with moderate amblyopia ages 3 to 7 years who are not nearsighted or myopic (22; 35). Atropine is also effective if given for 2 consecutive days a week, or “weekend atropine,” instead of daily (40). Atropine blurs or penalizes the better-seeing eye and thereby improves the vision of the amblyopic eye without a patch. A slightly higher degree of acceptability has been reported for atropine compared with patching treatment (41).

Dichoptic treatment. Dichoptic treatment, where the amblyopic eye receives a higher contrast stimulus and the better-seeing eye contrast is reduced during visual tasks, has also shown for amblyopia treatment. Initial trials showed mixed results, but effectiveness may have been limited by games that were relatively unappealing to children (17; 46; 20; 21; 16; 30). A dichoptic device that provides a menu of age-appropriate video media using a virtual reality (VR) headset (Luminopia One) showed an improvement of one-line of vision compared to a control group at 12 weeks in children ages 4 to 7 compared to full-time glasses use. The device is FDA-approved for the treatment of strabismic or refractive amblyopia in children ages 4 to 7.

Surgery. For deprivation amblyopia, it is essential that the structural issue underlying the amblyopia (eg, cataract, ptosis) be treated, usually with surgical intervention. In the case of strabismus, surgical correction will not improve an associated strabismic amblyopic. Treatment for strabismic amblyopia is often begun prior to surgical correction of the strabismus.

For children with refractive amblyopia from large refractive error who do not tolerate glasses or contact lenses, refractive surgery such as photorefractive keratectomy (PRK) laser-assisted in situ keratomileusis (LASIK) may be used (34).

Other treatments. Perceptual learning techniques that present images hypothesized to correspond to the receptive field of the visual cortex may be effective in treating amblyopia, although further research is needed (56; 57; 24). RevitalVision, a computerized perceptual learning amblyopia treatment system, is presently FDA-approved for the treatment of amblyopia in individuals 9 years of age and older.

Levodopa has been studied as a potential pharmacologic therapy to augment occlusion therapy, but results have not been definitively positive (25; 33; 37; 12). A randomized, double-masked placebo-controlled study of the use of levodopa/carbidopa for the treatment of refractory amblyopia in older children did not demonstrate any benefit over 2 hours of daily patching (37).

There is insufficient evidence to support the use of vision therapy eye exercise for the treatment of amblyopia (52).