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Jun. 07, 2021
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Amblyopia is a reduction of vision produced by abnormal central visual processing. This common disorder occurs in an estimated prevalence of 2% (MPEDS 2008; 13; 27; 26). Unless treated during childhood, the loss of vision is permanent. Amblyopia therapy often requires penalization of the normal eye. The daily amount of time and the best penalization methods are unsettled and controversial. In this article, the author describes studies that investigate to quantitate the time and methods of penalization required for treatment and the ages most appropriate for their use in childhood as well as newer treatment modalities.
• Amblyopia is a reduction in visual acuity in 1 or both eyes due to refractive error, strabismus, or visual deprivation.
• Treatment of amblyopia involves treatment of the underlying cause of vision loss with or without penalization by occlusion or optical penalization.
• Amblyopia treatment is most effective at younger ages.
• Vision loss from amblyopia can be permanent if it is not treated in a timely fashion.
Amblyopia, or lazy eye, is the reduction in the best corrected visual acuity that occurs during childhood that cannot be explained by a known structural abnormality. The term “amblyopia” is derived from the Greek amblys, meaning “blunt,” and ops, meaning “eye,” indicating a “dullness” or incomplete loss of vision rather than complete blindness (11). The early clinical understanding of this disorder can be traced to George Louis Leclerc, Comte de Buffon, who in 1743 proposed the use of occlusion of the sound eye to “force” the amblyopic eye to see better (11). The scientific study of amblyopia was advanced by the work of Hubel and Wiesel, who won the Nobel Prize in 1981 for their work demonstrating physiologic and anatomic changes in the visual system of kittens and monkeys that had been visually deprived during the critical period of visual development (49; 50). As a result of their work and subsequent studies by other investigators, the concept of amblyopia as a developmental visual disorder of childhood was established (44; 24; 39).
Amblyopia is subnormal vision of 1 or both eyes since childhood that cannot be directly attributed to any structural abnormality of the affected eye. Abnormal central processing of visual input results from a period of reduced visual acuity during the immature stages of visual development. The degree of vision loss may vary from a very minimal decrease of acuity to as severe an impairment as light-perception only vision. Total loss of vision (no light perception) does not occur in amblyopia without other pathology. Unless treated during childhood, this visual deficit will persist unchanged through adulthood (40).
Amblyopia is diagnosed when the best-corrected vision of the eye is lower than expected for their age in association with an amblyopia-inducing abnormality of the eye(s) and with the absence of visual system pathology that could otherwise explain the visual loss. Amblyopia may be caused by a misalignment of the eyes (strabismus), refractive error, or reduced visual input (deprivation). 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 old, an irreversible reduction in vision from amblyopia can develop and will not improve if 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 usually results in better visual outcomes, although there may be partial improvement in teenage years (38). Therefore, the American Academy of Ophthalmology Preferred Practice Patterns suggests offering treatment to children of any age, even those in their adolescent years (01).
The diagnosis of unilateral amblyopia is more common than bilateral amblyopia. Unilateral amblyopia presents 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.
Bilateral amblyopia may be suspected if the acuity of both eyes is below age-adjusted norms. For example, in children 3 years of age or under, a best-corrected distance visual acuity worse than 20 out of 50 may be due to amblyopia, whereas children 4 to 5 years of age should have a visual acuity of at least 20 out of 40. In a preverbal patient, if the visual behavior appears inadequate in each eye, it may also be due to amblyopia. It is important that visual acuity testing be conducted with either a line of several optotypes or with a single optoype surrounded by crowding bars because of the crowding phenomenon. The crowding phenomenon makes it more difficult for an amblyopic eye to distinguish an optotype when surrounded by other objects, such as other figures or bars. Children with amblyopia often have better acuity with optotypes presented individually instead of in a line or with crowding bars. Using a single figure for visual acuity testing may, therefore, overestimate the visual acuity in amblyopic children and lead to a false negative screening.
To further establish the diagnosis of amblyopia, the vision will not be normal with correction of any refractive error with glasses. In addition, this vision loss cannot be completely attributable to structural abnormalities (such as a cataract), which, if corrected, would return the acuity to normal. In a young child, removal of a visually significant cataract is unlikely to return visual acuity to normal as in an adult. There is often a refractive and structural disorder with superimposed amblyopia to explain the reduced vision. Therefore, as is the case of most childhood cataracts, the patient may require treatment for the specific refractive or structural abnormality in addition to therapy for the amblyopia.
Amblyopia-inducing risk factors, in order of frequency, are strabismus (ocular misalignment), refractive error causing optical defocus and visual deprivation. Correction of strabismus does not treat the associated amblyopia and is not required to improve an associated amblyopia. However, treatment of a preexisting optical defocus problem or a structural disorder producing occlusion of the visual axis, such as a congenital cataract, is required in order to treat the induced amblyopia.
Strabismus is believed to produce amblyopia as a result of abnormal binocular interaction. The disparate images of the misaligned eyes are projected to the visual cortex where those from the nondominant eye are suppressed. Isolated strabismic amblyopia is always unilateral, and not all patients with strabismus develop amblyopia. Amblyopia is more commonly associated with constant esotropia (convergent eye deviation or crossed eyes) than with exotropia (divergent eye deviation or “walleyed”) (45). Intermittent exotropia, where the eyes are only deviated at times, has the lowest incidence of pure strabismic amblyopia.
Optical defocus produces amblyopia by degrading the retinal image that is sent to the brain. Refractive amblyopia may be further subdivided into anisometropic or isoametropic amblyopia. Anisometropic amblyopia is more common and develops when 1 eye has a higher refractive error than the other eye that may or may not have caused decreased vision if it were present in both eyes. Isoametropic amblyopia is bilateral and develops from a high refractive error of both eyes. Full-time correction of the refractive error may improve vision to normal in all types of refractive amblyopia, but anisometropic amblyopia may require amblyopia therapy to improve the vision of the amblyopic eye (07).
Visual deprivation or occlusion amblyopia is the least common and the most difficult form of amblyopia 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. Examples of these occlusions include congenital or acquired cataracts, corneal opacities, ptosis occluding the pupil, or vitreous hemorrhage. As demonstrated by Hubel and Wiesel, there is a “critical period” following birth when an unimpeded visual axis is required if the newborn is to develop normal vision. It is believed that this period in humans born with unilateral visual axis occlusion is certainly within the first 6 weeks of life, and possibly sooner. As a result, occlusive disorders, such as congenital cataracts, should be treated soon after diagnosis in order to permit normal visual development.
The age at risk for the development of amblyopia is from birth to approximately 9 years of age. This is also the period of time when treatment is effective. The earlier treatment is initiated, the better the prognosis. Unless treated before 9 years of age, amblyopia is thought to persist unchanged into adulthood (40). Amblyopia may improve with occlusion or blurring with atropine or an opaque lens filter of the eye with better visual acuity, although other therapies are being studied. A study investigating the use of patching, with accompanying near visual activities, in patients 13 to 17 years of age, demonstrated a partial improvement of visual acuity in some individuals when there was no history of prior amblyopia therapy (38). In the same study, children 7 to 12 years of age had some benefit even with prior history of amblyopia therapy. The regression rate is unknown and may be high in these older children (18). Other studies have suggested that even adults with amblyopia may be amenable to treatment with a wide range of methodology from monocular to binocular therapies. Levodopa has been studied as a potential pharmacologic therapy to augment occlusion therapy, but results have not been definitively positive in younger or older children (33; 12). Other treatments may improve vision in adults and children, including monocular perceptual learning or video game play with repetitive fine-discrimination tasks (05; 42). Binocular dichoptic training, where the amblyopic eye receives a higher contrast stimulus and the sound eye contrast is reduced during visual tasks, has also shown some promise as another form of therapy, but it has not been shown to be as effective as patching in children and not effective in adolescents and adults with randomized control trials (15; 43; 17; 19; 14; 25; 32).
A 10-month-old 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 this problem. Medical and family histories were noncontributory.
Examination. This patient was an infant and was, therefore, preverbal. In order to evaluate his vision, 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 left eye was covered. When the occluder was then switched to the right (normal vision) eye, the child objected and moved the examiner’s hand away or tried to move his own head in order 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. When the right eye was covered, it was inward toward the nose behind the occluder but immediately became aligned straight ahead, whereas the left eye turned towards the nose. This inability of the left eye to “maintain” fixation and the objection to occlusion of the right eye indicated that the vision of the left eye was significantly less than that of the right and that amblyopia was present.
This esotropia measured 50 prism diopters, with otherwise normal extraocular movements. External examination, pupils, and anterior segment were within normal limits. The patient had a low degree of hyperopia, and the fundus examination was within normal limits.
Although practice patterns may differ between ophthalmologists, it is common to treat amblyopia before correcting the associated strabismus. This is done for 2 reasons: (1) It is the purpose of strabismus treatment to attempt to restore binocularity, ie, the use of both eyes together; if the patient required patching treatment for amblyopia after the strabismus surgery was performed, the occlusion therapy would interfere with this binocularity. (2) The ability or inability of an eye to “maintain” fixation is a useful guide to determine if a preverbal child is amblyopic and specifically which eye is abnormal. As a result, if strabismus surgery were to be performed on a child known to be amblyopic, and the eyes were straight postoperatively, it would subsequently be difficult to monitor and treat the amblyopia.
In this patient’s case, the amblyopia was treated with patching of the normal-vision right eye. It should be noted that patching itself poses a risk for producing an occlusion or deprivation amblyopia. This risk is inversely proportional to the patient’s age or level of visual immaturity. However, if an occlusion amblyopia is induced by patching, it is almost always reversible by patching the now visually improved, but originally amblyopic eye.
This patient continued patching of the right eye until he was noted to be able to maintain fixation equally with each eye, which was noted as either eye crossing towards the nose equally. This indicated that the amblyopia had been treated with equal vision in each eye. Strabismus surgery was then performed to correct the esotropia. Continued follow-up was warranted as amblyopia may recur, and refractive error may change necessitating correction with glasses, despite correction of the strabismus.
Amblyopia may be produced by strabismus, optical defocus (anisometropia or isometropia), or occlusion of the visual axis. Strabismus results in unilateral amblyopia, whereas optical defocus and deprivation may cause unilateral or bilateral amblyopia.
The pathogenesis of amblyopia, especially those 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 (21). Optical defocus 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 (21). Occlusion of the visual axis has been shown to produce physiologic and anatomic changes of the visual pathways in animal models (49; 50). Occlusion amblyopia has been demonstrated experimentally to produce a loss of binocularly driven cortical neurons, as well as those neurons responding to the amblyopic eye (04; 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 (47; 46).
Amblyopia is a common visual disorder. Its estimated prevalence varies depending on the study but is approximately 2% (MPEDS 2008; 13; 27; 26). There are believed to be at least 80,000 new cases of amblyopia in the United States every year. Amblyopia has been reported to be the leading cause of monocular vision loss during the first 4 decades of life (37).
The major risk factors for amblyopia are: strabismus, optical defects (anisometropia and isometropia), and visual deprivation from occlusion of the visual axis.
Children with strabismus must be monitored for amblyopia, even after aligning the eyes. These patients must be monitored until 9 years of age, even after treatment of the strabismus, in order to detect and treat amblyopia, if needed. In addition, correction of strabismus by surgery alone will not correct amblyopia once it is established. Amblyopia therapy must be started to improve the vision of the affected eye. It should be noted that as a child approaches this upper age limit, the risk of developing amblyopia diminishes.
Refractive amblyopia secondary to a difference in the refractive error of the 2 eyes (anisometropia), a bilateral high refractive error (isometropia or ametropia), may be prevented with full-time correction of the refractive error with either glasses or contact lenses. Refractive amblyopia may be corrected with glasses alone with all types of refractive amblyopia, but anisometropic amblyopia may require amblyopia therapy (07).
Deprivation amblyopia from occlusion of the visual axis may also be prevented if treatment is begun at the time of diagnosis. Preventative treatment of deprivational amblyopia necessitates removal of the obstruction from the visual axis.
In order to distinguish amblyopia from other vision abnormalities, it is important to rule out other ocular or visual processing pathology. The examiner should also determine whether the individual has any of the associated risk factors such as strabismus, amblyopia-inducing refractive error, or occlusion of the visual axis. The presence of amblyogenic risk factors should not preclude a search for other causes of an acuity deficit. Careful documentation of the patient’s personal and family history is essential. If these risk factors are acquired subsequent to this upper age limit of 9 years, it would not likely produce amblyopia. In a child with vision loss associated with an abnormality of the visual pathway, such as optic nerve atrophy, strabismus may occur secondarily, and therefore, a full ophthalmologic examination is warranted. The development of a secondary strabismus may actually further worsen the visual acuity because of strabismic amblyopia. Therefore, when 1 or more of the amblyopia risk factors are present in a child under 9 years of age, treatment for presumed amblyopia may also be indicated in addition to addressing any organic visual pathway abnormalities.
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 (02). 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 1 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-norms 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 mandatory. If a patient is determined to be amblyopic, ophthalmologic examination of young siblings is recommended.
Spectacle correction. Treatment of refractive error alone can improve vision for amblyopia associated with refractive error (07; 06). Although not as successful as children with simple refractive amblyopia, children with strabismus have also been shown to improve with spectacle correction alone (Writing Committee for PEDIG et al 2012). Glasses are the most common modality and are often well tolerated by children if they are comfortable. Contacts may also be used, but the risks of contact lens use and proper care must be explained. 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 glasses.
Occlusion. The most widely accepted and time-proven treatment of an amblyopic eye is occlusion of the opposite eye. It is usually performed on a part-time basis, with studies demonstrating equivalent results between 2 and 6 hours of daily patching for moderate amblyopia (34). For severe amblyopia, 6 hours of patching a day is recommended (16). However, this treatment of covering the good eye obviously prevents the child from seeing well during occlusion therapy. As a result, compliance can be a serious problem limiting the effectiveness of the treatment (41). If well-explained by the physician to understanding parents, occlusion therapy is effective (10; 23).
During occlusion therapy for amblyopia, some practitioners suggest near visual activities for their patients (16; 34). 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 (31).
For investigative purposes, an electronic occlusion dose monitor patch worn by the child has been used to determine patching compliance (03). This system has confirmed the difficulty in obtaining compliance with occlusion therapy, as well as demonstrating the effectiveness of patching for the recovery of vision when there is adherence to this treatment. It is not used in clinical practice. More often, a patching log showing date and times of occlusion are used by clinicians if there is a question about the patching regimen.
Pharmacologic treatment. Chronic cycloplegia of the unaffected eye with 1 drop daily of atropine sulfate 1% solution was reported to be comparable in effect to occlusion therapy in children who are not nearsighted or myopic, or in children 3 to 7 years of age with moderate amblyopia (20 out of 40 to 20 out of 100) (20; 30). Atropine is also effective if given for 2 consecutive days a week, or “weekend atropine,” instead of daily (35). The purpose of this treatment is to blur or “penalize” the good eye and thereby improve the vision of the amblyopic eye without the need of the child to wear a patch. A slightly higher degree of acceptability was noted for the atropinization treatment. Atropine treatment has gained more acceptance after several randomized controlled trials demonstrated efficacy (36).
Studies using levodopa with a fixed combination of carbidopa (L-dopa) have demonstrated an improvement of visual acuity in children and adults with amblyopia. The precise site of action of dopamine in the development of amblyopia is uncertain, although animal models of this disorder have demonstrated a reduced dopamine level in the retina. Use of L-dopa for the treatment of amblyopia is experimental at this time (22; 28). A randomized, double-blinded 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 (33).
Surgery. For deprivation amblyopia, it is essential that the structural problems contributing to a deprivation amblyopia of the affected eye be treated, usually with surgical intervention. Surgical correction of strabismus will not improve an associated amblyopic loss of vision. Treatment for amblyopia is often begun prior to surgical correction of the strabismus. Any residual refractive abnormalities producing refractive amblyopia need to be addressed. Amblyopia therapy is often needed to restore visual acuity of the amblyopic eye.
For children that do not tolerate glasses or contact lenses, refractive surgery has been investigated as an alternative therapy for refractive correction. In a small study (n=11), photorefractive keratectomy was demonstrated to be a safe and effective method to decrease anisometropia (29). Although it is disputed whether this group of patients demonstrated an improvement of vision following this procedure, it is agreed that this treatment has the potential to become an effective therapy for anisometropic amblyopia (09). It is not FDA-approved nor widely available.
Other treatments on the horizon. Pharmacologic and refractive error correction with either refractive surgery or intraocular surgery are still not approved in children but remain an area of interest. New therapies to treat amblyopia are still being investigated. One study using liquid crystal intermittent glasses in children 3 to 8 years old with unilateral amblyopia has shown promise and was found to not be inferior to patching (48). Perceptual learning techniques have also been used with great promise in adults with amblyopia (52). Larger randomized clinical trials are needed.
Iris S Kassem MD PhD
Dr. Kassem of the Medical College of Wisconsin has no relevant personal financial relationships to disclose. She is married to an employee of AbbVie.See Profile
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