Background

Amblyopia refers to a decrease of vision, either unilaterally or bilaterally, for which no cause can be found by physical examination of the eye. The term functional amblyopia often is used to describe amblyopia, which is potentially reversible by occlusion therapy. Organic amblyopia refers to irreversible amblyopia.[1, 2, 3] Most vision loss from amblyopia is preventable or reversible with the right kind of intervention. The recovery of vision depends on how mature the visual connections are, the length of deprivation, and at what age the therapy is begun. It is important to rule out any organic cause of decreased vision because many diseases may not be detectable on routine examination.

Pathophysiology
Although many types of amblyopia exist, it is believed that their basic mechanisms are the same even though each factor may contribute different amounts to each specific type of amblyopia. In general, amblyopia is believed to result from disuse from inadequate foveal or peripheral retinal stimulation and/or abnormal binocular interaction that causes different visual input from the foveae.[4] Three critical periods of human visual acuity development have been determined.[5, 6] During these time periods, vision can be affected by the various mechanisms to cause or reverse amblyopia. These periods are as follows:

The development of visual acuity from the 20/200 range to 20/20, which occurs from birth to age 3-5 years. The period of the highest risk of deprivation amblyopia, from a few months to 7 or 8 years. The period during which recovery from amblyopia can be obtained, from the time of deprivation up to the teenage years or even sometimes the adult years.

Whether different visual functions (eg, contrast sensitivity, stereopsis) have different critical periods is not known. In the future, determination of these time frames may help modify treatment of amblyopia.

Epidemiology
Frequency
United States Prevalence of amblyopia is difficult to assess and varies in the literature, ranging from 13.5% in healthy children to 4-5.3% in children with ophthalmic problems. Most data show that about 2% of the general population has amblyopia. Amblyopia was shown in the Visual Acuity Impairment Survey sponsored by the National Eye Institute (NEI) to be the leading cause of monocular vision loss in adults aged 20-70 years or older. Prevalence of amblyopia has not changed much over the years.

Mortality/Morbidity
Amblyopia is an important socioeconomic problem. Studies have shown that it is the number one cause of monocular vision loss in adults. Furthermore, persons with amblyopia have a higher risk of becoming blind because of potential loss to the sound eye from other causes.

Race
No racial preference is known.

Sex
No gender preference is known.

Age
Amblyopia occurs during the critical periods of visual development. An increased risk exists in those children who are developmentally delayed, were premature, and/or have a positive family history. Elicit any previous history of patching or eye drops as well as past compliance with these therapies. Document previous ocular surgery or disease. In addition to the routine information, obtaining a family history of strabismus or other ocular problems is important because the presence of these ocular problems may predispose a child to amblyopia

Physical
Visual acuity
Diagnosis of amblyopia usually requires a 2-line difference of visual acuity between the eyes; however, this definition is somewhat arbitrary and a smaller difference is common.

Crowding phenomenon
A common characteristic of amblyopic eyes is difficulty in distinguishing optotypes that are close together. Visual acuity often is better when the patient is presented with single letters rather than a line of letters. Diagnosis is not an issue in children old enough to read or with use of the tumbling E.

Testing in preverbal children

If the child protests with covering of the sound eye, amblyopia can be diagnosed if it is dense. Fixation preference may be assessed, especially when strabismus is present.

Induced tropia test may be performed by holding a 10-prism diopter before one eye in cases of an orthophoria or a microtropia. In infants who cross-fixate, pay attention to when the fixation switch occurs; if it occurs near primary position, then visual acuity is equal in both eyes. Caution should be used when obtaining Teller acuity in children, as grating acuity may be less reduced than Snellen acuity, especially in strabismic amblyopia.

Contrast sensitivity
Strabismic and anisometropic amblyopic eyes have marked losses of threshold contrast sensitivity, especially at higher spatial frequencies; this loss increases with the severity of amblyopia.

Neutral density filters

Patients with strabismic amblyopia may have better visual acuity or less of a decline of visual acuity when tested with neutral density filters compared to the normal eye. This was not found to be true in patients with anisometropic amblyopia or organic disease.

Binocular function
Amblyopia usually is associated with changes in binocular function or stereopsis.

Eccentric fixation
Some patients with amblyopia may consistently fixate with a nonfoveal area of the retina under monocular use of the amblyopic eye, the mechanism of which is unknown. This can be diagnosed by holding a fixation light in the midline in front of the patient and asking them to fixate on it while the normal eye is covered. The reflection of the light will not be centered.

Refraction
Cycloplegic refraction must be performed on all patients, using retinoscopy to obtain an objective refraction. In most cases, the more hyperopic eye or the eye with more astigmatism will be the amblyopic eye. If this is not true, one needs to investigate further for ocular pathology.

Rest of examination
Perform a full eye examination to rule out ocular pathology

Causes
Many causes of amblyopia exist; the most important causes are as follows:[2, 1]

Anisometropia

Inhibition of the fovea occurs to eliminate the abnormal binocular interaction caused by one defocused image and one focused image. This type of amblyopia is more common in patients with anisohypermetropia than anisomyopia. Small amounts of hyperopic anisometropia, such as 1-2 diopters, can induce amblyopia. In myopia, mild myopic anisometropia up to -3.00 diopters usually does not cause amblyopia. Hypermetropic anisometropia of 1.50 diopters or greater is a long-term risk factor for deterioration of visual acuity after occlusion therapy.

Strabismus
The patient favors fixation strongly with one eye and does not alternate fixation. This leads to inhibition of visual input to the retinocortical pathways. Incidence of amblyopia is greater in esotropic patients than in exotropic patients.

Strabismic anisometropia
These patients have strabismus associated with anisometropia.

Visual deprivation
Amblyopia results from disuse or understimulation of the retina. This condition may be unilateral or bilateral. Examples include cataract, corneal opacities, ptosis, and surgical lid closure.[7]

Organic
Structural abnormalities of the retina or the optic nerve may be present. Functional amblyopia may be superimposed on the organic visual loss.

Imaging Studies
If suspicion exists of an organic cause for decreased vision and the ocular examination is normal, then further investigations into retinal or optic nerve causes should be initiated. Studies to perform include imaging of the visual system through CT scan, MRI, and fluorescein angiography to assess the retina.

Other Tests
Although differences in the electrophysiologic responses of normal eyes versus amblyopic eyes have been reported, these techniques remain investigational and the differences are controversial

Histologic Findings

Histologic studies of the lateral geniculate nucleus in kittens with deprivation amblyopia have shown that cells receiving input from the deprived eye were shrunken and atrophied, while cells receiving input from the nondeprived eye were expanded.

Medical Care
The clinician must first rule out an organic cause and treat any obstacle to vision (eg, cataract, occlusion of the eye from other etiologies). Remove cataracts in the first 2 months of life, and aphakic correction must occur quickly. Treatment of anisometropia and refractive errors must occur next.[8, 9, 10, 11] The amblyopic eye must have the most accurate optical correction possible. This should occur prior to any occlusion therapy because vision may improve with spectacles alone. Full cycloplegic refraction should be given to patients with accommodative esotropia and amblyopia. In other patients, a prescription less than the full plus measurement that was refracted may be prescribed given that the decrease in plus is symmetric between the two eyes. Because accommodative amplitude is believed to be decreased in amblyopic eyes, one needs to be cautious about cutting back too much on the amount of plus. Refractive correction alone has been shown to improve amblyopia in up to 77% of patients in a nationwide trial. Patients with bilateral refractive amblyopia do well with spectacle correction alone, with most children aged 3-10 years achieving 20/25 or better within a year.[12, 13] The next step is forcing the use of the amblyopic eye by occlusion therapy. Occlusion therapy has been the mainstay of treatment since the 18th century. The following are general guidelines for occlusion therapy:

Patching may be full-time or part-time. Standard teaching has been that children need to be observed at intervals of 1 week per year of age, if undergoing full-time occlusion to avoid occlusion amblyopia in the sound eye. The Amblyopia Treatment Studies (ATS) have helped to provide new information on the effect of various amounts of patching.[14, 15] Always consider lack of compliance in a child where visual acuity is not improving. Compliance is difficult to measure but is an important factor in determining the success of this therapy. In addition to adhesive patches, opaque contact lenses, occluders mounted on spectacles, and adhesive tape on glasses have been used. Establishing the fact that the vision of the better eye has been degraded sufficiently with the chosen therapy is important. The Amblyopia Treatment Studies have helped to define the role of full-time patching versus part-time patching in patients with amblyopia. The studies have demonstrated that, in patients aged 3-7 years with severe amblyopia (visual acuity between 20/100 and 20/400), full-time patching produced a similar effect to that of 6 hours of patching per day. In a separate study, 2 hours of daily patching produced an improvement in visual acuity similar to that of 6 hours of daily patching when treating moderate

amblyopia (visual acuity better than 20/100) in children aged 3-7 years. In this study, patching was prescribed in combination with 1 hour of near visual activities.

Data from the Amblyopia Treatment Studies are also available for older patients. For patients aged from 7 years to younger than 13 years, the Amblyopia Treatment Studies have suggested that prescribing 2-6 hours a day of patching can improve visual acuity even if the amblyopia has been previously treated. For patients aged from 13 years to younger than 18 years, prescribing 2-6 hours a day of patching might improve visual acuity when amblyopia has not been previously treated; however, this is likely to be of little benefit if amblyopia was previously treated with patching. Long-term results from these studies are still pending.[16] The Amblyopia Treatment Studies have also found that about one fourth of children with amblyopia who were successfully treated experience a recurrence within the first year after discontinuation of treatment. Data from these studies suggest that patients treated with 6 or more hours a day of patching have a greater risk of recurrence when patching is stopped abruptly rather than when it is reduced to 2 hours a day prior to cessation of patching. Randomized studies have still yet to be performed.[17]

In the past, penalization therapy was reserved for children who would not wear a patch or in whom compliance was an issue. The Amblyopia Treatment Studies, however, have demonstrated that atropine penalization in patients with moderate amblyopia (defined by the study as visual acuity better than 20/100) is as effective as patching. The Amblyopia Treatment Studies were performed in children aged 3-7 years.[18, 19, 20, 21] The Amblyopia Treatment Studies have also demonstrated that weekend use of atropine provided an improvement in visual acuity similar to that of daily use of atropine when treating moderate amblyopia in children aged 3-7 years. Atropine drops or ointment is instilled in the nonamblyopic eye. This therapy is sometimes used in conjunction with patching or occlusion of the glasses (eg, adhesive tape, nail polish) by individual practitioners. In the Amblyopia Treatment Studies that evaluated patching versus atropine penalization, atropine penalization and patching were used in conjunction with 1 hour of near visual activities. This technique may also be used for maintenance therapy, which is useful, especially in patients with mild amblyopia. Other options include optical blurring through contact lenses or elevated bifocal segments.[22] The endpoint of therapy is spontaneous alternation of fixation or equal visual acuity in both eyes.[23] When visual acuity is stable, patching may be decreased slowly, depending on the child's tendency for the amblyopia to recur. Because amblyopia recurs in a large number of patients (see Prognosis), maintenance therapy or tapering of therapy should be strongly considered. This tapering is controversial, so individual physicians vary in their approaches. Treatment of strabismus generally occurs last. The endpoint of strabismic amblyopia is freely alternating fixation with equal vision. Surgery generally is performed after this endpoint has been reached.

Surgical Care

Surgical therapy for strabismus generally should occur after amblyopia is reversed. Disadvantages to surgical therapy prior to correction of amblyopia include difficulty in telling if amblyopia is present because there is no longer a strabismus to assess fixation preference and higher potential to being lost to follow-up, as the child cosmetically looks better. The improved cosmesis gives the parents a false sense of security about the vision improving

Activity
Close supervision during occlusion therapy is necessary to make sure children do not peek. Various methods of preventing children from removing patches have been considered, from a reward system for older children to arm splints and mittens for infants.

Medication Summary
Pharmacologic treatment with levodopa has been investigated and has showed transient improvement of vision in amblyopic eyes. However, the exact role of such pharmacologic agents has not been determined. Levodopa currently is not being used clinically. Atropine penalization (with either ointment or drops) is an alternative method of blurring vision in the sound eye of patients who refuse patching. It may be applied once a day to patients in the preferred eye only.

Cycloplegics
Class Summary
These agents are used to blur vision in one eye to treat amblyopia in the contralateral eye. View full drug information

Atropine ophthalmic (Isopto, Atropair, Atropisol)

A topically applied muscarinic antagonist, which blocks the action of acetylcholine. This results in paralysis of the iris sphincter and resultant pupillary dilation. Paralysis of the ciliary muscles also occurs, which inhibits accommodation and relieves pain in iridocyclitis. The medication is dispensed in a topical formulation, either an ointment or a solution.

Further Outpatient Care

Outpatient follow-up care needs to continue beyond the primary completion of amblyopia treatment because visual deterioration occurs in many children. In a multicenter study conducted as part of the Amblyopia Treatment Studies, one fourth of patients experienced recurrence of amblyopia within the first year after treatment, with the risk of recurrence greater if the treatment was stopped abruptly rather than tapered. One study by Levartovsky et al showed deterioration in 75% of children with anisometropia of 1.75 diopters or more after occlusion therapy.[24] Recidivism can occur, even several years after the initial treatment period, and is as high as 53% after 3 years.

Deterrence/Prevention
Vision screening programs
Studies have shown these programs to be technically easy and that they help reduce cost as well as incidence of amblyopia because of early treatment and detection. Current programs include use of the photorefractor and school vision screening programs. Longmuir et al reported the results of a 9-year, volunteer photoscreening program.[25] From 2000-2009, 147,809 children underwent photoscreening to detect amblyopic risk factors; 6247 children (4.2%) were referred to local eye care professionals. Of the children referred, 24.3% were evaluated by local ophthalmologists and 76.7% were seen by local optometrists. The follow-up rate ranged from 36.1-89.5%, with an overall program follow-up rate after the addition of a follow-up coordinator of 81.3%. Including the overall operational budget, the cost of screening was reduced to $9 per child. Although the Medical Technology and Innovations (MTI) photoscreener used in this program is no longer manufactured, this report does illustrate that cost-effective screening can be done using a volunteer system and demonstrates the problem of successful screening that is not followed with a visit to an eye care professional.

Conclusions
The addition of a part-time follow-up coordinator to the photoscreening program produced 89.5% follow-up rate when screening 147 809 children for amblyopia risk factors over a 9year period.

Amblyopia after trauma

Young patients who have trauma to their eyes often are at risk for occlusion amblyopia. Possible reasons include lid edema, hyphema, occlusive dressing, vitreous hemorrhage, and traumatic cataract. This amblyopia often is superimposed on a visual deficit caused by any structural abnormality and needs to be taken into account when treating these children. Vision needs to be monitored closely in children after ocular trauma, especially in those aged up to 6 years and in nonverbal children. Occlusive therapy needs to be instituted if there is any suggestion of decreased vision in the injured eye.

Complications
The main complication of not treating amblyopia is long-term irreversible vision loss. Most cases of amblyopia are reversible if detected and treated early, so this vision loss is preventable.

Prognosis

After 1 year, about 73% of patients show success after their first trial of occlusion therapy. Studies have shown that the number of patients who retain their level of visual acuity decreases over time to 53% after 3 years. Risk factors for failure in amblyopia treatment include the following:

Type of amblyopia: Patients with high anisometropia and patients with organic pathology have the worse prognosis. Patients with strabismic amblyopia have the best outcome. Age at which therapy began: Younger patients seem to do better. Depth of amblyopia at start of therapy: The better the initial visual acuity in the amblyopic eye, the better the prognosis.

A study by Mirabella et al determined that even with successful treatment of an amblyopic eye, perception of images in real-world scenes remains altered in patients with a history of amblyopia.[26]

Strabismic amblyopia
Strabismus, sometimes erroneously also called ''lazy eye'', is a condition in which the eyes are misaligned. Strabismus usually results in normal vision in the preferred sighting (or "fellow") eye, but may cause abnormal vision in the deviating or strabismic eye due to the discrepancy between the images projecting to the brain from the two eyes. Adult-onset strabismus usually causes double vision (diplopia), since the two eyes are not fixated on the same object. Children's brains, however, are more neuroplastic, and therefore can more easily adapt by suppressing images from one of the eyes, eliminating the double vision. This plastic response of the brain, however, interrupts the brain's normal development, resulting in the amblyopia. Strabismic amblyopia is treated by clarifying the visual image with glasses, and/or encouraging use of the amblyopic eye with an eyepatch over the dominant eye or pharmacologic penalization of it. Penalization usually consists of applying atropine drops to temporarily dilate the pupil, which leads to blurring of vision in the good eye. This helps to prevent the bullying and teasing associated with wearing a patch, although application of the eyedrops is more challenging. The ocular alignment itself may be treated with surgical or non-surgical methods, depending on the type and severity of the strabismus.

Refractive or anisometropic amblyopia

Refractive amblyopia may result from anisometropia (unequal refractive error between the two eyes). Anisometropia exists when there is a difference in the refraction between the two eyes.

The eye which provides the brain with a clearer image (closer to 20/20) typically becomes the dominant eye. The image in the other eye is blurred, which results in abnormal development of one half of the visual system. Refractive amblyopia is usually less severe than strabismic amblyopia and is commonly missed by primary care physicians because of its less dramatic appearance and lack of obvious physical manifestation, such as with strabismus. Frequently, amblyopia is associated with a combination of anisometropia and strabismus. Amblyopia in those that maintain binocular functions can be treated successfully up to a later age than those with strabismic amblyopia. Pure refractive amblyopia is treated by correcting the refractive error early with prescription lenses and patching or penalizing the good eye. Meridional amblyopia is a mild condition in which lines are seen less clearly at some orientations than others after full refractive correction. An individual who had an astigmatism at a young age that was not corrected by glasses will later have astigmatism that cannot be optically corrected.

Form-deprivation and occlusion amblyopia

Form-deprivation amblyopia (''Amblyopia ex anopsia'') results when the ocular media become opaque, such as is the case with cataracts or corneal scarring from forceps injuries during birth. These opacities prevent adequate visual input from reaching the eye, and therefore disrupt development. If not treated in a timely fashion, amblyopia may persist even after the cause of the opacity is removed. Sometimes, drooping of the eyelid (ptosis) or some other problem causes the upper eyelid to physically occlude a child's vision, which may cause amblyopia quickly. Occlusion amblyopia may be a complication of a hemangioma that blocks some or all of the eye.