Amblyopia is a relatively common disorder and a major cause of visual impairment in children. It represents an insult to the visual system during the critical period of development whereby an ocular pathology (ex. strabismus, anisometropia, high refractive error, or deprivation) interferes with normal cortical visual development. Approximately 3-5% of children are affected by amblyopia.
Amblyopia represents diminished vision occurring during the years of visual development secondary to abnormal visual stimulation or abnormal binocular interaction. It is usually unilateral but it can be bilateral. The diminished vision is beyond the level expected from the ocular pathology present.
Bilateral amblyopia is less common than unilateral amblyopia. Bilateral cases are caused by bilateral image blur (anterior visual pathway). Examples of etiologies for bilateral amblyopia include bilateral media opacities (including corneal opacities, infantile or childhood cataracts, or vitreous hemorrhages), or ametropia (bilateral high astigmatism or high hypermetropia). Unilateral causes of amblyopia also include the same types of media opacities seen in bilateral cases. However, the most common causes of unilateral amblyopia are strabismus and anisometropia, or a combination of the two
The etiologies of amblyopia can be easily remembered with the following pnemonic: S.O.S. Spectacles (anisometropia or high myopic or hyperopic refractive error), Occlusion (media opacities, retinal disease, optic nerve pathology, corneal disease, etc.), and Strabismus.
A positive family history of strabismus, amblyopia, or media opacities would increase the risk of amblyopia in the child. Children who have conditions that increase the risk of strabismus, anisometropia, or media opacities (including Down syndrome) would also be at increased risk for the development of amblyopia. The risk of developing amblyopia, from a condition that is known to cause amblyopia, diminshes as the child approaches 8-10 years of age. As a corollary to this, the depth of amblyopia is typically less severe the older the child is at the time of onset of the amblyogenic factor.
In cases of bilateral amblyopia, the basic pathology is a significant blurred retinal image in each eye causing a disruption of normal visual development. This disruption must occur during the critical period of visual development (the first 8-10 years of life). The depth of damage depends on the severity of the blur, the length of time of the abnormal vision, and the age of onset of the insult. The pathology involved in unilateral amblyopia can be twofold. Retinal image blur in one eye can inhibit cortical activity from one eye, preventing normal visual development. Alternatively, misaligned eyes can prevent the normal process of fusion from taking place. This can result in suppression of the deviating eye, diminishing the acuity of the eye, and loss of binocularity. Sensory amblyopia is more severe than strabismic or anisometropic amblyopia and is tough to treat.
Abnormal visual stimulation during the critical period of visual development results in brain damage. Structural and functional damage occurs in the lateral geniculate nucleus and the striate cortex of the visual center in the occipital lobe in the form of atrophy of connections, loss of cross-linking between connections, and loss of laterality of connections.
The key to prevention is detection. There are numerous techniques to detect amblyopia, all with varying degrees of specificity, sensitivity, complexity, and cost. These include a complete ophthalmic examination, photoscreening, visual evoked potentials, acuity charts, and tests of stereopsis and binocular function. Children who are at higher risk for amblyopia should be watched closely for early signs of this condition. In general, the quicker amblyopia is detected and addressed, the less negative effect it has on the visual system. Vision screening is advocated on the state level to screen as many children as possible for this disease prior to the age of kindergarten. Early intervention results in better overall vision. This is why the American Association for Pediatric Ophthalmology and Strabismus, the American Academy of Pediatrics, and the American Academy of Ophthalmology all support pre-kindergarten vision screening for children.
Amblyopia should be considered as a possible diagnosis in children with asymmetric visual behavior or acuity. It can also complicate the course of children with strabismus, or unilateral ocular or adnexal pathology such as a cataract, eyelid capillary hemangioma, or corneal scar. Bilateral amblyopia can also occur and should be thought of when a bilateral ocular condition occurs and despite treatment, some degree of diminished acuity persists. A careful history, thorough physical examination, and knowledge of possible etiologies of amblyopia can help the clinician to diagnose this condition.
Parents will often bring their child to the Ophthalmologist because of the underlying cause of the amblyopia (ptosis, strabismus, leukocoria, eyelid hemangioma), without realizing that amblyopia is present. In fact, anisometropic amblyopia usually goes undetected until picked up by a vision screening. The overwhelming majority of children with unilateral amblyopia do not complain of decreased acuity because they do not notice it unless one eye is occluded. The history taking process should include any family history of vision problems (specifically amblyopia and strabismus). Parents should be asked if the child was premature, and if they have ever noted any eye misalignment. Any prior testing (including school or Pediatrician vision screening, neuroimaging) should be noted. If any abnormality in the child's visual behavior has been noted, the duration is important. Also, some children may already have received care for amblyopia somewhere else. If this is the case, type of treatment and duration should be determined. Old records can be helpful.
Examination should consist of the following:
- Acuity testing (age appropriate): Single optotypes (without crowding bar) are not recommended as a good acuity testing technique in amblyopes because this test will tend to underestimate the degree of amblyopia (crowding phenomenon).
- Record the power of any current spectacles
- Subjective refraction if age appropriate
- Tests of stereopsis and binocular function (including Worth 4 dot testing, TNO stereo test)
- External examination (looking for ptosis, lid hemangioma or other lesion which could affect visual development)
- Presence or absence of an afferent pupil defect
- Anterior segment examination (looking for any media opacity, or irregularity)
- Motility and ocular alignment
- Funduscopic examination
- Cycloplegic retinoscopy
The presence or absence of signs of amblyopia would depend on what the underlying etiology for the amblyopia is. Deprivational amblyopia could manifest with ptosis, an eyelid hemangioma, or a cataract for example. Strabismic amblyopia may show a constant or intermittent ocular deviation. Esotropia causes more amblyopia as compared to exotropia since esotropia is constant and exotropia is usually intermittent in nature. Anisometropic amblyopia often shows no obvious signs when observing the patient, but cycloplegic retinoscopy will reveal the anisometropia. On clinical examination, unilateral amblyopia will show asymmetric visual behavior or acuity testing results (although not all patients with asymmetric acuity have amblyopia). Severe cases may have a mild afferent pupillary defect. The crowding phenomenon is important to be aware of when testing visual acuity in an amblyope. The amblyopic eye of these patients will visualize individual letters better than a whole line of letters. Therefore, if the visual acuity tester uses individual letters (sans crowding bar), then they may underestimate the degree of amblyopia that is present or miss it entirely. A neutral density filter significantly reduces vision in organic disease, but generally does not in pure amblyopia.
Patients with unilateral amblyopia are often asymptomatic. Occasionally, patients will complain that one eye is blurry, or younger children may report discomfort in the affected eye. Torticollis occurs infrequently. Poor depth perception or clumsiness may be noted.
In cases of unilateral amblyopia, the diagnosis requires two components. First, the patient must have a condition that can cause unilateral amblyopia. Examples would include strabismus, anisometropia, or a deprivational cause (ptosis, cataract, etc.). Second, the patient must have residual asymmetric acuity beyond the level expected from the underlying condition or that persists after treatment of the underlying condition. For example, a child with anisometropic hyperopia receives proper spectacle correction. Acuity in the more hyperopic eye improves but is still below that of the less hyperopic eye. This asymmetry of acuity represents amblyopia. In cases of bilateral amblyopia, a condition must be present during the critical years of visual development which produces constant, significant visual blur. Examples of such conditions would include bilateral vitreous hemorrhages, bilateral cataracts, bilateral corneal pathology, bilateral high hypermetropia, or bilateral high astigmatism.
A normal, comprehensive ophthalmic examination is usually all that is necessary to diagnose amblyopia. Components of this examination include (but are not limited to): acuity testing, cycloplegic refraction and retinoscopy, tests of stereopsis and binocular vision, evaluation of pupillary responses, anterior segment examination, cover-uncover and alternate-cover testing, and dilated funduscopic examination. See the Physical Examination section above.
Laboratory testing is not a typical feature of amblyopia diagnosis. Certainly if the etiology of the amblyopia was unclear, or if vision was deteriorating despite treatment, neuroimaging would be considered. Fundus dystrophies (specifically Stargatdt disease) may have normal appearing fundus in early stages with unexplained vision loss. Such patients may need fundus photo, fluorescein angiogram, optical coherence tomography of macula, and electrophysiological tests. Patients with high astigmatism may need corneal topography to rule out keratoconus.
There are cases of decreased acuity in children in which amblyopia is not present. Ocular pathology or refractive error (or even improper spectacle correction) may cause decreased acuity without any superimposed amblyopia. Prechiasmal lesions or optic nerve insult can also produce unilateral decreased acuity.
Although there is much practitioner variability in the treatment of amblyopia, the general idea is to first treat the underlying cause for the amblyopia. Examples of this treatment would include prescribing glasses for anisometropia, strabismus surgery or spectacles to eliminate strabismus, or removal of a unilateral cataract to eliminate the media opacity. In unilateral or asymmetric cases of amblyopia, if there is a residual visual deficit after the underlying etiology is treated then amblyopia is said to exist. This can be addressed with occlusion therapy, pharmacologic therapy, or some other less commonly used modalities. Much of the data on the success of various treatment modalities for amblyopia through the years has come from retrospective, single site chart-review type studies. Over the last decade, there has been an explosion of amblyopia research. The need for prospective randomized trials in the treatment of amblyopia has begun to be met by the Pediatric Eye Disease Investigator Group (PEDIG). This is an NEI-funded network including both University-based and community-based clinicians. The power of such a group lies in its ability to conduct multiple trials in a cost-effective fashion, with simple protocols implemented as part of routine practice. Patients are enrolled at multiple clinical sites in a prospective randomized fashion, with standardized visual testing protocols..Important data derived from these studies is present throughout this section on amblyopia.
The key to optimal treatment of amblyopia is early detection and intervention. In symmetric bilateral cases, treatment consists of addressing the etiology of the diminished vision. Often there is residual bilateral amblyopia which may improve over time. In asymmetric cases or unilateral cases, active treatment with patching, pharmacologic agents, or some less commonly used modalities can often improve the residual visual deficit.
In anisometropic patients, some improvement in amblyopia can occur with glasses alone. Starting treatment in this manner may lessen the burden of subsequent amblyopia therapy for those with denser levels of amblyopia and in some cases may obviate the need for patching or pharmacologic penalization. Patching of the sound eye to improve the acuity of the amblyopic eye is the most commonly used technique to treat amblyopia. Patching compliance is a major concern, with high rates of poor compliance or noncompliance in some studies. Compliance with therapy can be bolstered by parental education and improving parental attitudes towards patching therapy. The number of prescribed patching hours per day varies widely between practitioners. In general most doctors recommend heavier patching regimens for worse degrees of amblyopia. The thought behind this is that heavier patching would improve results and the rapidity of obtaining them. However this practice has been called into question by recent PEDIG studies.
A study of severe amblyopes randomized the patching regimen to 6 hours of prescribed patching per day versus 12 hours per day. At the 4-month outcome visit, acuity improvements and rapidity of improvement were essentially identical between the groups. A similar study of moderate amblyopes comparing 2 hours of prescribed patching per day to 6 hours per day, also found no difference in results. Some clinicians also prescribe 'near activities' in conjunction with patching but this was not found to be beneficial in a recent study.
Pharmacologic penalization of the sound eye is another commonly used modality to treat amblyopia. Dosing can be a drop in the sound eye daily, or on weekends only. A recent study showed results with weekend-only dosing to be similar to daily dosing for moderate amblyopes. In children who wear hyperopic spectacles, Atropine usage is sometimes combined with replacing the hyperopic lens over the sound eye with a plano lens. This wass felt to 'enhance' treatment, but a recent study showed only a minimal benefit of this additional step in therapy. Atropine is the most commonly used pharmacologic agent. A common assumption is that atropine use in the amblyopic patient can only be effective if it induces a fixation switch. This assumption has been called into question by a recent study. Often the decision whether to treat the amblyopic child with patching or pharmacologic agents, is based on the practitioner's practice patterns and parental wishes.
A head-to-head study showed that 6 hours a day of patching therapy produced a slightly more rapid and beneficial effect than daily instillation of Atropine 1%, in moderate amblyopes younger than 7 years of age. However, the final difference at 6 months was not statistically significant and a parental questionnaire showed families preferred pharmacologic therapy over patching.
Other modalities of medical amblyopia management include optical penalization with an occlusive Bangerter filter placed on the glasses lens or the use of a high plus lens to blur the sound eye, as well as contact lenses used as occlusion or for blurring.
Dichoptic video games and dichoptic movies are being studied as potential novel therapies for amblyopia. PEDIG studies showed that patching was superior to the use of an earlier, less engaging, dichoptic falling blocks video game for amblyopia treatment  . More recently, PEDIG showed that in children aged 7 to 12 years who received previous treatment for amblyopia other than spectacles, the dichoptic adventure video game Dig Rush showed no benefit to vision or stereoacuity after 4-8 weeks of treatment over spectacle use alone. 
A novel digital therapeutic, Luminopia One, delivers dichoptic amblyopia therapy while providing an engaging patient experience. Therapeutic visual stimuli are presented using real-time modification of patient-selected, cloud-based video content (e.g., television shows or movies) within a head-mounted display. In a randomized clinical trial of 105 children aged 4-7 years across 21 sites with anisometropic or strabismic amblyopia, amblyopic eye visual acuity improved by 1.8 lines in the Luminopia One treatment group compared to 0.8 lines in the spectacles-alone control group.  This digital therapy has yet to be compared to other methods of amblyopia treatment.
CureSight is a promising dichoptic treatment for amblyopia that uses eye-tracking to induce real-time blur around the fellow eye fovea in dichoptic streamed video content. CureSight (90 min/day, 5 days/week) was found to be non-inferior to patching (2 hours/day, 7 days/week) in a 16 week multicenter trial of 103 children 4 to < 9 years with anisometropic, small-angle strabismic or mixed-mechanism amblyopia. 
Medical follow up
Follow up during treatment is typically somewhere between every 1-3 months. When treatment is discontinued, follow-up is necessary to ensure there is no regression of effect.
Amblyopia itself is not a surgical condition, but there are times when surgery may treat the underlying cause of the amblyopia. Refractive surgery may be used to correct anisometropia. However, refractive surgeries are not approved by the Food and Drug Administration (FDA, USA) below 18 years of age. Eye muscle surgery can correct strabismus. Cataract, ptosis, vitrectomy, or corneal surgery may alleviate causes of deprivation.
Even though surgery may be performed to alleviate some of the etiologies of amblyopia, most cases will still require follow-up to treat the amblyopia that is present. For example, in a child with strabismic amblyopia, eliminating the ocular misalignment does not automatically fully correct the amblyopia which resulted from the strabismus.
Overly aggressive amblyopia therapy (especially in younger patients) can produce reverse amblyopia of the sound eye. A new strabismus or a decompensation of an exisiting strabismus can also occur. Patches can be irritating to the skin, and the skin underlying the patch can become hypopigmented relative to the rest of the facial skin. There is also a potential social stigma associated with wearing the patch to school in some cases. Atropine use can cause side effects related to the use of this medication: flushing, rapid heart rate, mood changes (uncommon) and photophobia (common) would be examples of side effects occurring with the use of this medication. Reverse amblyopia can also occur with Atropine use as can decompensation of existing strabismus or development of a new strabismus. Cases of reverse amblyopia are infrequent and usually mild. Most cases resolve with discontinuation of treatment.
The keys to treatment success are younger age at detection/treatment, short course until intervention, and compliance with treatment. The effectiveness of intensive screening protocols to detect amblyopia at a young age has been shown to result in a better acuity of the amblyopic eye at age 7.5 years. Most patients do improve with treatment, but often residual amblyopia remains. With cessation of amblyopia treatment there is a risk of recurrence. In one study, the risk of recurrence was higher with better visual acuity at the time of cessation of treatment, a greater number of lines improved during the previous treatment, and a prior history of recurrence. Orthotropia or excellent stereoacuity at the time of patching cessation did not appear to have a protective effect on the risk of recurrence. In a prospective study of cessation of treatment in children aged 3 to <8 years with successfully treated amblyopia due to anisometropia, strabismus or both, the risk of amblyopia recurrence was found to be 24%. Patients treated with 6 to 8 hours of daily patching had a 4-fold greater odds of recurrence if patching was stopped abruptly rather than when it was reduced to 2 hours per day prior to cessation. Careful and prolonged follow-up during the amblyogenic years, is needed for all children who have been previously treated for amblyopia to prevent a recurrence. In general, the younger amblyopes are treated, the better the likelihood of improvement.
Most textbooks do not recommend trying amblyopia therapy in the second decade of life but some improvement can be obtained in few cases. A study of amblyopia therapy in children aged 7-17 years found that amblyopia improves to some degree with optical correction alone in about one fourth of patients. However most required additional treatment for amblyopia. For patients aged 7 to 12 years, 2 to 6 hours per day of patching with near visual activities and atropine improved visual acuity even if the amblyopia had been previously treated. For patients 13 to 17 years, improvement was only noted in those children who had not been previously treated. The degree of improvement in these older children was much more modest than results from other studies of younger children, so the importance of early detection and treatment remains.
Studies have demonstrated that amblyopic children read significantly more slowly than controls, even when the vision in the amblyopic eye is only reduced to 20/30 vision.   Amblyopia can also impact academic related fine-motor outcomes, such as multiple-choice answer completion time. 
Pertinent clinical trials
Pediatric Eye Disease Investigators Group Study (PEDIG) –or– Amblyopia Treatment Study
Arch Ophthalmol 2002;120:268 | Arch Ophthalmol 2003;121:603 | Ophthalmol 2003;110:2075 | J AAPOS 2004;8:420 | Arch Ophthalmol 2005;123:437 | Ophthalmol 2006;113:895 | Ophthalmol 2006;113:904.
The goal was to determine if correcting the refractive error alone can treat amblyopia, the benefits of patching, and the risks of recurrence after suspension of treatment. In addition, it wanted to know until what age can amblyopia be treated and the management with atropine and occlusion.
This trial tried to facilitate an evidence-based approach to the treatment of amblyopia.
Clinical trials involving
- Observational study of spectacles alone for anisometropic amblyopia.
- Amblyopia treatment randomized to daily atropine to the fellow eye or at least 6 hours of patching per day.
- 2 concurrent randomized trials of patching, prescribed 2 hours/day versus 6 hours/day for moderate amblyopia and prescribed 6 hours/day versus full-time for severe amblyopia.
- Patching in older children: children randomised to receive optical correction ± patching for near activities.
- Recurrence of amblyopia: children treated with patching or atropine for at least three months with at least three lines of improvement were brought off therapy, and followed up for one year.
Moderate amblyopia was defined as 20/40 to 20/80. Severe amblyopia was defined as 20/100 to 20/400. Successful treatment was defined as the improvement of VA to within one line of the non-amblyopic eye. Recurrence of amblyopia was defined as a reduction in at least two lines after cessation of amblyopia therapy or when treatment was restarted at an investigator’s discretion.
Inclusion criteria were children less than seven years, BCVA in the better eye better than 20/40, and the amblyopic eye less than 20/40. Previous refractive error corrected for at least four weeks before the study.
Main outcome measures
Primary endpoint: BCVA.
More than 4000 subjects have participated in 19 Amblyopia Treatment Studies (ATS). The main ones were:
- Observational study of spectacles alone for anisometropic amblyopia: 84 children, 3 to 6 years of age and VA from 20/40 to 20/250 at enrollment. 77% of the children improved at least 2 lines, and 27% showed resolution within 1 line of the fellow eye. Maximum improvement was achieved by 83% of subjects by 10 weeks, but some children improved for 30 weeks. Improvement was found in children with moderate and severe amblyopia. The key lesson was that spectacles are an effective initial tool in managing amblyopia.
- Amblyopia treatment randomized to daily atropine to the fellow eye or at least 6 hours of patching per day. 419 children, 3 to 6 years of age with amblyopia 20/40 to 20/100. VA improved in both groups at 6 months; during the initial treatment phase, the patching group did improve more quickly, but the atropine group caught up by 6 months. Thus, atropine and patching are effective in the treatment of amblyopia. Parental questionnaires found atropine to be better tolerated in terms of social stigma and compliance. The amblyopia treatment benefit persisted through age 10 years without a mean VA loss, but residual amblyopia remains in a large proportion of children. The mean amblyopic eye VA at 10 years was approximately 20/32, with 46% of amblyopic eyes 20/25 or better. After the initial 6-months, children were treated at the investigator's discretion with occlusion or atropine, and more than 85% of children continued to be prescribed treatment. So, amblyopia treatment is not a short-term task; it represents a long-term effort.
- 2 concurrent randomized trials of patching, prescribed 2 hours/day versus 6 hours/day for moderate amblyopia and prescribed 6 hours/day versus full-time for severe amblyopia in 3 to 6-year-olds children. 175 severe amblyopes were randomised to receive full-time patching vs. six hours/day patching for four months. 189 moderate amblyopes were randomised to receive either two or six hours a day of patching for four months. VA improved with both patching regimens without differences. Therefore, it is reasonable to initiate therapy with a lower dose and increase treatment intensity if the response is not good.
- Patching in older children: 507 children with amblyopia aged 7 to 18 were recruited and randomised to receive optical correction ± patching for near activities. There was a significant improvement in BCVA in those treated with patching in the 7-12 age group but not in the 13 -17 age group. When only the 13-17-year olds with no previous treatment for amblyopia were considered, there was an improvement in the patched group.
- Recurrence of amblyopia: 156 children who had been treated with patching or atropine for at least three months with at least three lines of improvement were brought off therapy at the investigator's discretion and followed up for one year. The average age was 5.9 years, and no child was older than eight. 21% of children experienced amblyopia recurrence, with 40% occurring within the first five weeks.
Children younger than three were not included
Refractive correction alone may be effective in the treatment of amblyopia. There is no benefit in patching moderate amblyopes for longer than two hours and severe amblyopes for more than six hours per day. Children need close follow-up after discontinuation of occlusion therapy. There may be a benefit in treating amblyopia until 12 years of age. Teenagers with amblyopia who have never before received treatment may benefit from a trial of patching. There is no clinical difference in using atropine vs. patching in moderate amblyopes.
Pearls for clinical practice
Refraction helps amblyopia.
Moderate amblyopes can be treated using atropine or patching.
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