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 Table of Contents  
MAJOR REVIEW
Year : 2021  |  Volume : 33  |  Issue : 1  |  Page : 14-21

Amblyopia – An update


Department of Ophthalmology, Government Medical College, Thrissur, Kerala, India

Date of Submission14-Jan-2021
Date of Decision16-Jan-2021
Date of Acceptance17-Jan-2021
Date of Web Publication19-Apr-2021

Correspondence Address:
Dr. Sujatha Nambudiri
Department of Ophthalmology, Government Medical College, Thrissur, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_13_21

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  Abstract 


Amblyopia is the most common cause for preventable monocular visual loss in children. Visual system at birth is at a stage of dramatic developmental neural plasticity. Abnormal visual impulses from eyes (e.g., visual deprivation and refractive error) can affect normal anatomical and functional organization of the system. Abnormal cortical changes thus produced can be reversed if proper treatment is instituted during this time. This so-called critical period was thought to extend from birth to 7–8 years. However, now, it is understood that cortical plasticity though reduced may extend up to 6th decade of life and this accounts for increased interest in the management of adult amblyopia. Early detection and instituting treatment on detection are important for achieving better outcomes. Classical amblyopia treatment modalities include optical correction of significant refractive errors, occlusion therapy and penalization. Pharmacologic therapy, binocular therapy, and liquid crystal display eyeglasses are the newer treatment options. This review gives a simplified update of amblyopia including simplified pathophysiological concept in different types of amblyopia which will be useful to the clinician. Recent treatment options available for treatment including that in adult amblyopia are also discussed. Literature search using Google scholar, PubMed with a combination of words appropriate to this article was done and relevant articles were reviewed.

Keywords: Amblyopia, occlusion therapy, orthoptic therapy, penalization, refractive correction


How to cite this article:
Nambudiri S, Geetha Kumari P V, Sudha V, Sinumol S. Amblyopia – An update. Kerala J Ophthalmol 2021;33:14-21

How to cite this URL:
Nambudiri S, Geetha Kumari P V, Sudha V, Sinumol S. Amblyopia – An update. Kerala J Ophthalmol [serial online] 2021 [cited 2021 May 7];33:14-21. Available from: http://www.kjophthal.com/text.asp?2021/33/1/14/314085




  Introduction Top


Amblyopia or “Dullness of vision” is the most common cause for visual loss in children that originates in childhood and demands early intervention. Defined as unilateral or occasionally bilateral reduction in best-corrected visual acuity (VA) which occurs in otherwise normal eye or eye with structural abnormality in which decrease in vision cannot be attributed solely to the abnormality.[1]

Clinically, amblyopia is diagnosed by a difference in VA between the eyes of two lines or more by any VA table, or VA worse than 20/30 with best refractive correction.[2] Amblyopia is usually unilateral and rarely bilateral. The prevalence of amblyopia varies in different parts of the world. In India, it has been documented to be between 1% and 6%.[3],[4] Amblyopia is more than four times as common in infants who are premature, small for gestational age or who have a first-degree relative with amblyopia.[5]


  Pathophysiology Top


Visual system is not fully developed at birth and is in a stage of dramatic developmental neural plasticity. For proper development of visual functions, three fundamental conditions are required-adequate stimuli from both eyes, ocular parallelism, and integrity of visual pathways. At this stage, abnormal visual inputs from the eyes (e.g., visual deprivation, refractive error) can affect normal anatomical and functional organization of the system. Asymmetry of visual inputs from right and left eye make the visual cortex prefer one eye over the other, leading to a number of functional deficiencies in the eye, altered visual function like decreased vernier acuity, and impaired contrast sensitivity, particularly to detect high spatial frequency stimuli and impaired motor signs like hand-eye coordination and spatial localization. Abnormal cortical changes thus produced can be reversed if prompt treatment is instituted during this time. This so called “critical period” continues postnatally till age of 7 years. After this cortical plasticity decreases but is never lost till one is in the 6th decade.[6] This is the basis of increased interest in the management of adult amblyopia. Maturation of visual system is completed by inhibitory gamma-aminobutyric acid genic interneurons in layer 2 and 3 of V1.[7] The inhibition of these interneurons is thought to prolong plasticity.[8]

Understanding pathophysiology can be considered under two headings:

  1. Normal organization of retino-geniculo-cortical pathway


  2. There are two major groups of ganglion cells in retina responsible for processing light energy into electrical impulses. They are Parvocellular (P cells) involved in VA, fine stereopsis and color vision and magnocellular (M cells) cells in gross stereopsis and movement recognition.[9] P cells have higher representation in sensory cortex areas. After partial decussation in chiasma nerve fibers enter lateral geniculate body (LGB). Here, fibers from right and left eyes are distinctly separate and parvocellular and magnocellular fibers end in different layers. Mono-ocular separation of corresponding retinal areas continues through lateral geniculate laminae into striate cortex V1 where geniculate axon terminals from right and left eyes are segregated into a system of alternating parallel stripes called ocular dominance columns (ODC). From there, paired right and left monocular cells finally converge in first binocular cells in layers 2, 3, 4α, 4Cβ of V1. Binocular vision and motor fusion are made possible by horizontal connections from monocular columns to be shared[10] [Figure 1].
    Figure 1: Retino-geniculo-cortical pathway

    Click here to view


  3. Corticogeniculate changes occurring in common types of amblyopia.



  Stimulus Deprivation Amblyopia Top


Usually seen associated with conditions such as congenital cataract and ptosis. Abnormal visual experience strongly affects retino-geniculate-cortical pathway. The two eyes compete for synaptic contacts in cortex. Affected eye loses connections already formed with post synaptic cortical targets and excessive pruning of terminal axons of geniculate cells driven by the affected eye. Hubel and Wiesel in their classical studies in macaque monkeys showed that when one eye was sutured close soon after birth lead to radically narrowed ODC in that side [Figure 2] and shrinkage of lateral geniculate laminae required to sustain reduced arbor of cells in 4c of amblyopic eye. Whereas ODC of other eye was found to expand and enlargement of LGB cells occur in normal side. In visual cortex number of synaptic connections continue to increase until 6 months of age and gradually fall back to normal adult levels.[11] Maximum interconnections are formed between parvocellular fibers and they also are more susceptible to visual deprivation. But, during this critical period, reopening of sutured eye and closure of other eye will cause the ODC of initially closed to become normal. This did not happen if eye was reopened after critical period. Little change was observed in LGB laminae in the affected eye if eye was closed after 2 months indicating a second sensitive period where changes occurring are different.[12] Profound cortical anatomical changes and greatest impact of all visual functions is seen in this type of amblyopia.
Figure 2: Ocular dominance columns

Click here to view



  Anisometropic Amblyopia Top


Anisometropic amblyopia can be associated with any type of refractive error especially with hypermetropia where a clear defined image is never obtained. Difference in refractive error between the two eyes to cause amblyopia varies with the type of refractive error. There should be at least a difference of 1 diopter between the two eyes.[13] Although anisometropia may be considered as a moderate form of stimulus deprivation amblyopia anatomical and functional changes found are different. Critical period in this amblyopia occurs much later than strabismic type and requires longer periods of optical blur. It is seen that proportion of cortical neurons responding to affected eye are much smaller. Optical defocus causes the cortical neurons driven by the defocused eye to be less sensitive to higher spatial frequencies because they are most affected by blur and send out weaker signals.[14],[15] There is little narrowing of ODC and cell shrinkage of parvocellular pathway.

In this condition, congruent images are received by the brain despite difference in output from both eyes. Suppression is foveal and peripheral retinae continue to fuse images.[16],[17] Anisometropic amblyopia leads to significant visual deficits compatible with loss of contrast sensitivity of all spatial frequencies with relative sparing of binocular vision.


  Strabismic Amblyopia Top


Strabismic amblyopia occurs in a child with unilateral squint and more so in esotropes. Deviation of one eye causes loss of parallelism. Fovea of the fixing eye and extra foveal point of deviating eye are stimulated (noncorresponding points). Uncorrelated images reaching brain results in inhibition of retino cortical path way from the deviating eye. There occurs active suppression of affected eye, loss of retinal correspondence and cellular interactions are altered. Studies done in monkeys showed that parvocellular recipient layer to be most affected with loss of binocular cells. ODC remain structured even in case of moderate amblyopia and only in deep amblyopia are there reports of alteration of ODC.[18] Strabismus cause a loss of connectivity to spatial information pathways causing defects in integration of contour and shapes. This affects numerous discriminating visual tasks including VA, vernier VA and crowding.[19],[20],[21] In strabismic amblyopia, there is no binocular facilitation of any stimulus and suppression is constant and strong. Suppression is also found in the fovea of the normal eye when amblyopic eye is fixing showing that lost VA is not related solely to suppression. Thus, it is suppression that leads to amblyopia in an individual who has strabismus and not vice versa, because the inactivity of the system may interfere with the process of synaptic development.[22] Loss of binocularity also affects stereopsis but contrast sensitivity is less affected than in other types of amblyopia with changes mainly to high spatial frequencies.[23],[24],[25] Strabismic amblyopia has major impact on VA and binocularity and contrast sensitivity is relatively spared.


  Newer Understanding in Pathophysiology in Amblyopia Top


The presence of higher order cortical defects such as deficiency in movement integration, perception of shape and global contour, crowding phenomenon and visual decision making made researchers suspect involvement of extra striate areas in amblyopic patient. Investigations such as positron emission tomography, magneto encephalography, functional magnetic resonance imaging were used to demonstrate involvement of V1 and also involvement of ventral V2, 4, 8 and dorsal median temporal area MT(V5). Studies with fMRI are also confirming different impacts on visual cortex related to different types of amblyopia. Recent findings suggest a more profound disorganization of the cortical arrangement in patients with strabismic amblyopia, in which the interhemispheric asymmetry for parvo- and magnocellular input processing was lost, whereas normal cortical asymmetry was present in those with anisometropic amblyopia.[26],[27],[28]


  Management of Amblyopia Top


Comprehensive work up of the patient including relevant history helps in accurate diagnosis and suitable treatment. Minimum work up as per AIOS guidelines[29] include:

  1. VA both eyes (in the case the child can read)
  2. Fixation of either eye to be noted and recorded
  3. Glow of each eye to look for gross refractive error and media clarity
  4. Worth four dot test
  5. Cover and uncover tests to rule out strabismus
  6. Bruckner's red reflex test
  7. Baglioni's striated glass test
  8. Fundus examination.


The goal of treatment is equal VA between the two eyes, which may or may not be achieved in all cases. The treatment should be based on the child's age, VA, and compliance and response to previous treatment as well as the child's physical, social, and psychological status.

Principles of amblyopia management:

  1. Eliminate the cause for amblyopia
  2. Correct any refractive error
  3. Force the use of amblyopic eye by limiting the use of normal eye.



  Preventive Screening Top


This is the most important part of the treatment strategy. Success rates of amblyopia treatment decline with increasing age.[30],[31] The American Association of Ophthalmologists suggests visual screening of all children at least once by 3–5 years.[32] Screening improves vision outcomes, decreasing the prevalence of amblyopia by as much as 60%. A study by Pediatric Eye Disease Investigator Group of treatment of moderate strabismic and/or anisometropic amblyopia demonstrated that the VA of the amblyopic eye improved to 20/30 or better 6 months after initiating treatment in approximately three-quarters of children under 7 years of age.[33] When amblyopia is present, it appears that the potential for successful treatment is greatest in young children, although improvement in VA can reasonably be expected in older children and teenagers.[34],[35],[36] However, treatment should be offered to all regardless of age. Primary care providers may be equipped with novel technologies, such as instrument-based devices (vision screeners) like to diagnose amblyopia in the early stages.[37] Recent studies in India with the Spot PS vision screener showed that it can be used to detect amblyogenic factors in children younger than 5 years of age keeping its limitations in consideration.[38]

Factors affecting treatment success

Prognosis for attaining normal vision in an amblyopic eye depends on many factors, including the age of onset; the cause, severity, and duration of amblyopia; the history of and response to previous treatment;[30] adherence to treatment recommendations and coexisting conditions.

Treatment options include

Refractive correction

In children of age 0–17 years with amblyopia initial treatment is correction of refractive error.[30],[34],[39] Cycloplegic refraction and adequate optical correction given in all patients [Figure 3]. There occurs improvement in 77% and resolves in 25% of patients (amblyopia treatment study [ATS] 5).
Figure 3: Refractive correction addressing squint and amblyopia

Click here to view


Occlusion therapy

Occlusion therapy is based on principle of creating new neural connections through the property of neural plasticity of brain and retrains the visual system to use both eyes equally. In this method, the “stronger” eye is patched so that the “weaker” eye is forced to break any suppression and use its visual pathway.

  1. Whom to patch: Patching[33],[40],[41] is initiated for children in whom amblyopia persists after treatment for 4 months with eye glasses alone. This treatment is most effective with younger children under 7 years of age. Significant improvement in vision with patching can be achieved in children up to 13 years of age, although they may require a higher dose of patching, the rate of response to treatment may be slower, and the extent of recovery may be less complete. Patching should be considered for older children and teenagers, particularly if they have not previously been treated[30]
  2. How much to patch: The ATS found that 6 h of prescribed daily patching produces an improvement in VA that is similar in magnitude to full time occlusion therapy prescribed for treating severe amblyopia (20/100–20/400) in children under 7 years of age.[42] In children who have moderate amblyopia (20/40–20/80), initial therapy of 2 h of prescribed daily patching produces an improvement in VA that is similar in magnitude to the improvement produced by 6 h of daily patching.[40] Higher hours of patching were associated with worse compliance: Only 6% of patients with higher hours of patching complied for the prescribed time.[43] The treatment benefit achieved by the patching appears stable through at least 15 years of age. Occlusion amblyopia and appearance of a constant deviation are important complications of this treatment
  3. Patching continued till equal or optimum VA or equal preference of fixation is achieved and no further improvement of VA is obtained in two successive follow-up visits.


Liquid crystal display glasses: In this novel therapy, eyeglasses alternate between clear and opaque lens before the fellow eye. Principle of intermittent occlusion is employed and may be associated with better compliance. Few authors report that LCD glasses to be efficacious to patching.[44],[45]

Penalization

Here, eye with better vision is defocused by using cycloplegics or altering spectacle glass lens. Indications are noncompliance to patching, presence of latent nystagmus and as a maintenance therapy. Works best when non amblyopic eye is hypermetropic.

Atropine for penalization proved to be as effective as occlusion. Although the occlusion group had a quicker VA improvement, at the end of 6 months of treatment, there was an equal improvement of VA for the 2 groups, and it was maintained in long-term follow-up (up to 15 years). In addition to those who used daily atropine, patients who used atropine once a week showed improvement in VA and had better compliance.[46] Modest improvement of 4.5 lines (95% confidence interval, 3.2-5-8 lines) was obtained in severe amblyopic patients in 3 to12 years of age group.[47]

There is a high rate of recurrence after the end of amblyopia treatment with similar rates for occlusion and atropine (approximately 25%). This rate was 4 times higher in children who did not have a gradual taper of their treatment for at least 5 weeks following the resolution of amblyopia. Factors also linked with greater recurrence rates included better VA at the end of treatment, greater number of lines of improvement, and previous history of recurrence.[48] Children patching with near work for part of the patching time had no significant improvement than children who patched with no near work as part of the patching regimen[49] (ATS 6).

Surgery to treat cause of amblyopia

The ideal period to treat the causes of deprivation in humans is within the first 6 months of life; after that, the chance to ensure the effectiveness of treatment and achieve normal results decreases rapidly. Unilateral cataracts are more ambyogenic and should be tackled energetically. Dense bilateral cataracts not treated by 3 months of age will almost assuredly lead to the development of nystagmus, which will severely limit VA permanently.[50] In all cases, surgery should be followed by intense amblyopic treatment [Figure 4].
Figure 4: Occlusion therapy after uniocular cataract surgery

Click here to view


Ideal management option in children with strabismic amblyopia is that alignment surgery should be performed after amblyopia is treated completely. However, Guidelines by the American Academy of Ophthalmology indicate that strabismus surgery may be done prior to completion of amblyopia therapy (AAO PPP Esotropia and Exotropia 2012; RCO Guidelines 2000) and each case is to be individualized and treated accordingly.

Pharmacological therapy

Inadequacy and noncompliance of conventional occlusion therapy led to greater interest in pharmacological therapy.

Levodopa-carbidopa

Levodopa-Carbidopa combination is the most extensively studied drug. Levodopa is a precursor of dopamine known to influence visual system at cortical level (levels of retinal dopamine was found to be decreased in deprivation amblyopia).[51] It either extends or reactivates the visual systems sensitive period of neural plasticity. Carbidopa was included which prevents peripheral conversion of dopamine and prevent its gastrointestinal side effects. Augmenting conventional occlusion, effect in older age groups and treatment of residual amblyopia were thought to be its advantages. However, it was seen that daily levodopa + 2-h patching does not produce statistical improvement in VA compared to patching alone (PEDIG2015). And also, there was regression of treatment effect after cessation of therapy. Sofia et al. reported statistically significant visual gains sustained at 1 year of follow up in treatment naïve children who had full time patching and levodopa compared to group with patching and placebo (levodopa dose was 3 times higher than in PEDIG study).[52]

Citicoline (cytidine 5'-diphosphocholine)

Citicoline is an important constituent involved in the biosynthesis of cell membrane phospholipids on administration crosses the blood–brain barrier and gets incorporated into the cell membrane phospholipids. It has been shown to increase the levels of norepinephrine and dopamine levels in CNS, offering neuroprotection in hypoxic and ischemic condition. Initially adults in whom citicoline + patching was tried demonstrated improvement in VA but it was not sustained on cessation of the drug. Similarly, studies in children also showed promising results. However, most of these studies of citicoline failed to include follow-up periods beyond 3–6 months and are to be cautiously interpreted.[53],[54]

Newer drugs

Citalopram is a selective serotonin reuptake inhibitor (SSRI) which is thought to work on neuro modulatory systems of brain. Clinical trials are going on in the field of adult amblyopia. In normal human subjects, SSRI treatment has been shown to augment visually evoked potentials. In a few adult patients with amblyopia SSRI (citalopram) enhanced VA improvement when combined with 2 weeks of occlusion therapy, but effects in the population were not significantly different from placebo.[55] Another study pairing SSRIs with video game training demonstrated that while video games improved VA, no added value of the SSRI treatment was observed.[56] It is thought that such behavioral and pharmacological manipulations engage similar neuro modulatory pathways, and a ceiling effect is reached and further improvements are not possible.

Another drug mentioned under trial is Donepezil, a cholinesterase inhibitor that is typically used to treat Alzheimer's disease, to boost cholinergic signaling, and recover vision in amblyopic patients.

Researchers are of opinion that pharmacologic therapy is to be combined with other treatment strategies to target plasticity within specific brain regions. Results in research studies in this matter are awaited.

Refractive Surgery

Refractive surgery is indicated in children who are noncompliant to spectacle wear and children with neuro behavioral disorders in whom standard treatment modalities are not possible. Photorefractive keratectomy is the preferred method. A study is underway comparing PRK versus nonsurgical treatment of anisometropic amblyopia in children who have failed conventional treatment (PEDIG2019).

Orthoptic therapy

Vision therapy

This modality of treatment (orthoptics) includes a program of visual activities to improve VA and binocular vision. Includes computer programs, prisms, filters, vergence, anti-suppression, and accommodative activities. Eye hand coordination exercises done in office set up followed by home exercises.[56] These activities were promoted as adjuncts to patching. However, there are insufficient evidence to support efficacy of this treatment.[57]

Binocular (dichoptic) therapy

This treatment is based on the idea amblyopia is a binocular disease though it mostly presents uniocularly, and forms of balanced binocular (dichoptic) treatment are ideal for restoring normal visual function.[58] These are indicated in children with no squint and those with small angle strabismus (with some amount of binocularity) [Figure 5]. High contrast image is projected in front of amblyopic eye and low contrast image in front of normal eye. Children playing the game employ allocation of spatial localization and localization of low contrast fast moving targets. This is thought to improve vision in amblyopic eye. Several games incorporated to iPad are available. For example, “Falling blocks” game (anaglyphic red green glasses used for dichoptic presentation), and Dig Rush game. Early nonrandomized studies were promising.[59],[60] Results from a recent randomized trial failed to demonstrate that game play prescribed 1 h/day was as good as patching prescribed 2 h per day.[61] Although research is ongoing, there is insufficient evidence to recommend binocular therapy for treatment of amblyopia.
Figure 5: Dichoptic therapy

Click here to view



  Adult Amblyopia Top


It was found out that visual cortex retains its plasticity into adulthood.[62] Therefore, adult amblyopia may also benefit with treatment. Proper refractive correction is to be instituted followed by patching. Modalities of treatment include perceptual learning, dichoptic treatment, and video games.

Perceptual learning

Principle of perceptual learning is based on the considerable evidence that residual plasticity is present in adult visual brain which can be harnessed to improve functional vision in adult patients with amblyopia. Perceptual training protocols have been developed in which patients practice visual discrimination tasks employing positional acuity, stereo acuity, contrast sensitivity, etc.[63] The performance of repeated activities act by either development of new connections, compensate by unmasking connections that were suppressed or enabling attention to signals that were present but weak. Improved pretest to posttest performance and gains in VA were reported when subjects participated in a learnt trial of Gabor signals in a series of 77 adult amblyopes. The neural basis for this is postulated to result from a reduction in lateral inhibition within the brain with training.[64],[65],[66] However, perceptual learning has to gain acceptance. Reasons are that outcome measures obtained in amblyopic eye by treatment do not transfer to novel situations (improvement only for task practiced). Studies were conducted with small number of participants. Long-term follow-up of perceptual learning is also lacking. Irrespective of these controversies perceptual learning may become useful in the management of adult amblyopia.


  Conclusion Top


Abnormal visual inputs to visual cortex (visual deprivation, strabismus, and anisometropia occurring in critical period of development cause this developmental cortical disorder. Cortical area primarily affected in amblyopia isV1 area but the involvement of higher processing areas is also suggested. The prevalence of amblyopia can be decreased by early screening of children prior 2–3 years. Better outcomes are obtained by early detection and treatment of amblyopia. Conventional treatment methods such as penalization and occlusion are still holding strong. Success rate of amblyopic treatment is about 63% to 83%.[30] No studies are available comparing conventional modalities like occlusion and penalization to newer modalities such as dichoptic treatment and liquid crystal glasses.

It is now thought that there is considerable neural plasticity in amblyopic eye beyond the so-called critical period opening newer avenues for the treatment of adult amblyopia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Pathophysiology
Stimulus Depriva...
Anisometropic Am...
Strabismic Amblyopia
Newer Understand...
Management of Am...
Preventive Screening
Adult Amblyopia
Conclusion
References
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