Hyperopic Anisometropia
Anisometropic Amblyopia
Key points at a glance
Section titled “Key points at a glance”1. What is Anisometropic Amblyopia?
Section titled “1. What is Anisometropic Amblyopia?”Anisometropic amblyopia is a unilateral amblyopia that occurs in the eye with the stronger refractive error when there is a difference in refractive status between the two eyes. It is considered the most common cause of amblyopia. Because the eye with the weaker refractive error can see clearly, the other eye does not attempt to see more clearly even if its retinal image is blurry, leading to the condition.
The prevalence of amblyopia is reported to be 2–4% in North America 1). Amblyopia is a major cause of unilateral visual impairment in children. About one-third of amblyopia is attributed to anisometropia, one-third to strabismus, and the remaining one-third to a combination of both, although some reports indicate that anisometropia accounts for 50%.
Amblyopia is broadly classified into the following four types by cause:
- Ametropic amblyopia: Bilateral amblyopia due to high refractive error of similar degree in both eyes
- Anisometropic amblyopia: Unilateral amblyopia due to a difference in refractive error between the eyes
- Strabismic amblyopia: Amblyopia due to suppression of the non-dominant eye
- Form deprivation amblyopia: Amblyopia due to deprivation of visual stimulation
Unilateral amblyopia is accompanied by strabismus in 19–50% of cases and by refractive error in 46–79% of cases1). Approximately one-third of children with 2D anisometropia have amblyopia, and even 1–2D spherical equivalent anisometropia increases the odds of amblyopia by 4.5 times1).
Unlike strabismic amblyopia, anisometropic amblyopia is a covert disease because the eyes appear normal externally. It is often detected during 3-year-old health checkups or preschool vision screening.
Q
How is anisometropic amblyopia different from strabismic amblyopia?
A
Anisometropic amblyopia is caused by blurred retinal images due to a difference in refractive error between the two eyes, with no apparent misalignment of the eyes. Strabismic amblyopia is caused by suppression of the non-dominant eye due to eye misalignment. Both conditions can coexist. For details, see the section “Causes and Risk Factors”.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”Subjective Symptoms
Section titled “Subjective Symptoms”Anisometropic amblyopia is a disease with no external abnormalities and few subjective symptoms.
- Decreased vision in one eye: Because the child sees with both eyes, they often do not notice it.
- Impaired stereopsis (depth perception): Loss of stereopsis has been reported even with anisometropia of 1D or more2). In daily life, it may become difficult to judge distances.
- Crowding phenomenon: In the amblyopic eye, identifying letters in a row is more difficult than identifying a single letter.
Because symptoms of anisometropic amblyopia are inconspicuous, it is often discovered incidentally during vision screening.
Clinical Findings
Section titled “Clinical Findings”Amblyopia is a developmental visual impairment without structural abnormalities, and no specific organic findings are observed. The following examination findings provide the basis for diagnosis.
- Visual acuity difference: A difference in corrected visual acuity between the eyes is observed. The corrected visual acuity of the amblyopic eye does not reach the age-appropriate level.
- Refractive difference: Confirm anisometropia under cycloplegic refraction.
- Relative afferent pupillary defect (RAPD): In severe amblyopia, RAPD may be observed in the amblyopic eye 2).
- Reduced contrast sensitivity: In anisometropic amblyopia, reduced contrast sensitivity in the mid-to-high spatial frequency range is characteristic, affecting the entire visual field (central and peripheral). In strabismic amblyopia, only the central visual field is reduced, which is a difference.
- Loss or reduction of stereopsis: Assessed using the Worth 4-Dot Test, Titmus stereo test, Lang stereo test, etc. 1).
The diagnostic criteria for amblyopia are shown below 1).
| Age | Unilateral amblyopia | Bilateral amblyopia |
|---|---|---|
| 3–4 years | Interocular difference ≥2 lines | Both eyes ≤20/50 |
| ≥5 years | Interocular difference ≥2 lines | Both eyes ≤20/40 |
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”The mechanism of anisometropic amblyopia involves two factors: direct effects on visual development due to blurred retinal images, and interocular competition/suppression 1). In anisometropia, the eye closer to emmetropia becomes the dominant eye, and the eye with stronger refractive error is suppressed in the visual cortex.
The degree of anisometropia that causes amblyopia varies depending on the type of refractive error.
Myopic Anisometropia
Amblyopia risk: Can occur with a difference of 3 D or more between eyes.
Characteristics: At near, the more myopic eye obtains a clearer image, so it is less likely to become amblyopic.
Astigmatic Anisometropia
Amblyopia risk: Can occur with a difference of 2 D or more between eyes.
Characteristics: The meridian direction affects visual development.
The following shows the approximate degree of anisometropia that requires correction by age.
| Age | Myopia | Hyperopia | Astigmatism |
|---|---|---|---|
| 0 to 1 year | ≥4.00D | ≥2.50D | ≥2.50D |
| 1 to 2 years | ≥3.00D | ≥2.00D | ≥2.00D |
| 2 to 3 years | ≥3.00D | ≥1.50D | ≥2.00D |
Even anisometropia below the AAO criteria can cause amblyopia, and anisometropic amblyopia can occur even with 0.5D of anisometropia. The greater the degree of anisometropia or astigmatism, the higher the risk and severity of amblyopia 1).
Q
By what age should it be detected for treatment to be effective?
A
The sensitive period of vision is generally considered to be until around 8 years of age, and starting treatment within this period is expected to lead to good visual recovery. However, since some cases respond even if treatment starts late, treatment should not be abandoned based on age alone. For details, see the section on “Standard Treatments”.
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”The diagnosis of anisometropic amblyopia is a “diagnosis of exclusion” after ruling out organic diseases and strabismus. It is diagnosed when the following conditions are met:
- A refractive difference of 2 diopters or more on cycloplegic refraction
- Corrected visual acuity in the eye with greater refractive error does not reach the age-appropriate level
- Organic diseases (such as congenital cataract or corneal opacity) and strabismus are excluded
Refraction Examination
Section titled “Refraction Examination”Cycloplegic refraction is essential. Children have strong accommodation, and subjective tests or standard autorefractors cannot accurately measure the degree of anisometropia. Objective refraction is performed after instillation of cycloplegic agents (atropine or cyclopentolate).
Visual Acuity Testing
Section titled “Visual Acuity Testing”Age-appropriate visual acuity testing methods are used. Optotype visual acuity is the most common for detecting amblyopia. In amblyopic eyes, line acuity (testing with a line of letters) tends to be more reduced than single-letter acuity (crowding phenomenon).
Binocular Vision Testing
Section titled “Binocular Vision Testing”- Worth 4-Dot Test: Used to evaluate sensory fusion 1)
- Randot Stereo Test / Titmus test: Used to evaluate stereopsis 1)
- Prism bar: Used to evaluate fusional convergence
Anterior Segment and Fundus Examination
Section titled “Anterior Segment and Fundus Examination”This is essential to rule out organic disease as a cause of amblyopia. Slit-lamp microscopy and dilated fundus examination are performed.
Q
How is amblyopia detected during the 3-year-old health checkup?
A
In Japan, the visual health checkup for three-year-olds consists of three stages: a primary checkup conducted by parents at home, a secondary checkup performed by doctors, public health nurses, or orthoptists at health centers, and a detailed checkup at an ophthalmology clinic. Children with low visual acuity in one eye or large refractive errors are referred for detailed examination. Since home vision tests are often difficult to perform accurately, objective evaluation on the day of the checkup is important. The success rate of 5-meter visual acuity testing using a single Landolt ring optotype is reported to be 73.3% at 3 years 0 months and nearly 95% at 3 years 6 months.
5. Standard Treatment
Section titled “5. Standard Treatment”The goal of treatment for anisometropic amblyopia is to make the visual acuity of both eyes as equal as possible 1). The choice of treatment is based on the child’s age, visual acuity, and treatment compliance.
Refractive Correction (Full Correction Glasses)
Section titled “Refractive Correction (Full Correction Glasses)”The first step in treatment is constant wear of full correction glasses based on cycloplegic refraction. Simply wearing glasses constantly can improve visual acuity in the amblyopic eye to some extent.
In a PEDIG prospective study, 27% of children aged 3–6 years with anisometropic amblyopia were cured with glasses alone. An average improvement of 0.29 logMAR was achieved, and 77% showed improvement of 0.2 logMAR or more. Improvement sometimes persisted for 30 weeks or more 3).
When the anisometropia is small (about 2D), treatment with glasses alone is often possible. On the other hand, when the anisometropia is large (3D or more), glasses alone often do not provide sufficient visual improvement.
After prescribing glasses, the current standard approach is to observe with refractive correction alone until visual acuity stabilizes 3). Especially in young children, reducing the hyperopic prescription can lead not only to poor visual improvement but also to the development of esotropia, so caution is needed. In astigmatic anisometropia with a difference of 1.5D or more, early addition of occlusion of the sound eye is recommended.
Occlusion Therapy (Patching)
Section titled “Occlusion Therapy (Patching)”If visual acuity does not improve sufficiently with glasses alone, occlusion of the sound eye (patching) is added. An adhesive patch is applied directly to the sound eye to force use of the amblyopic eye.
- Moderate amblyopia (20/40 to 20/80): Patching for 2 hours per day is effective and has been reported to be as effective as full-time patching1)
- Severe amblyopia (20/100 to 20/400): Patching for 6 hours per day is recommended1)
During patching, it is important to actively use the amblyopic eye, focusing on near tasks such as reading or coloring.
Starting full correction glasses and occlusion of the healthy eye simultaneously can cause significant stress for the child. Therefore, it is better to start wearing glasses first and then instruct patching once the child is accustomed to the glasses.
Atropine Penalization
Section titled “Atropine Penalization”This method involves administering 1% atropine eye drops to the healthy eye, causing cycloplegia and blurring near vision in the healthy eye, thereby encouraging use of the amblyopic eye1).
- For moderate amblyopia, weekend-only atropine administration is effective1)
- It has been reported to have slightly higher acceptability compared to patching1)
- If the healthy eye has hyperopia, the effect can be enhanced by further reducing the correction (prescribing plano lenses)
Bangerter Filter
Section titled “Bangerter Filter”This method involves attaching a Bangerter (translucent) filter to the spectacle lens of the healthy eye. In a PEDIG study, the difference in visual acuity improvement compared to patching was within 0.5 lines after 24 weeks of treatment1). It is a useful alternative when compliance with patching is poor.
Refractive Surgery
Section titled “Refractive Surgery”In children who do not respond to conventional treatment, there are reports of PRK (photorefractive keratectomy) being performed for anisometropic amblyopia1). Improvement in corrected visual acuity and stereopsis has been reported, but sufficient evidence for its application in children has not been established.
Q
How many hours per day should occlusion therapy be performed?
6. Pathophysiology and Detailed Mechanisms
Section titled “6. Pathophysiology and Detailed Mechanisms”The pathophysiology of anisometropic amblyopia results from disruption of normal binocular vision during the sensitive period of visual development.
Visual Development and Sensitive Period
Section titled “Visual Development and Sensitive Period”The human visual system develops rapidly after birth, and synaptic formation in the cerebral visual cortex is completed during the sensitive period up to around age 8. If the retinal image in one eye is blurred during this period, development of visual cortex neurons corresponding to that eye is impaired.
Neuropathological Changes
Section titled “Neuropathological Changes”Changes due to amblyopia occur mainly in the primary visual cortex (V1) and the lateral geniculate nucleus (LGN).
- Lateral geniculate nucleus: Shrinkage of cell bodies in LGN neurons corresponding to the amblyopic eye has been reported.
- Primary visual cortex (V1): Neurological changes in layer IVc of V1 have been demonstrated in animal studies. However, in anisometropic amblyopia, reduction in the size of ocular dominance columns is not evident.
- Reduced visual cortex activity: Studies using PET, fMRI, and VEP have confirmed significant reduction in visual cortex activity when stimulating the amblyopic eye.
Mukit et al. (2023) reported a case of a 6-year-old girl with high anisometropic amblyopia (-17.50D) due to unilateral megalophthalmos associated with NF1 (neurofibromatosis type 1) 2). Axial lengths showed a marked difference of 22 mm and 27 mm between the eyes, and it is known that a 1 mm increase in axial length leads to myopia of -2 to -2.5 D. Because early ophthalmology referral was not made, at the time of discovery the amblyopic eye had decreased to light perception and stereopsis was completely lost.
Interocular suppression and binocular vision impairment
Section titled “Interocular suppression and binocular vision impairment”The pathophysiology of anisometropic amblyopia involves not only the direct effects of retinal image blur but also interocular suppression from the fellow eye 1). This is similar to interocular suppression in strabismic amblyopia, but the mechanisms are thought to be not entirely identical.
Contrast sensitivity is reduced in the medium to high spatial frequency range, and this reduction extends to both central and peripheral visual fields. This differs from strabismic amblyopia, which shows deficits only in the central visual field.
7. Latest research and future prospects (reports at research stage)
Section titled “7. Latest research and future prospects (reports at research stage)”Dichoptic digital therapy
Section titled “Dichoptic digital therapy”This treatment presents images with different contrast or content to each eye, encouraging the use of the amblyopic eye 3). Games and video viewing using VR headsets or tablets have been attempted.
Halicka et al. (2021) reported that a 22-year-old adult with anisometropic amblyopia underwent 44 hours of dichoptic training in a VR environment, and the corrected visual acuity of the amblyopic eye improved from 0.05 to 0.5 4). Furthermore, stereopsis was gradually acquired through training, and fMRI showed changes in visual cortex activity patterns. Visual acuity of 0.4 was maintained one year after training.
Xiao (Luminopia) et al. reported that 72 hours of headset use in children resulted in a visual acuity improvement of 0.15 logMAR 3). In adults with anisometropic amblyopia, the dichoptic treatment group also showed a visual acuity improvement of 0.15 logMAR (one line improvement per 27 hours) 3).
It is not yet clear whether dichoptic therapy is superior to conventional occlusion therapy 3).
Treatment potential for adult amblyopia
Section titled “Treatment potential for adult amblyopia”Conventionally, amblyopia in adults beyond the visual sensitive period was considered difficult to treat. However, animal experiments and human studies have shown that some degree of plasticity in the visual pathway remains even after the sensitive period 4).
Perceptual learning, anti-suppression training, and dichoptic training in VR environments have been attempted for adult amblyopia, and improvements in visual acuity and stereopsis have been reported 3)4). However, further research is needed on the long-term stability of these methods and comparisons with existing treatments.
Pharmacological adjunctive therapy
Section titled “Pharmacological adjunctive therapy”Attempts to enhance the therapeutic effect of amblyopia by combining levodopa (dopamine precursor) with patching have been reported. A multicenter randomized controlled trial by PEDIG is being conducted.
8. References
Section titled “8. References”- American Academy of Ophthalmology. Amblyopia Preferred Practice Pattern 2024 Update. Ophthalmology. 2024.
- Mukit FA, Cape HT, Huq SS, et al. An isolated case of unilateral macro-ophthalmia with resultant anisometropic amblyopia in neurofibromatosis 1. Cureus. 2023;15(9):e44679.
- Meier K, Tarczy-Hornoch K. Recent treatment advances in amblyopia. Annu Rev Vis Sci. 2022.
- Halicka J, Bittsansky M, Sivak S, et al. Virtual reality visual training in an adult patient with anisometropic amblyopia: visual and functional magnetic resonance outcomes. Vision. 2021;5(2):22.