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Anisometropia is a condition of asymmetric refraction between the two eyes. This condition is defined by a difference of 1 or more diopter in spherical equivalent. Its diagnosis and treatment in the first years of life are essential to optimize children's visual development and binocular function. The diagnosis and management of this condition are multidisciplinary and require periodic examinations to limit amblyopia. Anisometropia must be promptly diagnosed and treated to avoid any permanent reduction in vision associated with this condition. This activity reviews the evaluation and treatment of anisometropia and reports the importance of the interprofessional and familiar role in evaluating and treating the young individuals affected by this condition. Objectives: Describe the anisometropia diagnostic criteria. Identify possible causes of anisometropia and their related etiopathogenetic mechanisms in developing this condition. Summarize possible treatment options from the gold standard to more recent surgical procedures. Review the importance of timing and compliance in treating anisometropia to prevent or limit permanent functional limitations. Access free multiple choice questions on this topic.

Anisometropia is a condition of refractive interocular asymmetry and is usually referred only to as the clinically significant differences between the right and the left eye. According to studies conducted in different regions, the incidence of this common refractive abnormality ranges from 3.79% to 21.8%.[1][2][3][4] A difference of 1 diopter or more in spherical equivalent (SE) is usually reported to define this condition.[5][6][7] Its clinical relevance comes from the fact that in a minority of individuals, this refractive disparity, anisometropia, is not corrected and leads to permanently low visual acuity (amblyopia) configuring, in the absence of other abnormalities, anisometropic amblyopia (24-37% of all amblyopias).[8]

Changes in lens power and cataract development represent important causes of anisometropia in elderly patients, but when speaking of infantile anisometropia, most cases are axial in nature, with several studies, both on animals and humans, demonstrating a positive correlation between the anisometropia degree and the interocular asymmetry in axial length.[9][10][11][12] Axial elongation can occur in response to functional deprivation in a variety of unilateral damages in all ocular structures, such as eyelid closure, corneal opacification, congenital or traumatic cataracts, and vitreous opacity (hemorrhage or debris), and retinal diseases that disrupt the visual experience in the affected eye.[13][14] All the mentioned pathologies are easily identifiable, both in human and animal models, as the initial event leading to the function loss, but the retrospective design of the studies does not allow for the identification of the exact sequence of refractive and visual anomalies. Some authors noted that larger anisometropic refractive errors occur when the vision disruption occurs within the period of most rapid post-natal eye growth (up to 3 years of age). Retinopathy of prematurity (ROP) is associated with a higher prevalence of anisometropia and more severe anisometropia, less likely to resolve than in normally developed visual systems. The severity of ROP and birth weight are directly and inversely correlated with the prevalence of anisometropia, respectively.[15] For children not presenting obvious structural abnormalities, other factors like refractive changes must intervene in developing anisometropia, reflecting mechanisms that are still unclear. Anisometropia in young children can spontaneously resolve as the eyes naturally become emmetropic, but in general, ametropias, either myopias o hyperopias, are positively associated with anisometropia. Severe anisometropias (3 or more D) are more prone to persist in preschool age, causing a significant percentage (24 to 37%) of all amblyopias in young children.[16][17][18]

For children not presenting obvious structural abnormalities, other factors like refractive changes must intervene in developing anisometropia, reflecting mechanisms that are still unclear. Anisometropia in young children can spontaneously resolve as the eyes naturally become emmetropic, but in general, ametropias, either myopias o hyperopias, are positively associated with anisometropia. Severe anisometropias (3 or more D) are more prone to persist in preschool age, causing a significant percentage (24 to 37%) of all amblyopias in young children.[16][17][18] According to some studies, anisometropia tends to be higher amongst myopes rather than among non-myopes, and anisometropia diopters increase more during school age in cases of higher myopia progression. Significant astigmatism seems to increase the risk of developing anisometropia. Anisometropia of 1 or more spherical D and/or one or more cylinder D has been more frequently observed in young children (1 to 3.5 years of age) with astigmatism than without astigmatism.[19] Similar conclusions were obtained in adults, and in general, more anisometropic subjects can be found among more astigmatic individuals.[20] Hypermetropic anisometropia of 1.5 D or more increases the risk for visual deterioration in the long term, even after occlusion therapy. When early hyperopia does not spontaneously reduce within the first year and a half of life, esotropia with anisometropia and amblyopia can develop. The deviated eye in these subjects presents a defective emmetropization compared to the dominant eye, which is normally aligned. Fixation in these cases does not alternate between the two eyes causing the non-fixating eye to not provide visual input to the retinocortical pathways and to deviate, usually in an esotropic rather than exotropic fashion. The hypothesis emerging from cross-sectional studies in this field suggests that anisometropia is a risk factor for developing accommodative esotropia. The diagnosis of this esodeviation is often contemporary to amblyopia and anisometropia detection; therefore, no conclusive evidence can be obtained on the exact chronologic and causative relations between these three coexisting anomalies.[21][22] When strabismus is associated with anisometropia, it is usually convergent and found in anisohyperopes rather than in anisomyopes.[23][24]

Fixation in these cases does not alternate between the two eyes causing the non-fixating eye to not provide visual input to the retinocortical pathways and to deviate, usually in an esotropic rather than exotropic fashion. The hypothesis emerging from cross-sectional studies in this field suggests that anisometropia is a risk factor for developing accommodative esotropia. The diagnosis of this esodeviation is often contemporary to amblyopia and anisometropia detection; therefore, no conclusive evidence can be obtained on the exact chronologic and causative relations between these three coexisting anomalies.[21][22] When strabismus is associated with anisometropia, it is usually convergent and found in anisohyperopes rather than in anisomyopes.[23][24] A peculiar aspect of the refractive behavior of amblyopic hyperopic and esotropic eyes is that amblyopia prevents their emmetropization, meaning that there is no myopic shifting in such type of amblyopia, whereas in amblyopia due to early visual deprivation (ptosis, cataract, etc.) a significant myopization, as mentioned before, is observed.

The prevalence of anisometropia is age-dependent, with a higher prevalence amongst adults when compared to young children. Considering anisometropia as a difference of 1 or more D in SE, the prevalence is relatively high in newborns, which tends to resolve spontaneously in most individuals within the first year of life, then about 5% from the second year of life until puberty and teenage years. The prevalence increases with the onset of myopia during growth, which reaches about 10% in early adulthood, then tends to increase again in the elderly.[25] Higher refractive error (myopia in particular) and the presence of associated ocular diseases increase the prevalence of anisometropia. Gender does not seem to play a significant role; however, some differences can be observed based on race. Anisometropia of 1 or more D of SE has been found in 4.2% of African Americans and 4.3% of Hispanics 6-72 months old In the United States.[26] Other authors have reported 1% of this condition in African American babies and 1.5% in Caucasian babies between 6 and 71 months of age.[27] It is important to note that these data were collected in cycloplegia. With regards to non-cycloplegic refraction in adults, the same condition was found in 4.5% of African Americans between the ages of 6 and 49 years and in 14.1%, 15 to 9%, and 12,3% of Australian, Chinese-Singaporean, and Spanish adults ranging from 40 to 79, 49 to 97 and 49 to 79 years of age, respectively.[28][25][29]

Age-related ocular changes, such as cataracts, can lead to refractive changes due to refraction index alteration associated with lens opacification. The asymmetric occurrence of this phenomenon can cause anisometropia in the older population, whereas most of the anisometropia in younger subjects are attributed to the difference in axial length. Despite the documented association between anisometropia and interocular axial length growth asymmetries, evidence on the exact mechanism correlating these two conditions are lacking. A significant reduction in the visual input in one eye due to evident structural abnormalities, such as congenital cataracts, ptosis, or retinal alterations, like in prematurity, can induce axial elongation, but other mechanisms must be involved in the absence of evident structural alterations.[7] Anisometropia is often, but not always, associated with amblyopia. These two conditions are commonly found during school vision screening. Anisometropia is widely thought to cause amblyopia in the chronically defocused eye, although clear evidence of such a causative effect is lacking and have been challenged by many authors.[30][31][32][33] Prospective trials on animal models have shown that anisometropia can either precede or follow amblyopia. Several authors have also demonstrated how monocular deprivation can induce both anisometropia and amblyopia by interfering with ocular growth and synaptic and cortical development. These data have raised three possible hypotheses on how anisometropia and amblyopia appear, which include: anisometropia causes amblyopia via chronic visual blurring of the functionally deprived eye; amblyopia causes anisometropia interfering with the physiologic emmetropization process; and, visual deprivation intervenes disrupting emmetropization and ocular function contemporarily causing both amblyopia and anisometropia.

Prospective trials on animal models have shown that anisometropia can either precede or follow amblyopia. Several authors have also demonstrated how monocular deprivation can induce both anisometropia and amblyopia by interfering with ocular growth and synaptic and cortical development. These data have raised three possible hypotheses on how anisometropia and amblyopia appear, which include: anisometropia causes amblyopia via chronic visual blurring of the functionally deprived eye; amblyopia causes anisometropia interfering with the physiologic emmetropization process; and, visual deprivation intervenes disrupting emmetropization and ocular function contemporarily causing both amblyopia and anisometropia. The common feature of all these scenarios is reduced retinal activity in the affected eye by diminishing the image contrast or the neural function. The anomalous axial growth in the functionally impaired eye has also been observed to continue after the removal of the impairment in some cases. Persistent axial elongation has been reported after phacoemulsification and intraocular lens (IOL) implantation in eyes with congenital cataracts. This suggests the inability of accommodation postoperatively to have a role in the exaggerated eye growth, probably due to permanent defocus, at least at some visual distances.[34][14]

In anisometropic subjects, the history and physical signs of early monocular eye disruption must be considered in the differential diagnosis. These conditions include eyelid closure defects, congenital or post-traumatic cataracts, vitreous hemorrhage or other vitreous opacities, corneal opacification, and different types of retinal diseases. Anisometric amblyopia is commonly associated with strabismus; therefore, obvious ocular deviations, which normally include esotropia, associated abnormal head position, and other strabismic attitudes, must be anamnestically and objectively evaluated. Patients with ROP obviously present the ocular and anamnestic elements of such condition, including incomplete and abnormal retinal vascularization, vitreoretinal scarring, and tractions up to detachment in severe cases, especially in cases of premature birth (<31 weeks of gestation) and/or low birth weight (<1250 grams). Anisometropia has been demonstrated to be more frequent, more severe, and harder to treat when associated with ROP, being present in 13.8 to 15.4 % of ROP patients vs. 0 to 4.5 % of premature children without ROP at 1 year of age.[35][36] Two or more D of anisometropia have been more frequently observed in ROP children with severe ROP and la lower birthweight.[15] Several studies indicate that without ROP, anisometropia usually resolves within the first 12 months of life, with no effect, in this scenario, of prematurity, low birth weight, maternal smoke, or breastfeeding. Nevertheless, chances of anisometropia are increased, with or without ROP, in subjects that have undergone neonatal intensive care and in the presence of amblyopia or exotropia.[9]

Amblyopia and anisometropia are frequently diagnosed during school vision screening. Earlier diagnosis is rare due to the absence of obvious signs and symptoms in most cases. Amblyopia is generally found in the more ametropic eye, with a higher prevalence in anisohyperopes when compared to anisomyopes.[37][38] Hyperopic anisometropia of 1- 2 D can induce amblyopia, whereas myopic anisometropia up to 3 D usually does not cause amblyopia. This might be due to the earlier development of unilateral blur in the presence of hyperopic anisometropia, with a higher impact on the visual cortex maturation than in myopic anisometropia. This could also be due to the rarity of myopia in young children in these studies.[17] Amblyopia can be detected by measuring the natural and corrected visual acuity with normal or specific optotype charts, such as Landolt C or tumbling "E" charts, picture charts, or Tellers tables, according to the patient's age, compliance, and intellectual capability (See various optotype chart images). The refraction must be measured in cycloplegic conditions. Stereopsis screening tests, such as Lang's test I and II, Titmus test (see Titmus test image), or similar, can easily identify stereopsis defects associated with amblyopia and anisometropia. The presence of phorias and tropias must be investigated with an accurate orthoptic evaluation. Tests like cover tests, Maddox Rods, and Worth's Four Dot test (See Worth's Four Dot test images) are helpful to ascertain the presence of ocular deviation that may coexist with amblyopia and anisometropia. Accurate measurements of the deviation can be obtained by performing retinoscopy with prism bars (See prism bars image) or other methods like the synoptophore (See synoptophore image). Since anisometropia can be observed in the absence of any ambliogenic factor, more subtle, barely detectable etiopathogenetic elements can potentially also play a role. Microstrabismus with fixation instability is one of these conditions. Several authors have described a specific device called the Pediatric Vision Screener (PVS) to simultaneously assess ocular fixation bilaterally that can help to identify this condition, which would otherwise remain unnoticed with the clinical gold standard tests (photorefraction, prism-and-cover test).[39]

The current methods to treat amblyopia and anisometropia are optical correction and penalization of the better eye with patching or topical atropine 1%. A certain degree of natural iso-emmetropization has also been observed to intervene to prevent amblyopia; nevertheless, evidence exists that anisometropia and amblyopia tend not to resolve without treatment.[40] Optical correction is effective in preventing amblyopia only if it is done when the visual cortex synapses are still plastic. A lower amount of anisometropia and a better visual acuity in the amblyopic eye at baseline increase the probability of resolving amblyopia and anisometropia.[41] Patching or atropine 1% instillation in the better eye act by biasing the visual input to the amblyopic eye and favoring the development of its cortical synapses. This type of treatment, when amblyopia is not associated with strabismus, also acts on the anisometropic component inducing a certain degree of emmetropization.[42] Treatment compliance plays a prominent role in achieving functional results, with the best visual acuity being reached after 150 to 250 cumulative hours of therapy and 3 to 5 months for the amblyopia to be treated or stabilized.[43][44][45] Medical and parental monitoring is essential to optimize the response. The patient's age is also a key factor. Several studies have reported a minimal effect of age on treatment efficacy between 3 and 7 years of age and a reduced response after this age.[46][47][48] Alternative refractive treatments have also been reported to be safe and effective when spectacles and contact lenses are not well tolerated by the patient. Spectacles can cause prismatic aberrations (especially in peripheral gaze), reduced visual field, aniseikonia with impeded binocular vision, and social discomfort. Contact lenses tend to provide better contrast sensitivity and vision quality. However, drawbacks include intolerance to prolonged wear, risk of infection, economical cost, and inability to insert, remove and preserve the contact lenses correctly.

Alternative refractive treatments have also been reported to be safe and effective when spectacles and contact lenses are not well tolerated by the patient. Spectacles can cause prismatic aberrations (especially in peripheral gaze), reduced visual field, aniseikonia with impeded binocular vision, and social discomfort. Contact lenses tend to provide better contrast sensitivity and vision quality. However, drawbacks include intolerance to prolonged wear, risk of infection, economical cost, and inability to insert, remove and preserve the contact lenses correctly. Surgical refractive treatments of the cornea can be considered in some cases. Radial keratotomy has been described to treat anisometropic teenagers.[49] Several other corneal refractive procedures, such as photorefractive keratectomy (PRK), laser in situ keratomileuses (LASIK), and laser-assisted subepithelial keratectomy (LASEK) treatments have been reported to be safe and effective in improving visual acuity, binocular vision, preventing anisometropic amblyopia in children with anisometropia.[50][51][52][53] Corneal interventions can correct refractive errors within + 5 and - 10 D due to the high incidence of corneal haze and refractive regression out of this range of defect.[54] Several intraocular surgeries have also been proposed. Epikeratophakia consists of clear crystalline lens removal followed by corneal lens application. This approach has been updated to include the implant of an intraocular lens (IOL). This procedure is similar to cataract surgery (but in this case, the individual's lens is clear and does not have cataract opacities), which provides minimally invasive surgery to the cornea, is safe and relatively predictable, but is associated with considerable risk of retina detachment and glaucoma, especially in myopic eyes.[55] Another approach, sparing the clear lens and saving the advantages of IOL implantation, is the implantation of phakic IOLs, in front of the clear lens, either fixated to the iris or placed in the posterior chamber.[56][57] This procedure, however, in rare cases, can induce corneal endothelium loss over time or elevated intraocular pressure.

Changes in lens power that induce anisometropia can be diagnosed in adults and the elderly during a routine eye examination and are associated with lens opacities such as cataracts.[58][59] Transient anisometropia can be found in infants and, by definition, spontaneously disappear.[16][20]

All anisometropias (anisometropia > 2 D, anisohyperopia  > 1 D, and anisoastigmatism > 1.5 D) can cause amblyopia, with uncorrected anisometropia > 6 D and anisohyperopia > 4 D causing it in 100% of cases.[55] Conventional treatment with spectacles, lens patching, or atropine 1% in the good eye are effective in preventing most cases of anisometropic amblyopia, with patients presenting anisometropia from - 3 to 3 D having a 75 to 94% probability of reaching a BCVA of 20/40 or better as compared to only 25% of this result in anisomyopic patients with more than - 6 D of interocular difference.[55]

Optical correction and patching require compliance to maximize their capacity to improve visual acuity in eyes suffering from anisometropic amblyopia. This has been demonstrated in studies where a device to monitor occlusion compliance was used.[45] Other authors observed that the functional results are correlated with the amount of treatment time, reporting the best visual acuity to be reached after 150 to 250 cumulative hours of treatment.[39][45] The clinician must thus inform and motivate the patient parents/caregivers and involve them in the treatment supervision and optimization.

Anisometropia requires an interprofessional team of healthcare professionals, including ophthalmologists, optometrists, nurses, orthoptists, social workers, etc. This team is fundamental for correctly applying this tool in the clinical field and treatment. Anisometropia is a condition that requires proper diagnosis of the refractive abnormality.[60][61][4] A difference of 1 diopter or more SE needs to entice further examination and treatment of this condition.[5][6][7] If anisometropia is not corrected in time, this condition can lead to permanent low visual acuity (amblyopia).[28][8] [Level 3] Treatment compliance is imperative to achieving successful results at the best visual acuity possible.[44][45] Early diagnosis and treatment (preferably in childhood) from ophthalmologic health care professionals, in addition to parental monitoring, are essential to optimize the response.[47][48] Treatments range from spectacle correction, contact lenses, refractive laser procedures, and IOL implantation surgery, which need to be carefully planned and tailored for each individual.[52][53] Corneal interventions can correct refractive errors within + 5 and - 10 D due to the high incidence of corneal haze and refractive regression out of this range of defect.[56][62] [Level 1] An interprofessional team that provides an integrated approach to patient care and comprehensive diagnostic management can help achieve the best possible outcomes. Collaboration, multidisciplinary shared decision-making, and communication are crucial elements for a proper diagnosis and a good outcome. The interprofessional care provided to the patient must use an integrated care pathway combined with an evidence-based approach to planning and evaluating all joint activities.[63] The earlier signs and symptoms of anisometropia are identified, the better the prognosis and outcome. [Level 3]