What is anisometropia

Anisometropia mean two eyes have unequal refractive power or a difference in sphero-cylindrical refractive error between the right and left eyes ¹. Strictly speaking any interocular difference in refractive error could be termed anisometropia. However, since test-retest studies of refractive error measurement indicate a substantial degree of variability, measurement precision needs to be taken into account when defining and diagnosing anisometropia. Successive refractions of the same eye by different clinicians or repeated refractions by the same clinician can differ by up to 0.75 diopter ². For this reason, the term ‘anisometropia’ is usually reserved for clinically significant differences in spherical equivalent refraction that exceed some criterion amount, e.g. ≥±1.00 diopter ³. Anisometropia is typically considered a fundamental axial length anomaly in which the size of the right and left eyes differ ⁴, but in some instances it can be refractive when the optical power of the eyes differ. Anisometropia is not purely an issue of right- versus left-eye axial length difference in that individuals with anisometropia also tend to exhibit high levels of astigmatism ⁵ and individuals with aniso-astigmatism defined as the absolute difference in refractive astigmatism ⁴ exhibit differences in corneal toricity. When considering higher order monochromatic aberrations, it appears that there are no significant inter-ocular differences between the two eyes of anisometropic adults ⁶.

Anisometropia is a common cause of amblyopia. Amblyopia is also called lazy eye, is decreased vision due to the eye and brain not working together that occurs during the years of visual development secondary to abnormal visual stimulation. Amblyopia occurs early in life when the developing brain visual system fails to have a sharp image transmitted to the retina and from there to the visual brain cortex via the lateral geniculate ⁷. Amblyopia is usually affect one eye but it can affect both eyes. The diminished vision is beyond the level expected from the ocular pathology present. Amblyopia is the most common cause of decreased vision in a single eye among children and younger adults. Amblyopia is usually unilateral the result of media opacities, cataracts, and other conditions or because strabismus or anisometropic refractive errors place one eye at a developmental disadvantage to the other. Amblyopia occurs bilaterally with bilateral cataracts or high refractive errors ⁸. Amblyopia is present in 1-3% of humans and around one-half to two-thirds of amblyopes have anisometropia either alone or in combination with strabismus ¹.

Anisometropic amblyopia is the second most common cause of amblyopia ⁹. Anisometropic amblyopia occurs when unequal focus between the two eyes causes chronic blur on one retina. Anisometropic amblyopia can occur with relatively small amounts of asymmetric farsighted (hyperopia) or astigmatism. Generally, larger amounts of anisomyopia are necessary for amblyopia to develop.

Anisometropic amblyopia is an insidious disease because unlike strabismic amblyopia, the eyes appear normal to an observer. Anisometropic amblyopia is most commonly caught by vision screening either in a pediatrician’s office or in the school system.

The prevalence of amblyopia is reported as 2-4% in North America and is the primary cause of unilateral vision loss in children ¹⁰. According to Hess et al. ¹¹, one third of amblyopia cases are caused by anisometropia, one third by strabismus and one third from a combination of the two. However, other authors have reported that 50% of cases with amblyopia are caused by anisometropia ¹².

A determination of the prevalence of anisometropia has several difficulties. First of all, the measurement of refractive error may vary from one measurement to the next. Secondly, different criteria have been employed to define anisometropia, and the boundary between anisometropia and isometropia depend on their definition ¹. Previous cross-sectional studies showed that the prevalence of anisometropia is age-dependent, with a relatively low prevalence (1.6%–4.3%) among young children ¹³ and a higher prevalence among adults. A study using a slightly stricter definition for anisometropia (spherical equivalent refraction difference > 1.00 D) ¹⁴ found a prevalence of 7.7% among adults, whereas in studies using the traditional definition, the prevalence was slightly higher, ranging from 9% to 15% ¹⁵. The trend of more anisometropia with increasing age continues after the age of 60 years, climbing from about 10% for 60- to 69-year-olds to more than 30% for 80+ years ¹⁴. In older people, the anisometropia might be due to differential changes in lens power and the development of cataracts. Most anisometropia appears to be axial in nature, as demonstrated in studies of both animal and human eyes reporting a positive correlation between the degree of anisometropia and the interocular difference in axial length ¹³.

Infantile anisometropia can be transient and may disappear as eyes emmetropize ¹⁶. In contrast, the Multi-Ethnic Pediatric Eye Disease Study found that the prevalence of anisometropia was low (4%–5%) and remained almost constant between 1 and 6 years of age in both Hispanic and African American children ¹⁷. Severe infantile anisometropia (≥ 3.0 Diopters) may be sustained over a long period, and children with persistent anisometropia are more likely to develop amblyopia during the preschool years ¹⁸. Studies examining the association of anisometropia and amblyopia in young children found a significant association between the two ¹⁹, with a low prevalence of amblyopia overall (1.5%–2.6%),15,17–19 and part of it (24% ∼ 37%) due to anisometropia ²⁰.

There is limited evidence in the literature regarding the relationship between anisometropia and astigmatism. An early longitudinal study investigating refractive error change from age 1 to 3.5 years found that young children with significant astigmatism were more likely to be anisometropic (+1.00 D sphere and/or +1.00 D cylinder difference between the two eyes) compared with those without astigmatism ²¹. This result was echoed in elderly adults (50+ years) of the Blue Mountains Eye Study ²². In addition, higher proportions of anisometropia have been reported in populations with more astigmatism ²³, an association that seems to be largely independent of age.

A few longitudinal studies showed that anisometropia increases after children start school. A study in Japan found a small increase in the prevalence of spherical anisometropia (spherical difference ≥1.00 D), rising from 1.43% at 6 years to 3.14% at 11 years ²⁴. In addition, a similar increase in the prevalence of astigmatic anisometropia (cylinder difference ≥1.00 D), from 2.6% at 6 years to 4.3% at 11 years, was also found in that study ²⁴. Two other longitudinal studies in more myopic schoolchildren found larger increases (6% and 10% increase, respectively) in the prevalence of anisometropia after 3 years of follow-up ²⁵. An additional finding of the two studies was a link between myopia and anisometropia. Using data from children participating in a randomized trial of myopia treatment, Pärssinen ²⁶ found a significant association between the increase in the amount of anisometropia (spherical equivalent) and myopia progression, but not with the refractive error at baseline. In a study of Singaporean children aged between 7 and 11 years, a significantly higher amount of anisometropia was found in myopes versus nonmyopes ²⁵. There was also a significant association between anisometropia and more myopia progression, but no association between myopia at baseline and change in anisometropia over the 3 years of follow-up ²⁵. Even though these studies provided evidence for an association between myopia and anisometropia, the exact cause of anisometropia and its possible link to the mechanisms underlying refractive error development remain elusive. Evidence on the relationship between anisometropia and refractive error over time during childhood is generally lacking and is needed to help answer these questions.

Anisometropia types

There are three types of anisometropia:

1. Simple anisometropia. This is when one eye is affected while the other eye has no refractive error (or spectacle prescription). The affected eye can either be hyperopic (long-sighted) or myopic (short-sighted).
2. Compound anisometropia. This is when both eyes are myopic (short-sighted), although there will be a significant difference in their refractive errors (or spectacle prescriptions). This causes one eye to see a more blurred image than the other.
3. Mixed anisometropia. This is when both eyes have appreciable refractive errors, with one eye myopic and the other hyperopic.

Anisometropia causes

The underlying causes for anisometropia are still poorly understood.

Many studies have reported a positive association between the prevalence and severity of anisometropia, and the level of spherical ametropia ²⁷ and astigmatism ²³. Fledelius ²⁸ noted that anisometropia is more commonly found in cases of high ametropia, in particular amongst individuals with large amounts of myopia, and many others have corroborated these findings ¹⁵. For example, in their population study of over 3400 adults aged 49 years and above, Guzowski et al. (2003) reported that both the prevalence and the severity of anisometropia increased with increasing levels of ametropia in myopes and hyperopes, but the rise was more dramatic in myopic individuals. A large-scale study of 6-year-old children ²⁹ also noted a much greater prevalence of anisometropia (≥1.0D difference in spherical equivalent refractive error) in children with moderate hyperopia (≥+2D spherical equivalent, anisometropia prevalence 10.1%) compared to those with mild hyperopia (>0.51 to <+2D spherical equivalent, anisometropia prevalence 0.1%). Qin et al.’s ¹⁵ study of around 91,000 individuals employed a multiple regression model to examine whether spherical-equivalent ametropia and astigmatism are independently associated with anisometropia (factoring out potentially significant co-variates such as age). They showed that anisometropia is independently associated with both spherical ametropia and astigmatism. Anisometropia prevalence increased from 10% to almost 20% as the level of ametropia in the least ametropic eye increased from myopia of −1D to myopia of −3 to −4D. They found a roughly linear increase in anisometropia prevalence and severity with increasing levels of myopia. In hyperopes the trend was similar but less linear. It should be pointed out however, that although Qin et al. ¹⁵ found levels of spherical ametropia to be significantly associated with both the prevalence and severity of anisometropia, it was cylindrical refractive error that was the parameter most strongly associated with anisometropia.

Studies of anisometropia that are based on clinic records generally find anisomyopes to be about two to five times more prevalent than anisohyperopes ³⁰: 63% vs. 27%, United Kingdom, criterion ≥2D difference; ³¹: 71% vs. 22%, Thailand, criterion ≥2D difference;  ³¹: 76% vs. 16%, USA, criterion ≥1D difference. Antimetropia (where one eye is myopic, but the other eye is hyperopic) was reported in about 8% by Tanlamai and Goss ³¹ in both of their samples. One exception to this pattern was observed by de Vries (1985) in a sample of anisometropic (≥2D difference in spherical or cylindrical power) children attending a hospital eye clinic. The proportions of anisomyopes, anisohyperopes and antimetopes in that sample were 20%, 70% and 10%, respectively. The difference between de Vries ³² and other clinical populations ³¹ is probably accounted for by the fact that the de Vries sample contained only children (aged up to 10 years, who are less likely to exhibit myopia), and because a high proportion (42%) of them also had strabismus.

The link between the level of ametropia and the prevalence and severity of anisometropia indicates that an increasing failure of emmetropization is also associated with an increasing failure of coordinated eye growth across the eyes. Thus, understanding the origins of anisometropia could have important implications for our understanding of the origins of ametropia in general.

Anisometropia symptoms

Anisometropia has no symptoms. Anisometropia is commonly found during a routine vision exam.

There are a number of potential symptoms, including:

• Amblyopia (lazy eye). Usually, this is when reduced refractive power in one eye causes a lack of visual stimulation that results in insufficient information being transmitted through the optic nerve to the brain
• Strabismus (crossed eyes). When a patient is unable to align both eyes. This lack of coordination prevents both eyes being able to focus on the same point in space
• Diplopia (often known as double vision). The result includes:
  • Eyestrain
  • Headaches
  • Nausea
  • Light sensitivity
  • Tiredness
  • Dizziness.

Vision Screening is strongly recommended by the American Academy of Pediatrics over the course of childhood to detect amblyopia early enough to allow successful treatment. Pediatricians check newborns for red reflex to find congenital cataracts. Infants are checked for the ability to fix and follow and whether they have strabismus. Toddlers can have their pupillary red reflexes tested with a direct ophthalmoscope (Brückner Test) or by instruments that identify a significant refractive error that needs correction to prevent amblyopia. When children can consistently identify objects either by reading or by matching, the acuity of each eye (with the non-tested eye patched) is screened to identify amblyopia.

Anisometropia treatment

One of the most important treatments of anisometropia is correcting the refractive error with consistent use of glasses and/or contact lenses. Other patients may require corrective surgery. When contact lenses or corrective lenses are used, each lens will need to be a different prescription to be effective. Generally speaking, glasses are not suitable for those with very large degrees of anisometropia. Due to their magnification effect, glasses can create a considerable difference in the size of the image seen by each eye and can actually prevent good binocular vision.

Untreated, the brain can decide to select the eye that presents the clearer image, and then ignore the other eye. This can lead to a dependence on the stronger eye.

The neglected eye will become progressively weaker; therefore it is important to seek treatment before the issue becomes acute.

Treatment of anisometropic amblyopia starts with eliminating the competitive advantage of the dominant eye. This is usually done by prescribing the cyclopegic refraction to the child for full time wear. Sometimes children will not tolerate their full hyperopic correction and so symmetric decreases in plus lens power may be required. Some children will respond to refractive correction alone.

For those with residual amblyopia after refractive correction, the next step is optical penalizations for the dominant eye. There are a number of techniques for optical penalization including occlusion (both part time and full time), placement of filters, refractive defocus, and pharmacologic blurring. The positives and negatives of different penalization techniques are discussed below.

Refractive Correction

Studies have shown that some patients with anisometropic amblyopia may show improvement in visual acuity while wearing their glasses full-time, without concurrent patching. A retrospective study by Steel et al. ³³ showed that one third of the patients with pure anisometropic amblyopia resolved without the need of occlusion therapy. The length of recovery time was directly proportional to the severity of amblyopia. The mean time to resolution was 5.8 months ³³. In 2006 a prospective study by the Pediatric Eye Disease Investigator Group ³⁴ reported that 27% of children with anisometropic amblyopia aged 3 to 6 resolved with spectacles alone. Visual acuity continued to improve in 48% of patients beyond 5 weeks ³⁴.

Patching

Patching of the sound eye to improve the acuity of the amblyopic eye is the most commonly used technique to treat amblyopia. A child maintains a high level of cortical synaptic plasticity until they reach visual maturity (approximately 7 to 9 years of age). During these early years, amblyopic neural deficits and vision loss can be reversed by occluding the non-amblyopic eye. Visual plasticity is inversely related to a child’s age, thus patching is more effective at an early age. However, there are studies that have shown that occlusion therapy can be effective in adolescent children ³⁵.

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 Pediatric Eye Disease Investigator Group 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 ³⁶. 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 ³⁷. Some clinicians also prescribe ‘near activities’ in conjunction with patching but this was not found to be beneficial in a recent study ³⁸.

Other modalities of medical amblyopia management include foils placed on the sound eye lens of the glasses, contact lenses used as occlusion or for blurring.

Atropine

Pharmacologic penalization of the sound eye is another commonly used modality to treat amblyopia. Atropine is an anticholineric drug that works as a competitive inhibitor for the muscarinic acetylcholine receptor. Optical penalization is also used to treat amblyopia by using atropine 1% to paralyze accommodation and induce blur in the non-amblyopic eye. If a patient has a hyperopic refractive error in their dominant eye then reducing this lens to plano will enhance the affect of pharmacologic penalization ¹⁰.

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 ³⁹. 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 ⁴⁰. 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 ⁴¹.

Neutral Density Filter

A recent study by the Pediatric Eye Disease Investigator Group ⁴² analyzed the efficacy of Bangerter filters for the treatment of moderate amblyopia as compared to part-time patching. The authors ⁴² found that after 24 weeks of treatment, the mean visual acuity improvement in the patching group was only half a line better than the Bangerter filter group. The study also included a questionnaire to asses the negative impact of each treatment modality. They found that the Bangerter filter was a less disruptive treatment option for both the child and family. The authors concluded that the Bangerter filter is effective for treating moderate amblyopia and may be a useful alternative for patients with poor patching compliance. It is important to mention that patients with minimal refractive error in their non-amblyopic eye will likely look over their glasses. These patients will likely not respond as well to Bangerter filter treatment.

Neuro-pharmocology

A more recent treatment option is the use of pharmacologic neurotransmitters for patients that are non-responsive to standard amblyopia treatment. The neurotransmitters are believed to enhance cortical plasticity. Dopamine is a neurotransmitter that is active in the retina and the cortex but does not cross the blood brain barrier. A precursor molecule known as levodopa does cross the blood brain barrier and is converted to dopamine in the brain ⁴³. Levodopa is currently used to treat patients with Parkinson disease and children with dystonia. Numerous studies have reported that patients who receive levodopa-carbidopa with patching show more improvement than patients who receive a placebo and patching. However, there are conflicting results in the literature on the stability of visual acuity after cessation of treatment. In 2002 Leguire et al. ⁴³ analyzed the regression rates of three previous levodapa studies. They found that after the cessation of treatment, the regression rates of levodopa and patching treatment were similar to the regression rates of patching therapy alone ⁴⁴.

The Pediatric Eye Disease Investigator Group is currently conducting a multi-center, double-masked randomized study on levodopa-carbidopa for the treatment of amblyopia. This study will provide a better understanding of the efficacy and long-term stability of levodopa treatment for amblyopia.

Anisometropia prognosis

The prognosis for treatment varies significantly based on the age of the child and the type of treatment initiated. In general, treatment is more successful if the child is treated at a younger age. Although refractive amblyopia is more commonly associated with anisometropic hyperopia, unilateral high myopia tends to have a worse prognosis.

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