Elsevier

Survey of Ophthalmology

Volume 50, Issue 2, March–April 2005, Pages 123-166
Survey of Ophthalmology

Major Review
Amblyopia Characterization, Treatment, and Prophylaxis

https://doi.org/10.1016/j.survophthal.2004.12.005Get rights and content

Abstract

Amblyopia has a 1.6–3.6% prevalence, higher in the medically underserved. It is more complex than simply visual acuity loss and the better eye has sub-clinical deficits. Functional limitations appear more extensive and loss of vision in the better eye of amblyopes more prevalent than previously thought. Amblyopia screening and treatment are efficacious, but cost-effectiveness concerns remain. Refractive correction alone may successfully treat anisometropic amblyopia and it, minimal occlusion, and/or catecholamine treatment can provide initial vision improvement that may improve compliance with subsequent long-duration treatment. Atropine penalization appears as effective as occlusion for moderate amblyopia, with limited-day penalization as effective as full-time. Cytidin-5′-diphosphocholine may hold promise as a medical treatment. Interpretation of much of the amblyopia literature is made difficult by: inaccurate visual acuity measurement at initial visit, lack of adequate refractive correction prior to and during treatment, and lack of long-term follow-up results. Successful treatment can be achieved in at most 63–83% of patients. Treatment outcome is a function of initial visual acuity and type of amblyopia, and a reciprocal product of treatment efficacy, duration, and compliance. Age at treatment onset is not predictive of outcome in many studies but detection under versus over 2–3 years of age may be. Multiple screenings prior to that age, and prompt treatment, reduce prevalence. Would a single early cycloplegic photoscreening be as, or more, successful at detection or prediction than the multiple screenings, and more cost-effective? Penalization and occlusion have minimal incidence of reverse amblyopia and/or side-effects, no significant influence on emmetropization, and no consistent effect on sign or size of post-treatment changes in strabismic deviation. There may be a physiologic basis for better age-indifferent outcome than tapped by current treatment methodologies. Infant refractive correction substantially reduces accommodative esotropia and amblyopia incidence without interference with emmetropization. Compensatory prism, alone or post-operatively, and/or minus lens treatment, and/or wide-field fusional amplitude training, may reduce risk of early onset esotropia. Multivariate screening using continuous-scale measurements may be more effective than traditional single-test dichotomous pass/fail measures. Pigmentation may be one parameter because Caucasians are at higher risk for esotropia than non-whites.

Introduction

Amblyopia has traditionally been defined as a “decrease of visual acuity caused by pattern vision deprivation or abnormal binocular interaction for which no causes can be detected by the physical examination of the eye, and which in appropriate cases is reversible by therapeutic measures.”541 (Indeed, in some studies, demonstration of that reversibility from treatment has been required to confirm the diagnosis.11, 12) However, current findings, reviewed below (section I.B., I.C.), suggest that the situation is taxonomically more complicated.

Amblyopia is estimated to afflict 1–4% of children,126, 292, 293, 317, 321, 475, 559 with recent large population studies falling in the range of 1.6–3.6%,126, 292, 293, 298, 559 and with evidence that the rate is even higher in medically underserved populations (Dunbar J, Johnson T, Chapman D, et al: Family income influences prevalence of amblyogenic risk factors and health care delivery pattern following preschool vision screening [abstract]. Invest Ophthalmol Vis Sci 43[Suppl]:S106, 2002).414, 415, 563 Various studies have found it to be the first, second, or third leading cause of visual impairment in adults of various age distributions.26, 269, 378

As reviewed below (section I. D.), there is a variety of evidence that the eye contralateral to the amblyopic eye often has an array of small but measurable deficits. Wali et al thus suggest that the contralateral eye should not be referred to as the “normal” or “nonamblyopic” or “sound” eye, as it is none of those things.543 They suggest use of the term “dominant” eye.543 However, that term risks confusion with reference to the eye dominance of normal vision. In the present review, we instead use the term “better” eye.

Evidence of “convergence”181, 489, 523 and transient unilateral, alternating, or esodeviating, misalignment217, 218, 219 prior to the onset of binocularity, and improved “vergence” response gain at the age of binocularity onset,437, 523 suggest that the eyes begin life fixating independently181, 489, 523 (and doing bi-ocular adduction rather than true vergence243, 477). This is followed by the development of fusion and stereopsis.53, 63, 488 However, an interocular neural competition for synaptic space in the primary visual cortex in early visual development109 means that there remains a vulnerability to establishment of a monocular-dominated state. This vulnerability is demonstrated by findings that a) transient interocular visual acuity differences in normal infants, are negatively correlated with (binocular) stereoacuity;51, 54 b) 4 of 5 monkeys raised with bilaterally equal form deprivation nonetheless demonstrated a superiority of one eye over the other in terms of post-deprivation contrast sensitivity function;195 and c) humans develop (unilateral) amblyopia in response to bilateral astigmatism, especially mirror-image oblique astigmatism.14

The specific neurophysiologic mechanism of amblyopia may be that the interocular image conflict reduces interocular summation while promoting interocular inhibition, interpreted as reducing the effectiveness of excitatory neural connections in the cortex while sparing inhibitory connections.286

It has been conventional to divide amblyopia into these three classes,541 although anisometropic amblyopia involves both deprivation and “abnormal binocular interaction,”541 and factor analysis in a multi-measure study of a large group of amblyopes found no distinguishable functional difference between deprivation and anisometropic amblyopes.355

There has been extensive experimentation investigating whether the spatial distortion characterizing strabismic, but not anisometropic, amblyopia465, 484 is due to image “undersampling” like that of the large-receptive-field “coarse” grain of the normal periphery,326, 464 or whether the spatial image projected to the cortex is “scrambled,”113, 201 or whether elements of both are involved.566 A third hypothesis is that the distortions arise out of a diplopia-like neural misrepresentation, such as a single grating being perceived as two gratings at different orientations and, in some cases, different spatial frequencies.39 A simulation constructed under this latter hypothesis successfully modeled distortion patterns seen by amblyopes.39 Another report found that a measure of undersampling or disarray was correlated with the presence or absence of stereopsis, but not with anisometropic versus strabismic versus combined strabismic-anisometropic etiology (Bosworth R, Birch EE: Binocular function and optotype-grating acuity discrepancies in amblyopic children [abstract]. Invest Ophthalmol Vis Sci 44[Suppl]:S131, 2003).

In a cluster analysis of a set of tests of various characteristics of a large group of amblyopes of all types (by traditional classification), two distinguishable clusters were found, one primarily characterized by visual abnormalities, the other by oculomotor abnormalities.356 Another study found that improvements in nasal-temporal optokinetic slow-phase velocity as a result of occlusion treatment were not correlated with visual acuity improvements.556 A study comparing repeat-letter testing (a set of cards with a 12 × 12 array of copies of the same letter at a given visual acuity level) with standard chart visual acuity found evidence of both visual and gaze-control dysfunctions, cutting across the strabismic versus anisometropic classification, suggesting an orthogonal classification.428 Another study also found more improvement in single-letter than line acuity in one patient and the reverse in another patient.332 That the visual and motor components interact is suggested by a finding that fixation instability got worse, not better, with treatment,470 presumably due to the fact that contour interaction increases with treatment.470, 519 Similarly, more severe amblyopes were able to fixate more steadily on the basis of biofeedback than amblyopes with better visual acuity.136

A question raised by these findings is whether the better visual acuity on grating targets than on letter chart visual acuity in amblyopia (see section III.I) is due to a motor control component, because gratings, like the repeat-letter test, are redundant and so make less demands on gaze control. In support of this hypothesis is the finding that gratings typically indicated better visual acuity in amblyopes than did single isolated optotypes.447

Contrast loss appears independent of visual acuity loss in amblyopia. A large study found, using factor analysis, a visual sensitivity dimension independent of a visual acuity dimension.355 Contrast-loss findings takes a variety of forms: In strabismic204, 221, 325 and some,16, 280 but not all,485 anisometropic amblyopes, the sine-wave-grating-based contrast sensitivity function (CSF) may be normal (despite chart optotype visual acuity deficits) or show a pattern of sensitivity loss at high spatial frequencies only, or loss across all spatial frequencies. With treatment, strabismic amblyopes may show contrast sensitivity gain without optotype visual acuity change, and post-treatment follow-up measurements may show deterioration in visual acuity but not contrast sensitivity.280 Both single-optotype159, 427, 495 and chart159, 471 tests can show greater visual acuity loss at high contrast only, uniformly at high, intermediate, and low contrasts, or at intermediate and low contrasts only, due to the crowding effects being reduced at low contrast,159, 471 (and consequently normalization of function at lower contrast and/or illumination levels306, 339), and vice versa.159 Some amblyopes exhibit worse visual acuity for chart than single-optotype tests, that is, show a crowding effect, at high-contrast versus low-contrast, whereas others exhibit the same amount of difference between chart and single-optotype acuity at both high and low contrast.159 There are also differences reported following treatment, in the form of improvement, by anisometropes, at both high and low contrast versus more improvement, by strabismics, at low contrast.470

Contour integration loss (i.e., loss of perception of contours as continuous), a so-called “second order” measure of amblyopia, cannot be adequately explained by visual acuity or contrast sensitivity losses.205 Contour integration responds more rapidly and completely to occlusion than does visual acuity (Chandna A, Pennefather PM, Wood ICJ, et al: Contour detection thresholds and visual acuity in relation to occulsion therapy in amblyopia [abstract]. Invest Ophthalmol Vis Sci 39[Suppl]:S330, 1998),82 is only loosely correlated202 with visual acuity status, may thus show greater loss than visual acuity,570 and in normals continues to develop longer than visual acuity, up to 14 years of age.282

Amblyopic vision has been found to have longer reaction time than normal vision,38, 90, 186, 357, 531, 535, 541 particularly at higher spatial frequencies;327 increased VEP latency;549 deficits in time, velocity,505 and motion70, 119, 261 discrimination; in detection of motion-defined forms when visual acuity is normal (following treatment);158 and in “second order” global motion processing.473 It has been proposed that there is a specific global motion deficit and demonstrated that the detection of the motion component of a motion-defined form is not correlated with a measure of visibility (Simmers A, Ledgeway T, Hess RF, et al: Contrast and motion specific deficits in amblyopia using the global motion paradism [abstract]. Invest Ophthalmol Vis Sci 43[Suppl]:S158, 2002).

Although amblyopia has a cortical and lateral geniculate basis,39, 109, 541 there remain questions as to whether it has an ocular anatomic site as well, particularly the long-controversial question107, 167 of whether there is a locus in the retina.38, 100, 234, 562 Electroretinogram data are conflicting.107, 167 A histological study of the retina of the amblyopic eye of a monkey raised with artificially induced anisometropia found no retinal abnormality,199 nor did fluorescein angiography,441 psychophysical study of Stiles-Crawford effect and visual pigment,112 or clinical examination of the fovea197 in human amblyopes. However, it has been proposed that there could be an abnormality at the physiologic level due to dopaminergic mechanisms,562 to which the retina is sensitive (Doelemeyer A, Polska, EA, Malec, M, et al: Sensitivity and reproducibility of mfERG in assessing the effect of levodopa on retinal function [abstract]. Invest Ophthalmol Vis Sci 43[Suppl]:S187, 2002).406, 417, 429, 562

Two recent sets of findings bear on the question of possible ocular involvement: The first group of studies is of the retinal nerve fiber layer (RNFL). Several studies using scanning laser polarimetry found no significant difference in RNFL thickness between the amblyopic and better eyes of amblyopes.33, 61, 100 However, a study based on optical coherence tomography (OCT) found RNFL to be significantly thicker in refractive or anisometropic amblyopic eyes than fellow or normal eyes.576 This finding is counterintuitive, because there is some evidence of cell shrinkage in the lateral geniculate nucleus of human amblyopes,536, 537 which would suggest that the RNFL would be thinner in amblyopic than fellow or normal eyes, not thicker. Furthermore, the thickness difference was not found in strabismic amblyopia eyes.576 The amblyopic eyes that did show the greater RNFL thickness did not exhibit a significant correlation between that thickness and logMAR visual acuity, adjusted for age,576 as would be expected if the thickness were associated with the visual loss. Finally, another OCT study found, as in the case of the polarimetry studies, no RNFL difference between amblyopic and fellow eyes (Rabbione MM, Roagna B, Tonetti S, et al. Optical coherence tomography measurements of thickness in amblyopic and non-amblyopic eyes [abstract]. Invest Ophthalmol Vis Sci 45[Suppl]:S106, 2004).

A second set of studies reports evidence in amblyopes of subclinical anomalies of the optic disk, subnormal disk area and axial length,315, 316 assumed to imply a subnormal number of optic nerve fibers connecting to their target nuclei,315 and demonstrate an increased axial length/disc area ratio.311, 314 Evaluation of these reports is complicated by several factors. One study had no normal control group,316 an important factor because tilted disks may be more extensive in normal eyes than previously thought, as well as unilateral in more than 60% of such normals.542 Another study included glaucomatous and myopic patients in its control group. 315 Both conditions are associated with large disks,246 thus potentially providing an artifactually large disk size average in the control group. More fundamentally, although there is evidence of a statistically significant correlation between optic disc size and nerve fiber count, the correlation is modest, 0.37,247 0.47,418 and 0.497,154 indicating considerable variability. It has been suggested30, 31 that there may be a nonlinear relationship between axial length and disk area in at least one of these studies.314 In fact, the relationship is by definition nonlinear since it involves the area of the disk, which is πr2, where r = the disk radius. In other words, whereas there is presumably a linear relationship between axial length and disk radius, disk area increases as the square of both that radius and the axial length. This is an important point because the squared increase would tend to exaggerate interocular differences. (The investigator replies313 that a histopathologic study418 demonstrates that there is a linear relationship, but all that the cited study or related studies,154, 247 demonstrates is that there is correlation, without specifying if the relationship is linear.)

Two other studies used an axial length/disk area ratio measure.312, 314 However, on the one hand, these anomalies were found to occur in nonamblyopic anisometropes and esotropes and in the better eye of anisometropic and esotropic amblyopes,311, 314 and, on the other hand, in only about half or fewer of amblyopes.311, 316 Furthermore, 26% of esotropic amblyopes314 had the same axial length/disk area ratio as normal hypermetropes,314 and the ratio of a group of anisometropic amblyopes was within a standard deviation of normal.311 In other words, in these disk-related anomaly reports there seems reason to question whether the visual deficits reported here are associated with amblyopia risk factors rather than amblyopia itself.

One difficulty with all these studies33, 61, 100, 312, 314, 315, 316, 576 is that they used older children and adults as subjects, leaving unanswered the central question of whether the anatomic anomalies they report were the cause or the effect of the visual impairment. Another issue is that scanning laser polarimetry, which has been shown able to detect optic atrophy36, 358, 578—an apparent morphologic parallel to the reduced nerve fiber count proposed here314, 315, 316—found, as noted above, no anomaly in amblyopes.33, 61, 100

The most significant issue here, however, is the question of whether the visual impairment reported in these studies is in fact amblyopia or an organic defect. The conclusive diagnostic sign of amblyopia is that it responds to treatment.11, 12, 541 Because all the patients used in these studies appear to have been treatment failures (with the inclusion criterion in one study explicitly stated as nonresponse to treatment316), there appear grounds for considering whether their visual loss was in whole or part organic rather than amblyopia. A study of occlusion treatment of a small group (n = 7) of patients with optic nerve hypoplasia found uniformly poor results.64

The possibility of an anatomic defect co-occurring with, or in lieu of, amblyopia is interesting as a possible explanation for the fact that amblyopia treatment appears to be effective, as determined from long-term follow-up, in at least 63–83% of patients (see section III.B). Are some or all of those treatment failures due to something such as an RNFL or optic nerve hypoplasia-related anomaly? Some cases of optic nerve hypoplasia acuity have only minimal acuity deficits.579 A possible development mechanism that could account for a hypoplasia-related deficit has been suggested to be the postnatal reduction of axons, or apoptosis, being more extensive than normal.297, 579 Conversely, it has also been suggested that completion of the postnatal ganglion cell reduction requires a sharply focused image, with lack of such focus interfering with the reduction and leaving an abnormally thick RNFL.576

Few racial and ethnic data are available from non-Caucasian populations, but much of what exists17, 245, 335, 514, 575 does not appear to indicate an amblyopia prevalence substantially different from that of Caucasians,321 although varying visual acuity test methodologies make comparisons difficult, and no controlled studies have been made. However, there is a report of lower prevalence of strabismic amblyopia and later presentation of amblyopia in Asians than Caucasians.466 Perhaps more significantly, there is a higher incidence of the amblyopia risk factor of esotropia, and/or a higher ratio of esotropes to exotropes, in Caucasian than non-white populations,17, 80, 84, 130, 143, 172, 231, 264, 278, 279, 292, 348, 376, 557, 575, 577 and albinos have a higher incidence of esotropia than the general population.265 Furthermore, it has been proposed that inheritance of hyperopia rather than esotropia itself may be the operative variable in racial incidence differences,295 and a large (n = 2523) survey of African-American, Asian, Hispanic, and Caucasian elementary-school children in the U.S. found that Caucasians had the highest prevalence of simple hyperopia, and simple and compound hyperopic astigmatism, and lowest prevalence of myopia, and simple and compound myopic astigmatism, of the four groups.270 Finally, Caucasians have smaller optic disks than non-whites, 246 which may be significant if there are disk-size-related anomalies in nominal amblyopes.

The better eye in amblyopia is not in fact normal, but has, in the case of strabismic amblyopia: small deficits in visual acuity and small amounts of fixational eccentricity, unsteady fixation,46, 252, 253 and small deficits in tracking,46, 455 Vernier acuity,104, 329 on measures of spatial uncertainty47 and global motion processing,473 in contrast,216, 425 in pupillary response latency,38 and on an alignment task;426 greater neural “noise” than normal eyes,328 a less leptokurtic peak of visual acuity capability at the fovea than normal,252 increased VEP latency even in the presence of normal visual acuity (following treatment),549 subnormal scotopic sensitivity252 and dark adaptation,48 and more hyperopia, thicker lenses, and shallower anterior chambers than normal eyes (Lindberg L: The refractive components in binocularity disturbances. Ph.D. Thesis. Department of Ophthalmology. Helsinki, Finland: Helsinki University, 1999, p 89).334 In the case of both strabismic and anisometropic amblyopia, there have been found small deficits in contrast sensitivity,304, 498 deficits in detection of Gabor-patch-based contours, or “second-order” characteristics of the image,82, 283, 570 and deficits in ability to detect motion-defined forms in the better eye.158, 261

On the other hand, the better eye of amblyopes has also been found to have superior visual acuity to normal eyes for low-contrast charts at low luminance,306 and to show improvement in contrast sensitivity (measured on grating-based targets) following occlusion in some patients,280, 304, 543 although not others.304, 485

Some studies have been based on questionnaires rather than performance measures (Ahluwalia H, Datta AV, Weaks H, et al: A vision targeted survey of the disability of amblyopia [abstract]. Invest Ophthalmol Vis Sci 41[Suppl]:S705, 2000)394, 525 or failed to distinguish amblyopes from children with other dysfunctions in its analyses.198 A large study that defined its amblyopic population on the basis of visual acuity difference between eyes, although without cycloplegic refraction, found that children with marked amblyopia exhibited significantly worse reading and mathematics scores than normals.508 However, their amblyope sample had significantly below-normal performance on an intelligence test. The authors devised a statistical correction for intelligence (as well as sex and social class) and concluded reading and mathematics were no longer significantly different than normal, but they did not test an amblyopia sample of normal intelligence.

Although amblyopia is clinically defined by monocularly measured visual acuity, under everyday binocular viewing conditions there may be accompanying suppression that results in a worse level of visual acuity (Abrahamsson M: Monocular acuity in a binocular viewing situation in anisometropic subjects [abstract]. Invest Ophthalmol Vis Sci 42[Suppl]: S387, 2001).29, 146, 371, 475, 541 (Indeed, in some cases, visual acuity371 or contrast sensitivity216, 571 in the better eye is also reduced under binocular testing conditions.) Thus, the amblyope in everyday viewing conditions may be more nearly monocular than his or her amblyopic eye visual acuity would suggest.

No difference in speed of response on eye-hand coordination tasks (placing marbles or pegs in holes, throwing beanbags) was found between strabismic160 or non-strabismic (Howard M, Williams C, Bell JC, et al: Is the presence of strabismus and/or amblyopia associated with poorer motor skills in seven year olds? [abstract]. Invest Ophthalmol Vis Sci 45[Suppl]:S105, 2004) amblyopes and normals in two studies, but one study found non-amblyopic strabismics to have significantly poorer performance (Howard M, Williams C, Bell JC, et al: Is the presence of strabismus and/or amblyopia associated with poorer motor skills in seven year olds? [abstract]. Invest Ophthalmol Vis Sci 45[Suppl]:S105, 2004) than normals. Another study found, however, that motion parallax accuracy—a key cue to depth evaluation, especially in the amblyope's absence of normal stereopsis—to be substantially degraded in amblyopes.516

Monocular vision in normals has been shown to increase response latency, and duration of the deceleration phase in reaching and grasping, decrease perception of velocity, cause underestimation of object distance, and cause the use of an inappropriate grip aperture size, when executing prehensile movements, when compared to binocular vision.240, 248, 462, 463, 546 Time to collision,174 a parameter evaluating an individual's ability to accurately localize an approaching object, for purposes of either grasping/controlling it, alignment with it, or avoiding it, is degraded under monocular conditions.81, 173, 174, 175, 504 However, is purely monocular vision in these studies an adequate model of reduced vision in one eye in amblyopia? A study that compared results on reaching and grasping performance in monocular vision with performance of bi-ocular vision, that is, with no image difference between eyes and thus no stereoscopic disparity, found similarly reduced results compared to normal binocular vision in both conditions.65 In other words, loss of binocular disparity information is the critical loss, with the additional loss of vision altogether in an occluded eye not producing significantly worse performance on these measures.65 Other evidence also demonstrates the importance of binocular cues to accurate prehension,369 particularly when the reached-for object is surrounded by other objects.239 Non-binocularity appears to degrade prehension performance simply because it reduces the total number of position cues available and so increases positional uncertainty.342

It should be noted that there are conflicting reports as to whether younger children make more or less use of visual cues in guiding prehension than older children (and adults),285, 492, 493 including binocular cues.547

Amblyopes are at risk, if they lose vision in the better eye, of being, not only monocular, but further limited by the defective vision of the amblyopic eye. A population study found a 2.7 relative risk increase of such impairment in the better eye of amblyopes,86 and another study found a lifetime risk of visual impairment ranging from “socially significant” to severe in the better eye of amblyopes to be 0.03% by age 15 years, 0.6% by 64 years, and 3.3% by 95 years.420 Injury was the most important cause of such impairment in the two younger groups, and age-related macular degeneration the primary cause in those 65 and over. Impairment occurred in males more frequently than females, and increased risk of death, serious morbidity, and social isolation, with at least half of those in paid employment unable to continue as a result.420 The study design was such that these represent minimum figures;420 the actual incidence numbers are probably larger. Another study, of older amblyopes, also found that patients with trauma in the better eye were significantly younger than the mean age of the group as a whole.241 In the largest clinical series reported (n = 144), the findings were again similar: the proportion of cases due to accident, as opposed to disease, was significantly greater in patients under than age of 30 than over the age of 50 (my calculation: chi-square = 28.46, n = 82, p < 0.0001)526 and, in a subset of cases due to accident, 40/47 (85%) were male.526 Another small study also reported, although without numerical data cited, that loss of vision in amblyopes' better eye was more often due to accident than disease, and that the most common venue was at work.520

It should be noted that, although there are reports of improvement in the vision of amblyopic eyes when there has been loss of vision or enucleation of the better eye,86, 128, 268, 422, 425, 518, 520, 526, 567 the odds of such improvement occurring are not great: In a clinic series, only 28.5% (of 144) exhibited such improvement,526 and in two population series only 9.1%86 or 10%422 showed improvement, respectively, with a similar number (8%) showing a further decrease.422 In the clinic-based study, fewer than half (43%) of those showing improvement achieved a visual acuity of 20/30 or better.526

Studies of reading with amblyopic eyes alone have found impaired performance (Osarovksy-Sasin E, Richter-Mueksch, S, Pfleger T, et al: Reduced reading ability of eyes with anisometropic amblyopia [abstract]. Invest Ophthalmol Vis Sci 43[Suppl]: S187, 2002),32, 580 in some cases despite the presence of 20/20 vision on a standard chart (the letters of which are not as crowded as printed text),580 although correlation of reading speed was seen with visual acuity measured on a crowded chart.32 A study using a reading visual acuity equivalent of logMAR visual acuity found the reading visual acuity more degraded than logMAR chart visual acuity (OsarovksySasin E, Richter-Mueksch, S, Pfleger T, et al: Reduced reading ability of eyes with anisometropic amblyopia [abstract]. Invest Ophthalmol Vis Sci 43[Suppl]: S187, 2002). Even in nonamblyopic vision, as modest a visual loss as reduction to 20/40 vision has been shown to impair both reading speed and face recognition,486, 555 so even a “mild” amblyope, having lost vision in the better eye, can be expected to be all the more compromised.

As noted in section I.B.5, amblyopic eyes have limitations in dynamic performance, although there is evidence that the perception of motion is less impaired than visual acuity.114, 284

It is not clear that this question can be definitively answered, but variables that could be involved include amount of acuity gain, absolute level of acuity achieved, long-term stability of acuity achieved, functional implication of the level achieved, and expectations of the parent, patient, and/or physician of treatment outcome relative to normal vision.4, 32, 73, 86, 506, 580

A report from the United Kingdom,494, 509 although methodologically flawed,190, 480 raised question as to the demonstrated utility of both amblyopia screening and treatment. Older population studies272, 527 as well as recent studies, however, both retrospective,60, 101, 291, 480 and prospective (Anker S, Atkinson J, Braddick O, et al: Does videorefractive screening in infancy reduce prevalence of school-age vision problems? [abstract]. Invest Ophthalmol Vis Sci 43[Suppl]:S115, 2002; Anker S, Atkinson J, Braddick, O, et al: Acuity outcome at 4 years for treated and untreated hyperopes detected in the second Cambridge infant refractive screening programme [abstract]. Invest Ophthalmol Vis Sci 41[Suppl]: S730, 2000; Harrad R, Willlams C, Sparrow JM, et al: Visual acuity at 7 years after orthoptic screening at different ages - results of a randomised controlled trial [abstract]. Invest Ophthalmol Vis Sci 43[Suppl]: S118, 2002),93, 126, 148, 292, 293, 298, 318, 390, 436, 559, 561 have demonstrated that amblyopia screening and treatment are in fact effective in terms of clinical outcome and in the sense of reducing amblyopia prevalence. A long-term (7-year) follow-up study demonstrated that even infant vision screening that did not include refractive evaluation had a substantially better positive predictive value than a variety of other pediatric screening measures, such as for hearing impairment, congenital heart malformation, and developmental hip dysplasia.249, 291, 298 (One recent prospective study that questioned the utility of treatment of milder forms of amblyopia did not report how its baseline screening acuity measurements were made93 other than noting in a letter that “standard Snellen based screening tests”91 were used. Because the patient sample was too young for Snellen chart acuity, isolated optotype Snellen E acuity is presumably referred to, which has the familiar problems of single-optotype tests (section III.I.) and makes evaluation of the study's crowded-test-based outcome results difficult. (For further comment, see references.30, 91, 124, 192, 387, 499)

Nonetheless, the cost-effectiveness aspect of both screening41, 155, 273, 275, 276, 449, 482, 494, 509 and treatment43 of amblyopia remains a concern in this era of competing demands on limited health resources and declining reimbursements. Several factors play into determining cost effectiveness: screening accuracy and participation,249, 373, 560 compliance with treatment (section III.D), efficacy at long-term follow-up (section III.B), and functional significance of amblyopia at a given level of visual acuity274 (section I. E). Thus, for instance, an advisory group in the United Kingdom has recommended discontinuing screening for strabismus and amblyopia in infants and children less than 4 years of age, while mandating it for all 4–5 year olds, based on the rationale of the greater accuracy of visual acuity-based screening possible in the older age group.421, 423 The success of a program in Sweden based on multiple early screenings in reducing amblyopia prevalence, and related findings (see section III.E), and the success of an early screening and prophylactic intervention program (section VII.A), however, suggest just the opposite, that maximally efficacious treatment is achieved through detection and treatment as soon as possible after amblyopia onset.

Another aspect involved here is the fact that “The total cost of treating amblyopia … is miniscule compared to that of most interventions for restoring vision for other ophthalmologic disorders.”289 An index based on the formula: (cost of treatment)/([number of lines of visual acuity improvement] × [number of years of life expectancy]) showed amblyopia treatment in children to be 44 times more cost effective than cataract surgery and 85 times more cost effective than macular hole surgery in adults.443 However, arriving at a means of evaluating amblyopia treatment cost effectiveness more globally relative to other health care has to date proven somewhat problematic, heavily influenced by the assumptions made and algorithms used,43, 68, 274, 359 such as a model based on isolated optotype screening,274 or analyses done from the perspective of third-party insurers.274, 359 (The significance of the perspective chosen is illustrated in a study that found amblyopia treatment valued significantly higher by patients than by physicians.43)

Section snippets

Refractive Correction

Some cases of nonstrabismic anisometropic amblyopia can be partially or completely treated by refractive correction alone (Gonzalez-Martin J, Chandna, A: Recovery of visual functions in children with anisometropic amblyopia: a prospective longitudinal study [abstract]. Invest Ophthalmol Vis Sci 42[Suppl]: S398, 2001; Stewart C, Fielder AR, Moseley, MJ, et al: Visual function of children with amblyopia during refractive adaptation and occlusion therapy [abstract]. Invest Ophthalmol Vis Sci

Treatment Duration

Treatment duration data appear contradictory, ranging from no relationship between hours of treatment or treatment prescribed and visual acuity improvement at the end of treatment,4, 214, 290, 366, 432, 470 to a highly significant correlation,572 to an inverse relation between duration and visual acuity outcome, that is, those with the least treatment (milder amblyopes), produced the best results.206 The ATS found a significant relationship between number of hours of occlusion prescribed and

Treatment kinetics, Duration, and Long-Term Follow-Up Visual Acuity Outcome

For occlusion, maximum response is reported achieved within approximately 3 months or less (Stewart C, Fielder, AR, Moseley, MJ, Stephens, DA: Is it all over in 6 weeks? Intrerim analysis of the monitored occlusion treatment for amblyopia study (MOTAS) [abstract]. Invest Ophthalmol Vis Sci 42[Suppl]:S399, 2001)338, 380, 391, 397, 470 or 400 hours of treatment spread over as much as 6 months95 or in the first 4 to 6 visits, with those visits spaced 4–12 weeks apart. 470 The ATS found much of the

Adult Amblyopia Treatment

Although traditional clinical findings are that amblyopia can only be effectively treated up until about 9399, 541 (or 1158, 69, 207, 271, 364, 391, 395) years of age, the possibility of later treatment is suggested by reports of improved vision in a small minority (see section I.E.2) of adult amblyopic eyes following visual loss or enucleation of the better eye,128, 254, 268, 425, 518, 520, 526, 567 although it is not reported in some of these studies if the amblyopia had been treated in

Can Amblyopia Treatment Be Improved?

The fact of improvement of vision in the amblyopic eye of some adults, from loss of vision in the other eye (section I.E.2), catecholamine-based medication, or video-based treatment (last section)—even in cases where this improvement is only transitory—demonstrate that there is a physiologic basis for improving vision not adequately tapped by current treatment methodologies. (These findings also raise question about our current understanding of a neural plasticity “sensitive period” concluding

A Better Solution: Prophylaxis

Prevention of amblyopia in the first place would clearly be preferable to even the most optimum treatment. Achieving such prevention would require prophylaxis of the operative risk factor, typically esotropia or anisometropia, which means effective countering or elimination of the risk factors for those conditions in turn. As noted in section II.A, refractive correction could be used for anisometropia. What about esotropia?

The Next Step: Multifactorial Screening?

Improving the effectiveness of either early treatment or prophylaxis of esotropia and its amblyopic sequela would be aided by an ability to more accurately predict which infants will develop it. Of particular note is the possibility that there are not isolated risk factors but that any of a variety of risk factor combinations may cause onset. That is, it may be that early onset esotropia is a “heterogeneous condition with either multiple different causes or a single cause that manifests in

Summary and Conclusions

  • 1.

    Recent large population studies show an amblyopia prevalence of 1.6–3.6%, and higher in medically underserved populations (I).

  • 2.

    The contralateral eye of an amblyope is most accurately characterized as the “better” eye becasue it is neither non-amblyopic nor normal, but exhibits sub-clinical but measurable amblyopic deficits on a variety of visual and motor measures (I, I.D).

  • 3.

    The infant begins life in a state of semi-independence of the two eyes, which improves in early development to fusion and

Method of Literature Search

Literature was derived from the author's files, from broad searches of Medline (up to November 11, 2004) under headings related to esotropia, amblyopia, anisometropia, child vision screening, perinatal, binocular fusion, emmetropization/emmetropization, and, for older material, from library searches.

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    The author reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Supported by grants from Mr. Robert Feduniak and Mrs. Victoria Baks. The author is grateful for comments received on the manuscript by David L. Guyton, MD, Michael X. Repka, MD, and Kristina Tarczy-Hornoch, MD, DPhil.

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