Refractive Amblyopia
Included among the amblyopic patients are those whose amblyopia results from uncorrected refractive errors. Such amblyopia is of particular clinical importance because of its prevalence, prognosis, and relative ease of management. Because many patients with refractive amblyopia are not strabismic, their treatment requires only slight modification of the binocular procedures described in previous chapters.
The study of amblyopia is frequently a study of the effects of vision deprivation. From the investigations of Wiesel and Hubel1 to current studies, it is clear that deprivation occurring in early life has dramatic long-lasting effects on the visual system.2 The essence of animal research is that vision deprivation, such as is produced by lid suture, results in a variety of anatomic and physiologic changes throughout the visual pathway.3 Anatomic changes associated with lid suture are typically more extensive at the lateral geniculate nucleus,4 whereas physiologic changes are more pronounced and varied in the visual cortex.5 Detailed reviews of these findings often provide clinically relevant information,6 including two concepts that directly affect the management of anisometropic and isoametropic amblyopia. These concepts—abnormal binocular competition and the critical period—are discussed in the section on etiology.
This chapter describes examination techniques and differential diagnosis and presents a sequential management of refractive amblyopia that extends the treatment period well into adulthood. Virtually, all amblyopic patients should have careful diagnosis and aggressive management. It is important to treat these patients; it is not acceptable to simply monitor them, because it is possible to dramatically improve visual acuity (VA) and binocular function using sequential considerations of (a) correction of the refractive error; (b) added lenses or prisms, or both, to improve fusion; (c) passive therapy (either part-time direct occlusion or penalization of the sound eye with atropine drops); and (d) vision therapy to improve monocular and binocular function.
Etiology and Prevalence of Refractive Amblyopia
DEFINITION
Amblyopia is defined7 as a unilateral or bilateral condition in which the best corrected VA is poorer than 20/20 in the absence of any obvious structural or pathologic anomalies, but with one or more of the following conditions occurring before the age of 6 years:
Amblyogenic anisometropia
Constant unilateral esotropia or exotropia
Amblyogenic bilateral isometropia
Amblyogenic unilateral or bilateral astigmatism
Image degradation
Whenever VA is less than 20/20, it is clinically significant and needs to be investigated further. If one of the five conditions associated with amblyopia is not present, then possible organic changes should be investigated.
Refractive amblyopia may be subdivided into two categories: anisometropic and isoametropic. Anisometropic amblyopia occurs as a result of clinically significant and unequal amounts of uncorrected refractive error in each eye.8 The most ametropic eye develops amblyopia as a result of the unilaterally blurred retinal image. Isoametropic amblyopia results from the presence of very high, but clinically equal, uncorrected refractive errors.8 Both eyes become amblyopic as a result of bilateral visual deprivation from the significantly blurred retinal images of each eye.
CLASSIFICATION
Amblyopia has traditionally been classified in a dichotomy between organic and functional, with various subclassifications9 (Table 17.1). von Noorden suggested classification of functional amblyopias based on clinical causes.10
Such a classification is based on the clinical conditions thought to be responsible for creating the amblyopia. This chapter discusses two types of amblyopia, classified according to the refractive errors that result in a decrease in acuity and unilateral difference in refractive error (anisometropic) or significant bilateral refractive error (isoametropic).
Such a classification is based on the clinical conditions thought to be responsible for creating the amblyopia. This chapter discusses two types of amblyopia, classified according to the refractive errors that result in a decrease in acuity and unilateral difference in refractive error (anisometropic) or significant bilateral refractive error (isoametropic).
Table 17.1 CLASSIFICATION OF AMBLYOPIA | ||||||||||||||||
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ETIOLOGY
The factors that result in refractive amblyopia have been investigated in experimental studies on the effects of vision deprivation. In general, the primary factor that results in amblyopia is an uncorrected refractive error that does not permit clear retinal images of equal size or shape, or both, in each eye. These blurred images do not allow adequate stimulation of the visual system, and amblyopia develops. Although refractive amblyopia is regarded as functional, as opposed to organic, the basic amblyogenic factors are much better understood than the term functional implies. Indeed, investigations have correlated the clinical conditions that result in amblyopia with resulting deficits in the basic underlying neurophysiology.
Abnormal Binocular Competition
The effects of deprivation are most significant when there is an imbalance in the visual input between the eyes. A competitive interaction exists between the two eyes during early visual development,11 and conditions that allow one eye a competitive advantage result in dramatic changes in the visual pathway of the disadvantaged eye. The accepted explanation for these changes involves a competition for synaptic space on cortical neurons.12 Neurons in the visual pathway of the disadvantaged eye decrease in function and number as a result of this competition, and pathways from the advantaged eye gradually gain more synapses. Thus, this basic science research suggests that genetic coding determines the initial neural pathways and that early visual experience subsequently refines and maintains these connections. Abnormal visual experience disturbs the basic pattern and reduces visual capabilities in one or both eyes. Visual pathway changes are more difficult to demonstrate when the eyes are equally disadvantaged.
Anisometropic Amblyopia
In patients with uncorrected anisometropia, the images falling on the two foveae have the same common visual direction and give rise to a single percept. However, the images may be of substantially different clarity. As a result, in uncorrected anisometropia, the foveal image of the most ametropic eye is likely to be suppressed. This cortical suppression or signal inhibition can eventually result in amblyopia if it occurs for a sufficient time at the appropriate stage in development. Unfortunately, vision deprivation present in uncorrected anisometropia may escape early detection because one eye sees clearly and there may be no signs or symptoms.
Isoametropic Amblyopia
When there is an isoametropic refractive error, interference from dissimilar images does not occur. Thus, any resultant loss of acuity must be from lack of proper stimulation of the visual system (bilateral visual deprivation) during early development, rather than a result of congenital or organic amblyopia. For bilateral visual deprivation to occur, there must generally be a significant decrease in the visual input to both eyes. The most dramatic clinical example of bilateral visual deprivation occurs when an infant has congenital cataracts. Unless removal is initiated very early in life, the resultant acuity is substantially below normal.13 Refractive errors can also “deprive” the visual system of proper stimulation, but they must be very large, and even then the visual loss is seldom severe,14 at least in comparison to that seen in patients with congenital cataracts.
Critical and Sensitive Periods
Imbalances between the visual information reaching the two eyes have the most profound results early in development. Animal studies have established that there is a developmental period for anisometropic amblyopia that probably lasts through most of the first decade of life.15,16 Clinical observations also suggest a similar time course for amblyopia development.17,18 This developmental period can be roughly divided into two portions, a critical period and a sensitive period. The critical period is a relatively short duration of time of maximum sensitivity, perhaps lasting until age 3 in humans. During the longer lasting sensitive period, the visual system is still susceptible to change, but damage is progressively less severe. The sensitive period probably begins at about age 3 and may last until around age 10. Imbalances that occur later have reduced or nonexistent effects. Certain anatomic changes coincide with these periods, allowing vision researchers to predict that human visual development continues through at least the first decade.
Plastic Period
The critical period for amblyopia development does not necessarily follow the same time course as the plastic period, during which the amblyopic visual system is still amenable to successful treatment. Clinical evidence suggests that plasticity of the visual system remains for periods substantially longer than the first few years. For example, the dramatic response of adult patients with anisometropic amblyopia to treatment19 suggests that residual plasticity remains in the human visual system for much longer periods than the critical period for development of amblyopia. The ability of older patients to recover from cerebral vascular accidents is further evidence that the human nervous system retains some plasticity throughout life. Basic research studies in cats20 show that the plastic period, during which the visual system can still change, extends well into adulthood.
PREVALENCE
Anisometropic Amblyopia
Flom and Neumaier21 investigated the prevalence of amblyopia in 2,762 schoolchildren from kindergarten to the sixth grade. They found that 1% of the population had amblyopia, using a criterion of monocular uncorrected acuity of 20/40 or worse, with a difference between the eyes of more than one line of acuity. All children with amblyopia had either strabismus (38%), 1 diopter (D) or more of anisometropia (34%), or both conditions (28%).
The prevalence of amblyopia without strabismus was also summarized by Schapero,8 who determined (from data averaged from six studies) that 62% of amblyopes have binocular alignment of the visual axes. Although one cannot assume that all 62% of the cases of nonstrabismic amblyopia were of refractive etiology, amblyopia appears to occur quite frequently in patients without strabismus. Because anisometropia occurs more frequently than unilateral strabismus, it is not surprising that anisometropic amblyopia occurs more frequently than strabismic amblyopia.
Isoametropic Amblyopia
There is little epidemiologic information concerning the prevalence of isoametropic amblyopia. Theodore et al22 surveyed 190,012 inducted soldiers; in a group labeled “unexplained amblyopia”; they found that 14 of 2,509 men (0.56%) had bilateral amblyopia. In a similar study, Agatson23 found 7 of 20,000 inducted men to have bilateral amblyopia associated with high refractive errors. More recently, Abraham24 used an amblyopia criterion of correctable acuity less than 20/25 and reported that 162 of 7,225 patients had bilateral amblyopia. He included patients with 5.00 D or more of hyperopia or 1.25 D of astigmatism or both.
Linksz25 associated bilateral amblyopia with myopia and astigmatism rather than hyperopia. However, Abraham24 definitively demonstrated that bilateral amblyopia occurs in a substantial number of patients with significant hyperopia or astigmatism or both. Similarly, Friedman, Neuman, and AbelPeleg26 suggested that bilateral hyperopia was the most common cause of amblyopia, in a series of 39 patients with marked ametropia.
These studies suggest that bilateral amblyopia secondary to uncorrected isoametropia accounts for approximately 2% of nonstrabismic amblyopia. Although the true prevalence of bilateral amblyopia in the general population is unknown, Griffin27 implied that the prevalence of isoametropic amblyopia is decreasing in countries where early vision examinations are emphasized.
Characteristics of Amblyopia
SIGNS
Unfortunately, there are no reliable signs to make the patient, parent, or clinician suspect the presence of refractive amblyopia. When there is amblyopia, a very young child may rub his or her eyes, and an older child or
adult may squint to improve vision. However, these signs occur in a variety of refractive conditions and are not reliable indicators of the anisometropia that is most likely to produce refractive amblyopia.
adult may squint to improve vision. However, these signs occur in a variety of refractive conditions and are not reliable indicators of the anisometropia that is most likely to produce refractive amblyopia.
SYMPTOMS
Much of what was presented in regard to signs also applies to the presence of symptoms. Complaints of blurred vision, headaches, and ocular discomfort are potential symptoms that patients with amblyopia may report, but it is also very likely that there will be no symptoms. There are only a few refractive situations that create the proper conditions for anisometropic or isoametropic amblyopia. The patient’s age and visual requirements, along with the refractive status, all combine to determine whatever symptoms may be present, and there are many refractive conditions that cause symptoms without ever producing amblyopia.
CLINICAL CHARACTERISTICS
There are a variety of visual conditions that are characteristic of refractive amblyopia. Clinically, it is necessary to be familiar with the important characteristics of anisometropic or isoametropic amblyopia listed in this section.
Refractive Error
Jampolsky et al28 examined a sample of approximately 200 patients with nonstrabismic amblyopia and reported that the eye with the greater ametropia, regardless of the type of refractive error, had the greatest loss of acuity. However, this statement does not totally reflect the differential effect that hyperopia has on the development of amblyopia.
Hyperopia
Jampolsky et al28 found that hyperopia or astigmatism or both have a greater effect on VA loss than myopia. In their study, the difference in power between the horizontal and the vertical meridians of the eyes was closely related to unequal acuity—that is, the greater the anisometropia, the greater the amblyopia. Sugar29 found similar results and concluded that hyperopic anisometropia was the predominating factor associated with nonstrabismic amblyopia. Hyperopic anisometropes had more amblyopia, and the amblyopia increased with the amount of hyperopia and the amount of anisometropia.
The greater prevalence of amblyopia in hyperopic anisometropia is primarily a result of the different image clarity and the accommodative response. The more hyperopic eye has a blurred image, and the amount of blur depends on the amount of anisometropia. Because the eye with the lower refractive error typically accommodates for any near target, the more hyperopic eye always remains with a blurred image. Consequently, hyperopic anisometropia in amounts greater than 1.25 D may create sufficient long-term blur to cause a form of vision deprivation in the hyperopic eye. If this occurs during the critical period during development, amblyopia may result.
Myopia
These studies document that the prevalence of amblyopia is greater in patients with hyperopic anisometropia than in those with myopic anisometropia. Indeed, in simple myopic anisometropia or anisomyopia, an amount of 5 or 6 D (or perhaps more) is necessary before one image is sufficiently and continuously blurred so that vision deprivation and amblyopia result.27 Horwich30 concurs that refractive amblyopia is not expected unless the myopia in the amblyopic eye is more than 6 D. He suggests that the possibility of maculopathy be investigated whenever decreased VA is present in the most myopic eye.
Astigmatism
Astigmatic differences between the eyes can also contribute to the development of amblyopia. The reduction in acuity for a given amount of uncorrected astigmatism is usually less than would occur with an equal amount of spherical hyperopic anisometropia.31 However, astigmatism may be an even greater deterrent to fusion than simple anisohyperopia when combined with hyperopic anisometropia. It is possible that uncorrected astigmatism of 1.50 D or more (depending on axis position) might cause enough image blur to result in amblyopia, because accommodation is also unable to compensate for this refractive error.32
Fixation Characteristics
In almost all cases of anisometropic and isoametropic amblyopia, fixation is unsteady and central.33 Given central fixation as a primary characteristic, an important differential diagnostic test for refractive amblyopia is objective assessment of fixation. Assessment is facilitated using direct ophthalmoscopes with fixation targets incorporated in the illumination system34 (Fig. 17.1A). Because a characteristic of central fixation is stable subjective localization of objects in visual space, when the patient with central fixation fixates on the target
projected on the retina, the fovea will be within the circular portion of the target (Fig. 17.1B). If eccentric fixation is present during ophthalmoscopy in an eye that is apparently without ocular deviation, a microtropia is probably present.35 This is an important diagnostic point because the prognosis for successful remediation of anisometropic amblyopia is much higher than that for microstrabismus.
projected on the retina, the fovea will be within the circular portion of the target (Fig. 17.1B). If eccentric fixation is present during ophthalmoscopy in an eye that is apparently without ocular deviation, a microtropia is probably present.35 This is an important diagnostic point because the prognosis for successful remediation of anisometropic amblyopia is much higher than that for microstrabismus.
 ▪ Figure 17.1 A: Assessment of fixation is facilitated using direct ophthalmoscopes with fixation targets incorporated in the illumination system. The most common clinically available target is a circle with central grid lines. Each line represents 1 Δ of eccentric fixation. B: Because a characteristic of anisometropic amblyopia is central fixation, when the patient with central fixation fixates on the target projected on the retina, the fovea will be within the circular portion of the target. The presence of eccentric fixation during ophthalmoscopy generally indicates microtropia if there appears to be binocular alignment. |
Unilateral High Myopia
Patients with unilateral high myopia may be an exception to the rule that there is central fixation in anisometropic amblyopia. A high percentage of anisomyopic patients with amblyopia demonstrate eccentric fixation in
the eye with the greatest myopia.36 Eccentric fixation is a common, although not necessarily constant, feature of this type of amblyopia.
the eye with the greatest myopia.36 Eccentric fixation is a common, although not necessarily constant, feature of this type of amblyopia.
Suppression Characteristics
Anisometropic Amblyopia
The suppression characteristics of 13 patients with anisometropic amblyopia were investigated by Pratt-Johnson et al.37 Under binocular testing conditions, 10 of 13 patients had small relative foveal suppression areas in the amblyopic eye. The suppression areas were never absolute, and stimuli could always be perceived under binocular conditions, regardless of the acuity. While presenting similar results, Jampolsky38 reported great variability between the age of onset, depth of suppression, fixation distance, and size of the suppression area.
Isoametropic Amblyopia
Pratt-Johnson et al37 also reported the suppression characteristics of five patients with isoametropic amblyopia. Three patients had no suppression scotoma, one demonstrated alternating suppression, and one showed suppression in the more amblyopic eye.
Crowding Phenomenon
The crowding phenomenon, or separation difficulty, describes the clinical finding that resolution ability is related to the separation of acuity targets.39 This phenomenon exists in all eyes, although it is particularly important in amblyopes with strabismus. Linksz40 suggests that in cases of hyperopic anisometropic amblyopia, central fixation is present and there is also relatively normal separation difficulty. Maraini, Pasino, and Peralta41 found no significant difference in separation difficulty between anisometropic amblyopes and normal subjects. However, strabismic amblyopes had a significant difference in the ability to correctly identify single versus crowded Es. The crowding phenomenon is thus a useful method for differential diagnosis of anisometropic or isoametropic amblyopia from strabismic amblyopia.
Electrodiagnostic Tests
Electrodiagnostic tests such as the electroretinogram and the visually evoked response are used in the laboratory to investigate the visual system of subjects with amblyopia.42,43 These tests require a substantial commitment of cash and time and therefore are not yet useful clinically. Differences have been shown between the responses of patients with strabismic and anisometropic amblyopia on some testing protocols,44 and these tests may prove clinically useful in the future.
Course and Prognosis
The course of refractive amblyopia is that VA remains decreased as long as the underlying refractive condition goes untreated. The severity of the amblyopia depends on age of onset of the refractive error, the amount of anisometropia or isoametropia, changes in refractive error during the critical period, and perhaps on individual differences in sensitivity to vision deprivation.
The prognosis of refractive amblyopia is generally good for the recovery of improved levels of VA. Improvement in VA may also be found well into adulthood.19,45,46,47,48,49,50,51,52 Wick et al45 examined records of 19 patients over 6 years of age who had been treated for anisometropic amblyopia using refractive correction, added lenses, patching, and vision therapy. After 15.2 (±7.7) weeks of treatment, they found an average improvement in VA of 92.1% with a range from a low of 75% by a 49-year-old patient to a maximum of 100% achieved by 42.1% of the patients (8 of 19). Patients who had completed therapy one or more years ago maintained their acuity improvement. The authors concluded that the treatment of anisometropic amblyopia can yield substantial long-lasting improvement in VA and binocular function for patients of any age.
Although there are no published controlled clinical trials for treatment of amblyopia in adults, there are a number of case series that suggest that amblyopic adults can improve. For example, Carl Kupfer19 showed marked improvement in acuity in seven adult strabismic amblyopes, aged 18 to 22. All seven showed improvements ranging from 71% (20/70 to 20/20) to a very dramatic improvement from being able to report hand movements only, to an acuity of 20/25 after 4 weeks. Kupfer’s treatment was aggressive with patients hospitalized for 4 weeks during which time they were continuously patched and given fixation training. Since Kupfer’s study, there have been other reports of improvement in acuity of older people with amblyopia.45,53,54 Plasticity
in adults with amblyopia is also evident in reports of recovery of VA in the amblyopic eye of adults after the sound eye develops eye disease.55,56,57 These studies are consistent with the notion that the connections from the amblyopic eye may be suppressed rather than destroyed.50
in adults with amblyopia is also evident in reports of recovery of VA in the amblyopic eye of adults after the sound eye develops eye disease.55,56,57 These studies are consistent with the notion that the connections from the amblyopic eye may be suppressed rather than destroyed.50
The Pediatric Eye Disease Investigator Group (PEDIG) conducted one prospective study58 and two randomized clinical trials to investigate the treatment of amblyopia in older children 7 to 17 years old.59,60 In a major randomized clinical trial to evaluate the effectiveness of treatment of amblyopia in children aged 7 to 17 years, 507 patients with amblyopic eye VA ranging from 20/40 to 20/400 were provided with optimal optical correction and then randomized to a treatment group (2 to 6 hours/day of prescribed patching combined with near visual activities for all patients plus atropine sulfate for children aged 7 to 12 years) or an optical correction group (optical correction alone). Patients whose amblyopic eye acuity improved 10 or more letters by 24 weeks were considered responders. The authors found that in the 7- to 12-year-olds, 53% of the treatment group were responders compared with 25% of the optical correction group. In the 13- to 17-year-olds (n = 103), the responder rates were 25% and 23%, respectively, overall but 47% and 20%, respectively, among patients not previously treated with patching and/or atropine for amblyopia. In a long-term follow-up study of these patients, the authors found a very low recurrence rate of about 5%.61 Discussing the results of this study, Chen and Cotter62 hypothesize that the lesser treatment effect in children 13 to 17 years might be because it was more difficult for them to comply with 2 to 6 hours of daily patching with their overscheduled lives and/or they were not prescribed atropine. They conclude that treatment should not be withheld from children ages 13 to 17 years, even with a history of prior treatment.
Levi and his co-investigators have explored46,47,49,50,51 another approach to study plasticity in adult amblyopia using a training approach referred to as Perceptual Learning. Li et al51 examined whether playing video games can induce plasticity in the visual system of adults with amblyopia. Specifically, 20 adults with amblyopia (age 15 to 61 years) were allocated into three intervention groups: action videogame group, nonaction videogame group, and crossover control group. They found that playing video games (both action and nonaction games) for a short period of time (40 to 80 hours, 2 hours/day) using the amblyopic eye results in a substantial improvement in a wide range of fundamental visual functions, from low level to high level, including VA (33%), positional acuity (16%), spatial attention (37%), and stereopsis (54%). A large-scale randomized clinical study is needed to confirm the therapeutic value of video game treatment in clinical situations.
Holmes and Levi,52 in a summary paper entitled “Treatment of Amblyopia as a Function of Age,” state that “treatment beyond the age of 7 years tends to be, on average, less effective than in younger children.” Based on the high degree of variability in treatment response, they hypothesize that age may be only one factor determining success rates.
Sequential Management Protocol
The ultimate goal of all therapy protocols for amblyopia is to achieve functional binocular vision with equal VA. According to Flom,63 a functional cure results in equal VA in each eye, along with comfortable single binocular vision at all distances, from the far point to a normal near point of convergence. There should be stereopsis and normal ranges of motor fusion. Corrective lenses and small amounts of prism may be worn if necessary; however, prismatic power is limited to 5 Δ.
This section describes and gives the rationale for treatment of refractive amblyopia. Our management recommendation for anisometropic amblyopia is a sequential program that consists of four steps: (a) full refractive correction, (b) added lenses or prism when needed to improve alignment of the visual axes, (c) passive therapy utilizing either 2 to 6 hours per day of direct occlusion or atropine penalization (one drop of atropine sulfate in the better-seeing eye at bedtime two times/week), and (d) active vision therapy to develop best acuity and improve binocular function (Table 17.2).
Isoametropic amblyopia can best be treated by simply prescribing the full refractive correction (Case 17.1).14,64 Occasionally, antisuppression therapy is also indicated, but generally the full refractive correction will yield the best possible result; usually there is gradual improvement in vision over the next few years after the full correction is prescribed. In a prospective study, 113 children (mean age 5.1 years) with previously untreated isometropic amblyopia were treated with eyeglasses alone for 1 year. The authors reported that the average VA improved from 20/63 to 20/25 at 1 year, with an average improvement of 3.9 lines.64
Table 17.2 SEQUENTIAL MANAGEMENT OF ANISOMETROPIC AMBLYOPIA | ||||||||||||||||||||||||
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