52 Developmental Amblyopia

A demonstrate many and various visual deficits, involving loss of spatial range, contrast and positional deficits (reviewed by Hess46), but the most widely accepted clinical definition of amblyopia is based on visual acuity. This suggests that amblyopia is a unilateral or bilateral decrease of visual acuity caused by a deprivation of form vision and/or an abnormal binocular interaction (usually early in life) for which no organic causes can be detected by physical examination of the eye and which, in appropriate cases, is reversible by therapeutic measures.117

Estimates of the prevalence of amblyopia are wideranging; it is said to affect between 1.6% and 3.5% of the population. This variation reflects the nature of the population studies from which the data are derived88 and the arbitrary defining of amblyopia as two or more lines interocular difference on a recognition chart or more than one octave interocular difference, and the difficulty of clinically untangling subcategories of amblyopia. Subcategories, which relate to the etiology of amblyopia,22 were introduced in an attempt to explain the varying degrees of success in amblyopia therapy.

The subcategories of functional amblyopia in which no organic lesion exists are broadly as follows:

1.Stimulus deprivation amblyopia, for example, due to media opacity (and occlusion amblyopia, the iatrogenic visual loss of the good eye after patching)

2.Strabismus amblyopia

3.Anisometropic amblyopia

4.Refractive or isometropia amblyopia with bilateral high refractive error (this includes meridional amblyopia)

5.Psychogenic amblyopia, a visual conversion reaction (treated separately in chapter 51)

Organic amblyopias, such as those due to nutritional or toxic effects, are dealt with separately in chapters 54 and 55.

Screening

In a population under 20 years of age, amblyopia is ten times more common a cause of visual loss than all other causes taken together.40 Yet there is an absence of any rigorous clinical trials to demonstrate the worth of treatment or the impact on the quality of life of no treatment.113 This has triggered a vigorous debate about the effectiveness of screen-

ing for amblyopia (e.g., at the Novartis meeting in the United Kingdom in 1999),11 and has driven different international responses, governed, it seems, by public health resource and private insurance issues.74 The outcome of these studies should begin to become available in the next few years and, it is hoped, will allow evidence-based decisions about screening to be reached.16,49

Within this general discussion, there is consensus that earlier detection has a better chance of remedy.120 Of importance, only a minority of patients (10% of 253 patients) who lose their fellow eye after 11 years of age will subsequently show any improvement in the amblyopic eye.86 Indeed, the projected lifetime risk of visual loss to an individual with amblyopia less than 6/12, or driving standard vision, is 1.2%, higher than was previously thought.87 The outcome of therapy appears to be stable at least for anisometropia,33,83 which prognostically has a better visual outcome and shows less sensitivity to the patient’s age at presentation. Recent recommendations have suggested treatment for anisometropic amblyopia whatever the age.28

There continues to be some despair at both the lack of methods robust enough to reliably detect amblyopia in restless toddlers and the lack of coherence between centers using different test procedures.58 Attempts are now being made to standardize ways in which individual tests are administered in different centers (e.g., Holmes et al.48 and the HOTV test), but the range of behavioral tests for children is suboptimal for the detection of strabismic amblyopia,35,91 for which crowded recognition acuity tests are best.72 Testing visual acuity in young children is inherently noisy59 and is all the more difficult because any measurements are taken on a moving staircase of visual maturation.31 Some methods have reported interocular differences as little as 1/4 octave (e.g., Hamer et al.41 reporting on sweep VEPs), and others recount difficulties in securing a reliable measure of interocular difference less than one octave.10

The site of amblyopia

The neurophysiological basis of amblyopia is still not fully understood. Amblyopia manifests as loss of spatial properties of neurons in the primary visual cortex, but there are

almost certainly additional deficits at higher levels of the visual pathways.2,45,54,60,65 There have been some discrepant reports that V1 might not be involved, such as early PET30 and fMRI studies,98 but other imaging studies provide evidence of deficits in V1, fMRI,1,15 and MEG data.2 These authors suggest that the discrepancies have arisen largely because of differences in the chosen stimuli, the temporal resolution of the techniques, and selecting patients with differing depths of amblyopia.

Evidence for a primary retinal involvement in amblyopia, suggested by animal work,52 has not been substantiated (reviewed by Hess45 and Simons97), and the flash electroretinogram (ERG) is normal in amblyopia.56,75,123 Recently, Williams and Papkostopoulos121 described a reduced electro-oculogram from amblyopic eyes (12 adults), implicating retinal pigment epithelial involvement in amblyopia. The authors speculate that this might reflect a deficiency in retinal dopaminergic function. Following levodopa ( -dopa) therapy in adult amblyopes and controls, there have been changes in spatial sensitivity related to both retinal and cortical changes.37,38 Regression of visual acuity is similar in children who are given -dopa and occlusion or occlusion alone, but Leguire et al.64 suggest that the initial acuity gain after -dopa therapy may beneficially reset the acuity baseline and produce a longer-term advantage. Pattern ERGs (PERGs) have been reported to be diminished in amblyopia,8,9,84,107 but in other studies, when stimulus contrast and the retina area stimulated were compensated to provide good-sized PERGs, there was no difference between the amblyopic eye and the fellow

eye.39,45,47,48

For the purposes of clinical detection, amblyopia is regarded as a predominantly cortical effect, and pattern visual evoked potentials (VEPs) are the electrophysiological test of choice. The amplitude attenuation and latency changes that are seen in association with amblyopia lend electrophysiological support to involvement of V1.93

Visual evoked potentials in amblyopia

There are three amblyopia challenges in clinical visual electrodiagnostic practice: whether VEPs can identify amblyopia and distinguish it from other causes of visual loss, whether VEPs can predict if the amblyopia is likely to respond to treatment, and whether VEPs can monitor the effect of patching treatment. Because amblyopia is frequently defined by the “bottom line,” that is, the best recognition acuity at high contrast and luminance, many VEP studies have been directed toward making rapid assessment of the VEP acuity of each eye.116 An alternative strategy is to assess the disruption to binocularity caused by reduced uniocular vision, but accounting for anomalous retinal correspondence can make this a complex task.

Interocular VEP differences

In amblyopia, pattern VEPs tend to be of reduced amplitude,13,62,70,106,108 with increased latency to smaller check sizes,6,118 akin to the effect of uncorrected refractive error.73 Levi and Harwerth66 showed that slopes of the regression of VEP amplitude versus stimulus contrast (below saturation) had a lower slope in the amblyopic eye than the fellow eye and suggest that this can demonstrate how amblyopia differs from optical blurring.90

Illiakis et al.53 have suggested that the presence of pVEPs of normal latency, just smaller in amplitude, prior to occlusion has a better prognosis for eventual visual outcome (see also Hoyt51). This was related to central fixation. Others have found limited prognostic value in pattern-reversal VEPs.34,43 However, Good et al.36 have cautioned that pattern-reversal VEP grating acuity is superior to pattern ON/OFF grating acuity in detecting amblyopia. Pattern ON/OFF VEPs in amblyopia are found to be similar to those recorded when the central 3 degrees of visual field are occluded.108 Shawkat et al.95 further demonstrated that amblyopia can be detected with increased sensitivity if components of known macula predominance are measured, such as the n80 and p100 of the reversal VEP and, to a lesser extent, the onset contralateral p105 and Clll.

Recently, Davies et al.29 have distinguished earlyfrom late-onset strabismic amblyopes on the basis of the latency of the pattern onset VEP Cll in adults. Those with earlieronset amblyopia tended to have pVEP Cll components of earlier latency and smaller amplitude in both eyes compared with normals. Late-onset strabismic amblyopes had attenuated pVEPs of markedly increased latency from the amblyopic eye, while the fellow eye was within normal range. Davies et al.29 suggest that this could reflect an enhancement of magnocellular contribution relative to parvocellular contribution. (Cll shows almost complete interocular transfer thought to relate to a prestriate origin and greater proportion of binocularly driven cells, in contrast to Cl.103) Others have reported motion-onset VEPs are relatively robust compared to pattern-reversal VEPs in amblyopia,61 and there is a report of an isolated reduction of P-stimuli steady-state responses in anisometropic amblyopia.94 Alternatively, it is possible that an alteration in a preceding component of a composite waveform, such as the pattern-onset VEP, could also result in a shorter Cll latency peak.

Vision measures using pattern VEPs

It is unrealistic to expect pattern VEP acuity assessment to correlate directly to behavioral measures. Resolution and recognition acuity demand different levels of processing and are influenced by different factors. The pattern-reversal VEP is a direct reflection of neural activation, or the extent of

neural network stimulated per eye by the afferent impulses in V1, rather than an assessment of how these visual data are then processed by other areas. The distinction between the pathways tested by each acuity method is exceptionally important. There can be striking clinical discrepancies; for example, it is possible in optic atrophy to obtain fairly good 6/9–6/12 acuity yet for the pattern VEP to be very small and degraded. This may be explained if the few remaining functioning fibers are clustered sufficiently well centrally to give 6/9 at high contrast and good luminance but the overall volume of activation of the brain and the reduced VEP spatial frequency profile; normally the relation between VEP amplitude and pattern size has a “bandpass” function that causes considerable deficits in VEP. This indicates a significant deficit of cortical innervation that suggests that the patient will experience visual difficulties under less than optimal conditions. VEP abnormalities in amblyopia can persist despite normal acuity.119 The spatial profile of the pattern VEP tends to be flattened in the amblyopic eye and the fellow eye if occlusion therapy has been carried out.82

Interocular differences in VEP amplitude and latency in normals are on the order of 10%.3,104 Interocular differences in amplitude identify amblyopes with sensitivity between 46% and 85%. This is improved if amplitude is used in conjunction with latency.105 Weiss and Kelly119 noted a better prediction of final visual acuity if they made a linear combination of latencies of pattern-onset VEPs across three spatial frequencies. Occasionally, the amplitude of the amblyopic eye exceeds that of the fellow eye,35,110 and a history of occlusion therapy and pressure of eccentric fixation then becomes very important in the analysis. Certainly, one measure is inadequate to detect amblyopia, and it is essential to assess a range of stimulus sizes.80

Effects of latent nystagmus and patching on pattern VEP

If there has been disruption to binocularity early on in life, monocular pattern VEP testing can be confounded by latent nystagmus (figure 52.1). This can in part be overcome by head positioning, by placing the eye that is being tested in adduction, and by using pattern-onset stimuli, but occasionally, the nystagmus will be too coarse for these strategies to compensate, and pattern VEPs will be confounded.

Similarly, when the effect of occlusion therapy is being monitored, a child will often attend wearing the patch. A few hours of patching will increase the response of the unoccluded eye in normals116 and diminish the response of the patched eye.6,7,81 It is possible that an interocular pattern VEP difference may decrease because the fellow eye response is diminished by patching rather than the amblyopic eye being improved. With prolonged occlusion, such as the extensive early occlusion used for unilateral cataract

0 10 20 30

spatial frequency (log cpd)

spatial frequency (log cpd)

10 20 30

0

spatial frequency (log cpd)

F 52.1 These three graphs are pattern-reversal VEP spatial tuning profiles for three patients operated on at 2 years, 10 weeks, and 2 weeks of age, respectively, for congenital cataract. The two patients operated on at 10 weeks and 2 weeks followed a patching regime of at least 50% of waking hours in the first year of life. Of note, the fellow eye acuities are similar, yet the spatial profiles of the fellow eye pattern VEP tuning are very different, changing from a bandpass function in the top trace to a broader bandpass with a lower spatial frequency peak in the second trace (patient operated on at 10 weeks) and becomes a low-pass function in the patient operated on at 2 weeks. This demonstrates the possible iatrogenic amblyogenic effect of early patching on the fellow eye and illustrates the importance of testing several spatial frequencies to uncover the extent of amblyopic loss rather than relying on the threshold measurement.

treatment, the changes to the fellow eye can be profound and in our experience sometimes irreversible.115 It becomes important to compare the profile of spatial responses for both eyes across visits, noting the hours of pretest occlusion.

Threshold measurements of VEP acuity

To gain a threshold measurement, i.e., a VEP “acuity” measure, an extrapolation of the spatial profile of small check responses to baseline or noise level is necessary (e.g., Chan et al.23). In a group that was treated for congenital cataract, threshold check size was the only VEP parameter that correlated with single-letter visual acuity. This led to a suggestion that threshold check size may have greater clinical use than measures of pattern VEPs based on latency, amplitude, or waveform.71

Transient pattern-reversal and pattern-onset VEPs need 20–40 s of fixation per stimulus size, and a spatial profile may take 5–10 minutes per eye to acquire. Attempts have been made to speed things up with presentation rates approaching 8 Hz or 16 reversals per second with sweep techniques running through a series of different pattern sizes every second.77,89,116 There are theoretical advantages that suggest that the regression to a threshold, either noise level or baseline, should be amplitude independent. Yet it is very difficult to regress low-amplitude signals, as might be recorded in amblyopia, with confidence. Also, sweep VEP stimulation rates are fast, and as the temporal frequency increases, the correlation with recognition acuity diminishes.36,44 The spatiotemporal tuning profile that the sweep techniques tap into will not be at the high-recognition, static acuity range of older children. This is one of the reasons why the correlation of behavioral visual acuity matures with electrophysiological or sweep measures is higher in the first year, after which behavioral measures exceed the sweep VEP. The net result is an underestimate of high acuity and an overestimate of low acuity—the converse of the optimum that is required to detect mild amblyopia.

Vernier acuity

Vernier acuity is a hyperacuity measure that can take until 10 years of age to mature. As a positional acuity, it is considered the most sensitive measure of amblyopic deficit because it usually produces the greatest magnitude of deficit in comparison to other spatial measures (reviewed by Simmers et al.96). Transient vernier-offset VEPs are confounded by simultaneous motion stimulus. Levi et al.67 noted that breaking collinearity elicited a greater response than the transition from noncollinearity to collinearity. This asymmetry uniquely manifests as odd harmonic components in the steady-state VEP. Skoczenski and Norcia100 have reported steady-state recording of vernier-offset VEPs, distinct from the motion response, elicited by horizontal disparity of a vertical square wave grating in normal infants, but this has not yet been applied in amblyopia. Stereoscopic VEPs are also possible by using these techniques but are of small amplitude.24,78

As an alternative approach to measuring interocular differences in VEPs, there have been attempts to study the binocular consequences of amblyopia, i.e., suppression, lack of stereopsis, and fusion. This has been done indirectly with motion VEPs that show a nasotemporal asymmetry in normal infants of 2–3 months old that diminishes by 6–8 months. This shows a strong concordance with fusion.19 Other, more direct studies are described below, but as yet, none of these techniques have proved to be a robust clinical screening method.

Binocular VEPs

There is a hierarchy of tests to assess binocular interaction that relies on (1) comparing monocular with binocular elicited VEPs, (2) using dichoptic stimulation to independently control the input of each eye and look at the resultant combination, and (3) cyclopean stimuli with, for example, random dot stereograms.

B S F Binocular and monocular preferential looking (PL) acuity are comparable during the first 4–6 months; after this, binocular acuity is superior (reviewed by Birch17). VEPs to binocular stimulation (both eyes viewing the same stimulus) are greater, usually by the order of 1.4 (square root 2), than monocular responses, but there has been a large variation in findings owing to differences in stimuli, the VEP component measured, and electrode position.4,5,63,70,90 If pattern VEPs are elicited by high-contrast patterns alone, the presence of summation cannot identify amblyopes. In general, summation is best seen to low-contrast (less than 40%), low-mean luminance, spatial frequencies less than 5 cycles per degree (cpd) and temporal frequencies less than 8 Hz.11,26 Summation will be present with abnormal retinal correspondence but not with suppression.25,79 At less than 6 months of age, binocular VEP acuity superiority is only 0.2 octaves; after this, monocular and binocular growth functions are almost identical.41 When noted, even in subjects with normal vision, binocular summation has been termed ephemeral,80 and an unreliable clinical index of normal binocularity.67 Alternatively, the binocular response may be greater than the sum of the two monocular responses. This is called binocular facilitation.12

A reduction in binocular enhancement (1.6–1.2) of the pattern-reversal VEP during development has been reported to accompany increasing stereoacuity.102 Others have suggested that the binocular advantage remains the same regardless of age.114

D S When two different stimuli are presented to each eye, the perception may be summation, suppression, or rivalry. Suppression is most easily observed

if the same spatial frequency is presented to each eye at high contrast and luminance. Size-specific suppression of the VEP is abnormal in amblyopes. It is a more robust phenomenon than summation, but it is still inadequate to reliably detect in individual patients.27,42,55,122

Dichoptically presented stimuli may also test a hierarchy of binocular function:99

1. Binocular fusion/dichoptic luminance or checkerboard stimuli.

Dichoptic checkerboard stimuli are regular checkerboard patterns that reverse at different rates or frequencies for each eye. Fourier analysis reveals beat VEPs generated at a nonlinear difference frequency that can come only from an interaction of monocular inputs; that is, this frequency is not present in the stimulation frequencies.13,57,113 Stevens et al.111 looked at dichoptic luminance beat VEPs and found that stereo-blind children had significantly lower dichoptic signal- to-noise ratios than did stereo-normal children. Sato et al.92 have used pseudo-binary sequences dichoptically to record speedier simultaneous monocular VEPs and to remove any ambiguity induced by temporal correlation between eyes that may arise from analysis in the frequency domain.

2.Dynamic random dot correlograms. Correlograms are generated when moving random dot patterns that are presented to each eye alternate between two phases: correlated and anticorrelated.

3.Dynamic random dot stereograms. With the stereograms, portions of random dot patterns that are presented to each eye are shifted horizontally relative to each other at a fixed rate, alternately producing crossed and uncrossed binocular disparities. Subjectively, these patterns appear to shift in depth.

Data suggest that sensory fusion, when measured by VEP responses to dynamic random dot correlograms, is more robust than is stereopsis to abnormal binocular experience and support the notion that pathways processing correlated/ anticorrelated stimuli might not completely overlap with pathways processing disparity information.32 Skrandies101 demonstrated with topographic techniques that higher visual processing areas are most likely involved in stereoscopic vision, for example, V2. Rivalry appears to become more prominent as the extrastriate regions are ascended, but it has not yet been resolved where in the brain rivalry occurs.20

In the human visual cortex, rivalry is undetectable by fMRI in Brodman’s areas 17 and 18, is weak in area 19, and becomes increasingly prominent in frontoparietal cortex,69 but in another study using stimuli of different contrast, area V1 was as active as other higher areas.85 Lumer68 suggests that a relative asynchrony in the timing of firing in V1 distinguishes conflicting from congruent stimuli.

It has been noted that binocular rivalry in human infants seems to develop rapidly over the same developmental

period as do horizontal disparity and interocular correlation: age 3–5 months.18 However, Brown et al.21 have recently shown electrophysiologically that infants between 5 and 15 months of age do not demonstrate a VEP marker of physiological rivalry to dichoptically presented phase-reversing gratings despite the presence of binocular interactions. These electrophysiological data suggest that unlike stereopsis, rivalry does not require separate eye-of-origin information and appears to be a competition between percepts, that is, beyond binocular convergence, a higher-level mechanism compared to the interocular comparisons that are required for stereopsis. It is not yet clear how useful this higher-level test will be clinically.

Summary

Interocular assessment of pattern VEPs to assess the spatial profile of each eye before patching can indicate poor vision levels consistent with amblyopia.

Monitoring patching therapy demands a critical appraisal of amount and timing of pretest patching to account for the possible iatrogenic effects of patching.

Distinguishing amblyopia from other causes of postretinal dysfunctions depends on the relative effect and combination with other clinical data. This can be especially difficult when amblyopia is gross, for example, if it is of early onset and untreated.

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