Amblyopia is primarily a cortical phenomenon, caused by unequal competitive input from the two eyes into the primary visual cortex (V1), although the exact extent of the visual cortex deficit is unknown.1,2 Electrophysiological and histological studies in animal models have shown that the number of cortical neurons responding to the amblyopic eye is much smaller than that driven by the unaffected eye.3–5
Multifocal visual evoked potential (VEP) provides an objective identification of the distribution of the depression of visual function in amblyopia.6–8 Previous studies, using either conventional or multifocal VEP, have reported significant changes in response latencies and amplitudes in amblyopes.9–14 Conventional VEP is limited to obtaining responses to stimulation in only a few field locations and it cannot measure local damage quantitatively in amblyopia, but these limitations can be overcome by the multifocal VEP technology.
Early histological and electrophysiological studies of the neural retina in the amblyopic process have been inconclusive.15,16 More recently, with the availability of optical coherence tomography (OCT), a large number of studies have tried to assess the retinal nerve fiber thickness and macular volume and thickness in amblyopes but the results are still at variance.17–21
In this context, the present study has tried to further assess the relationship between structure and function in adult amblyopic subjects and to establish their visual impairment. The relationships of the multifocal VEP results with the clinical findings and psychophysical (Humphrey visual field [HVF]) and structural (spectral domain [SD]-OCT) diagnostic test data were investigated.
This observational, cross-sectional study assessed 24 consecutive patients (7 men and 17 women; median age, 44.5 years, range, 20 to 62 years) with anisometropic and/or strabismic amblyopia. For the purpose of this study, amblyopia was defined as an interocular difference in best-corrected visual acuity (BCVA) of greater than or equal to 2 Snellen lines. Anisometropia was defined as a difference in spherical equivalence of 2 diopters (D) or more between the two eyes, but only eyes with a refractive error less than 5 D equivalent sphere or 3 D of astigmatism were included. Patients with unsteady foveal or eccentric fixation in the amblyopic eye, other eye disease like a history of intraocular surgery, laser treatment, cataract, glaucoma or retinal disorders, and/or systemic disease that could impair vision were excluded. The study protocol was approved by the ethics committee of the University Hospital General de Guadalajara and adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent.
The anisometropic and strabismic amblyopic subjects were separated into three study groups: anisometropic amblyopes (n = 15), strabismic amblyopes (n = 5), and strabismic amblyopes with anisometropia (n = 4). In addition, one eye each from 19 age-matched healthy subjects (7 men and 12 women; median age, 42 years; range, 21 to 64 years) were included as a control group. All participants underwent a complete ophthalmologic and orthoptic examination that included BCVA using the Snellen chart, manifest and cycloplegic refraction, cover test, duction and version testing, slit-lamp biomicroscopy, applanation tonometry, and fundoscopy. The visuscope was used to determine whether fixation is foveal or eccentric, as well as to evaluate the preferred retinal locus used for fixation and the stability of fixation.9 Steady foveal fixation was present in all amblyopic eyes and none had either unsteady foveal or eccentric fixation. SITA-standard 24-2 program automated perimetry (Humphrey Visual Field Analyzer II; Carl Zeiss Meditec, Inc, Dublin, CA) was performed by one experienced perimetrist (IRD). All visual field tests were repeated, and the amblyopic eye was always tested after the fellow eye, and only tests with fewer than 15% fixation losses, false positives, and false negatives were accepted for analysis. Spectral domain OCT examinations were obtained with the Cirrus HD-OCT Model 4000 (Carl Zeiss Meditec, Inc).
Multifocal VEP Recordings and Analysis
Multifocal VEP recordings were obtained using VERIS software 5.9 (Electro-Diagnostic Imaging, San Mateo, CA). The stimulus was a scaled dartboard with a diameter of 44.5 degrees, containing 60 sectors, each with 16 alternating checks, 8 white (luminance, 200 cd/m2) and 8 black (luminance, <3 cd/m2) with a Michelson contrast of about 99%. The sectors were cortically scaled with eccentricity to stimulate approximately equal areas of the visual cortex.22 The dartboard pattern reversed according to a pseudorandom m-sequence at a frame rate of 75.23
Three channels of continuous VEP recordings were obtained with gold cup electrodes. For the midline channel, the electrodes were placed 4 cm above the inion (active), at the inion (reference), and on the forehead (ground). For the other two channels, the same ground and reference electrodes were used, but the active electrodes were placed 1 cm above and 4 cm lateral to the inion on either side. By taking the difference between pairs of channels, three additional “derived” channels were obtained. The records were amplified with the high- and low-frequency cutoffs set at 3 and 100 Hz, respectively (half amplitude preamplifier P511J; Grass Instruments, Rockland, MA), and sampled at 1200 Hz (every 0.83 milliseconds). The impedance was less than 5 K for all subjects. In a single session, two 7-minute recordings were obtained from monocular stimulation of each eye and were averaged for analysis. Second-order kernel best channel responses were then extracted.24,25 This averaging, as well as all other analyses, was computed with custom-made programs written in commercial software (Matlab; Mathworks Inc, Natick, MA).26
Response amplitudes were calculated by obtaining the root-mean-square (RMS) of the amplitude for each multifocal VEP response over time intervals from 45 to 150 milliseconds. Signal-to-noise ratios were calculated for each response by dividing the RMS of the signal window by the average of the 60 RMS values of the noise-only window. Each of these values was compared with values from the normative group subjects27 and monocular probability plots were derived. Interocular amplitude differences for each patient were also calculated by taking the logarithm of the interocular ratio at each location26 and the interocular probability plot was derived. The amplitude probability plot was color coded with saturated red squares (left eye) and saturated blue squares (right eye), with a significant difference being determined at p < 0.01 and, for desaturated colors, at p < 0.05.
Monocular and interocular latencies were measured as the temporal shift producing the best cross-correlation value between the corresponding responses of the patient’s eye and a template based on control eyes (monocular analysis) or between the corresponding responses from two eyes (interocular analysis). The latency probability plots were color coded in a manner similar to the amplitude plots using ovals instead of squares.
To evaluate the multifocal VEP and HVF total deviation results, we analyzed cluster defects: a defective cluster had two or more contiguous points at p < 0.01, or three or more contiguous points at p < 0.05 with at least one point at p < 0.01.28
During recording, the nonstimulated eye was patched and the position of the stimulated eye was monitored constantly by the examiner via the camera display provided in the VERIS hardware. Patients were recorded twice within a 1-week period and only records with topographic relationship regarding clusters defects were selected for analysis. The topographic relationship between HVF and multifocal VEP was based on a previous study by Garway-Heath et al.29 that mapped each test location of the HVF to the entry location of the axons of local retinal ganglion cells, in degrees, to the optic nerve head. The multifocal VEP output array was also divided into four quadrants, in this study using the interpolation of the HVF 24-2 test locations to the multifocal VEP sectors described by Hood et al.26 The nasal sector was not well represented in the HVF and multifocal VEP tests and so we excluded it from topographic comparison.
All data are expressed as the median and interquartile amplitude. Differences in proportions were evaluated by the χ2 test or the Fisher exact test, as appropriate. Differences of two means were evaluated by the Student t test if the normal distribution could be assumed or by the nonparametric Mann-Whitney U test if normality was not valid. Differences of more than two means were analyzed by the analysis of variance test if the normal distribution could be assumed or by the nonparametric Kruskal-Wallis test if normality was not valid, using the Bonferroni correction for multiple comparisons. The association between two quantitative variables was evaluated by the Spearman correlation coefficient. p values below 0.05 or below 0.025, when Bonferroni correction was used, were considered statistically significant.
Demographic and baseline clinical data are summarized in Table 1. Fifteen participants (62.5%) had a diagnosis of anisometropic amblyopia, five (20.8%) had a diagnosis of strabismic amblyopia, and four (16.7%) had a diagnosis of a combination of anisometropia and strabismus. All the subjects with anisometropia showed normal fundoscopy results. Four persons (44.5%) with strabismic amblyopia had esotropia, three (33.3%) had exotropia, and two (22.2%) had hypertropia. Stereopsis was significantly reduced as evaluated with the TNO test. Seven subjects had undergone prior treatment with either botulinum toxin and/or surgery.
Significant differences in the BCVA between amblyopic and nonamblyopic eyes were found (p < 0.0001) (Table 2); BCVA ranged from 20/200 to 20/30 in the amblyopic eyes and 20/25 to 20/20 in the nonamblyopic eyes. Significant differences were also found in the HVF indices, showing deeper changes in the amblyopic eyes (mean deviation [MD], p = 0.001; pattern standard deviation, p = 0.002). However, no significant differences in the average retinal nerve fiber layer thickness (RNFLT), foveal and macular thickness, and macular volume, as measured by SD-OCT, were present between the amblyopic and nonamblyopic eyes and the normative control group. Analyzing the interocular differences between nonamblyopic and amblyopic eyes for each individual patient, a significant correlation was revealed between the BCVA with the HVF MD (r = 0.482, p = 0.017) and the SD-OCT average RNFLT (r = 0.557, p = 0.031), as shown in Fig. 1.
In Table 3, the multifocal VEP recordings summary is shown. Statistically significant differences in the multifocal VEP amplitude responses (abnormal cluster defects), combining the interocular and monocular probability analysis, were observed between the amblyopic (80%) and nonamblyopic eyes (13.3%) of the anisometropic subjects (p < 0.001). On the other hand, abnormal amplitude cluster defects were found in all the amblyopic and nonamblyopic eyes of strabismic subjects and in 75 and 25% of the amblyopic and nonamblyopic eyes of mixed anisometropic and strabismic amblyopic subjects, with no significant differences between both group eyes (p = 0.143). No significant differences were found in the multifocal VEP latency (interocular and monocular probability analysis) response delays between the anisometropic amblyopic (66.6%) and nonamblyopic eyes (26.6%) (p = 0.065). Likewise, response delays were observed in 40% of amblyopic and nonamblyopic eyes of strabismic amblyopic subjects, whereas in combined anisometropic and strabismic amblyopes, such defects were found in 25% of both eyes, with no significant differences (p = 0.428). Amblyopic eyes with abnormal multifocal VEP amplitudes had lower BCVA (range, 20/200 to 20/30) than those with normal amplitudes (range, 20/40 to 20/30) (p = 0.032). Table 3 also shows abnormalities detected by the HVF test. Statistically significant differences were detected by the HVF between the anisometropic amblyopic eyes (53.3%) and its fellow nonamblyopic eyes (6.6%) (p = 0.014), but not in the strabismic amblyopia, where such defects were detected in 40% of both the amblyopic and nonamblyopic eyes (p = 1.0). The visual field changes detected by the multifocal VEP amplitude and/or latency were larger than those revealed by the HVF and, typically, affected the central area and extended into the mid periphery. The topographic correspondence between the multifocal VEP and HVF results is summarized in Table 4. In agreement with previous studies, we found that the multifocal VEP was able to detect more visual field scotomas than the 24-2 HVF.13,30 In the amblyopic eyes, a significant relationship between the multifocal VEP amplitude defects and HVF was shown in the central area of the visual field (p = 0.033), but not in superior and inferior peripheral hemifields. An example of multifocal VEP recording (60 traces array) and probability plots and HVF total deviation results for one of our amblyopic subjects is shown in Fig. 2. Abnormal visual field scotomas were detected in both the amblyopic and fellow eye on the multifocal VEP interocular and monocular amplitude and latency plots. Meanwhile, the HVF total deviation plot only showed abnormal visual defects in the right eye.
Relative multifocal VEP latencies (monocular analysis) were also investigated, and the data can be seen in Table 5 and Fig. 3. Multifocal VEP latencies were significantly delayed in the anisometropic amblyopic eyes compared with the strabismic amblyopic eyes (p = 0.036) and the control group (p = 0.007). An inverse, statistically significant correlation between the BCVA and the relative multifocal VEP latency (r = −0.482, p = 0.017) was observed when the interocular differences between the nonamblyopic and amblyopic eyes for each patient were analyzed and plotted (Fig. 4).
The amblyopic process may have a deleterious effect on various levels of the visual pathway, such as the lateral geniculate nucleus and visual cortex.31,32 In this sense, multifocal VEP has been shown to provide an objective measure of visual field integrity and the responses reflect activity primarily in V1.24,27,33 Our results showed that multifocal VEP amplitude and latency responses from both anisometropic and strabismic amblyopic eyes and the strabismic nonamblyopic fellow eyes were significantly abnormal, whereas the anisometropic nonamblyopic fellow eyes only showed increased response latencies with normal amplitudes. The presence of these anomalous multifocal VEP responses from the amblyopic and their fellow eyes could be the electrophysiological evidence of imbalanced inputs coming from the amblyopic and fellow retinas to the lateral geniculate nucleus and consequently to the visual cortex, as has been well described by Hubel and Wiesel.4 It is already known that the magnitudes of the deficits in multifocal VEP responses are correlated with the degree of fixation instability or eccentricity, and in these cases, the VEP results may not reflect the true nature and extent of sensory neural deficits in amblyopia.34,35 For this reason, subjects with unsteady or eccentric foveal fixation were not included in this study.
Our results are in agreement with previous studies using both conventional and multifocal VEP.9–11,14,36,37 Zhang et al.10 reported significant differences in latency or amplitude responses between amblyopic and fellow eyes for the early-onset strabismic amblyopes, whereas in the late-onset ones, these differences were only observed in the amblyopic eyes. In contrast, Greenstein et al.,13 using multifocal VEP, and Davis et al.,12 with conventional VEP, have found that responses in strabismic amblyopia were, in fact, associated with shortened latencies, specially in early-onset amblyopia. The authors suggested that the discrepancy between studies could be attributed to differences in methodology and/or data analysis. However, our adult subjects were unable to provide an unequivocal age of onset of amblyopia and all of them showed increased multifocal VEP response delays, most significantly in anisometropic eyes.
The multifocal VEP was able to detect more visual field defects than those revealed by the HVF. Most of the abnormal clusters were localized in the central 10-degree field area,9,38 showing that visual acuity was more severely impaired in the foveal area than in the periphery of amblyopic eyes. The result is not surprising as the 24-2 test has only one point within the fovea, and this was not tested in the study. Also, the 24-2 only tests four points within the central 4.2 degrees (radius) of fixation. The 10-2 HVF test on the other hand has 68 points within the central 10 degrees. The multifocal VEP also provides greater sampling of the central 10 degrees than the 24-2.39,40
It has been suggested that anisometropic and strabismic amblyopia do not originate from a common pathophysiological process.41 Some authors have hypothesized that the distinction between the two types of amblyopia may be a matter of severity of magnocellular or parvocellular visual pathway defects, with strabismic amblyopia producing qualitatively similar but quantitatively more severe deficits than anisometropic amblyopia.42 Hereof, Shan et al.36 found, with the conventional VEP, that only the amplitude for stimuli of the parvocellular visual system is abnormal in anisometropic amblyopic eyes. Wang et al.,43 combining functional magnetic resonance imaging and conventional VEP, reported that the calcarine activation via amblyopic eyes had reduced sensitivity for high spatial frequency stimuli in subjects with anisometropic amblyopia compared with subjects with strabismic amblyopia. Our results also showed that anisometropic amblyopic eyes had longer response delays, in agreement with McKerral et al.,44 that described how anisometropic amblyopes can differ from strabismic ones by their interocular differences in reaction time measurements.
Studies using OCT have shown conflicting results when evaluating the peripapillary RNFLT and foveal topography in amblyopic eyes.17–21,45 In this regard, our data suggest that the retinal structure, specially the RNFLT and foveal area, does not show any significant microstructural changes in the amblyopic retinas, in line with the findings of other recent studies.21,46–48 It could be argued that the observed differences may be attributed to the use of different instruments and the relative small number of subjects studied. Our data are also in agreement with neurophysiological studies that have showed normal electroretinogram recordings in subjects with anisometropic amblyopia.14 In addition, experimental studies in amblyopic monkeys found that the retinal structures and the function of the amblyopic eyes are indistinguishable from those in normal primates.49,50
The absence of structural abnormalities in the retina, as shown by the SD-OCT, in the present study is consistent with a cortical or extracortical origin for amblyopia.50 However, we are aware that one limitation of this study is that we were not able to fully explore other possibilities, either in the structure of the postretinal pathway or in function other than from a cortical test point. The finding of a delay in the multifocal VEP latency, for instance, could be consistent with a problem earlier in the anterior visual pathway.
In summary, SD-OCT tests of peripapillary RNFLT and foveal and macular thickness were not statistically different in amblyopes from control subjects. On the other side, multifocal VEP amplitudes and latencies were significantly affected in amblyopic eyes and, to a lesser extent, in nonamblyopic eyes. Multifocal VEP latencies were significantly more delayed in anisometropic eyes than in strabismic eyes, suggesting that anisometropic and strabismic may represent different cortical or extracortical abnormalities. However, this issue is still controversial and more research would be needed to specify the nature of the different types of amblyopia and a combination of multifocal VEP and functional magnetic resonance imaging could be very useful to noninvasively localize synaptic activity changes in space and time in these patients.
Department of Ophthalmology
University Hospital Principe de Asturias
University of Alcalá, Carretera Alcalá-Meco s/n
28805 Alcalá de Henares
e-mail: [email protected]
This study was supported by the Spanish government grants FIS PI11/00533 and RETICS RD12/0034/0006 to RB. The authors declare no financial conflict of interest.
Received May 19, 2014; accepted November 25, 2014.
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