Primer on visual field testing, electroretinography, and other visual assessments for patients treated with vigabatrin.

Vigabatrin, an irreversible inhibitor of γ-aminobutyric acid transaminase, is an antiepileptic drug indicated in the United States as adjunctive therapy for adult patients with refractory complex partial seizures who have responded inadequately to several alternative treatments and for monotherapy treatment of infantile spasms in patients 1 month to 2 years of age. Approval of vigabatrin in the United States was contingent on the implementation of a Risk Evaluation and Mitigation Strategy (REMS) to manage the threat of a progressive, permanent bilateral concentric peripheral visual field defects (pVFDs) that may occur in patients treated with vigabatrin. The REMS is designed to promote compliance with evidence-based recommendations for baseline (within 4 weeks of the start of treatment) ophthalmologic evaluations and ongoing vision monitoring in all patients treated with vigabatrin. In view of the challenges associated with visual field testing in patients with epilepsy and in infants, clinicians must understand the qualitative (pattern of damage), quantitative (degree of damage), electrophysiologic, and adjunctive techniques recommended for monitoring vigabatrin-treated patients. The objectives of ongoing research are to characterize the onset, progression, and risk of developing vision loss during the first year of vigabatrin treatment and to evaluate the potential of noninvasive imaging as a method for monitoring retinal changes corresponding to the pVFD. This article provides an overview of visual field testing procedures and electroretinography, summarizes the clinical characteristics of vigabatrin-associated pVFDs, and provides recommendations for visual field and visual electrophysiology testing relevant to both adult and infant patients treated with vigabatrin.

Eye-movement responses to disparity vergence stimuli with artificial monocular scotomas.

The effects of artificial monocular scotomas on eye-movement responses to horizontal disparity vergence stimuli were studied in six subjects with normal binocular vision. Subjects viewed stereoscopic 1.5 degrees horizontal step disparity vergence stimuli through liquid crystal shutter glasses. The central portion of the stimulus presented to the right eye was removed to simulate monocular artificial scotomas of variable diameters (2 degrees to 10 degrees ). Eye movements were recorded with a binocular head-mounted eye tracker. Responses included pure vergence, vergence followed by saccades, and pure saccadic eye movements. The rate of responses with saccadic eye movements increased with the diameter of the artificial scotoma (p < 0.0001); there was an increase in the rate of responses starting with saccades (p < 0.0001), as well as an increase in the rate of saccades after initial vergence responses (p < 0.01). The probability of saccades after initial vergence responses was affected by the open-loop gain of the vergence response (p < 0.001). The open-loop gain decreased with increased diameters of the artificial scotomas (p < 0.0001). As the diameter of the artificial scotomas increased, the amplitude of the initial vergence eye-movement responses decreased, and the prevalence of saccadic eye movements and asymmetric vergence increased. The effects of the diameter of artificial monocular scotomas on eye-movement responses in subjects with normal binocular vision are consistent with the effects of diameter of suppression scotomas on eye-movement responses to disparity vergence stimuli in patients with infantile esotropia.

A modified protocol for the assessment of visual function in patients with retinitis pigmentosa.

BACKGROUND: The assessment of visual function for retinitis pigmentosa routinely includes: electroretinography, visual acuity and visual field-testing. Patients with retinitis pigmentosa sometimes complain of changes in visual function, which are not paralleled by routine eye tests. AIMS AND OBJECTIVES: To determine which visual function test or group of tests can predict reliably perceived visual function in patients with retinitis pigmentosa METHODS: Subjects with progressive retinitis pigmentosa are recruited from the Ocular genetics program of The Hospital for Sick Children and Mount Sinai Hospital, Toronto. Subjects will be tested four times over the over the period of one year. On each visit they undergo following tests- 1) Central visual acuity (VA) using the crowded logMAR acuity chart, 2) Contrast Sensitivity (CS) using Pelli-Robson contrast sensitivity chart, 3) Visual field test (VF) using Humphrey (10-2), 4) Color vision using Mollon-Reffin 'minimalist' test and 5) Subjective visual function questionnaire testing near and global perceived visual function respectively. RESULTS: Phase I (baseline and visit I measure) results are reported. Total of sixty-eight patients with mean age of 41 years, age range of twelve to sixty seven were tested. Of these thirty-one were males and thirty-seven were females. Repeat testing correlation was high (r>0.8, p<0.05) for all parameters between baseline visit and visit I. The near perceived visual function correlated best with the combination of visual acuity and contrast sensitivity. The global perceived visual function correlated best with combination of visual field and visual acuity. Objective measure of central visual function (HVF 10-2) correlated best with contrast sensitivity. DISCUSSION: The addition of contrast sensitivity and Humphrey visual field to routine visual assessment should improve the quality of the longitudinal data of visual function recorded on these patients. Patients will be re- tested at six months and one-year interval. To date of the sixty-eight subjects twenty-seven have returned for their six-month visit (phase II).

Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases.

Chronic use of chloroquine and hydroxychloroquine inthe treatment of rheumatic disease carries a small risk of sight-threatening pigmentary retinopathy. To obtain safety data for its use in pregnancy, we did ophthalmic examinations in 21 children born to women who took these drugsduring pregnancy. Average daily maternal doses of the two drugs were 317 mg hydroxychloroquine and 332 mg chloroquine. The mean duration of gestational exposure was 7.2 months. No ophthalmic abnormality was detected in these children. Therapeutic use of these drugs during pregnancy may not pose a significant risk of ocular toxicity to offspring.

Effects of maternal occupational exposure to organic solvents on offspring visual functioning: a prospective controlled study.

BACKGROUND: Previous studies in adults and animals with high level exposure to organic solvents suggested impairments in visual functioning. The objective of this pilot study was to examine the effects of maternal occupational exposure to organic solvents during pregnancy on offspring color vision and visual acuity, the development of which may be especially vulnerable to organic solvent exposure. METHODS: We conducted a prospective cohort study of 32 offspring of women who were exposed occupationally to organic solvents during pregnancy compared with 27 nonexposed children. Monocular and binocular color vision and visual acuity were assessed using the Minimalist Test and the Cardiff Cards, respectively. Children with known hereditary color vision loss were excluded. RESULTS: Solvent-exposed children had significantly higher error scores on red-green and blue-yellow color discrimination, as well as poorer visual acuity compared with the control group. Exposure index (an estimated measure of exposure intensity) was not significantly related to color discrimination or visual acuity score. Despite excluding all children with a known family history of color vision loss, clinical red-green color vision loss was found among 3 of the 32 exposed children compared with none of the matched controls. CONCLUSIONS: These preliminary findings suggest that occupational exposure to organic solvents during pregnancy is associated with an increased risk of color vision and visual acuity impairment in offspring. The importance of routine visual function screening in risk assessment after prenatal exposure to chemicals warrants further attention.

Values of electroretinogram responses according to axial length.

Accurate interpretation of electroretinograms (ERGs) requires knowledge of effects of axial myopia on ERG responses. Our purpose was to derive expected changes of ERG responses according to axial length, to stimulus conditions that conform to the International Society for Clinical Electrophysiology of Vision (ISCEV) Standard for Electroretinography. ERGs from 60 subjects were recorded. The subjects were assigned to one of three groups according to the level of myopia. Thirty-three subjects had high myopia (-6.00 D to -14.50 D; mean age, 31 years), eight had mild myopia (-3.00 D to -5.00; mean age, 28 years), and 19 had a small refractive error (+0.75 D to -2.75 D; mean age, 27 years). No subjects had myopic retinopathy. Stimulus-response curves were fitted to dark-adapted b-wave amplitudes and maximum amplitude and semi-saturation constants derived. Axial lengths, measured with A scan ultrasound, ranged from 22.2 mm to 30.0 mm. Analysis of variance and post hoc t-tests revealed significant difference between subjects with high myopia and subjects with small refractive error for ERG amplitude data. There were no significant differences between the three groups for implicit times, the ratio of b- to a-wave and semi-saturation constant. There is linear reduction in the logarithmic transform of ERG amplitude with increasing axial length, related more to axial length than refractive error. We provide relative slope and intercept values, allowing labs to derive expected ERG amplitudes according to axial length. These derivations are valid for persons with no retinopathy.

Use of the Mollon-Reffin minimalist color vision test with young children.

PURPOSE: We evaluated the Mollon-Reffin Minimalist (M-R M) color vision test to determine how successfully young children can perform the task and to compare success rates with the American Optical Hardy Rand Rittler (HRR) test and a preferential-looking type test based on the F2 plates (the Pease-Allen color test [PACT]). METHODS: Participants included 146 children (aged 3-10 years) and 32 older subjects (aged 11-39 years). The M-R M test uses 3 series of colored caps coinciding with protan, deutan, and tritan confusion axes, with 6 saturations along each axis. The observer must identify a single colored cap from gray caps of varying lightness. The PACT test consists of 2 cards with targets for detecting red-green and blue-yellow color deficiencies. The tester judges the location of the target on the basis of the child's looking and/or pointing responses. The HRR was performed according to standard instructions, although a more flexible scoring protocol was also used. RESULTS: A significant difference in the children's performance between the "test" item of the 3 tasks emerged (Cochran Q test, P<.001): all children successfully completed the M-R M, 90% successfully completed the PACT, and 88% successfully completed the HRR. Few errors were made on the M-R M red-green series, even among children aged 3 to 4 years, although errors were made with the least saturated blue-yellow cap at all ages. Recommendations are made for the use of the M-R M with children. CONCLUSIONS: The M-R M test can be performed by young children and may prove to be especially useful for detecting and monitoring acquired color vision defects.

Which ocular and neurologic conditions cause disparate results in visual acuity scores recorded with visually evoked potential and teller acuity cards?

PURPOSE: We investigated whether disparity between visually evoked potential (VEP) acuity scores and Teller Acuity Card (TAC) scores varied according to presence of ocular or neurologic conditions. METHODS: Charts from 175 children (mean age, 34.8 months; range, 3 to 158 months) referred for visual acuity testing were examined. All children had been tested with pattern-alternation VEP and TAC and had undergone a complete eye examination. VEP and TAC acuity scores were relative to age-expected acuity scores for each acuity test. The absence and degree of macular abnormality, retinal abnormality, optic nerve hypoplasia, optic nerve atrophy, cortical visual impairment, developmental delay, cerebral palsy, seizures, and nystagmus were noted. Analysis of variance models were used to determine whether differences between VEP and TAC scores varied according to the presence of specific deficits. Logistic regression analysis determined whether degree of specific deficits was associated with a greater chance of inconsistency between VEP and TAC scores (>0.3 log unit difference). RESULTS: Inconsistent scores were found in 48% of children. Developmental delay was associated with relatively poorer TAC than VEP score, and the chance of inconsistency increased with severity of developmental delay. CONCLUSIONS: Diagnosis-dependent variability exists between TAC and VEP scores. Therefore knowledge of the clinical picture is necessary in interpretation of VEP and TAC scores. It is not clear which test is more useful when a disparity exists, either from this or previous studies. When visual acuity is assessed longitudinally in a given child, then consistency in method for acuity assessment is important.

Comparison of techniques for detecting visually evoked potential asymmetry in albinism.

PURPOSE: We compared techniques for analyzing visually evoked potential (VEP) asymmetry in children with albinism to find one that could be used effectively and efficiently. METHOD: Subjects included 21 child volunteers, ages 10 months to 6 years (control group) and 21 children with albinism, ages 2 months to 6 years (albinism group). Five-channel flash VEP was performed on all subjects. Electrodes were positioned at Oz, O1, O2, O3, and O4 (10/20 system). Data were analyzed by use of techniques previously described. These included inspection of the VEP waveforms, measurement of hemispheric waveform parameters, calculation of an asymmetry index, and use of a bipolar derivation between left and right hemispheric responses (interhemispheric difference potential). In addition, we quantified the interhemispheric difference potential by use of Pearson's correlation coefficient. Measurements of sensitivity and specificity determined the success of the 5 analysis paradigms. The accuracy of each paradigm represented the ability to classify the data according to volunteer or albinism group and is derived from both sensitivity and specificity measures. RESULTS: Measurement of hemispheric differences in VEP waveform parameters was the least sensitive measure method for detecting multichannel VEP asymmetry in albinism. Comparison of left and right eye interhemispheric difference potential increased accuracy to 67%. Nonquantitative inspection of waveform demonstrated an accuracy of 76%. The asymmetry index and Pearson's correlate measure yielded accuracy rates of 79% and 83%, respectively. CONCLUSION: The efficiency and capability of Pearson's correlate measure in quantifying interhemispheric difference potentials to detect albinotic misrouting makes this a useful and practical technique in a pediatric clinic.

Electrophysiological evidence of cortical fusion in children with early-onset esotropia.

PURPOSE: To investigate sensory fusion responses in infants and children with early-onset esotropia to gain insights into the sequence of events that leads to strabismus. METHODS: Sensory fusion was tested by measuring visual evoked potential (VEP) responses to dynamic random dot correlograms (DRDCs) in a group of children (n = 23) with early-onset esotropia. Thirteen children were tested before surgical alignment, and 13 children were tested after surgical alignment (three children were tested before and after surgery). If the angle of strabismus was larger than 5 prism diopters, it was corrected with Fresnel prisms (Fresnel Prism and Lens, Scottsdale, AZ). RESULTS: Five (38%) of the 13 children who were tested before surgery showed detectable VEP responses to correlogram stimuli compared with 11 (85%) of the 13 children who were tested after surgical alignment. There were no significant statistical differences between VEP responses to DRDCs from the postsurgery group and VEP responses from an age-matched control group with normal binocular vision. CONCLUSIONS: The presence of cortical sensory fusion in children with early-onset esotropia suggests that a congenital defect of sensory fusion cannot be the root cause of esotropia in most children. The data suggest that sensory fusion, when measured by VEP responses to DRDCs, is more robust than stereopsis to abnormal binocular experience and support the notion that pathways processing correlated/anticorrelated stimuli may not completely overlap with pathways processing disparity information.

Cortical binocularity and monocular optokinetic asymmetry in early-onset esotropia.

PURPOSE: To investigate the correlation between directional asymmetry in ocular responses to monocularly viewed optokinetic stimuli (monocular optokinetic nystagmus, MOKN) and sensory fusion in infants and toddlers with early-onset esotropia. METHODS: Subjects were 14 infants and toddlers with early-onset esotropia (7-26 months old; median, 10 months), and 16 with no esotropia (6-22 months; median, 11 months) who provided control data. Monocular optokinetic nystagmus in response to a 30 degrees/sec square-wave grating (0.25 cycles/degree) was measured by electro-oculogram. Sensory fusion was assessed with visual evoked potentials (VEPs) to random-dot correlograms after correction of the strabismus angle with Fresnel prisms. RESULTS: All subjects with early-onset esotropia had MOKN with a faster slow-phase component for temporal-to-nasalward (TN) than nasal-to-temporalward (NT) motion. Ninety-three percent of subjects had MOKN asymmetry higher than the 95th percentile of the control group. Of subjects who cooperated with VEP fusion testing, 5 subjects with early-onset esotropia (45%) and 11 control subjects (92%) showed evidence of sensory fusion. CONCLUSIONS: Symmetrical MOKN did not develop in infants and toddlers with early-onset esotropia. This deficit existed in most infants who showed sensory- cortical fusion. These results are consistent with the belief that optokinetic nystagmus asymmetry may not be associated with a deficit in the cortical fusion facility, but rather with deficits in binocular pathways projecting to MOKN control centers. These deficits may be associated with abnormal processing subsequent to sensory fusion or with abnormal processing in motion pathways, which run parallel to sensory fusion pathways.

Time courses for maturation of electroretinogram responses from infancy to adulthood.

The purpose of this study was to determine how responses in the normal human electroretinogram (ERG) change with subject age. We studied 62 children, 10 days to 15 years old, and 30 subjects 15-37 years old, using the standard protocol established by the International Society for Clinical Electrophysiology of Vision, with Burian-Allen bipolar contact-lens electrodes. We measured rod response, maximal response, oscillatory potentials (OPs), cone response, flicker response, and b-wave amplitude/log intensity (V/log I) curve. A logistic growth curve was used to describe the developmental changes. Dark- and light-adapted ERG a- and b-wave amplitudes reached adult levels by three to five years of age. although b-wave amplitudes of scotopic rod-mediated responses were slower to reach maturity than mixed rod-cone mediated responses. In early infancy OPs were the most immature of the ERG responses, although the rate of development thereafter exceeded that of the other responses such that OP amplitudes were within adult levels by two years of age. Amplitudes of the ERG responses in 21 children sedated with chloral hydrate did not differ significantly from 21 who had not been sedated. ERG responses developed at varying rates, reflecting different developmental stages in photoreceptors, middle retinal layers and more proximal retina.

The modified frisby stereotest.

BACKGROUND: The Frisby stereotest commonly is used in clinical practice to estimate stereoacuity. Assessment of the presence or absence of stereopsis is valuable particularly in toddlers because of the difficulties encountered in this age group with assessment of other aspects of visual function, such as monocular visual acuities. METHODS: The present study describes two modifications to the Frisby stereotest: 1) the introduction of a nonstereo practice plate; and 2) the use of an auditory "reward" for correct identification of the target. These modifications aim to increase the success rate of the test and provide a means to discriminate between testable and untestable children. Subjects were 165 children aged between 0.5 and 47 months. RESULTS: The modifications improved the age range over which results could be obtained with the Frisby test, allowing infants as young as 7 months to complete testing. By 12 months of age, more than 60% of children were able to complete testing. The modifications also allowed the examiner to distinguish untestable children from those without stereopsis. CONCLUSIONS: By simple modification of the Frisby stereotest, the authors have increased the ease with which the Frisby stereotest can be used to assess stereoacuity in infants and children and provided a means by which children unable to cooperate with testing can be distinguished from those without stereopsis.

A comparison of tests to determine acuity deficits in children with amblyopia.

The usefulness of the Cardiff Acuity Test in the detection of amblyopia was evaluated. Visual function was measured using pattern visual evoked potentials (VEPs), the Cardiff test, and the Bailey-Lovie Chart in 21 visually normal children and 12 children with amblyopia. The Cardiff test gave higher scores than the Bailey-Lovie test. The Cardiff test identified five of the 12 children who were classified as amblyopic by the Bailey-Lovie test. Interocular VEP latency differences identified eight of the 12 children with amblyopia; interocular VEP amplitudes correctly identified nine. We suggest that the challenging Bailey-Lovie test be used for older children who know their letters well. If the Bailey-Lovie test cannot be used, VEPs give the most accurate assessment of interocular differences. The Cardiff test holds a bored child's attention and allows the examiner to obtain a useful measure of visual acuity, but it cannot detect mild amounts of amblyopia.

Emmetropisation in human infancy: rate of change is related to initial refractive error.

Animal studies show that the rate of recovery from experimentally induced refractive errors is related to the level of ametropia induced. The present study examined the rate of emmetropisation occurring in a sample of 22 human infants refracted by near retinoscopy during the first six months of life and then again between 12 and 17 months old. None of the subjects were myopic. Regression analysis revealed that emmetropisation occurred more rapidly in the presence of high refractive errors (P < 0.005 and P = 0.001 for hyperopia and astigmatism respectively). These data confirm the findings of the animal studies and suggest that non-reducing hyperopia and astigmatism in the second year of life may require correction.

Characterization of the ocular phenotype of Duchenne and Becker muscular dystrophy.

PURPOSE: Dystrophin, the Duchenne muscular dystrophy gene product, has been localized to the outer plexiform layer of normal human retina. The purpose of this study is to define completely the ocular phenotype associated with mutations at Xp21, the Duchenne muscular dystrophy gene locus. METHODS: Twenty-one patients with a diagnosis of Duchenne muscular dystrophy and five patients with Becker muscular dystrophy had ophthalmologic examinations, including electroretinograms (ERGs). Electroretinogram results were correlated with respect to patient DNA analysis. RESULTS: Twenty-three (88%) patients had reduced scotopic b-wave amplitudes to bright-white flash stimulus, including nine with negative-shaped ERGs. Rod-isolated responses were reduced or not recordable above noise in 14 (67%) patients. Most isolated cone responses (92%) were normal. Flicker amplitudes were reduced in seven patients. Two of these patients with proximal (5' end) deletions had normal scotopic b-waves to dim blue and bright-white flash stimulus. Patients with deletions toward the middle of the gene had greater reductions in their scotopic b-wave amplitudes than patients with deletions located toward the 5' end. Most patients had normal color vision, extraocular muscle function, and Snellen visual acuity. Increased macular pigmentation was seen in 16 patients with Duchenne muscular dystrophy. CONCLUSION: Most patients with Duchenne or Becker muscular dystrophy have evidence of abnormal scotopic ERGs. Patients with deletions in the central region of the gene had the most severe ERG changes. This study supports previous suggestions that dystrophin may play a role in retinal neurotransmission. The presence of increased macular pigmentation and normal photopic ERGs distinguishes patients with Duchenne muscular dystrophy mutations from other X-linked retinal disorders with negative-shaped ERGs.

Comparison between near retinoscopy and cycloplegic retinoscopy in the refraction of infants and children.

We investigated the validity of replacing cycloplegic retinoscopy with a noncycloplegic, "near" retinoscopy technique. We refracted a group of 31 infants (less than 2 years) and 43 children (greater than 2 years) with both techniques, grading our level of confidence in the result. Near retinoscopy gave on average a less hypermetropic result than cycloplegic retinoscopy by 0.39 D. The difference was significant in infants and for low levels of examiner confidence. However, a repeatability study showed that much of the variability in the infant group could be attributed to the poor repeatability of either retinoscopy technique. Agreement between the two techniques is improved by changing the suggested adjustment factor from 1.25 to 1.00 D for children and to 0.75 D for infants.

OKN asymmetries in orthoptic patients: contributing factors and effect of treatment.

Monocular optokinetic nystagmus (MOKN) was measured (EOG) in response to horizontally moving square wave gratings (0.2 c/deg, 27 and 35 deg/s) in 58 children with amblyopia and/or strabismus (experimental group); the data were compared with that collected from 24 children (aged 3-8 years) with no visual problems (control group). We found OKN asymmetries most often associated with strabismus of early age of onset (less than 2 years). In these children the MOKN asymmetry often occurred in both eyes. In children with later onset strabismus the asymmetry was often confined to the amblyopic eyes. We repeated the measurements on 18 experimental children after 1-3 years of treatment (patching the dominant eye) and compared the results with those recorded in 12 fully binocular control children retested after 1-2 years. Large OKN asymmetries before treatment were still present after the patching treatment. However there was a small, but significant (P = 0.05, t-test), improvement in the nasal-temporal (N-T) slow-phase velocity in the affected eyes of the experimental group, which was not correlated with improvements in visual acuity or linked to the presence of strabismus and/or amblyopia. The main contributing factors to asymmetric OKN affecting both eyes of early onset strabismus seem to be to poor binocularity which would not improve during patching treatment. OKN asymmetries in amblyopic eyes may also result from reduced cortical sensitivity from that eye, which may be minimally improved by patching treatment. Our results suggest a shorter sensitive period of development for OKN pathways than for the development of cortical visual pathways.

Problems measuring contrast sensitivity in children.

A preliminary study measured the contrast sensitivity function (CSF) in 30 children (aged 3 months-5 years). Preferential looking techniques were used to assess CSF to sine wave gratings displayed on one of two screens. To find a meaningful contrast sensitivity procedure we compared the results with a shorter procedure using an edge stimulus. The following problems were encountered: measuring the contrasts required to detect four or five different spatial frequencies took time, resulting in boredom and loss of attention in our subjects; there was poor correlation between CSF and edge detection; an interesting artefact resulted in a plateau rather than a low frequency fall-off in the CSF of five of the children greater than 30 months old. This artefact may have resulted from peripheral rather than central retinal responses and/or motion artefacts in the stimulus onset. A follow up study with 41 additional children aged 3-36 months limited the contrast testing to that of the spatial frequency corresponding to the peak of the CSF. The shortened procedure, plus a lot of encouragement, resulted in higher contrast sensitivities in all but the oldest age group and successful monocular contrast measurements. In order to avoid artefacts arising from peripheral vision, children were encouraged to look at each screen before responding.