Impaired vision in children prenatally exposed to methadone: an observational cohort study.

BACKGROUND/OBJECTIVES: To examine prevalence of failed visual assessment at 8-10 years in children born to methadone-maintained opioid dependent (MMOD) mothers and relate this to known in utero substance exposure. SUBJECTS/METHODS: Follow up of observational cohort study of methadone-exposed and comparison children matched for birthweight, gestation and postcode of residence at birth. Participants were 144 children (98 exposed, 46 comparison). Prenatal drug exposure was previously established via comprehensive maternal and neonatal toxicology. Children were invited to attend for visual assessment and casenotes were reviewed. Presence of acuity poorer than 0.2 logMAR, strabismus, nystagmus and/or impaired stereovision constituted a 'fail'. Fail rates were compared between methadone-exposed and comparison children after adjusting for known confounding variables. RESULTS: 33 children attended in person: data were also derived from casenote review for all children. After controlling for maternal reported tobacco use, methadone-exposed children were more likely to have a visual 'fail' outcome, adjusted odds ratio 2.6, 95% CI 1.1-6.2; adjusted relative risk 1.8 (95% CI 1.1-3.4). Visual 'fail' outcome rates did not differ between methadone-exposed children who had (n = 47) or had not (n = 51) received pharmacological treatment for neonatal abstinence/opioid withdrawal syndrome (NAS/NOWS); fail rate 62% vs 53% (95% CI of difference-11-27%). CONCLUSIONS: Children born to MMOD mothers are almost twice as likely as unexposed peers to have significant visual abnormalities at primary school age. Prenatal methadone exposure should be considered in the differential diagnosis of nystagmus. Findings support visual assessment prior to school entry for children with any history of prenatal opioid exposure. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03603301), https://clinicaltrials.gov/ct2/show/NCT03603301 .

Clinical electrophysiology and visual outcome in optic nerve hypoplasia.

AIMS: In optic nerve hypoplasia (ONH), the extent of functional loss of retinal ganglion cells cannot be determined by ophthalmoscopic examination. The prognostic value of visual electrodiagnostic tests in infants and toddlers with ONH was assessed by comparison with visual outcome. METHODS: 85 participants with ONH had electroretinogram (ERG) and visual-evoked potential (VEP) testing to flash and to pattern-reversal checks and ocular fundus photography prior to 36 months of age. These initial measures were compared with visual acuity outcomes at 5 years of age in the better-seeing eye. RESULTS: Visual outcomes ranged from normal to no light perception. Electrodiagnostic tests with prognostic value were: the amplitude of the flash VEP (Spearman's rank correlations, p<0.001), the threshold category of stimulus (flash or check size) that elicited a VEP (p<0.001) and the amplitude of the N95 component of the pattern ERG (PERG) to 4-degree checks (p<0.02). Optic nerve size and co-existing pallor were also significant correlates. Stepwise regression analysis composed a best prediction model from VEP threshold category, optic nerve size and optic disc pallor (R(2)=58%; p<0.001). CONCLUSIONS: Optic disc diameter, observation of disc pallor, VEP and PERG testing in infancy are useful for establishing the visual prognosis at 5 years of age in children with ONH. This is consistent with the notion that these parameters are related to the anatomic and functional preservation of retinal ganglion cells.

Maturation of steady-state flicker VEPs in infants: fundamental and harmonic temporal response frequencies.

Transient flash VEPs allow objective assessment of visual function and are easily recorded in young infants. However, due to their high variability, they are an insensitive surrogate marker of visual development. The aim of our study was to investigate the early maturation of temporal characteristics of steady-state flicker VEPs. Data from 53 VEP sessions were analyzed in term-born infants between birth and 20 months of age. The stimulus was a square-wave modulated luminance flicker with 80% modulation depth at temporal frequencies of 4.7, 7.5, 12.5, and 19 Hz. A total of 18 healthy adults aged between 21 and 54 years served as controls. Contingent on the stimulus frequency, we found pronounced changes of the flicker VEP with age. Regression lines fit to the first harmonic VEP magnitude as a function of age between 3 and 88 weeks of age indicated increases at 7.5 (P = 0.004), 12.5 (P < 0.001), and 19 Hz (P = 0.07) and a non-significant decrease at 4.7 Hz (P = 0.3). The magnitude of the second harmonic increased for all frequencies (4.7 (P = 0.05), 7.5 (P = 0.01), 12.5 (P = 0.13), and 19 Hz (P = 0.18)). Over the whole infant age range, the flicker VEP was dominated by the first harmonic, in contrast to adults, where the response was typically shifted to a higher harmonic at low stimulus frequencies. The optimal stimulus frequency, defined as the frequency eliciting the highest magnitude for F1, shifted to higher rates with age. Due to the difference from adult responses, further developmental changes of the temporal properties must be assumed to occur after the age of 20 months. Changes in temporal characteristics of the flicker VEP with age may be useful as an indicator of visual system maturation and a useful tool to detect visual delay.

Visual evoked potentials in infants exposed to methadone in utero.

We investigated the effects of maternal drug misuse on neonatal visual evoked potentials (VEPs). Flash VEPs were recorded within 4 days of birth from 21 term infants of mothers misusing drugs and prescribed substitute methadone and 20 controls. Waveforms were classified as typical, atypical, immature or non-detectable, and amplitude and latencies were measured. VEPs from drug-exposed infants were less likely to be of typical waveform and more likely to be immature or non-detectable (p<0.01) than those of control infants. They were also smaller in amplitude (median 10.8 vs 24.4 microV, p<0.001). VEPs of drug-exposed infants had matured after 1 week but remained of lower amplitude than VEPs of newborn controls (p<0.01) and were non-detectable in 15%. Flash VEPs differ between maternal drug-exposed and non-drug-exposed newborns. Future research should address the specific effects of maternal methadone and/or other illicit drug misuse on infant VEPs, and associations between neonatal VEPs and subsequent visual development.

A visual skills inventory for children with neurological impairments.

Children with neurological impairments often have visual deficits that are difficult to quantify. We have compared visual skills evaluated by carers with results of a comprehensive visual assessment. Participants were 76 children with mild to profound intellectual and/or motor impairment (33 males, 43 females; age range 7mo-16y; mean age 5y 1mo [SD 4y 2mo]) who completed a visual skills inventory before attending a special vision clinic. The inventory included 16 questions about visual skills and responses to familiar situations. Responses were augmented by taking a structured clinical history, compared with visual evoked potential (VEP) and/or acuity card measures of visual acuity, and examined using exploratory factor analysis. Acuity ranged from normal to no light perception, and was positively associated with responses to individual questions. After excluding four uninformative questions, an association between the remaining questions and two significant independent factors was found. Factor 1 was associated with questions about visual recognition (e.g. 'Does your child see a small silent toy?') and these items were correlated with both the VEP and acuity card thresholds. Factor 2 was associated primarily with questions about visually mediated social interactions (e.g. 'Does he/she return your silent smile?'). Evaluation of visual skills in children with neurological impairment can provide valid information about the quality of children's vision. Questions with the highest validity for predicting vision are identified.

The luminance-response function of the human photopic electroretinogram: a mathematical model.

The luminance-response function of the brief flash full-field photopic electroretinogram (ERG) rises to a peak before falling to a sub-maximal plateau -- the 'photopic hill'. The combination of on- and off-responses inherent in the brief flash photopic ERG suggests that this luminance-response function could be modelled by the sum of a Gaussian function and a logistic growth function. Photopic ERGs to a luminance series of brief flashes against three different background luminances recorded from seven healthy adults showed the characteristic 'photopic hill' function for b-wave amplitudes which were satisfactorily fitted with the sum of a Gaussian curve and a logistic growth curve. As background luminance increased, both components shifted to the right on the luminance axis. The Gaussian component increased in amplitude while the logistic growth function component decreased in amplitude. The luminance-response function of a complete congenital stationary night blindness patient had almost no logistic growth component.

Retinal function in infants with optic nerve hypoplasia: electroretinograms to large patterns and photopic flash.

AIMS: Optic nerve hypoplasia (ONH), which is defined as a congenital deficiency of retinal ganglion cells, may also involve more distal layers of the retina. We investigated electrophysiological function of the retina in ONH using electroretinograms (ERGs). METHODS: ERGs were recorded from 48 subjects (3.5-35 months) with unilateral or bilateral ONH. Pattern reversal (4 degrees checks) was presented under chloral hydrate sedation, using an optical system to correct a cycloplegic refraction. A photopic flash stimulus was also used. Fundus photographs were used to measure the disk diameter/disk macula ratio (DD/DM), and to document other clinical signs. Eyes were classified as moderate (0.15-0.3) or severe (<0.15) ONH, and those with DD/DM greater than 0.3 were used as reference eyes. RESULTS: Pattern ERG recording was completed in 89 eyes and was detectable in 80% of eyes with ONH (61/76 tested) and in all 13 reference eyes. Photopic flash ERGs were of good quality in all eyes. The severity of ONH correlates with the amplitude of the photopic flash b-waves and with the amplitude of the N95 component of the pattern ERG (P<0.01). However, the ERGs to large patterns were well preserved (>3.5 microV) in 10 of 35 eyes with severe ONH. Tortuous retinal vessels in eyes with either moderate or severe ONH were associated with smaller amplitude photopic b-waves and markedly diminished or undetectable pattern ERGs. CONCLUSIONS: This study supports the hypothesis that retinal dysfunction distal to the ganglion cells is common in ONH, but is not predictable on the basis of ONH severity alone. Additionally, tortuous retinal vessels in ONH may be a sign associated with retinal dysfunction.

Maternal docosahexaenoic acid supplementation during pregnancy and visual evoked potential development in term infants: a double blind, prospective, randomised trial.

AIM: To test the hypothesis that maternal docosahexaenoic acid (DHA) supplementation during pregnancy enhances maturation of the visual evoked potential (VEP) in healthy term infants. METHODS: One hundred women were supplemented with either fish oil capsules rich in DHA (n = 50) or placebo capsules (n = 50) from week 15 of pregnancy until delivery. Total fatty acids in red blood cells and plasma were measured at weeks 15, 28, and 40 of pregnancy and at delivery in umbilical cord blood. Infant visual pathway development was assessed using VEPs recorded to flash stimuli shortly after birth and to both flash and pattern-reversal stimuli at 50 and 66 weeks post-conceptional age (PCA). RESULTS: Maternal supplementation did not significantly elevate the level of DHA in umbilical cord blood. Moreover, there were no significant differences in any of the VEP measures observed between supplementation groups. However, maturity of the pattern-reversal VEP at 50 and 66 weeks PCA was associated with DHA status of the infants at birth. Infants with higher DHA status, both as a concentration and as a percentage of total fatty acids, showed shorter P100 peak latencies of the pattern-reversal VEP than those with lower DHA status. CONCLUSIONS: Maternal DHA supplementation during pregnancy did not enhance VEP maturation in healthy term infants. However, these results show an association between the DHA status of infants at term and early postnatal development of the pattern-reversal VEP, suggesting that DHA status itself may influence maturation of the central visual pathways.

Emmetropisation following preterm birth.

BACKGROUND/AIMS: Even in the absence of retinopathy of prematurity (ROP), premature birth signals increased risk for abnormal refractive development. The present study examined the relation between clinical risk factors and refractive development among preterm infants without ROP. METHODS: Cycloplegic refraction was measured at birth, term, 6, 12, and 48 months corrected age in a cohort of 59 preterm infants. Detailed perinatal history and cranial ultrasound data were collected. 40 full term (plus or minus 2 weeks) subjects were tested at birth, 6, and 12 months old. RESULTS: Myopia and anisometropia were associated with prematurity (p<0.05). More variation in astigmatic axis was found among preterm infants (p<0.05) and a trend for more astigmatism (p<0.1). Emmetropisation occurred in the preterm infants so that at term age they did not differ from the fullterm group in astigmatism or anisometropia. However, preterm infants remained more myopic (less hyperopic) than the fullterm group at term (p<0.05) and those infants born <1500 g remained more anisometropic than their peers until 6 months (p<0.05). Infants with abnormal cranial ultrasound were at risk for higher hyperopia (p<0.05). Other clinical risk factors were not associated with differences in refractive development. At 4 years of age 19% of the preterm group had clinically significant refractive errors. CONCLUSION: Preterm infants without ROP had high rates of refractive error. The early emmetropisation process differed from that of the fullterm group but neither clinical risk factors nor measures of early refractive error were predictive of refractive outcome at 4 years.

Pattern-reversal visual evoked potentials in infants: gender differences during early visual maturation.

This paper investigates gender differences in the peak latency and amplitude of the P1 component of the pattern-reversal visual evoked potential (pattern-reversal VEP) recorded in healthy term infants. Pattern-reversal VEPs in response to a series of high contrast black and white checks (check widths 120', 60', 30', 24', 12', 6') were recorded in 50 infants (20 males, 30 females) at 50 weeks post-conceptional age (PCA) and in 49 infants (22 males, 27 females) at 66 weeks PCA. Peak latency of the major component, P1, was considerably shorter in female compared with male infants. Differences in head circumference do not entirely account for the gender differences in peak latency reported here. A gender difference in P1 amplitude was not detected. These findings stress the importance of considering gender norms as well as age-matched norms when utilizing the pattern-reversal VEP in clinical investigations. Studies including a wider range of ages are clearly necessary in order to establish whether the earlier peak latencies in female infants represents a difference in the onset or rate of visual maturation.

Spatial summation of peripheral Gabor patches.

Previous studies have specified the foveal pattern that is seen most efficiently, with the assumption that the waveform of the best pattern matches the impulse response of the most sensitive visual filter. We measured the threshold contrast for circular, collinear, and orthogonal Gabor stimuli of 6 Hz temporal frequency presented 7 deg above the fixation point. We found that the threshold contrast energy is minimal for a class of stimuli whose Fourier-spectra bandwidth is less than approximately 1 octave. These findings suggest that an energy algorithm might underlie spatial summation of peripheral Gabor patches. The different behavior of spatial summation in fovea and periphery might reflect the differences in pattern detectability across space in the central and peripheral visual fields. It is also possible that a coherent (cross-correlation) algorithm is employed in detection of foveal stimuli and that an incoherent (energy) algorithm is employed in detection of peripheral stimuli.

Visual event-related potentials in children with phenylketonuria.

Visual event-related potentials (ERPs) were examined in 16 children (aged 5-14 y) with phenylketonuria (PKU) and 16 age- and sex-matched controls. Lifetime median measures of phenylalanine (Phe) were 230-460 micromol/l. The most recent Phe levels were 56-624 micromol/l. ERPs were recorded whilst the children performed a discrimination task. All stimuli were square wave gratings degree, which appeared for 33 ms. A response to an infrequent grating that differed in orientation or spatial frequency was required. The older children with PKU had a delay in the first peak (P1) of the ERP, and age-related changes in the amplitude of P1. There was attenuation of the second peak across age groups in PKU. There was no evidence of reduced response accuracy or longer reaction times in children with PKU. Latencies of the cognitive P3 were not delayed in PKU. The delayed early peaks are consistent with previous studies that have shown delayed visual evoked potentials in PKU. The lack of differences in reaction time and P3 may be due to relatively good Phe control in children with PKU, or to the simplicity of the task. Suggestions are made for future ERP studies of PKU.

Prognostic value of flash visual evoked potentials in preterm infants.

This paper investigates the prognostic value of flash visual evoked potentials (VEPs) recorded in preterm infants at birth and at term age with respect to severe neurological outcome. Flash VEPs were recorded in 81 preterm infants at birth (i.e. <35 weeks' gestation) and repeated in 56 of these infants at term age. The preterm infants were assigned to either a healthy or at-risk subgroup based on clinical birth factors. Normal ranges of flash-VEP latencies, amplitudes, and number of components present were obtained from the subgroup of healthy preterm infants and from 68 term infants tested postnatally. The flash-VEP results of the entire preterm group were compared with the normal ranges and any abnormalities noted. Seven preterm infants in the at-risk group died, six of whom had abnormal flash VEPs before term age. Of the five infants from the at-risk group diagnosed with cerebral palsy (CP), three had abnormal flash VEPs before term age. Thus the sensitivity and specificity of the flash VEP with respect to survival was 86% and 89% respectively, and with respect to the development of CP was 60% and 92%. The abnormal features of the flash VEP associated with adverse outcomes comprised a delayed N3 component before term age and the absence of a positive component (P2) at term age.

A VEP investigation of parallel visual pathway development in primary school age children.

Different features of visual function mature along unique timescales through infancy and early childhood. It is not clear which functions continue to mature in school age children. Functions believed to be mediated by the Magnocellular (M) and Parvocellular (P) pathways were compared in five- (n=25), eight- (n=21) and eleven-year-old children (n=21) and young adult controls (n=20). Steady-state visual evoked potentials were recorded from occipital electrodes in response to very low spatial frequency gratings, at a series of contrasts (M), and to high contrast gratings at a series of spatial frequencies (P). No evidence was found to indicate M pathway development across these age groups. However, the youngest children demonstrated elevated VEP thresholds to the high contrast gratings compared with either the adults or eleven-year-olds. This difference in threshold implies an immaturity of the high contrast, high spatial frequency stream, i.e. the putative P pathway.

Maturation of the pattern-reversal VEP in human infants: a theoretical framework.

Visual evoked potentials to pattern reversal (PR-VEPs) are used to assess the integrity and maturation of the visual pathways in infants and young children. To establish normal ranges and to facilitate interpolation, we consider the maturation rate of PR-VEPs using published normative data. Curves based on the logistic function (a sigmoid model) are introduced and compared with three other models: (1) the power law function; (2) the sum of two decaying exponentials; and (3) a two-stage linear model. Although methods vary somewhat, remarkable consistency among laboratories is found for the maturation of the major positivity (P1) of PR-VEP. The P1 occurs at approximately 260 ms in neonates and is quite variable. It matures rapidly before 12-14 weeks of age and becomes much less variable. The logistic model provides a parsimonious description of P1 maturation with most rapid maturation at around 6 weeks of age for large patterns and around 9 weeks for small patterns. As inter-laboratory agreement is generally good, the normal ranges based on this model could be used in centres, which do not have their own normative databases for infant VEPs.

The infant patient.

The infant patient presents a challenge to the optometrist who must structure an examination within the infant's limited capabilities and then manage a rapidly developing visual system. The present paper provides an overview of infant visual development and the visually guided behaviours expected during normal development. Techniques for assessing vision in infant are reviewed and a recommendation is given for the optometric examination of infants. Some important urgencies, emergencies and causes of visual impairment are highlighted.

A 'passive' event-related potential?

Event potentials (ERPs) were recorded in response to visual patterns in two conditions: (1) where no instructions were given to subjects; and (2) where subjects pressed a button whenever a rare stimulus was detected. P3 amplitudes for the No Instructions condition were smaller than for the Active condition, but the latency of the P3s did not differ across conditions. In both conditions, the P3 was either absent or significantly smaller for frequent stimuli than for rare stimuli. It appears a 'passive' visual P3 is measurable, and it occurs at the same latency as a P3 recorded in association with an active response. Thus, it may be possible to record P3s in response to visual stimulation in subjects who cannot follow instructions to respond to rare events.

Relation between neurological status, refractive error, and visual acuity in children: a clinical study.

The aims of the present study were: (1) to determine the refractive status and visual acuity of a group of 75 neurologically impaired children (5 to 192 months of age); and (2) to investigate the relation between the visual and neurological status of these children. Refractive error was determined using non-cycloplegic near retinoscopy and visual acuity was estimated using acuity cards (Keeler or Cardiff) and pattern-onset visual evoked potentials (VEP). Subjects demonstrated a markedly different distribution of refractive error from that of a neurologically normal age-matched population. Refractive error anomalies were more prevalent in children older than 5 years, suggesting abnormal refractive development. A wide range of visual acuity was found with both tests (acuity cards, 0.07 to 2.08 logMAR; VEP, O.78 to 2.68 logMAR). Visual acuity and refractive status varied with level and type of physical impairment. Level of intellectual impairment exhibited a weak relation with visual status.

Pattern-onset visual evoked potentials: more useful than reversal for patients with nystagmus.

PURPOSE: The visual evoked potential is often used to assess visual function in neurologically impaired patients, a group in whom nystagmus is a common feature. Pattern-reversal stimuli are commonly used to produce visual evoked potentials in clinical practice. Previous reports have shown that this stimulus is not optimal when subjects have nystagmus. The present study aimed to compare the efficacy of pattern-onset and reversal stimuli when used to measure visual evoked potentials from subjects with idiopathic nystagmus. METHODS: In five adults with congenital nystagmus and 10 visually normal adults, VEPs were recorded and reproduced for checkerboard stimuli of two sizes (120' and 60'). Each size was presented as both pattern-onset and reversal check. RESULTS: Visually normal adults demonstrated similar visual evoked potential amplitudes and quality in response to pattern-reversal and pattern-onset. However, in the presence of nystagmus, visual evoked potentials recorded to pattern-reversal stimuli were significantly smaller and of poorer quality than those obtained to pattern-onset stimuli (analysis of variance p<0.05; Kendall's tau, p<0.05). CONCLUSIONS: Pattern-onset stimuli produce larger and clearer visual evoked potentials in patients with nystagmus compared with those produced to pattern-reversal stimuli.