The role of visual electrodiagnostics in management of children with neurofibromatosis type 1.

PURPOSE: To evaluate the role of visual electrodiagnostic testing in children with neurofibromatosis type 1 (NF1) despite improved accessibility to magnetic resonance imaging (MRI). METHODS: The records from 39 children (78 eyes, 15 boys, 24 girls, average age at last visit of 11.5 ± 4.3 years, average follow-up time of 7.8 ± 3.9 years) with genetically confirmed NF1 were retrospectively analysed. They all underwent a thorough ophthalmological investigation, including age-appropriate visual acuity testing, anterior segment evaluation for Lisch nodules and a dilated fundus examination. If children were cooperative enough, colour vision was tested using the Hardy-Rand-Rittler test, visual fields were evaluated with Goldmann perimetry. All performed MRI of the brain and orbits as part of the standard of care protocol. Visual electrodiagnostics included electroretinography (ERG) and visual evoked potentials (VEP) using a standard protocol in older children, whereas with less cooperative children a modified protocol according to the Great Ormond Street Hospital (GOSH protocol) was used. RESULTS: The average visual acuity was 0.8 ± 0.3, colour vision was abnormal in 6%, perimetry in 8%, Lisch nodules were present in 62%, and the optic disc was pale in 66% of all eyes. Plexiform neurofibroma of the eyelid/orbit was present in 4%. Optic pathway glioma (OPG) was detected with MRI in 22 (57%) and in 6/22 treatment was indicated. Other intracranial NF1-related lesions were documented in 70% of children. VEP were abnormal in 16/39 of all children with NF1 (41%) comprising 14/22 (65%) of children with confirmed OPG and 2/17 (12%) of children without OPG. All full-field and pattern ERG responses were within normal limits. All individual VEP results are described and three cases from this cohort of children are presented in detail to illustrate the importance of VEP testing. In Case 1, VEP abnormality suggested subsequent MRI of the brain under general anaesthesia, which was otherwise contraindicated according to normal clinical findings and his young age. In Cases 2 and 3, VEP provided more precise functional information during the follow-up of OPG, while other psychophysical tests remained unchanged. CONCLUSIONS: Electrodiagnostics has multifactorial role and importance in children with NF1, either when visual pathway function is impaired in young children, even before MRI under general anaesthesia and other psychophysical tests can be performed, as well as for a more precise monitoring of the visual pathway function before potential treatment of OPG, or after it, to evaluate its success.

Disease Progression in CNGA3 and CNGB3 Retinopathy; Characteristics of Slovenian Cohort and Proposed OCT Staging Based on Pooled Data from 126 Patients from 7 Studies.

Achromatopsia has been proposed to be a morphologically predominately stable retinopathy with rare reports of progression of structural changes in the macula. A five-grade system of optical coherence tomography (OCT) features has been used for the classification of structural macular changes. However, their association with age remains questionable. We characterized the Slovenian cohort of 12 patients with pathogenic variants in CNGA3 or CNGB3 who had been followed up with OCT for up to 9 years. Based on observed structural changes in association with age, the following four-stage classification of retinal morphological changes was proposed: (I) preserved inner segment ellipsoid band (Ise), (II) disrupted ISe, (III) ISe loss and (IV) ISe and RPE loss. Data from six previously published studies reporting OCT morphology in CNGA3 and CNGB3 patients were additionally collected, forming the largest CNGA3/CNGB3 cohort to date, comprising 126 patients aged 1-71 years. Multiple regression analysis showed a significant correlation of OCT stage with age (p < 0.001) and no correlation with gene (p > 0.05). The median ages of patients with stages I-IV were 12 years, 23 years, 27 years and 48 years, respectively, and no patient older than 50 years had continuous ISe. Our findings suggest that achromatopsia presents with slowly but steadily progressive structural changes of the macular outer retinal layers. However, whether morphological changes in time follow the proposed four-stage linear pattern needs to be confirmed in a long-term study.

Automated Visual Acuity Evaluation Based on Preferential Looking Technique and Controlled with Remote Eye Tracking.

OBJECTIVE: To establish an automated visual acuity test (AVAT) for infants, based on preferential looking technique and controlled with remote eye tracking. To validate the AVAT in a group of healthy children. To compare AVAT visual acuity (VA) values with corresponding VA values acquired with standard tests (ST). METHODS: ST, adapted for age (Keeler Acuity Cards in preverbal children and LEA symbols in verbal children), was performed to obtain monocular VA in a group of 36 healthy children. During AVAT, 9 different stimuli with grating circles that matched spatial frequencies of 9 Keeler Acuity Cards (ranging between 0.29 and 14.5 cycles per degree) were projected on a screen. Three repetitions of each stimulus were shown during 9-s intervals, interchanging with an attention grabber. The remote eye tracker was used to evaluate the proportion of time a child spent looking at each grating circle compared to a homogeneous gray background that matched the grating stimuli in average luminance. From this proportion of time, child's binocular VA was evaluated. RESULTS: Ninety-seven percent (35/36) of healthy children successfully completed ST and AVAT. There was an agreement between the results of an ST and AVAT, with Lin's concordance coefficient being 0.53 (95% CI = 0.31-0.72). A tendency was observed toward VA overestimation on AVAT for children with VA >0.4 logMAR on ST and toward VA underestimation on AVAT for children with VA ≤0.4 logMAR on ST. CONCLUSIONS: AVAT requires a minimally skilled investigator. The evaluation of better eye monocular VA on ST and binocular VA on AVAT was comparable for healthy children.

Chromatic visual evoked potentials indicate early dysfunction of color processing in young patients with demyelinating disease.

PURPOSE: Chromatic visual evoked potentials (cVEP) primarily reflect the parvocellular visual pathway function, which has been shown to be predominantly affected in demyelinating disease (DD). The purpose of this study was to evaluate cVEP responses and to compare them with other structural and functional findings in young patients with DD. METHODS: Thirty patients (8-28 years of age) with DD with or without a history of optic neuritis (ON) were investigated. Twenty-five eyes had at least one episode of ON (ON-group) and 35 eyes had no clinically evident episode of ON (nON-group). OCT imaging was performed using a high-resolution spectral-domain OCT (SD-OCT), measuring retinal nerve fiber layer (RNFL) thickness. Pattern reversal electroretinography (PERG) and visual evoked potentials (VEP) were recorded according to the ISCEV standard, and chromatic visual evoked potentials (cVEP) were recorded to isoluminant red-green (R-G) and blue-yellow (B-Y) 7° circle stimuli, composed of horizontal sinusoidal gratings with spatial frequency 2 cycles/°, 90% chromatic contrast and onset-offset (300:700 ms) mode of stimulation. Structural and functional measures were analyzed and compared between the groups. RESULTS: Both general (G) and temporal (T) RNFL thicknesses were reduced below normal limits in most of the eyes. However, in the ON-group (G: 77.5 ± 20.6, T: 51.4 ± 23.4 µm), the thinning was more significant (p < 0.001) than in the nON-group (G: 95.4 ± 12.1, T: 70.1 ± 11.5 µm). PERG N95 was within normal limits in the nON-group, while it was significantly more affected in the ON-group (7.4 ± 1.0 vs. 5.1 ± 2.0 µV; p < 0.0001). Similarly, also VEP P100 latency and amplitude showed a greater percentage of abnormality in the ON-group, the latency being longer (117.2 ± 16.9 vs. 99.4 ± 4.6 ms; p < 0.0001) and the amplitude lower (9.1 ± 5.1 vs. 16.4 ± 7.5 µV; p < 0.0001). The cVEP N-wave amplitude to R-G and B-Y stimuli was reduced below normal limits in both ON- and nON-groups; however, cVEP to B-Y stimulation were slightly more affected in the ON-group (4.0 ± 3.8 vs. 5.9 ± 3.3 µm; p = 0.02). A positive correlation between cVEP amplitude and RNFL thickness and between cVEP amplitude and PERG N95 amplitude, as well as a strong negative correlation between cVEP amplitude and P100 latency was observed. CONCLUSIONS: These findings demonstrate that cVEP indicate early abnormality of parvocellular pathway function in eyes with or without a history of optic neuritis and can be used together with other structural and functional parameters to evaluate visual pathway integrity of young patients with DD.

Vision training with VEP biofeedback in amblyopia after the critical period.

PURPOSE: The purpose of this study was to investigate the benefits of vision training with visual evoked potentials (VEP) biofeedback in amblyopia after the critical period in 8 to 17-year (11.5 ± 3.1) old children. METHODS: Ten participants with monocular amblyopia after the critical period underwent a 10-week, 20-session vision training program with the Retimax Vision Trainer device. During each session, the participants were instructed to be as focused as possible onto the fixation point in the middle of the screen. The size of the fixation point and the pitch of the background sound were changing according to VEP parameters and thus provided the participants real-time feedback of their visual performance. RESULTS: The mean BCVA improvement across our group was 0.12 LogMAR (p < 0.01). There was also a significant increase in contrast sensitivity to the FACT chart across all spatial frequencies (all p < 0.05). Electrophysiologic data revealed higher steady-state visual evoked potentials (SS-VEP) amplitudes and correspondingly lower fixation point values in the last 2 weeks of training compared to the first 2 weeks (both p < 0.01). Due to unexplainably low VEP amplitude levels in later trainings compared to those in the beginning in two participants, we have not found a significant correlation between the increase in BCVA and the increase in SS-VEP amplitude (p = 0.88). At the follow-up at 2 and 12 months following the end of training, both BCVA and contrast sensitivity remained within the levels achieved at the end of training. In some participants, however, no improvement of BCVA was observed. CONCLUSIONS: The tested vision training approach demonstrates modest but stable improvement of psychophysical parameters as well as objective characteristics in amblyopia after the critical period. Real-time SS-VEP can be used as an objective parameter to monitor participants' attention during vision training stimulation.

Flicker electroretinogram recorded with portable ERG device in prematurely born schoolchildren with and without ROP.

PURPOSE: The purpose of this study was to compare electroretinographic (ERG) responses of preterm schoolchildren, with and without a history of retinopathy of prematurity (ROP) with those of full-term schoolchildren by using a portable ERG device (RETeval system). METHODS: Twenty five prematurely born schoolchildren with a mean gestational age of 27 + 1/7w (range 23-30w) and a mean birth weight of 1030 g (range 580-1700 g) who were 6.9 ± 2.2 years old participated in the study (premature group). A further subdivision according to a history of ROP (ROP+ group) or its absence (ROP- group) was introduced. Twenty eight healthy full-term schoolchildren with an average age of 8.6 ± 1.9 years participated as the control group. 30-Hz flicker ERG responses were obtained, and implicit times and amplitudes were compared between the groups. RESULTS: 30-Hz flicker ERG implicit times showed a significant difference between all three groups of children. The mean value of the implicit time in the term group was 25.76 ± 0.9 ms, whereas in the preterm ROP + group it was 28.96 ± 1.0 ms and in the preterm ROP- group it was 26.87 ± 1.5 ms. 30-Hz flicker ERG amplitudes did not show significant difference between term children and children born prematurely with or without ROP. CONCLUSIONS: Prematurely born schoolchildren exhibit longer implicit time of the 30-Hz flicker ERG response compared to controls, suggesting a possible abnormality of the retinal cone system function. Under such circumstances, portable ERG device might be used clinically as a screening tool for retinal function evaluation in prematurely born children.

Chromatic visual evoked potentials: A review of physiology, methods and clinical applications.

Objective assessment of the visual system can be performed electrophysiologically using the visual evoked potential (VEP). In many clinical circumstances, this is performed using high contrast achromatic patterns or diffuse flash stimuli. These methods are clinically valuable but they may only assess a subset of possible physiological circuitries within the visual system, particularly those involved in achromatic (luminance) processing. The use of chromatic VEPs (cVEPs) in addition to standard VEPs can inform us of the function or dysfunction of chromatic pathways. The chromatic VEP has been well studied in human health and disease. Yet, to date our knowledge of their underlying mechanisms and applications remains limited. This likely reflects a heterogeneity in the methodology, analysis and conclusions of different works, which leads to ambiguity in their clinical use. This review sought to identify the primary methodologies employed for recording cVEPs. Furthermore cVEP maturation and application in understanding the function of the chromatic system under healthy and diseased conditions are reviewed. We first briefly describe the physiology of normal colour vision, before describing the methodologies and historical developments which have led to our understanding of cVEPs. We thereafter describe the expected maturation of the cVEP, followed by reviewing their application in several disorders: congenital colour vision deficiencies, retinal disease, glaucoma, optic nerve and neurological disorders, diabetes, amblyopia and dyslexia. We finalise the review with recommendations for testing and future directions.

Genetic background of high myopia in children.

OBJECTIVE: High myopia is a significant risk factor for irreversible vision loss and can occur in isolation or as a component of various syndromes. However, the genetic basis of early-onset high myopia remains poorly understood. We aimed to identify the causative genetic variants for high myopia in a cohort of Slovenian children. METHODS: The study included children referred to a tertiary paediatric ophthalmology centre at the University Eye Clinic in Ljubljana between 2010 and 2022. The participants met the following inclusion criteria: age ≤ 15 years and high myopia ≤-5.0 D before the age of 10 years. Genetic analysis included exome sequencing and/or molecular karyotyping. Participants were categorized based on clinical presentation: high myopia with systemic involvement, high myopia with ocular involvement, and isolated high myopia. RESULTS: Genetic analysis of 36 probands revealed a genetic cause of high myopia in 22 (61.1%) children. Among those with systemic involvement (50.0%), genetic causes were identified in 13 out of 18 children, with Stickler's and Pitt-Hopkins being the most common syndromes. Among cases of high myopia with ocular involvement (38.9%), a genetic cause was found in 8 out of 14 probands, including (likely) pathogenic variants in genes related to retinal dystrophies (CACNA1F, RPGR, RP2, NDP). The non-syndromic ARR3- associated high myopia was identified in the isolated high myopia group. CONCLUSIONS: A genetic cause of high myopia was identified in 61.1% of children tested, demonstrating the value of genetic testing in this population for diagnosis and proactive counseling.

Perinatal risk factors associated with central retinal changes in former preterm children on optical coherence tomography angiography.

PURPOSE: To assess the association between perinatal risk factors for retinopathy of prematurity (ROP) and central retinal structures of former preterm children seen on optical coherence tomography angiography (OCTA). METHODS: This prospective cohort study included 40 children with a history of preterm birth and 33 healthy full-term children. We documented their birth weight, gestational age, other significant risk factors for ROP development and presence of ROP. Imaging was performed using swept-source OCTA, and quantitative evaluation was performed. Analytic parameters included the area of foveal avascular zone (FAZ), foveal depth (FD), central subfoveal retinal thickness (CSFT) and capillary density index (CDI) of the deep and superficial capillary plexus. RESULTS: Preterm children had significantly smaller FAZ, lower FD and higher CSFT compared to controls (all p < 0.001). Both groups exhibited no differences in total CDI at the superficial (p = 0.969) and deep capillary plexus (p = 0.370). The duration of mechanical ventilation correlated negatively with FAZ and FD but positively with CSFT. The duration of supplemental oxygen treatment correlated negatively with FD. The presence of intraventricular haemorrhage correlated negatively with FAZ and FD but positively with CSFT. Regression analysis found that the duration of mechanical ventilation and the presence of bronchopulmonary dysplasia were associated with lower FD (p = 0.002 and 0.01, respectively) and higher CSFT (p = 0.002 and 0.028, respectively). CONCLUSION: Central retinal anomalies were identified in former preterm children using OCTA. Macular changes were associated with several risk factors for ROP development.

What can visual electrophysiology tell about possible visual-field defects in paediatric patients.

Recognising a potential visual-field (VF) defect in paediatric patients might be challenging, especially in children before the age of 5 years and those with developmental delay or intellectual disability. Visual electrophysiological testing is an objective and non-invasive technique for evaluation of visual function in paediatric patients, which can characterise the location of dysfunction and differentiate between disorders of the retina, optic nerve and visual pathway. The recording of electroretinography (ERG) and visual-evoked potentials (VEP) is possible from early days of life and requires no subjective input from the patient. As the origins of ERG and VEP tests are known, the pattern of electrophysiological changes can provide information about the VF of a child unable to perform accurate perimetry. This review summarises previously published electrophysiological findings in several common types of VF defects that can be found in paediatric patients (generalised VF defect, peripheral VF loss, central scotoma, bi-temporal hemianopia, altitudinal VF defect, quadrantanopia and homonymous hemianopia). It also shares experience on using electrophysiological testing as additional functional evidence to other tests in the clinical challenge of diagnosing or excluding VF defects in complex paediatric patients. Each type of VF defect is illustrated with one or two clinical cases.

Noninvasive ventilation for respiratory distress syndrome is a potential risk factor for retinopathy of prematurity : Single Slovenian tertiary center study.

Retinopathy of prematurity (nROP) among extremely low gestational age newborns (ELGAN) in Slovenia has increased in recent years. At the same time mortality has further decreased and less invasive approaches for treatment of respiratory distress syndrome have been established. With the aim to study the possible association between the incidence of ROP and the duration of noninvasive ventilation, this retrospective study comprised ELGANs born during the first period (2010/2011), when invasive respiratory support was the prevalent method and in the second period (2015/2016), when noninvasive respiratory support was adopted. The results showed that the duration of noninvasive ventilation is a potential risk factor for ROP. Controlling for known risk factors for ROP and then adjusting for gestational age, number of transfusions and fraction of inspired oxygen (FiO2), the odds of ROP were 1.22 times greater (95% confidence interval, CI 1.01-1.48) with every additional week of noninvasive ventilation (p = 0.03).

Genetic Variability in Slovenian Cohort of Patients with Oculocutaneous Albinism.

Oculocutaneous albinism (OCA) is an inherited disorder affecting the visual system and skin pigmentation. Our aim was to evaluate genetic and clinical heterogeneity in a cohort of Slovenian paediatric patients with clinically suspected OCA using advanced molecular-genetics approach. In as much as 20 out of 25 patients, genetic variants explaining their clinical phenotype were identified. The great majority of patients (15/25) had genetic variants in TYR gene associated with OCA type 1, followed by variants in TYRP1, SLC45A2 and HPS1 genes causative for OCA3, OCA4 and Hermansky-Pudlak syndrome type 1, respectively. We concluded that OCA phenotype could not predict genotype and vice versa. Nevertheless, the diagnostic yield after targeted next generation sequencing (NGS) was 80% and proved to be affective in our paediatric cohort of patients with various degree of OCA. Even in 16 patients with normal complexion the diagnostic yield was 62,5%. Interestingly, we have identified a patient of white European ancestry with OCA3, which is an extremely rare report, and one patient with OCA due to the Hermansky-Pudlak syndrome type 1.

Chromatic VEP in children with congenital colour vision deficiency.

Visual evoked potentials to chromatic stimulus (cVEP) are believed to selectively test the parvocellular visual pathway which is responsible for processing information about colour. The aim was to evaluate cVEP in children with red-green congenital colour vision deficiency. VEP responses of 15 colour deficient children were compared to 31 children with normal colour vision. An isoluminant red-green stimulus composed of horizontal gratings was presented in an onset-offset manner. The shape of the waveform was studied, as well as the latency and amplitude of positive (P) and negative (N) waves. cVEP response did not change much with increased age in colour deficient children, whereas normative data showed changes from a predominantly positive to a negative response with increased age. A P wave was present in 87% of colour deficient children (and in 100% of children with normal colour vision), whereas the N wave was absent in a great majority of colour deficient children and was present in 80% of children with normal colour vision. Therefore, the amplitude of the whole response (N-P) decreased linearly with age in colour deficient children, whereas in children with normal colour vision it increased linearly. P wave latency shortened with increased age in both groups. cVEP responses differ in children with congenital colour vision deficiency compared to children with normal colour vision.

Choroidal structural changes in preterm children with and without retinopathy of prematurity.

PURPOSE: Evaluate choroidal structural changes in preterm children with and without retinopathy of prematurity (ROP) using image binarization technique on swept-source optical coherence tomography (SS-OCT) scans. METHODS: Prospective case-control study. Forty-one (79 eyes) children aged 5-15 years with a history of preterm birth and 33 (63 eyes) age-matched full-term children were recruited. Demographics including gestational age at birth, birth weight and history of ROP were documented. All subjects had undergone complete eye examinations, including best-corrected visual acuity and SS-OCT imaging. Subfoveal choroidal thickness (SFCT) was calculated, and images were binarized to obtain stromal and luminal areas (LA). The choroidal vascularity index (CVI) was derived from the proportion of LA to the total subfoveal choroidal area. RESULTS: There were no significant differences in SFCT between the preterm children with (286.63 ± 83.98 µm) or without (306.59 ± 77.29 µm) ROP and the full-term children (311.82 ± 42.87; p = 0.20 and 0.67, respectively). The CVI was significantly reduced in the preterm children with ROP (68.66 ± 3.24%; p = 0.005) compared with the CVI in the full-term control group (71.37 ± 3.63%); however, the CVI in the preterm children without ROP (71.68 ± 3.09%; p = 0.93) was not significantly affected. CONCLUSION: The reduced CVI in preterm children with ROP may indicate compromised choroidal vascularity. The CVI was found to be a more sensitive OCT biomarker than the SFCT and may be helpful in evaluating associated choroidal structural changes in preterm children, especially those with a history of ROP.

Color vision in the tritan axis is predominantly affected at high altitude.

The purpose of this study was to evaluate color vision during high altitude mountain climbing by applying the Mollon-Reffin Minimalist test to 14 climbers, all of whom were participating in the expedition to Ama Dablam (6,812 m) in Nepal. Before leaving for Nepal (at 300 m), all 28 eyes showed normal color vision in all 3 axes. At 1,300 m, 100% of eyes showed normal color vision in the protan and deutan axes, while 25% showed minimally reduced color discrimination in the tritan axis. At 4,000 m, 100% showed normal deutan axis, 4% minimally reduced protan axis, and 72% minimally reduced tritan axis discrimination. At 5,400 m 100% of eyes tested showed normal protan and deutan axis discrimination, while 75% showed minimally and 25% moderately reduced tritan axis discrimination. Back home at 300 m 3 days after return, 100% showed normal deutan, 4% minimally reduced protan, and 38% minimally reduced tritan axis discrimination. One year later, all eyes showed normal color vision in all three axes. Changes in tritan axis discrimination correlated well with increased heart rate (r = 0.69; p = 0.0001) and decreased oxygen saturation (r = 0.71; p = 0.001) at high altitude. This study shows that the tritan color vision axis is predominantly affected at high altitude, but that this reduced color discrimination is transient.