Full-field Scotopic Threshold Improvement after Voretigene Neparvovec-rzyl Treatment Correlates with Chorioretinal Atrophy.

PURPOSE: To analyze demographic and ophthalmic data in patients with and without chorioretinal atrophy after voretigene neparvovec-rzyl (VN) to identify possible causes for this phenomenon. DESIGN: Retrospective cohort study with longitudinal follow-up. PARTICIPANTS: A total of 71 eyes of 38 patients aged 2 to 44 years with RPE65-mediated retinal dystrophy treated with VN across 2 large gene therapy centers in the United States and Germany. METHODS: Patients treated with VN who developed atrophy were compared with those who did not. MAIN OUTCOME MEASURES: Gender, age, surgical center, spherical equivalent refraction, best-corrected visual acuity (BCVA), baseline full-field scotopic threshold testing (FST), and posttreatment change in FST. RESULTS: A total of 20 eyes of 12 patients developed atrophy after treatment with VN (28% of all eyes). There was no significant difference in gender, age, surgical center, or spherical equivalent refraction between the atrophy group and the no atrophy group. However, patients between school age and young adulthood were predominantly affected, whereas the youngest and the oldest patients did not develop atrophy. Baseline BCVA was better in patients who developed atrophy than those who did not (P = 0.006). The postoperative improvement in FST at 1 month was significantly higher in the atrophy group than in the no atrophy group (P = 0.0005), and this difference remained statistically significant at 1 year (P = 0.0001). There was no correlation to baseline FST, to inflammation, or to which eye was treated first. CONCLUSIONS: The degree of FST improvement after VN appears to be strongly correlated with the development of VN-related chorioretinal atrophy. This finding raises the possibility that atrophy may develop as a toxic or metabolic sequela of vector-mediated RPE65 expression. In light of the expanding number of retinal gene therapy clinical trials, this complication warrants further study because it may not be limited to VN. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The Pediatric Optic Neuritis Prospective Outcomes Study: Two-Year Results.

PURPOSE: Pediatric optic neuritis (ON) is a rare disease that has not been well characterized. The Pediatric ON Prospective Outcomes Study (PON1) was the first prospective study to our knowledge aiming to evaluate visual acuity (VA) outcomes, including VA, recurrence risk, and final diagnosis 2 years after enrollment. DESIGN: Nonrandomized observational study at 23 pediatric ophthalmology or neuro-ophthalmology clinics in the United States and Canada. PARTICIPANTS: A total of 28 (64%) of 44 children initially enrolled in PON1 (age 3-<16 years) who completed their 2-year study visit. METHODS: Participants were treated at the investigator's discretion. MAIN OUTCOMES MEASURES: Age-normal monocular high-contrast VA (HCVA). Secondary outcomes included low-contrast VA (LCVA), neuroimaging findings, and final diagnoses. RESULTS: A total of 28 participants completed the 2-year outcome with a median enrollment age of 10.3 years (range, 5-15); 46% were female, and 68% had unilateral ON at presentation. Final 2-year diagnoses included isolated ON (n = 11, 39%), myelin oligodendrocyte glycoprotein-associated demyelination (n = 8, 29%), multiple sclerosis (MS) (n = 4,14%), neuromyelitis optica spectrum disease (NMOSD) (n = 3, 11%), and acute disseminated encephalomyelitis (n = 2, 7%). Two participants (7%; 95% confidence interval [CI], 1-24) had subsequent recurrent ON (plus 1 participant who did not complete the 2-year visit); all had MS. Two other participants (7%) had a new episode in their unaffected eye. Mean presenting HCVA was 0.81 logarithm of the minimum angle of resolution (logMAR) (∼20/125), improving to 0.14 logMAR (∼20/25-2) at 6 months, 0.12 logMAR (∼20/25-2) at 1 year, and 0.11 logMAR (20/25-1) at 2 years (95% CI, -0.08 to 0.3 [20/20+1-20/40-1]). Twenty-four participants (79%) had age-normal VA at 2 years (95% CI, 60-90); 21 participants (66%) had 20/20 vision or better. The 6 participants without age-normal VA had 2-year diagnoses of NMOSD (n = 2 participants, 3 eyes), MS (n = 2 participants, 2 eyes), and isolated ON (n = 2 participants, 3 eyes). Mean presenting LCVA was 1.45 logMAR (∼20/500-2), improving to 0.78 logMAR (∼20/125+2) at 6 months, 0.69 logMAR (∼20/100+1) at 1 year, and 0.68 logMAR (∼20/100+2) at 2 years (95% CI, 0.48-0.88 [20/50+1-20/150-1]). CONCLUSIONS: Despite poor VA at presentation, most children had marked improvement in VA by 6 months that was maintained over 2 years. Associated neurologic autoimmune diagnoses were common. Additional episodes of ON occurred in 5 (18%) of the participants (3 relapses and 2 new episodes).

Etiology and Outcomes of Acquired Pediatric Sixth Nerve Palsies.

BACKGROUND: Acquired sixth nerve (CN6) palsies in children may be benign or associated with an underlying neurologic condition. In children who presented with isolated (no associated neurologic or ophthalmic symptoms or signs) CN6 palsies, the rate of newly diagnosed neurologic disorders (such as tumors) is unclear. Moreover, the factors associated with spontaneous resolution and amblyopia in children with acquired CN6 palsies are unknown. METHODS: We retrospectively reviewed the charts of all children younger than 18 years diagnosed with CN6 palsy at our institution from 2010 to 2020. We recorded ophthalmologic and neurologic history and examination findings, neuroimaging results, etiology of CN6 palsy, and outcomes including spontaneous resolution and amblyopia. We assessed etiologies of isolated and nonisolated CN6 palsies as well as frequency and factors associated with spontaneous resolution and amblyopia (in children ≤7 years). RESULTS: One hundred seventy-two children met inclusion criteria. Twenty CN6 palsies (12%) were isolated at presentation. Most isolated cases were presumed postviral or postvaccination (50%) or idiopathic (30%), but 2 cases (10%) were associated with newly diagnosed tumors. Spontaneous resolution occurred in 59% of CN6 palsies at a median of 12.3 weeks and was associated with older age (P = 0.03) and nontumor etiology (P = 0.006). Amblyopia developed in 18% of children at risk, exclusively in those with anisometropia, pre-existing strabismus, or younger than 12 months. CONCLUSIONS: Our findings and chart reviews suggest that approximately 10% of isolated acquired pediatric CN6 palsies are associated with a newly diagnosed brain tumor. This risk must be discussed with parents when considering immediate vs delayed neuroimaging. In addition, infants and children ≤7 years with secondary amblyogenic risk factors (anisometropia or pre-existing strabismus) require close follow-up to monitor and treat amblyopia.

Increase in Pediatric Pseudotumor Cerebri Syndrome Emergency Department Visits, Inpatient Admissions, and Surgeries During the COVID-19 Pandemic.

BACKGROUND: Pediatric pseudotumor cerebri syndrome (PTCS) is a vision-threatening condition that is associated with female sex and obesity in pubertal and postpubertal children. It is unknown whether the increase in childhood obesity during the COVID-19 pandemic has affected the rates and characteristics of pediatric PTCS. METHODS: We conducted a retrospective study of children evaluated for PTCS (inpatient or emergency department) at our children's hospital before (March 19, 2015 to March 19, 2020) and during (March 20, 2020 to February 20, 2021) the pandemic. We compared the monthly number of inpatient and emergency department encounters for pediatric PTCS before and during the pandemic. In addition, anthropometric and ophthalmologic characteristics of children evaluated for pediatric PTCS before and during the pandemic were compared. RESULTS: A total of 36 encounters in the 5 years before the pandemic and 26 encounters in the 11 months during the pandemic were identified. The median monthly number of encounters for pediatric PTCS was significantly higher during the pandemic compared with the 5 years before the pandemic (2 vs 0, P = 0.0021). Compared with prepandemic patients, children evaluated during the pandemic were older (median age 16 vs 14 years, P = 0.02), with higher rates of obesity (85% vs 66%, P = 0.05) and lower likelihood of reporting Caucasian race (4% vs 31%, P = 0.02). Pandemic patients had worse presenting visual acuity (median logMAR 0.14 vs 0.05, P = 0.05) and were more likely to have fulminant presentation (23% vs 6%, P = 0.04) and require surgical intervention (23% vs 6%, P = 0.04). CONCLUSIONS: At our children's hospital, the rate of inpatient admissions and emergency department visits for pediatric PTCS increased during the pandemic. The severity of disease and frequency of surgical treatment also increased. Racial and ethnic minorities seem to be disproportionately affected. These changes may be related to increasing rates of childhood obesity during the pandemic.

Methods of visual assessment in children with cortical visual impairment.

PURPOSE OF REVIEW: Cortical visual impairment (CVI) is the leading cause of pediatric visual impairment in developed countries. Currently, there is no standardized method of visual assessment in these children, who usually cannot participate in tests designed for typically developing children. A reproducible method of visual assessment that accurately reflects the multitude of visual deficits in CVI is critical to evaluate proposed therapies for this disorder. This review analyzes current research on methods of visual assessment in children with CVI. RECENT FINDINGS: Earlier studies focused on measuring visual acuity in children with CVI. More recent studies have emphasized other aspects of visual function, such as contrast sensitivity, motion detection, and visual search. Current research topics include questionnaires, functional vision assessment (CVI Range), neuropsychological tests of visual perception, and eye tracking. Eye tracking shows promise for visual assessment in both clinical and research settings because it is objective and quantitative, with the ability to assess diverse visual parameters. SUMMARY: Current research on visual assessment in children with CVI focuses on measuring deficits of visual function beyond visual acuity. This research represents an important step toward designing clinical trials to identify effective therapeutics for this increasingly prevalent disorder with heterogeneous manifestations.

Repeated measurements of ERGs and VEPs using chloral hydrate sedation and propofol anesthesia in young children.

PURPOSE: Sedation with chloral hydrate or anesthesia using propofol allow ocular examination and testing in young children, but these drugs may affect electrophysiologic recordings. We compared the flash and pattern ERGs and VEPs recorded with each drug in a cohort of young children enrolled in a prospective study of optic nerve hypoplasia (ONH) syndrome. METHODS: ERGs and VEPs to light-adapted, standard, full-field flashes, to standard and steady-state pattern-reversal (PR) were recorded with cycloplegia in 9 participants. Age range at the first session, with chloral hydrate was 8-23 mo; at the second session with propofol it was 20-29 mo. Examiners masked to the drug and clinical conditions measured the waveforms for longitudinal, paired comparisons between the sessions. RESULTS: Flash ERG amplitudes did not differ between sessions; peak times were longer at the second session (propofol) by clinically insignificant amounts (< 2 ms, p = 0.002). Standard PERGs had larger amplitudes and later peaks in the second session (propofol) than with chloral hydrate (P50 2.9 vs 4.7 µV, p = 0.016 and 43 vs 52 ms, p < 0.001; N95 4.0 vs 6.1 µV, p = 0.003 and 91 vs 98.5 ms p = 0.034.). These differences were present for those with an interval of  > 10 mo between sessions (n = 5, 10 eyes) but not for those with a shorter inter-test interval (< 8 mo, p > 0.05, n = 4). Magnitudes of the steady-state PERGs did not differ between tests but the waveforms had earlier peaks at the second test with propofol. Flash VEP waveforms were present in 10/18 eyes and showed 72% agreement for recordability between sessions. Standard pattern VEPs were recordable in only a few eyes in this cohort with ONH. CONCLUSIONS: Light-adapted flash ERG waveforms were generally similar with chloral hydrate and with propofol. Larger PERGs with later peaks, found in the second session (propofol) could reflect maturation of the PERG generators, as the differences found were associated with a greater age difference between the sessions, but we do not rule out that small differences in the waveforms may be drug-related. There are insufficient VEP data from these children with ONH to identify drug-related or maturational effects on VEPs.

Factors Associated With Lack of Vision Improvement in Children With Cortical Visual Impairment.

BACKGROUND: Improvement in vision has been noted in children with cortical visual impairment (CVI), resulting from disparate types of brain injury. The purpose of our study was to determine the risk factors associated with poor recovery of vision in this group of patients. METHODS: Case records of children who were born before 2010 with at least 4 follow-up visits for CVI were reviewed for underlying etiologies of CVI, visual acuity (VA), and associated neurological and ophthalmological disorders. VA was assessed in 6 qualitative grades. Changes in VA were recorded as the difference between the grades of VA at presentation and the last follow-up visit. The outcome was calculated as a ratio of actual improvement to potential improvement in grades of qualitative VA. Multiple linear regression determined factors associated with lack of vision improvement in all children and based on etiology. RESULTS: Fifty-three children with CVI were identified. The median age at presentation was 13.6 months (range: 2.9-76.4 months) and the median follow-up was 5.8 years (1.1-16.3 years). CVI resulted from central nervous system (CNS) malformation (9.4%), hypoxic/inflammatory injury (15.1%), seizures (24.5%), and combined causes (51.0%). Vision improvement was noted in 83% of children. Lack of VA improvement was associated with older age at presentation in all children with CVI and within each etiological group except CNS malformation. None of the other investigated variables were associated with poor recovery of VA. CONCLUSIONS: Most of the children with CVI showed improvement in vision. Older age at presentation, but not etiology of CVI, was associated with poor improvement in VA.

Predictive value of N95 waveforms of pattern electroretinograms (PERGs) in children with optic nerve hypoplasia (ONH).

PURPOSE: As part of a long-term, prospective study of prenatal and clinical risk factors for optic nerve hypoplasia (ONH) at Children's Hospital Los Angeles, pattern ERGs (PERGs) were evaluated for prognostic value using an automated objective and robust analytical method. METHODS: Participants were 33 children with ophthalmoscopically diagnosed ONH [disc diameter-to-disc macula ratio (DD/DM) less than 0.35 in one or both eyes on fundus photographs]. Using cycloplegia and chloral hydrate sedation in one session before 26 months of age, we recorded PERGs to checkerboard reversal using five check sizes. Participants were followed with clinical and psychometric testing until 5 years of age. PERGs were analysed using automated robust statistics based on magnitude-squared coherence and bootstrapping optimized to objectively quantify PERG recovery in the challenging recordings encountered in young patients. PERG measures in the fixating or better-seeing eyes were compared with visual outcome data. RESULTS: PERG recording was complete to at least three check sizes in all eyes and to all five sizes in 79%. Probability of recording a PERG that is significantly different from noise varied with check size from 73% for the largest checks to 30% for the smallest checks (p = 0.002); smaller waveforms were associated with earlier implicit times. The presence of significant PERGs in infancy is associated with better visual outcomes; the strongest association with visual outcome was for the threshold check size with a significant N95 component (ρ = 0.398, p = 0.02). CONCLUSIONS: Automated statistically robust signal-processing techniques reliably and objectively detect PERGs in young children with ONH and show that congenital deficits of retinal ganglion cells are associated with diminished or non-detectable PERGs. The later negativity, N95, was the best indicator of visual prognosis and was most useful to identify those with good visual outcomes (≤0.4 LogMAR). Although PERGs reflect function of the inner layers of the central retina, they lack the specificity required to determine prognosis reliably in individual cases.

Pediatric Optic Neuritis: What Is New.

Few diseases blur the margins between their childhood and adult-onset varieties as much as optic neuritis. This report will review our state of knowledge of pediatric optic neuritis, as well as its relationship to the latest consensus definitions of neuroinflammatory disease. Current diagnostic and treatment options will be explored, as well as our potential to uncover an understanding of pediatric optic neuritis through systematic prospective studies. The risk of evolving multiple sclerosis is probably less than in adults, but pediatric optic neuritis is more likely to be an initial manifestation of acute disseminated encephalomyelitis. Steroids may hasten visual recovery, but they do not change visual outcome except in cases because of neuromyelitis optica. The role of puberty in modifying the presentation and risk associations is unknown. Prospective studies are required to resolve these diagnostic and management issues.

Yucca brevifolia fruit production, predispersal seed predation, and fruit removal by rodents during two years of contrasting reproduction.

PREMISE OF THE STUDY: The distribution of Yucca brevifolia, a keystone species of the Mojave Desert, may contract with climate change, yet reproduction and dispersal are poorly understood. We tracked reproduction, seed predation, and fruit dispersal for two years and discuss whether Y. brevifolia is a masting species. METHODS: Fruit maturation, seed predation (larval yucca moths), and fruit dispersal (rodents) were monitored on a random sample of panicles during 2013 and 2014, which were years of high and low reproduction, respectively. Fates of fruits placed on the ground and in canopies were also tracked. Rodents were live-trapped to assess abundance and species composition. KEY RESULTS: In 2013, 66% of inflorescences produced fruit of which 53% escaped larval predation; 19.5% of seeds were destroyed in infested fruits. Total seed production was estimated to be >100 times greater in 2013 than 2014. One-third of the fruit crop fell to the ground and was removed by rodents over the course of 120 d. After ground fruits became scarce, rodents exploited canopy fruits. Rodent numbers were low in 2013, so fruits remained in canopies for 370 d. In 2014, fruit production was approximately 20% lower. Larvae infested the majority of fruits, and almost twice the number of seeds were damaged. Fruits were exploited by rodents within 65 d. CONCLUSIONS: High fertilization, prolific seed production, and low predispersal predation in 2013 suggests that pollinator attraction and satiation of seed predators influence masting in Y. brevifolia. Abundant, prolonged fruit availability to seed-dispersing rodents likely extends recruitment opportunities during mast years.

Comparison of human expert and computer-automated systems using magnitude-squared coherence (MSC) and bootstrap distribution statistics for the interpretation of pattern electroretinograms (PERGs) in infants with optic nerve hypoplasia (ONH).

PURPOSE: Pattern electroretinograms (PERGs) have inherently low signal-to-noise ratios and can be difficult to detect when degraded by pathology or noise. We compare an objective system for automated PERG analysis with expert human interpretation in children with optic nerve hypoplasia (ONH) with PERGs ranging from clear to undetectable. METHODS: PERGs were recorded uniocularly with chloral hydrate sedation in children with ONH (aged 3.5-35 months). Stimuli were reversing checks of four sizes focused using an optical system incorporating the cycloplegic refraction. Forty PERG records were analysed; 20 selected at random and 20 from eyes with good vision (fellow eyes or eyes with mild ONH) from over 300 records. Two experts identified P50 and N95 of the PERGs after manually deleting trials with movement artefact, slow-wave EEG (4-8 Hz) or other noise from raw data for 150 check reversals. The automated system first identified present/not-present responses using a magnitude-squared coherence criterion and then, for responses confirmed as present, estimated the P50 and N95 cardinal positions as the turning points in local third-order polynomials fitted in the -3 dB bandwidth [0.25 … 45] Hz. Confidence limits were estimated from bootstrap re-sampling with replacement. The automated system uses an interactive Internet-available webpage tool (see http://clinengnhs.liv.ac.uk/esp_perg_1.htm). RESULTS: The automated system detected 28 PERG signals above the noise level (p ≤ 0.05 for H0). Good subjective quality ratings were indicative of significant PERGs; however, poor subjective quality did not necessarily predict non-significant signals. P50 and N95 implicit times showed good agreement between the two experts and between experts and the automated system. For the N95 amplitude measured to P50, the experts differed by an average of 13% consistent with differing interpretations of peaks within noise, while the automated amplitude measure was highly correlated with the expert measures but was proportionally larger. Trial-by-trial review of these data required approximately 6.5 h for each human expert, while automated data processing required <4 min, excluding overheads relating to data transfer. CONCLUSIONS: An automated computer system for PERG analysis, using a panel of signal processing and statistical techniques, provides objective present/not-present detection and cursor positioning with explicit confidence intervals. The system achieves, within an efficient and robust statistical framework, estimates of P50 and N95 amplitudes and implicit times similar to those of clinical experts.

ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous.

The vertebrate basic helix-loop-helix (bHLH) transcription factor ATOH7 (Math5) is specifically expressed in the embryonic neural retina and is required for the genesis of retinal ganglion cells (RGCs) and optic nerves. In Atoh7 mutant mice, the absence of trophic factors secreted by RGCs prevents the development of the intrinsic retinal vasculature and the regression of fetal blood vessels, causing persistent hyperplasia of the primary vitreous (PHPV). We therefore screened patients with hereditary PHPV, as well as bilateral optic nerve aplasia (ONA) or hypoplasia (ONH), for mutations in ATOH7. We identified a homozygous ATOH7 mutation (N46H) in a large family with an autosomal recessive PHPV disease trait linked to 10q21, and a heterozygous variant (R65G, p.Arg65Gly) in one of five sporadic ONA patients. High-density single-nucleotide polymorphism analysis also revealed a CNTN4 duplication and an OTX2 deletion in the ONA cohort. Functional analysis of ATOH7 bHLH domain substitutions, by electrophoretic mobility shift and luciferase cotransfection assays, revealed that the N46H variant cannot bind DNA or activate transcription, consistent with structural modeling. The N46H variant also failed to rescue RGC development in mouse Atoh7-/- retinal explants. The R65G variant retains all of these activities, similar to wild-type human ATOH7. Our results strongly suggest that autosomal recessive persistent hyperplastic primary vitreous is caused by N46H and is etiologically related to nonsyndromic congenital retinal nonattachment. The R65G allele, however, cannot explain the ONA phenotype. Our study firmly establishes ATOH7 as a retinal disease gene and provides a functional basis to analyze new coding variants.

Autism assessment in children with optic nerve hypoplasia and other vision impairments.

AIM: This study examined the utility of standard autism diagnostic measures in nine children (aged 5-9y) with severe vision impairment and a range of social and language functioning. METHOD: The Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) were systematically modified and used to assess symptoms of autism in children with vision less than or equal to 20/800, the majority of whom had optic nerve hypoplasia. The results of the assessments, including analysis of symptom patterns, were compared with expert autism diagnoses. RESULTS: Modified autism measures demonstrated good agreement with clinical diagnoses. Symptoms found to be most and least reliable in discriminating autism from behaviors common to most children with congenital vision impairment are described. Comparisons of current behavior with parent-reported behaviors from a younger age suggested that some symptoms of autism in very young children who are congenitally blind may improve with age. INTERPRETATION: The ADOS and ADI-R are useful for clinical assessment and for advancing research efforts to understand autism symptoms in children with vision impairment. However, some autistic symptoms in very young children may change over time, and developmental changes should be closely monitored.

Comparison of Eye Tracking and Teller Acuity Cards for Visual Acuity Assessment in Pediatric Cortical/Cerebral Visual Impairment.

PURPOSE: To compare eye tracking and Teller acuity cards (TAC) for assessment of visual acuity in children with cortical, or cerebral, visual impairment (CVI). DESIGN: Reliability and validity study. METHODS: We recruited 41 children with CVI from a single academic pediatric neuro-ophthalmology clinic. All children performed eye tracking to measure visual acuity, and 26 children completed TAC assessment by a masked examiner. Additionally, 2 pediatric neuro-ophthalmologists graded visual behavior using the 6-level Visual Behavior Scale (VBS). Eye tracking and TAC were performed at baseline and at 1 month. Test-retest reliability of eye tracking and TAC were assessed using the intraclass correlation coefficient (ICC). Eye tracking and TAC visual acuities were correlated with one another and VBS scores using the Spearman correlation coefficient. RESULTS: Test-retest reliability was excellent for eye tracking measurement of visual acuity (ICC = 0.81, P < .0001). For pediatric CVI, TAC test-retest reliability was fair (ICC = 0.42, P = .04). There was a moderate correlation between eye tracking and TAC (r = 0.43, P = .03) and between TAC and VBS score (r = 0.50, P = .009), and a strong correlation between eye tracking grating acuity and VBS score (r = 0.72, P < .0001). CONCLUSIONS: In our cohort of children with CVI, grating acuity measured by eye tracking demonstrated higher test-retest reliability and stronger correlation with pediatric neuro-ophthalmologic assessment of visual behavior than Teller acuity. Objective determination of gaze direction by an eye tracking camera may be more accurate than human assessment in this population. Future research is needed to determine the optimal methods of longitudinal assessment of visual function and functional vision in children with CVI.

An unexpected turn: a case of torsional anomalous retinal correspondence after myectomy of previously anteriorized inferior oblique muscles in a child.

We report a case of torsional diplopia caused by presumed torsional anomalous retinal correspondence after myectomy of previously asymmetrically anteriorized inferior oblique muscles for inferior oblique overaction. Given this patient's experience, it may be prudent to operate with caution on previously anteriorized inferior oblique muscles, especially when anteriorization is performed at a very young age.