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PURPOSE: To report an anatomic change observed in a series of patients who underwent subretinal injection of voretigene neparvovec-rzyl (VN) for RPE65-mediated Leber congenital amaurosis. DESIGN: Multi-center retrospective chart review. PARTICIPANTS: Patients who underwent subretinal VN injection at each of four participating institutions. METHODS: Patients were identified as having perifoveal chorioretinal atrophy if: i) the areas of atrophy were not directly related to the touch-down site of the subretinal cannula; and ii) the area of atrophy progressively enlarged over time. Demographic data, visual acuity, refractive error, fundus photos, optical coherence tomography, visual fields, and full-field stimulus threshold (FST) were analyzed. MAIN OUTCOME MEASURES: Outcome measures included change in visual acuity, FST, visual fields, and location of atrophy relative to subretinal bleb position. RESULTS: 18 eyes of 10 patients who underwent subretinal injection of VN were identified as having developed perifoveal chorioretinal atrophy. 8/10 patients (80%) developed bilateral atrophy. The mean age was 11.6 years (range: 5–20), and 6 patients (60%) were male. Baseline mean logMAR visual acuity and FST were 0.82 (standard deviation (SD): 0.51) and −1.3 log cd.s/m(2)(SD: 0.44), respectively. The mean spherical equivalent was −5.7 diopters (range: 11.50 to +1.75). Atrophy was identifiable at an average of 4.7 months (SD: 4.3) following surgery, and progressively enlarged in all cases up to a mean follow-up period of 11.3 months (range: 4–18). Atrophy developed within and outside the area of the subretinal bleb in 10 (55.5%) eyes, exclusively within the area of the bleb in 7 (38.9%) eyes, and exclusively outside the bleb in 1 (5.5%) eye. There was no significant change in visual acuity (p=0.45). There was a consistent improvement in FST with a mean improvement of −3.21 log cd.s/m(2)(p

We report a series of three young patients (ages: 22 months, 2 years, and 5 years) who developed subretinal deposits at post-operative week one following subretinal voretigene neparvovec-rzyl treatment for RPE65-mediated retinal dystrophy. In the 5-year-old, subretinal deposits were also observed in the inferior periphery of both eyes. All three patients experienced improved visual function with treatment, and both the macular and inferior subretinal deposits have improved or resolved over the follow-up period. These findings may inform the delivery parameters and safety profile of AAV-based gene therapy as the number of retinal gene therapy trials continues to grow.

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.

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. 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. Flash ERG amplitudes did not differ between sessions; peak times were longer at the second session (propofol) by clinically insignificant amounts ( 10 mo between sessions (n = 5, 10 eyes) but not for those with a shorter inter-test interval ( 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. 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.

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.

IntroductionIn patients with optic nerve hypoplasia (ONH), the visualisation of the optic disc can be challenging and the definitive diagnosis difficult to ascertain without fundus photography. The use of MRI for diagnosis has been reported as a diagnostic alternative with conflicting results. We retrospectively analysed a disease registry to determine the reliability of orbital MRI measurements of the optic nerve diameter to diagnose ONH, and the correlation with vision outcomes.Materials and methodsFrom a cohort of 140 patients with ONH (13% unilateral) that had reached age 5 years, we identified 43 subjects who had orbital MRI in addition to fundus photography performed prior to 2 years of age. We compared measurements of the optic nerve diameter from orbital MRI scans to the standard relative optic disc size (disc diameter/disc-macula (DD/DM) distance) by fundus photography. All patients had visual acuity tested at age 5 years. Spearman’s correlation coefficient was used to determine the correlation of orbital MRI measurements and fundus photography with the diagnosis of ONH, and with vision outcomes.ResultsRelative disc size (DD/DM)s=0.471; ps=−0.869; ps=−0.635; pDiscussionOrbital optic nerve diameter from MRI scans has moderate reliability in diagnosing ONH and predicting vision outcomes. Fundus photography for measurements of the optic nerve size should remain the reference for diagnostic confirmation of ONH. These data further support the prognostic value of fundus photography for eventual vision outcomes in this population.

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.

Background Cortical visual impairment (CVI) is the leading cause of pediatric visual impairment in developed countries, but there is currently no evidence-based treatment. A method of visual assessment that captures multiple domains of visual functioning may facilitate evaluation of proposed therapies. We have developed an eye-tracking protocol that evaluates afferent, efferent, and higher-order visual parameters in children with CVI. We report its validity and reliability in assessing visual acuity. Methods We recruited 16 children with CVI between the ages of 12 months and 12 years. Visual acuity was assessed clinically using a previously published six-level scale of visual behavior. Grating acuity was assessed by eye tracking using forced-choice preferential looking, which was performed at baseline and 1 month for reliability testing. Validity was assessed by correlating clinical acuity with grating acuity by eye tracking. Results Clinical visual acuity ranged from 3 to 6 on the six-level scale, and grating acuity ranged from 0.25 to 20 cycles per degree (logMAR 0.18-2.08). There was strong correlation between grating acuity by eye tracking and clinical acuity assessment (ρ = −0.82; P = 0.0002). Test–retest reliability was excellent, with an intraclass correlation coefficient of 0.96 (95% CI, 0.88-0.99). Conclusions Eye tracking demonstrates excellent reliability for visual acuity assessment and high correlation with clinical assessment of visual acuity in pediatric CVI. Future research is necessary to determine whether eye tracking can assess other visual and oculomotor parameters in children with CVI, a prerequisite for incorporating this technique into future clinical trials and patient care.

Background Cortical visual impairment (CVI) is the most common cause of pediatric visual impairment in developed countries, and cerebral palsy (CP) is diagnosed in approximately half of children with CVI. It is unknown whether children with CVI who also have CP (CVI+CP) have different characteristics and outcomes (with regard to visual acuity, strabismus, and response to strabismus surgery) than children with CVI without CP (CVI−CP). Methods The medical records of all children with CVI, with and without CP, evaluated at our institution between 2013 and 2019 were retrospectively reviewed. Presentation and outcomes of children with CVI+CP were compared to those with CVI−CP. Results A total of 151 children with CVI+CP and 153 children with CVI−CP were included. Children with CVI+CP were more likely to be diagnosed with significant refractive error (53.6% vs 41.2%; P = 0.03), optic atrophy (46.4% vs 32.7%; P = 0.01), and strabismus (82.8% vs 72.5%; P = 0.03) at presentation. Good ocular alignment after strabismus surgery was achieved in 30% of children with CVI+CP and 63.6% of children with CVI−CP (P = 0.48). Of 9 children with long-term (≥8 years) postoperative follow-up, 100% of CVI−CP patients achieved good outcomes compared with 0% of CVI+CP patients (P = 0.0079). Visual acuity at presentation and the percentage of patients who experienced improvement in visual acuity did not differ between groups. Conclusions In our study cohort, children with CVI+CP had a higher likelihood of ophthalmic comorbidities and may have worse long-term strabismus surgery outcomes than children with CVI−CP.

Importance Optic neuritis (ON) in children is uncommon. There are limited prospective data for visual acuity (VA) outcomes, associated diseases, and neuroimaging findings. Prospective data from a large sample would be useful for counseling families on treatment decisions and prognosis. Objective To prospectively study children with a first episode of ON, describe VA after 6 months, and ascertain the network's (Pediatric Eye Disease Investigator Group and Neuro-Ophthalmology Research Disease Investigator Consortium) ability to enroll pediatric patients with ON prospectively. Design, Setting, and Participants This nonrandomized cohort study was conducted from September 20, 2016, to July 20, 2018, at 23 sites in the United States and Canada in pediatric ophthalmology or neuro-ophthalmology clinics. A total of 44 children (aged 3-15 years) presented with a first episode of ON (visual loss, pain on eye movements, or both) within 2 weeks of symptom onset and at least 1 of the following in the affected eye: a distance high-contrast VA (HCVA) deficit of at least 0.2 logMAR below age-based norms, diminished color vision, abnormal visual field, or optic disc swelling. Exclusion criteria included preexisting ocular abnormalities or a previous episode of ON. Main Outcomes and Measures Primary outcomes were monocular HCVA and low-contrast VA at 6 months. Secondary outcomes were neuroimaging, associated diagnoses, and antibodies for neuromyelitis optica and myelin oligodendrocyte glycoprotein. Results A total of 44 children (mean age [SD], 10.2 [3.5] years; 26 boys [59%]; 23 White individuals [52%]; 54 eyes) were enrolled in the study. Sixteen patients (36%) had bilateral ON. Magnetic resonance imaging revealed white matter lesions in 23 children (52%). Of these children, 8 had myelin oligodendrocyte glycoprotein-associated demyelination (18%), 7 had acute disseminated encephalomyelitis (16%), 5 had multiple sclerosis (11%), and 3 had neuromyelitis optica (7%). The baseline mean HCVA was 0.95 logMAR (20/200), which improved by a mean 0.76 logMAR (95% CI, 0.54-0.99; range, -0.70 to 1.80) to 0.12 logMAR (20/25) at 6 months. The baseline mean distance low-contrast VA was 1.49 logMAR (20/640) and improved by a mean 0.72 logMAR (95% CI, 0.54-0.89; range, -0.20 to 1.50) to 0.73 logMAR (20/100) at 6 months. Baseline HCVA was worse in younger participants (aged

Cortical/cerebral visual impairment (CVI) is the most frequent cause of pediatric visual impairment in developed countries and is increasing in prevalence in developing nations. The most common underlying etiology is hypoxic-ischemic encephalopathy, particularly in premature children. Other causes include seizures, hydrocephalus, trauma, and infections. Because of neurologic comorbidities, children with CVI often present challenges in diagnosis and characterization of visual deficits. Caregiver questionnaires may aid in assessment of visual functioning, while newer types of neuroimaging, including functional neuroimaging and diffusion tensor magnetic resonance imaging, may provide further insights on structure-function relationships. Genetic testing may assist in identification of underlying genetic or metabolic syndromes. Although no standard therapy for pediatric CVI exists, advances in care of preterm children and those with hypoxic-ischemic encephalopathy may in future reduce the incidence of this disorder. In addition, various methods of visual stimulation and stem cells have been advocated as treatment for pediatric CVI. Future controlled trials using standardized methods of visual assessment are necessary to establish whether these interventions are superior to observation. Practitioners should work with families and teachers of children with CVI to optimize their environment for visual functioning. Comorbid ocular and systemic disorders, which are common, should be managed appropriately.

Joshua trees (Yucca brevifolia) produce large, indehiscent fruits that contain numerous large seeds. Seed dispersal in this species depends on rodents to dismantle fruits and extract the seeds which they disperse tens of meters from the source. Using camera trapping and fruits tied to bobbins, I show that white-tailed antelope squirrels (Ammospermophilus leucurus) and kangaroo rats (Dipodomys spp.) moved intact, fallen fruits 6 to 7 m from trees before opening them. Pocket mice (Chaetodipus fallax and Perognathus longimembris) and pinyon mice (Peromyscus trueii) dismantled fruits and harvested loose seeds but did not appear to move them although they readily harvested loose seeds. Mobilizing fruits may be an important, overlooked step in the seed dispersal process, especially if the fruits are indehiscent. Fruit-carrying behavior of rodents described in this study adds to the dispersal distance of Joshua tree seeds.

Anna Ryabets-Lienhard, DO*, Carly Stewart, MHA, Mark Borchert, MD, Mitchell E. Geffner, MD Center for Endocrinology, Diabetes, and Metabolism, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA; The Vision Center, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA; The Saban Research Institute, Children’s Hospital Los Angeles, 4661 Sunset Boulevard, Los Angeles, CA 90027, USA

Mark Borchert,1 Suzanne Bruce,2 David Wirta,3 Steven G Yoelin,4 Sungwook Lee,5 Cheri Mao,5 Amanda VanDenburgh5 1Children’s Hospital Los Angeles, Los Angeles, CA, USA; 2Suzanne Bruce and Associates, PA, Houston, TX, USA; 3David Wirta and Associates, Newport Beach, CA, USA; 4Medical Associates Inc., Newport Beach, CA, USA; 5Allergan plc, Irvine, CA, USA Purpose: Evaluate the safety and effectiveness of bimatoprost 0.03% for treatment of eyelash hypotrichosis in a pediatric population. Patients and methods: This multicenter, randomized, double-masked, parallel-group study was conducted at seven sites in the US and Brazil. Subjects with eyelash hypotrichosis caused by chemotherapy or alopecia areata (aged 5–17 years) or healthy adolescents aged 15–17years were enrolled (N=71). Subjects applied bimatoprost 0.03% or vehicle to upper eyelid margins once nightly for 4 months and were followed for 1 month post-treatment. Eyelash prominence was assessed using the validated 4-grade Global Eyelash Assessment scale with photonumeric guide. Changes in eyelash length, thickness, and darkness were measured by digital image analysis. Safety was assessed by adverse events and ophthalmic observations. Results: Eyelash prominence improved in a significantly greater proportion of subjects treated with bimatoprost compared with vehicle at month 4 (70.8% versus 26.1%; P

INTRODUCTION Because treatment and clinical management decisions for children with NF1-OPG remain challenging, we sought to establish evidence-based guidelines. We prospectively enrolled children with newly-diagnosed NF1-OPGs, and gathered standardized clinical neuro-oncology and ophthalmology assessments. METHODS Only children with NF1 and newly diagnosed OPGs, confirmed by central review, were eligible. Indications for obtaining the initial MRI, as well as factors associated with the decision to treat with chemotherapy or observe without treatment, were obtained. Quantitative visual acuity (VA), other ophthalmic features, and imaging were captured at standard time points. Goal enrollment is 250 subjects. RESULTS One-hundred thirty-three children (52% female) from 20 institutions met inclusion criteria, and were included in this preliminary analysis. Eighty-six percent of subjects were able to perform quantitative VA testing at enrollment. The most common reasons for the diagnostic MRI included screening related to NF1 diagnosis (36.8%), ophthalmologic concerns (29.3%), and non-ophthalmologic concerns (24.8%), such as headache. To date, twenty subjects have initiated treatment with chemotherapy, twelve (9%) at the time of the initial OPG diagnosis. Median age at OPG diagnosis was 3.1 years. Age and sex distribution were similar in subjects immediately entering the observation and treatment arms (median age 3.0 versus 3.5 years, respectively). CONCLUSION Most children with NF1-OPGs are observed at time of their initial OPG diagnosis, rather than treated. Importantly, a large proportion of children are able to complete quantitative VA testing at enrollment. Once enrollment is complete, these data will help to establish evidence-based guidelines for clinical management of NF1-OPGs.

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. 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 ). 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

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.

AimTo evaluate whether people with age-related macular degeneration (AMD) and a history of amblyopia have equal severity of AMD in both eyes.MethodsBilling records were used to locate all people with a history of amblyopia and AMD evaluated between 1 January 2003 and 1 June 2015 at a single ophthalmology institute. Two ophthalmic graders blinded to amblyopia status determined the severity of AMD in each eye using fundus photos and a validated grading scale.ResultsA total of 14 people were found to have AMD and a documented history of amblyopia. Average patient age was 77.0 years and average best corrected visual acuity was 20/160 in eyes with a history of amblyopia and 20/40 in fellow eyes without amblyopia. Eyes with a history of amblyopia were found to have a lower AMD severity score (mean lower score: −1.38; paired t-test P=0.019). Of the 11 people with asymmetric disease severity, 10 individuals had worse AMD in the non-amblyopic eye while one person had worse AMD in the amblyopic eye (P=0.0067).ConclusionsOur pilot study suggests that eyes with a history of amblyopia may manifest decreased severity of AMD compared with non-ambylopic eyes in the same patient. Further research is warranted to investigate this clinical observation.

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.

Background: Optic nerve hypoplasia (ONH), a leading cause of pediatric blindness, is associated with brain malformations and hypopituitarism in the constellation known as septo-optic dysplasia. Neuroimaging is used to anticipate hypopituitarism, but with unconfirmed reliability. We report prospective findings on the association of hypopituitarism with brain malformations. Methods: Children (n = 146; 87% bilateral) underwent baseline MRI and annual examinations and hormonal testing. Hypopituitarism status at age 5 years was classified. Results: A total of 74% had brain malformation(s). Hypopituitarism (69%) was not associated with brain malformations (p = 0.351); this persisted after adjusting for the laterality of ONH and the timing of MRI (padj = 0.869). No association was noted for absent septum pellucidum (38%; p = 0.073), corpus callosum abnormality (51%; p = 0.625), and major malformations (22%; p = 0.407). A malformation conferred a positive predictive value of 71% (95% CI: 62%, 80%), and a negative predictive value of 37% (95% CI: 22%, 54%). Overall, 10% (n = 15) of the cohort presented with a triad of absent septum pellucidum, corpus callosum abnormality, and other major malformation; only half (n = 8) of these had hypopituitarism. All 13 subjects with pituitary malformations manifested hypopituitarism, conferring predictive values of 100% (positive) and 34% (negative). Conclusions: Hypopituitarism and brain malformations are highly prevalent, but have unrelated associations with ONH. Brain MRI in infants and toddlers with ONH is an unreliable screen for hypopituitarism risk.

Wildfires are becoming more prevalent in montane conifer forests of the San Bernardino Mountains of southern California. The effects of fire on stand structure and composition of these forests has been extensively studied but there are far fewer studies on how wildfires affect the fauna. For five years after a wildfire in 2007, we live-trapped small mammals in three burn types: unburned, moderate-severity and high-severity. A primary objective of this study was to document the response of the small mammal community to high-severity fire. Pinyon mice were consistently more abundant in unburned forests and declined by 69–76% between unburned forests and moderate-severity and high-severity burns. In contrast, deer mice responded positively to fire. Their numbers increased by 72%–87% between unburned forests and moderate-severity and high-severity burns. Compared to unburned forests, chipmunk numbers were 43%–64% lower in moderate and high-severity burns. California ground squirrels were unaffected b...

This report describes gelastic seizures in patients with optic nerve hypoplasia and hypothalamic dysfunction without hypothalamic hamartoma. All participants (n = 4) from the optic nerve hypoplasia registry study at Children’s Hospital Los Angeles presenting with gelastic seizures were included. The clinical and pathology characteristics include hypothalamic dysgenesis and dysfunction, but no hamartomas. Optic nerve hypoplasia is the only reported condition with gelastic seizures without hypothalamic hamartomas, suggesting that hypothalamic disorganization alone can cause gelastic seizures.

IMPORTANCE: Next-generation sequencing can detect variants of uncertain significance (VUSs), for some of which gene therapy would not be advantageous. Therefore, the pathogenicity of compound heterozygous or homozygous variants should be confirmed before bilateral vitrectomy and administration of voretigene neparvovec-rzyl. OBJECTIVE: To describe an in vitro mutagenesis assay for assessing the pathogenicity of variants in the RPE65 gene. DESIGN, SETTING, AND PARTICIPANTS: This case series was conducted at 2 tertiary referral centers. Clinical history, imaging, and electrophysiologic testing results were reviewed from September 5, 2008, to December 31, 2019. Participants were 4 pediatric patients with Leber congenital amaurosis who were evaluated for or met the inclusion criteria for phase 1 to 3 clinical trials or were referred for voretigene neparvovec-rzyl treatment. MAIN OUTCOMES AND MEASURES: A functional assay was used to confirm the pathogenicity of novel RPE65 VUSs in 4 patients with Leber congenital amaurosis. RESULTS: Four patients with Leber congenital amaurosis had VUSs in RPE65. Patients 1 and 2 were siblings with the homozygous VUS c.311G>T p.(G104V). Patient 3 was a compound heterozygote with 1 known pathogenic allele, c.1202_1203insCTGG p.(Glu404AlafsTer4), and 1 VUS, c.311G>T p.(G104V), which segregated to separate alleles. Patient 4 was also a compound heterozygote with 1 pathogenic variant, c.11 + 5G>A, and 1 variant in trans, c.1399C>T p.(P467S). In vitro mutagenesis revealed that the G104V and P467S RPE65 proteins were catalytically inactive (0% isomerase activity). Patients 1 and 2 were excluded from participation in a phase 1 trial owing to high Adeno-associated virus 2 capsid-neutralizing antibodies. Patients 3 (G104V) and 4 (P467S) underwent successful surgical gene therapy with voretigene neparvovec-rzyl, and their response to lower white light intensity and visual field increased in fewer than 30 days after gene therapy intervention. CONCLUSIONS AND RELEVANCE: Findings from this study suggest that, in patients with missense mutations in RPE65, functional assays of protein function can be performed to assess the pathogenicity of variants in both compound heterozygous and homozygous cases. Given the potential risks of gene therapy operations, in vitro RPE65 activity testing should be considered to avoid the possibility of treating a false genotype.

Objective To determine the age- and race-specific prevalence of amblyopia in Asian and non-Hispanic white children aged 30 to 72 months and of strabismus in children aged 6 to 72 months. Design Cross-sectional survey. Participants A population-based, multiethnic sample of children aged 6 to 72 months was identified in Los Angeles and Riverside counties in California to evaluate the prevalence of ocular conditions. Methods A comprehensive eye examination and in-clinic interview were conducted with 80% of eligible children. The examination included evaluation of ocular alignment, refractive error, and ocular structures in children aged 6 to 72 months, as well as a determination of optotype visual acuity (VA) in children aged 30 to 72 months. Main Outcome Measures The proportion of 6- to 72-month-old participants with strabismus and 30- to 72-month-olds with optotype VA deficits and amblyopia risk factors consistent with study definitions of amblyopia. Results Strabismus was found in 3.55% (95% confidence interval [CI], 2.68–4.60) of Asian children and 3.24% (95% CI, 2.40–4.26) of non-Hispanic white children, with a higher prevalence with each subsequent older age category from 6 to 72 months in both racial/ethnic groups ( P= 0.0003 and 0.02, respectively). Amblyopia was detected in 1.81% (95% CI, 1.06–2.89) of Asian and non-Hispanic white children; the prevalence of amblyopia was higher for each subsequent older age category among non-Hispanic white children ( P= 0.01) but showed no significant trend among Asian children ( P= 0.30). Conclusions The prevalence of strabismus was similar in Asian and non-Hispanic white children and was found to be higher among older children from 6 to 72 months. The prevalence of amblyopia was the same in Asian and non-Hispanic white children; prevalence seemed to be higher among older non-Hispanic white children but was relatively stable by age in Asian children. These findings may help clinicians to better understand the patterns of strabismus and amblyopia and potentially inform planning for preschool vision screening programs. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Purpose To evaluate the effectiveness of stem cell therapy in improving visual acuity or optic nerve function in children with optic nerve hypoplasia (ONH). Methods Subjects with ONH aged 7-17 years who voluntarily elected to undergo stem cell therapy in China were matched with controls on age, visual acuity, and communication level. Visual acuity, optic nerve size, and sensitivity to light were assessed before stem cell therapy and twice after. Controls were evaluated on the same schedule. Results Two case–control pairs were enrolled. There were no clinically significant changes in pupillary constriction or optic nerve measurements in any participant eye. Improvement in visual acuity was noted in study participants regardless of treatment status. Conclusions On the basis of this small sample, there is no evidence that stem cell therapy improves visual acuity in children with ONH.

Purpose To determine the age-, gender-, and ethnicity-specific prevalence of myopia, hyperopia, and astigmatism in non-Hispanic white (NHW) and Asian preschool children. Design Population-based, cross-sectional study. Participants A population-based sample of 1501 NHW children and 1507 Asian children aged 6–72 months from Los Angeles County and Riverside County, California. Methods Eligible children underwent an in-home and in-clinic interview and a comprehensive eye examination including cycloplegic autorefraction from 100 census tracts. Main Outcome Measures The proportion of children with myopia (spherical equivalent [SE] ≤−1.00 diopter [D]), hyperopia (SE ≥ +2.00 D) and cylindrical refractive error ≥1.50 D in the worse eye. The astigmatism type was defined as with-the-rule (WTR; +cylinder axis 90°±15°) and against-the-rule (ATR; + cylinder axis 180°±15°); all other orientations were considered oblique (OBL). Results The prevalence of myopia, hyperopia, and astigmatism in NHW children was 1.20% (95% confidence interval [CI], 0.76%–1.89%), 25.65% (95% CI, 23.5%–27.9%), and 6.33% (95% CI, 5.21%–7.68%), respectively. The prevalence of WTR, ATR, and OBL astigmatism in NHW children was 4.33%, 1.00%, and 1.00%, respectively. Prevalence was lower with older age groups for astigmatism ( P = 0.0002), but not for myopia ( P = 0.82) or hyperopia ( P = 0.31). In Asian children, the prevalence of myopia, hyperopia, and astigmatism was 3.98% (95% CI, 3.11%–5.09%), 13.47% (95% CI, 11.8%–15.3%), and 8.29% (95% CI, 7.01%–9.80%), respectively. The prevalence of WTR, ATR, and OBL astigmatism was 6.50%, 0.80%, and 1.00% respectively. The prevalence of hyperopia was higher in girls than boys ( P = 0.0002), but no differences were found for myopia and astigmatism. Conclusions Hyperopia was the most common refractive error in both Asian and NHW children. However, compared with NHW children, myopia was relatively more prevalent, and hyperopia less prevalent, among Asian children. The prevalence of astigmatism was greatest in infants, and WTR astigmatism predominated at all ages. Myopia showed relatively stable prevalence across age groups, whereas hyperopia prevalence decreased after infancy and then increased again in older age groups; however, longitudinal studies are needed to evaluate refractive changes over time in individual children. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Wildfires in southern California chaparral burn at high intensities and often cover thousands of hectares. Some small mammals survive the fire, while others colonize from scattered unburned islands and from intact vegetation bordering the main fire perimeter. For ten years (2002–2011) we live-trapped two grids and used the number of captures to examine post-fire small mammal use of a narrow 65-m zone straddling the high-contrast edge between burned and unburned chaparral on the perimeter of a high-intensity wildfire. Results indicate that agile kangaroo rats (Dipodomys agilis) were captured more often in open, burned areas than in unburned chaparral. Deer mice (Peromyscus maniculatus) were captured equally in burned and unburned chaparral but did not show an affinity for either habitat or the edge of the burn. Pinyon mice (Peromyscus truei) were captured most often in unburned chaparral throughout the study but were prevalent on the burn edge in years one and four. In the first year post-fire, Ca...

Purpose To determine the prevalence and causes of decreased visual acuity (VA). Design Population-based cross-sectional study. Participants Multi-ethnic sample of children 30 to 72 months of age identified in Los Angeles. Methods All eligible children underwent a comprehensive ophthalmic evaluation including monocular VA testing, cover testing, cycloplegic autorefraction, fundus evaluation, and VA retesting with refractive correction. Decreased VA was defined as presenting or best-measured VA worse than 20/50 in children 30 to 47 months of age and worse than 20/40 for children 48 months of age and older. The prevalence and causes of decreased VA were determined, for both presenting and best-measured VA, in the better-seeing and the worse-seeing eyes. Main Outcome Measures Prevalence and causes of decreased vision. Results Presenting VA was assessed in 1840 children and best-measured VA was assessed in 1886 children. Presenting VA was decreased in the worse eye of 4.2% of Asian children and of 3.6% of non-Hispanic white (NHW) children. Close to one-fourth of these cases had no identifiable cause, and 81% of these resolved on retesting. Decreased presenting VA in the worse eye with an identifiable ophthalmic cause was present in 3.4% of Asian children and in 2.6% of NHW children. Decreased presenting VA attributable to simple refractive error (myopia ≥0.5 diopters [D]; hyperopia ≥3.0 D; astigmatism ≥2.0 D or ≥1.5 D for children older than 36 months) was present in the worse eye of 2.3% of Asian children and of 1.4% of NHW children and in the better eye of 0.5% of Asian children and of 0.3% of NHW children. Decreased best-measured VA attributable to a cause was present in the worse eye of 1.2% of both Asian children and NHW children and in the better eye of 0.2% of Asian and of 0.3% of NHW children. Amblyopia related to refractive error was the most common cause, and was 10 times as common as ocular disease. Severe visual impairment was rare. Conclusions Seventy percent of all decreased VA in Asian and NHW preschool children and more than 90% of decreased VA with an identifiable cause is related to refractive error—either uncorrected refractive error or amblyopia resulting from refractive error. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Background Hypopituitarism and obesity are causes of major lifelong morbidity in patients with optic nerve hypoplasia (ONH). Growth hormone deficiency (GHD) affects the majority of children with ONH, though the degree of deficiency and variability of early growth patterns range from early severe retardation to normal initial growth. The utility of early GH replacement for improving anthropometric, body composition, and lipid outcomes in patients with ONH and GHD, especially those with normal initial height velocity, is unknown. This study examines the effects of GH replacement in a cohort of children with ONH and GHD. Methods Controlled clinical trial from 2005–2014. The study included 17 children with ONH and untreated GHD. Those meeting criteria for growth deceleration were assigned to treatment with recombinant human growth hormone (n = 5) while those with normal height velocity were randomized either to treatment (n = 5) or to observation (no intervention, n = 7). Study duration was 3 years. Primary outcome measures included stature, weight, weight-for-stature, and BMI standard deviation score (SDS) at study completion. Results Subjects on GH, irrespective of entry growth trajectory, grew more on average in stature than controls by a difference of 0.98 SDS by study end; this effect persisted after adjusting for baseline overweight status. Treatment had an effect on weight SDS only after adjusting for initial overweight status, resulting in an average increase of 0.83 SDS more than controls. Subjects who were overweight at the outset experienced greater gains in both weight and stature SDS. Treatment had no statistically significant impact on weight-for-stature or BMI SDS. A reduction in body fat percentage was observed in those treated, both before (−6.1 %) and after (−4.3 %) adjustment for initial overweight status. Conclusion Early GH replacement has a positive effect on short-term statural outcomes in children with ONH and GHD, even in those exhibiting normal initial linear growth. Results were less conclusive regarding treatment effects on body composition and lipids.

Optic nerve hypoplasia (ONH) has been described as an increasingly prevalent cause of congenital blindness. Its association with hypopituitarism and absent septum pellucidum has been recognized for more than 40 years as "septo-optic dysplasia" or "de Morsier syndrome." More recent studies have suggested that these associations are independent of one another. This review was designed to assess the historical and recent evidence for associations of neuroradiologic, endocrinologic, and developmental problems in patients with ONH.Historical and contemporary literature review.The medical literature does not support the notion that Georges de Morsier ever described a case of ONH or recognized its association with hypopituitarism or missing septum pellucidum. Recognition of the critical association of ONH with hypopituitarism should be attributed to William Hoyt. Hypopituitarism and other more recently identified associations with ONH, such as developmental delay, hypothalamic dysfunction, and autism, are independent of septum pellucidum development. Other common neuroradiographic associations, such as corpus callosum hypoplasia, gyrus dysplasia, and cortical heterotopia, may have prognostic significance.Children with ONH need to be monitored for many systemic, developmental, and even life-threatening problems independent of the status of the septum pellucidum. "Septo-optic dysplasia" and "de Morsier syndrome" are historically inaccurate and clinically misleading terms that should be abandoned.

Objective To investigate risk factors associated with unilateral or bilateral decreased visual acuity (VA) in preschool children. Design Population-based, cross-sectional prevalence study. Participants Population-based samples of 6504 children ages 30 to 72 months from California and Maryland. Methods Participants were preschool African-American, Hispanic, and non-Hispanic white children from Los Angeles, California, and Baltimore, Maryland. Data were obtained by a parental interview and a detailed ocular examination. Logistic regression models were used to evaluate the independent associations between demographic, behavioral, and clinical risk factors with unilateral and bilateral decreased VA. Main Outcome Measures Odds ratios (ORs) for various risk factors associated with interocular difference (IOD) in VA of ≥2 lines with ≤20/32 in the worse eye, or bilateral decreased VA Results In multivariate logistic regression analysis, 2-line IOD with a VA of ≤20/32 was independently associated with Hispanic ethnicity (OR, 2.05), esotropia (OR, 8.98), spherical equivalent (SE) anisometropia (ORs ranging between 1.5 and 39.7 for SE anisometropia ranging between 0.50 to Conclusions Anisometropia and esotropia are risk factors for IOD in VA. Astigmatism and high hyperopia are risk factors for bilateral decreased VA. Guidelines for the screening and management of decreased VA in preschool children should be considered in light of these risk associations. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Objective To evaluate risk factors for astigmatism in a population-based sample of preschool children. Design Population-based cross-sectional study. Participants Population-based samples of 9970 children ages 6 to 72 months from Los Angeles County, California, and Baltimore, Maryland. Methods A cross-sectional study of children participating in the Multiethnic Pediatric Eye Disease Study and the Baltimore Eye Disease Study was completed. Data were obtained by clinical examination or by in-person interview. Odds ratios and 95% confidence intervals (CI) were calculated to evaluate potential associations between clinical, behavioral, or demographic factors and astigmatism. Main Outcome Measures Odds ratios (ORs) for various risk factors associated with astigmatism. Results Participants with myopia (≤−1.0 diopters) were 4.6 times as likely to have astigmatism (95% CI, 3.56–5.96) than those without refractive error, whereas participants with hyperopia (≥+2.00 diopters) were 1.6 times as likely (95% CI, 1.39–1.94). Children 6 to Conclusions In addition to infancy, Hispanic and African-American race/ethnicity and correctable/modifiable risk factors such as myopia, hyperopia, and maternal smoking during pregnancy are associated with a higher risk of having astigmatism. Although the prevalence of smoking during pregnancy is typically low, this association may suggest etiologic pathways for future investigation. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Purpose To describe the risk factors associated with hyperopia and myopia among children 6 to 72 months of age. Design Population-based cross-sectional study. Participants Population-based samples of 9970 children 6 to 72 months of age from Los Angeles County, California, and Baltimore, Maryland. Methods Participants were preschool African-American, Hispanic, and non-Hispanic white children (n = 9770) from Los Angeles, California, and Baltimore, Maryland. Parental questionnaires and a comprehensive eye examination were administered. Demographic, behavioral, and clinical risk factors associated with hyperopia (≥2.00 diopters [D]) and myopia (≤−1.00 D) were determined. Main Outcome Measures Odds ratios (ORs) for risk factors associated with myopia and hyperopia. Results Compared with non-Hispanic whites, African-American (OR, 6.0) and Hispanic (OR, 3.2) children were more likely to be myopic. Children 6 to 35 months of age were more likely to be myopic compared with those 60 to 72 months of age (OR, ≥1.7). Compared with African-American children, non-Hispanic white (OR, 1.63) and Hispanic (OR, 1.49) children were more likely to be hyperopic. Children whose parents had health insurance (OR, 1.5) and those with a history of maternal smoking during pregnancy (OR, 1.4) were more likely to have hyperopia. Astigmatism of 1.5 D or more at any axis was associated with myopia (OR, 4.37) and hyperopia (OR, 1.43). Conclusions Children in specific racial or ethnic groups and age groups are at higher risk of having myopia and hyperopia. Cessation of maternal smoking during pregnancy may reduce the risk of hyperopia in these children. Given that both myopia and hyperopia are risk factors for the development of amblyopia and strabismus, these risk factors should be considered when developing guidelines for screening and intervention in preschool children. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Autism is a developmental disorder characterized by impaired social interaction, problems in verbal and nonverbal communication, and stereotyped or repetitive activities and interests. Rather than a single condition, autism is today generally regarded as consisting of a spectrum of pervasive developmental disorders that together are known as autism spectrum disorders (ASDs). Optic nerve hypoplasia (ONH) is a congenital condition characterized by underdeveloped optic nerves and neurological impairment involving endocrine dysfunction and developmental delay, with or without brain malformations that are visible by way of neuroimaging tools. Increasing in prevalence, ONH is now the leading single ocular cause of blindness in children in the developed world, affecting 10.9 per 100,000 births (Patel, McNally, Harrison, Lloyd, & Clayton, 2006; Hatton, Schwietz, Boyer, & Rychwalski, 2007). Clinical observations and recent reports indicate a high frequency of ASDs in children with ONH (Ek, Fernell, & Jacobson, 2005; Parr, Dale, Shaffer, & Salt, 2010). In children with ONH, there are additional characteristics of ASD beyond those attributable to visual impairment alone, such as echolalia and stereotypic motor movements. We argue that ONH, like ASDs, should be considered a spectrum disorder to account for the range of severity in outcomes and symptoms associated with this condition. In addition, we believe the similarities in the two conditions illustrate the possibility of a shared neurodevelopmental origin. Comparing the similarities in these conditions may lead to a greater understanding of the risk factors contributing to either condition, as well as potential clinical outcomes, as the relationship is further explored. ASD AND BLINDNESS It is not surprising that ASDs are prevalent in children with ONH when one considers that published data indicate ASDs are overrepresented in the visually impaired population, with prevalence estimates as high as 1 case of autism in every 4 visually impaired persons (Brown, Hobson, Lee, & Stevenson, 1997), compared to 1 out of 110 in the general population (Rice, 2009). The behaviors and characteristics of children with vision impairment that resemble those of children with ASDs, including echolalia, pronoun reversal, stereotypic motor movements, and delays in developing pretend play, are often attributed to the vision impairment itself (Andrews & Wyver, 2005). These behaviors may be termed "blindisms," since they are explainable in the context of vision impairment. (For example, rocking or spinning may provide needed vestibular stimulation in a child with limited mobility due to lack of vision; language development and social interactions may be impaired in congenitally blind children due to their lack of concrete experiences and visual models.) The similarity of these "blindisms" to "autistic-like" behaviors, coupled with the absence of autism diagnostic measures designed for use with people who are blind or visually impaired, complicates the diagnosis of ASDs in children who are visually impaired." Thus, the debate concerning whether "true" autism is prevalent in children who are visually impaired remains unresolved. ASDs AND ONH Most reports of ASDs in children with vision impairment (ASDVI) are limited to children who have severe congenital blindness regardless of any cause (Brown, Hobson, Lee, & Stevenson 1977; Ek, Fernell, Jacobson, & Gillberg, 1998). There are a few reports focused specifically on children with ONH. In a group of 13 Swedish children with ONH and blindness, 6 had ASDs and 3 had "autistic-like" conditions. The remaining 4 children did not fall on the autism spectrum (Ek, Fernell, & Jacobson, 2005). Parr and colleagues reported in a sample of 83 children with ONH and severe vision impairment (with acuities of worse than 6/30), 31 (37%) had social, communicative, and repetitive or restricted behavioral difficulties. …