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.

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.

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.

Kids N Fitness Junior: Outcomes of an Evidence-Based Adapted Weight Management Program for Children Ages Three-Seven Years.

Background: Few weight management interventions target young children with obesity from low-income minority families. Objective: To conduct a nonrandomized, pragmatic, pilot study of an adapted, evidence-based, weight management program (Kids N Fitness [KNF]) customized for children ages 3-7 years (Kids N Fitness Jr. [KNF-JR]) on changes in adiposity, nutrition, and physical activity behaviors. Methods: One hundred eighty children (ages 3-16) with ≥85th percentile BMI and their parents participated in one of two 6-week weight management interventions dependent on the child's age: KNF-JR: 3-7 or regular KNF: 8-16. Comparisons were made between baseline anthropometrics and health questionnaire responses, and those from weeks 6 to 18. Two-sample tests for equality of proportions with continuity were used to measure proportions of success between KNF-JR and KNF. Results: At week 6, both cohorts showed a mean decrease in BMI z-score (zBMI) of -0.02 (p = 0.3 for KNF-JR [n = 43]; p = 0.02 for KNF [n = 59], with no significant group differences. Among program completers, 75% of KNF-JR and 83% of KNF maintained or lowered zBMI at week 18 (within-group difference p < 0.01). On average across all participants, at week 18 vs. baseline, improvements occurred in screen time (p < 0.01 KNF-JR, p < 0.02 KNF), sweetened beverage intake (p < 0.01 KNF-JR, p = 0.03 KNF), physical activity (p < 0.01 KNF-JR and KNF), and water (p = 0.01 KNF-JR, non-significant KNF) and vegetable (p < 0.01 KNF-JR, p = 0.02 KNF) consumption. Conclusion: This pilot demonstrated that an evidence-based weight management program can be adapted for all age groups and results in improved BMI status. Larger, randomized controlled trials are needed to verify effectiveness and sustained impact.

Executive Functioning, Depressive Symptoms, and Intervention Engagement in a Sample of Adolescents Enrolled in a Weight Management Program.

Purpose: This study examines how baseline demographics, psychosocial characteristics, and intervention delivery predict engagement among adolescents with overweight and obesity seeking treatment. Methods: Data originates from a multisite randomized control trial evaluating the efficacy of an app-based weight loss intervention, compared with standard in-clinic model in adolescents with overweight and obesity. Participants were randomized to one of the three arms: (1) AppCoach, (2) AppAlone, or (3) Control. Demographic, executive functioning (EF), and depression questionnaires were completed at baseline. Percent engagement was compared within and between groups defined by demographics and depressive symptoms. Quantile regression was used to evaluate the association between age and EF on percent engagement. Results: Baseline demographics were not associated with engagement within or between groups. Neither baseline self-reported depressive symptoms (p = 0.244) nor deficits in EF (p = 0.34) were predictors of engagement. Univariate analysis found that the control arm had the highest engagement (83%) compared with AppCoach (63.5%) and AppAlone (22.5%, p = 0.02). Hispanic ethnicity was predictive of higher engagement in the control arm (p = 0.02). On multivariate quartile regression no other baseline characteristics were significant predictors of engagement. Conclusion: Baseline demographics and individual psychosocial characteristics were not related to engagement in this cohort. The intervention arm that required parental involvement resulted in the greatest engagement suggesting that family involvement may overshadow individual behavioral phenotype and thus promote better engagement. Further investigation is needed to understand how program delivery can be leveraged to optimize treatment engagement and outcomes in adolescence. Clinical Trial Registration number: NCT03500835.

Evolving central hypothyroidism in children with optic nerve hypoplasia.

BACKGROUND: Children with optic nerve hypoplasia (ONH) are at high risk for early-onset congenital central hypothyroidism (CH); however, reports of evolving, late-onset CH are rare and poorly documented. AIM: To examine the clinical and biochemical data of children with ONH who developed CH after documented normal thyroid function tests at an earlier age. PATIENTS AND METHODS: Children who developed late-onset CH were selected for review from an observational study (n = 214) that examined clinical risk factors for endocrinological abnormalities in children with ONH. RESULTS: Eight patients with ONH developed CH between the ages of 20-51 months. One child at age 28 months developed CH within 4 months of prior normal thyroid function tests. There were no associations among clinical, neuroradiographical, vision, and/or pituitary outcomes. CONCLUSIONS: Children with ONH may develop CH over time, and surveillance thyroid function tests may be necessary as frequently as every four months.

Time limited eating in adolescents with obesity (time LEAd): Study protocol.

BACKGROUND: Time limited eating (TLE) has been shown to be effective for weight loss and improvement of glycemic control in adults with obesity and type 2 diabetes (T2D), but has not been well studied in adolescents. TLE may be a more feasible, flexible and effective dietary intervention for adolescents because it removes the need for intensive counting of calories or macronutrients, and emphasizes eating during a specified time period. OBJECTIVES: The aim of this study is to assess the feasibility of a TLE approach in adolescents with obesity using a continuous glucose monitor (CGM) to promote adherence to the intervention. METHODS: We propose a prospective, randomized controlled trial, in 60 adolescents (ages 14-18) with obesity (BMI% ≥ 95th percentile). Youth will be randomized to one of three treatment groups for a 12-week intervention: Group 1) Low sugar and carbohydrate education (LSC, 5% of total daily calories from sugar (<35 g)/day; <90 g carbohydrate (CHO)/day) + blinded CGM (used to monitor adherence and glycemic outcomes without real time feedback), Group 2) LSC + TLE (16-h fast/8-h feed for 5 days per week) + blinded CGM, and Group 3) LSC + TLE+ real time feedback via CGM (to evaluate effect of providing CGM data on intervention efficacy). Outcomes will include change in total body fat (TBF) percentage measured on DEXA scan, BMI status and fasting blood glucose at 12 weeks compared to baseline. CONCLUSIONS: TLE is a potentially powerful lifestyle intervention that could be readily integrated into pediatric weight management programs to optimize their impact and accelerate healthy changes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03954223.

Light-adapted electroretinograms in optic nerve hypoplasia.

The purpose of the study is to characterise retinal function using light-adapted electroretinograms (ERGs) in a series of young children with ONH, congenital dysplasia of retinal ganglion cells. ERGs were recorded with chloral hydrate sedation in 27 children with ONH (18 with bilateral and 9 with unilateral ONH, age 4-35 months) and an adult reference population (n = 12). Stimuli included ISCEV standard flash, oscillatory potentials (OPs) and standard flicker as well as a light-adapted luminance-response series (photopic hill). The disc diameter to disc macula (DD:DM) ratio was measured from fundus photographs. The results are eyes with ONH, classified by DD:DM, were severe (0.35, n = 9), all had prolonged ERG implicit times and smaller i-waves than those of adults. Eyes with moderate or severe ONH also had smaller amplitudes for OPs and flicker ERGs and required stronger flashes to obtain the peak b-wave amplitude. Abnormalities of the photopic hill were a common but inconsistent feature of ONH and were not indicative of ONH severity. Abnormalities of the photopic hill of the ERG suggest that some cases of ONH may have retinal dysfunction with specific deficits in the ON or OFF pathways of the retina. ONH is a complex and heterogeneous condition that may involve dysfunction distal to the retinal ganglion cells.

An addiction-based mobile health weight loss intervention: protocol of a randomized controlled trial.

BACKGROUND: The notion of obesity as an addictive process is controversial. However, studies show that between 5.9 and 30.7% of adolescents with obesity report food or eating addiction. Few weight management interventions have tested techniques based on addiction medicine principles. METHODS: This multi-center randomized control trial (RCT) is designed to test the effectiveness of a mobile health (mHealth) weight-loss intervention based on addiction principles, such as withdrawal and tolerance, in a sample of 180 adolescents (ages 14-18) recruited from four pediatric weight management clinics in Southern California. Akin to a Multiphase Optimization Strategy (MOST) design evaluating multicomponent behavioral interventions, we will compare the combination of an app + phone coaching (App+Coach) to app alone (App) and in-clinic multi-disciplinary (Clinic) intervention arms. The primary outcome is mean change in zBMI and %BMIp95 over 18 months. We hypothesize that youth who receive App+Coach will have a greater reduction in body weight over the 18-month study period at a lower cost than standard of care models. Secondary outcomes include adherence to treatment regimen, intervention satisfaction, effect of the intervention on metabolic factors and activity level. We will also explore potential moderators of intervention effectiveness such as addictive eating habits, self-regulation and executive functioning. CONCLUSIONS: New and creative approaches are needed to address pediatric obesity. If successful, this RCT may provide an innovative and cost-effective mHealth approach, based on addiction methods, for weight loss among adolescents with overweight and obesity.

Brain Malformations Do Not Predict Hypopituitarism in Young Children with Optic Nerve Hypoplasia.

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 (<24 months) with ONH (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.

Efficacy of growth hormone replacement on anthropometric outcomes, obesity, and lipids in children with optic nerve hypoplasia and growth hormone deficiency.

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.

Hypothalamic dysfunction without hamartomas causing gelastic seizures in optic nerve hypoplasia.

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.

Failure of stem cell therapy to improve visual acuity in children with optic nerve hypoplasia.

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.

Serum prolactin concentrations in relation to hypopituitarism and obesity in children with optic nerve hypoplasia.

BACKGROUND/AIMS: The majority of children with optic nerve hypoplasia (ONH) develop hypopituitarism and many also become obese. These associated conditions are a major cause of morbidity and are possibly due to hypothalamic dysfunction. Because mild hyperprolactinemia often occurs in subjects with disorders of the hypothalamus, we examined whether hyperprolactinemia was present in children with ONH during the first 3 years of life and whether it was a marker for hypopituitarism and/or obesity. METHODS: Data were retrospectively analyzed from a registry study of children with ONH. The initial serum prolactin was obtained prior to age 36 months (n = 125) and compared with pituitary function and body mass index at age 5. RESULTS: 72% of subjects had an elevated initial serum prolactin and 60% had hypopituitarism. An elevated initial prolactin was associated with hypopituitarism (OR 2.58; 95% CI 1.16, 5.73), specifically with growth hormone deficiency (OR 2.77; 95% CI 1.21, 6.34). 31% of subjects had a body mass index ≥ 85th percentile, but this did not correlate with initial hyperprolactinemia. CONCLUSIONS: Early hyperprolactinemia correlates with the presence of hypopituitarism in children with ONH, but it is not a reliable prognosticator of hypopituitarism. Additionally, hyperprolactinemia does not predict future weight excess.

Newborn thyroid-stimulating hormone in children with optic nerve hypoplasia: associations with hypothyroidism and vision.

PURPOSE: To assess in children with optic nerve hypoplasia (ONH) whether newborn screening (NBS) thyroid-stimulating hormone (TSH) measurements can detect central hypothyroidism and whether newborn TSH or subsequent thyroidal status is associated with visual function. METHODS: From a registry of children with ONH at Children's Hospital Los Angeles, post-natal thyroidal status was retrospectively compared with NBS TSH levels in the subset of subjects born in California. The subset of subjects with outcome data at age 5 years was assessed for relationship of vision to NBS TSH levels and ultimate thyroidal status. RESULTS: A total of 135 subjects from the ONH registry were included in this study. Approximately 50% of subjects in each analysis were hypothyroid. Those diagnosed with hypothyroidism had lower median NBS TSH levels than did euthyroid subjects (3.2 vs 4.5 µIU/mL; P = 0.006) and significantly worse quantitative vision outcomes (median visual acuity, logMAR 3.0 vs 1.0; P = 0.039). Receiver operating characteristic analysis suggested an optimal NBS TSH cut-point of 3.3 µIU/mL. Serum TSH levels greater than this (30/43) were associated with relatively better vision outcomes (median visual acuity, logMAR 1.2 vs 3.3; P = 0.04). CONCLUSIONS: Children with ONH and lower NBS TSH levels are more likely to have central hypothyroidism and less likely to experience good vision than those with greater NBS TSH levels.

Presenting features and long-term effects of growth hormone treatment of children with optic nerve hypoplasia/septo-optic dysplasia.

BACKGROUND: Optic nerve hypoplasia (ONH) with/or without septo-optic dysplasia (SOD) is a known concomitant of congenital growth hormone deficiency (CGHD). METHODS: Demographic and longitudinal data from KIGS, the Pfizer International Growth Database, were compared between 395 subjects with ONH/SOD and CGHD and 158 controls with CGHD without midline pathology. RESULTS: ONH/SOD subjects had higher birth length/weight, and mid-parental height SDS. At GH start, height, weight, and BMI SDS were higher in the ONH/SOD group. After 1 year of GH, both groups showed similar changes in height SDS, while weight and BMI SDS remained higher in the ONH/SOD group. The initial height responses of the two groups were similar to those predicted using the KIGS-derived prediction model for children with idiopathic GHD. At near-adult height, ONH/SOD and controls had similar height, weight, and BMI SDS. CONCLUSIONS: Compared to children with CGHD without midline defects, those with ONH/SOD presented with greater height, weight, and BMI SDS. These differences persisted at 1 year of GH therapy, but appeared to be overcome by long-term GH treatment.

Optic nerve hypoplasia in North America: a re-appraisal of perinatal risk factors.

PURPOSE: The purpose of this study is to describe and clarify the birth and prenatal characteristics of a large cohort of children with optic nerve hypoplasia. METHODS: This is a descriptive report of 204 patients aged

Neuroradiographic, endocrinologic, and ophthalmic correlates of adverse developmental outcomes in children with optic nerve hypoplasia: a prospective study.

BACKGROUND: Developmental delay has been reported to occur with optic nerve hypoplasia, a leading cause of pediatric blindness, but has not been systematically examined for its prevalence and correlation with associated pathologies of optic nerve hypoplasia. OBJECTIVE: The purpose of this study was to determine the developmental outcomes of children with optic nerve hypoplasia and the correlation of development with neuroradiographic, endocrinologic, and ophthalmic findings. METHODS: We conducted a prospective analysis of 73 subjects diagnosed with optic nerve hypoplasia at <36 months of age for developmental outcomes at 5 years of age. Subjects underwent neuroradiographic imaging, endocrinologic testing and examination, and ophthalmologic examination; developmental outcomes were assessed by using the Battelle Developmental Inventory. RESULTS: At 5 years of age, developmental delay was present in 71% of subjects with optic nerve hypoplasia. Of patients with unilateral (18%) and bilateral optic nerve hypoplasia, 39% and 78%, respectively, experienced developmental delay. Corpus callosum hypoplasia and hypothyroidism were significantly associated with poor outcome in all of the developmental domains and an increased risk of delay. Absence of the septum pellucidum was not associated with adverse development. Six subjects had neither a neuroradiographic nor an endocrinologic abnormality, and of those, 4 were developmentally delayed. CONCLUSIONS: These prospective data confirm the significant association of developmental delay with optic nerve hypoplasia and identify corpus callosum hypoplasia and hypothyroidism as strong correlates. A diagnosis of optic nerve hypoplasia warrants neuroradiographic and endocrinologic testing for risk factors of delay and developmental assessments for early intervention planning.