Cassandra Fink

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. CONCLUSIOONS. 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.

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.

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.

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.

Clinical electrophysiology and visual outcome in optic nerve hypoplasia.

Aims In optic nerve hypoplasia (ONH), the extent of functional loss of retinal ganglion cells cannot be determined by ophthalmoscopic examination. The prognostic value of visual electrodiagnostic tests in infants and toddlers with ONH was assessed by comparison with visual outcome. Methods 85 participants with ONH had electroretinogram (ERG) and visual-evoked potential (VEP) testing to flash and to pattern-reversal checks and ocular fundus photography prior to 36 months of age. These initial measures were compared with visual acuity outcomes at 5 years of age in the better-seeing eye. Results Visual outcomes ranged from normal to no light perception. Electrodiagnostic tests with prognostic value were: the amplitude of the flash VEP (Spearmans rank correlations, p<0.001), the threshold category of stimulus (flash or check size) that elicited a VEP (p<0.001) and the amplitude of the N95 component of the pattern ERG (PERG) to 4-degree checks (p<0.02). Optic nerve size and co-existing pallor were also significant correlates. Stepwise regression analysis composed a best prediction model from VEP threshold category, optic nerve size and optic disc pallor (R2=58%; p<0.001). Conclusions Optic disc diameter, observation of disc pallor, VEP and PERG testing in infancy are useful for establishing the visual prognosis at 5 years of age in children with ONH. This is consistent with the notion that these parameters are related to the anatomic and functional preservation of retinal ganglion cells.

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

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.

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 Childrens 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.

Prevalence and risk factors for disrupted circadian rhythmicity in children with optic nerve hypoplasia

Background/aims Children with optic nerve hypoplasia (ONH) have visual impairment and may have hypopituitarism and developmental delay. Children with ONH have also been reported to have abnormal sleep–wake cycles. We assessed the incidence and nature of sleep–wake abnormalities in children with ONH. Methods Rest–activity patterns were assessed in 23 children with ONH using actigraphy, which is a non-invasive method for continuously monitoring activity. The children also had formal assessment of pituitary function, visual acuity measurements, assessment of papillary responsiveness, MRI scans of the head and assessment of neurocognitive function. Results Sufficient actigraphy data were obtained on 19 of the children. Analysis of expressed rhythmicity revealed normal rest–activity patterns in 13 children (68%). Of the six children (32%) with abnormal rhythmicity, three had fragmented sleep, one had free-running rest–activity cycles and two were arrhythmic. Of the children with normal rhythmicity, the following were found: hypoplastic corpus callosum in 30%, growth hormone deficiency in 53%, hypothyroidism in 23%, adrenal insufficiency in 30%, diabetes insipidus in 0% and developmental delay in 15%. Of the children with abnormal rhythmicity, the following were found: hypoplastic corpus callosum in 66% (p>0.05), severe visual impairment in 100% (p=0.006), abnormal pupillary responsiveness in 85% (p=0.0084), cognitive impairment in 100% (p=0.04) and multiple hormonal deficiencies in 66% (p=0.03). Conclusions Abnormal rest–activity rhythmicity patterns are present in 30% of children with ONH. The best predictors of abnormal rhythmicity are severe vision impairment, abnormal pupillary responsiveness, developmental delay and multiple hormonal deficiencies.

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

BackgroundOptic nerve hypoplasia (ONH) with/or without septo-optic dysplasia (SOD) is a known concomitant of congenital growth hormone deficiency (CGHD).MethodsDemographic 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.ResultsONH/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.ConclusionsCompared 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.

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

BackgroundHypopituitarism 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.MethodsControlled 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.ResultsSubjects 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.ConclusionEarly 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.