Pamela Garcia-Filion

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.

Prenatal determinants of optic nerve hypoplasia: review of suggested correlates and future focus.

Optic nerve hypoplasia (ONH), a congenital malformation characterized by an underdeveloped optic nerve, is a seemingly epidemic cause of childhood blindness and visual impairment with associated lifelong morbidity. Although the prenatal determinants of ONH are unknown, early case reports have led to a longstanding speculation that risky health behaviors (e.g., prenatal use of recreational drugs, alcohol) are a likely culprit. There has yet to be a systematic review of the epidemiology of ONH to assess the common prenatal features that may help focus research efforts in the identification of likely prenatal correlates. A review of the past 50 years of epidemiologic research was conducted to examine the prenatal features linked with ONH and provide direction for future research. There are select prominent prenatal features associated with ONH: young maternal age and primiparity. Commonly implicated prenatal exposures (recreational or pharmaceutical drugs, viral infection, etc.) were rare or uncommon in large cohort studies of ONH and therefore unlikely to be major contributors to ONH. Familial cases and gene mutations are rare. The preponderance of young mothers and primiparity among cases of ONH is striking, although the significance is unclear. Recent research suggests a potential role for prenatal nutrition, weight gain, and factors of deprivation. With the rapidly increasing prevalence of ONH, future research should focus on investigating the relevance of young maternal age and primiparity and exploring the recently suggested etiologic correlates in epidemic clusters of 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.

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.

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.

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.