Pituitary Deficiencies Related to Optic Nerve Hypoplasia and Visual Acuity

Major Points and Findings:

This paper does not concern stem cells. It is a hospital record review of 197 children with optic nerve hypoplasia (ONH). The authors examined how likely a child with ONH is to develop hormone (pituitary) problems, which hormones are affected, and at what age. We include it because pituitary deficiencies, particularly low cortisol, low thyroid hormone and problems with water balance, can be dangerous if missed and are treatable with standard hormone replacement. Before any elective treatment is considered, this side of the condition should be checked and stable.

The evidence is observational and from one centre, so the percentages should be taken as approximate. As in earlier studies, ONH in both eyes with very poor vision carried the highest risk.

Aim:

To find out whether the health of the optic nerve, judged by visual acuity and by signs such as nystagmus, predicts how many pituitary deficiencies a child with ONH develops and how early, without relying on MRI findings.

Methods:

This was a retrospective chart review at a single freestanding children’s hospital in the United States (the authors are from Cincinnati Children’s Hospital Medical Center), covering patients seen by both endocrinology and ophthalmology between 1 January 2013 and 31 October 2022.

The review included 197 children with ONH. Children whose hormone deficiency was diagnosed, or whose eye examination was done, at another institution were excluded.

In this clinic the endocrine team aims to see a child within 2 to 7 days of an ONH diagnosis and to complete testing within a day of that visit. Children are then examined every 6 months, with screening blood tests every 6 to 12 months until age 3 and yearly after that.

The most recent best corrected distance acuity was graded on a modified WHO (ICD-11) scale as good, mild, moderate, severe (20/200 to better than 20/400) or profound (20/400 or worse, including light perception or none). In children who could not be tested, nystagmus (bilateral ONH) or an afferent pupillary defect (unilateral ONH) was taken as a marker of significant visual loss.

Hormone deficiencies were diagnosed using Endocrine Society guidelines:

• Growth hormone was assessed from growth measurements, IGF-1 and IGF-BP3, followed by stimulation testing. A peak below 10 ng/mL counted as deficient, a cut-off the authors note may over-diagnose.
• Thyroid function was measured as free T4 by equilibrium dialysis with TSH. Central hypothyroidism meant a low or rapidly falling free T4 with a TSH that failed to rise.
• Adrenal function was tested by first morning cortisol or low-dose ACTH stimulation. A peak cortisol below 18 mcg/dL was abnormal.
• Puberty was followed by yearly examination, with hormone tests if it was early or late.
• Water balance was screened with questions about thirst and urination, then sodium and osmolality, and a water deprivation test if needed.

Results:

Of the children, 51% were boys and 93% were non-Hispanic White. Only 4% were born before 32 weeks, so prematurity does not explain the visual loss. Median age at the first endocrine visit was 1.8 years, median follow-up 3.6 years, and median age at the end of the study 6.7 years. The main table accounts for 196 children, 139 (71%) with ONH in both eyes and 57 (29%) with ONH in one eye.

In total, 91 of 197 children (46%) had at least one pituitary deficiency and 63 (32%) had more than one.

Both eyes versus one eye:

• Any deficiency: 57% (79 of 139) with bilateral ONH against 21% (12 of 57) with unilateral ONH. The odds were 4.9 times higher (95% CI 2.4 to 10.1).
• Multiple deficiencies: 38% against 18% (odds ratio 2.9, 95% CI 1.3 to 6.2).
• Median age at first deficiency: 1.4 years (range 0 to 14.4) in bilateral and 3.1 years (range 0.2 to 15.4) in unilateral ONH (not statistically significant).
• Severe or profound loss in the worse eye: 80% of bilateral and 60% of unilateral cases.

Vision as a predictor: In bilateral ONH, the poorer the vision in the worse eye, the more deficiencies a child had, and first deficiencies appeared anywhere from birth to 15 years. Vision in the better eye did not predict anything. Among children with bilateral ONH, those with nystagmus (114 of 136, 84%) had any deficiency in 61% against 32% without nystagmus (p = 0.01), and multiple deficiencies in 41% against 14% (p = 0.02). In unilateral ONH, neither acuity nor an afferent pupillary defect (present in 70%) predicted hormone problems.

Across all children, the first deficiency to appear was central hypothyroidism in 45%, growth hormone in 22%, arginine vasopressin deficiency (the newer name for central diabetes insipidus) in 20%, ACTH (cortisol) deficiency in 11% and a puberty disorder in 2%.

Median age at diagnosis, regardless of order, was 0.6 years for vasopressin deficiency, 1.3 for hypothyroidism, 2.8 for growth hormone, 3.2 for ACTH, 7.3 for precocious puberty and 13.7 years for hypogonadotropic hypogonadism. Several ranges stretched to 15 or 16 years.

Conclusions:

The authors conclude that every child with ONH needs an urgent endocrine referral and continuing surveillance. Within that group, children with ONH in both eyes and moderate, severe or profound visual loss, or with nystagmus when vision cannot yet be measured, are at the highest risk and should be seen first when clinic capacity is limited. The authors suggest that routine laboratory screening might be relaxed at about 8 to 10 years in children with good or only mildly impaired vision, but should continue past 10 in children with profound impairment, and that puberty should be monitored to completion in everyone. They state that their flow chart reflects this study only and is not a consensus guideline.

Limitations stated by the authors: The design was retrospective, and practice may have varied between clinicians. Visual acuity could not be measured in every child and was measured by different methods. Unilateral ONH tends to be picked up later because the good eye masks the problem. The cohort was young, so puberty disorders are under-counted, and the population was 93% non-Hispanic White.

Background Information:

The introduction notes that ONH accounts for up to 12% of visual impairment in the United States and Europe, and that earlier studies found pituitary deficiencies in up to 72% of children with ONH. Older work tied hormone risk to MRI findings such as an absent septum pellucidum. More recent studies, which this one supports, indicate that the risk comes with ONH itself, whatever the midline brain structures look like.

Normal hormone tests at diagnosis do not rule out later problems. New deficiencies appeared in this cohort well into the teenage years.