American Academy of Ophthalmology Web Site: www.aao.org
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March 2006

 
Ophthalmic Pearls: Neuro-Ophthalmology
Diagnosing Septo-Optic Dysplasia
By Philip M. Smith, MD, and Vivian Rismondo, MD
Edited By Ingrid U. Scott, MD, MPH, and Sharon Fekrat, MD
 
 

Optic nerve hypoplasia is the most common congenital optic nerve anomaly. It is characterized by a reduced number of ganglion cell axons within the optic nerve, and it can occur in isolation or associated with other CNS abnormalities. When optic nerve hypoplasia occurs in conjunction with midline brain abnormalities, the absence of the septum pellucidum and agenesis or thinning of the corpus callosum, it is known as septo-optic dysplasia or de Morsier’s syndrome.

Septo-optic dysplasia is a rare congenital anomaly and has a reported prevalence of 6.3 per 100,000. It has a near equal distribution among males and females,¹ and it is typically diagnosed in newborns and infants. While absence of the septum pellucidum is not associated with specific cognitive or developmental abnormalities, visual loss and hypopituitarism associated with the midline brain abnormalities contribute to significant morbidity. Early detection and treatment of endocrine deficits can be life saving.

Patients with septo-optic dysplasia may present to medical professionals for a variety of reasons. From 60 to 90 percent of these patients present with blindness or symptoms of visual impairment. Signs related to visual loss include absent fixation, searching nystagmus, visual inattentiveness and strabismus. Three-fourths of patients may have other systemic conditions such as mental retardation, epilepsy or cerebral palsy or behavioral problems such as attention deficit disorder or autism. Other developmental abnormalities include underdeveloped midfacial structures, hypoglycemia, hyperbilirubinemia, disturbance in temperature regulation, muscular hypotonia, microgenitalism, low Apgar scores and failure to thrive.2

Optic Nerve Hypoplasia

Optic nerve hypoplasia is always present in septo-optic dysplasia. The optic nerve head is often gray or pale and typically one-third to one-half normal size. Classically, the optic nerve is surrounded by a ring of visible sclera and annular pigmentation, the “double ring” sign. The outer ring is the junction of the sclera and the choroidal pigment with the lamina cribrosa, and the diameter corresponds approximately to the size of a normal disc. The inner ring is darker and represents the junction of the termination of the retinal pigment epithelium with the hypoplastic optic nerve. The disc may or may not have significant cupping, and it can have spotted intradisc pigmentation. The nerve fiber layer can be thin due to the varying degrees of absent ganglion cells and their axons. Retinal vessel tortuosity may also be present.

The visual acuity with optic nerve hypoplasia ranges from 20/20 to no light perception, with most patients having visual acuity of 20/200 or worse. Because visual acuity is determined by the integrity of the papillomacular bundle, it does not necessarily correlate with the overall size of the optic disc. Invariably, however, affected eyes will show localized visual field defects, often combined with a general constriction of the visual fields. Optic nerve hypoplasia can occur unilaterally or bilaterally, and if bilateral it can be asymmetric. When it is unilateral or bilaterally asymmetric, there can be an associated relative afferent pupillary defect.

Other CNS Abnormalities

If optic nerve hypoplasia is suspected, workup for other CNS abnormalities is imperative. MRI, the optimal neuroimaging diagnostic tool for CNS abnormalities, provides high-contrast resolution and multiplanar images that show the anterior visual pathways distinctly. In optic nerve hypoplasia, coronal and sagittal MRI scans show a reduction in the intracranial optic nerve diameter, and in those with bilateral optic nerve hypoplasia there is thinning of the optic chiasm as well. MRI can be used to document an absent septum pellucidum and thinning or agenesis of the corpus callosum to confirm the diagnosis of septo-optic dysplasia.

Of patients with optic nerve hypoplasia, 45 percent also have cerebral hemispheric migration anomalies (schizencephaly, cortical heterotopias) or hemispheric injury (periventricular leukomalacia, encephalomalacia), which can be detected with MRI.3 These abnormalities are highly predictive of neurodevelopmental deficits. Absence of the septum pellucidum alone is not predictive of visual acuity, specific cognitive abnormalities or spatial orientation deficits. Thinning or agenesis of the corpus callosum alone is not predictive of neurodevelopmental defects; however, it is frequently associated with cerebral hemispheric abnormalities.

Fifteen percent of patients with optic nerve hypoplasia demonstrate neurohypophyseal abnormalities on MRI.3 In normal patients, the anterior and posterior pituitary and the infundibulum appear as a bright spot on high-resolution MRI. This is thought to be due to the posterior pituitary hormones and the phospholipid content of the vesicles harboring the hormones. Endocrine dysfunction is associated with absence of the infundibulum and with posterior pituitary ectopia. Absence of the infundibulum and its surrounding portal venous system results in the inability of the hypothalamus to stimulate the anterior pituitary, resulting in anterior pituitary hormone deficiency. The posterior pituitary hormones accumulate proximal to the site of injury and form an ectopic nodule, which shows as a hyperintense nodule at the median eminence on T1-weighted images. This bright spot is where the infundibulum is normally located. Hormone secretion from the ectopic tissue is sufficient to maintain posterior pituitary function; however, ectopia is nearly always associated with anterior pituitary dysfunction.

Endocrine Abnormalities

Growth hormone deficiency is the most common endocrinological abnormality, followed by deficiencies of thyroid-stimulating hormone, of corticotropic hormone and of vasopressin.

Growth hormone deficiency. Clinical signs of growth hormone deficiency include a decreased growth rate and neonatal hypoglycemia. The former may not be clinically evident within the first four years of life because of elevated prolactin levels that stimulate normal growth during this period.

Hypothyroidism. Clinical signs of hypothyroidism include prolonged neonatal jaundice, decreased growth rate and developmental delay.

Hypocorticalism. Clinical signs of hypocorticalism are neonatal hypoglycemia, hypotension, recurrent infections, seizures, developmental delay and poikilothermia (impaired temperature regulation). Low corticotropin levels are quite dangerous because they place children at risk for sudden death during physical stress such as febrile illness (the child is unable to regulate blood pressure and blood sugars in response to the physical stresses). Owing to the poikilothermia, such children also experience dangerously high fevers during illness and unusually low body temperatures during healthy periods.

Diabetes insipidus. Children with optic nerve hypoplasia also may have coexisting diabetes insipidus due to posterior pituitary abnormalities. The absence of the pituitary infundibulum and the posterior pituitary bright signal on MRI indicates posterior pituitary deficiency with consequent diabetes insipidus. Clinical signs of diabetes insipidus include polydipsia, polyuria and hypernatremia. This further increases the risk of death in response to physical stress, as children with diabetes insipidus often become severely dehydrated during stress, which hastens the development of shock.

Early identification and treatment of endocrine deficits has the potential to prevent significant mortality. Once a diagnosis of septo-optic dysplasia has been confirmed, an extensive evaluation of the hypothalmic-pituitary axis is necessary, and appropriate hormone replacement should be initiated. The endocrine deficits can be progressive; therefore, continued follow-up is indicated even if deficits are not initially identified.

Etiology

The etiology and pathogenesis of septo-optic dysplasia is not fully understood, but it is believed to be multifactorial, involving both environmental and genetic factors.

Pathogenesis. Early researchers attributed optic nerve hypoplasia to a primary failure of retinal ganglion differentiation. This, however, fails to explain the frequent coexistence of optic nerve hypoplasia with other CNS abnormalities. The frequent association of cerebral hemispheric abnormalities with optic nerve hypoplasia led to the hypothesis that there may be a disruption of neuronal guidance mechanisms that regulate the migration of both cerebral hemispheric neurons and optic nerve axons in utero.

Maternal age. Young maternal age has been associated with septo-optic dysplasia as well. The syndrome has been found to occur with increased frequency in the children of mothers who give birth in their middle to late adolescence. Maternal insulin-dependent diabetes mellitus is also associated with superior segmental optic nerve hypoplasia.

Both genetic and teratogenic causes also have been identified as possible causes of septo-optic dysplasia.

Genetic factors. Although familial cases of septo-optic dysplasia have been reported, most cases are sporadic. Mutations in the homeobox containing transcription factor HESX1 have been implicated. HESX1 has been identified as having a role in forebrain, midline and pituitary development. Individuals with mutations of HESX1 who have homozygous inheritance demonstrate a more severe phenotype, and those with a heterozygous inheritance have a milder phenotype.4

Teratogenic factors. Recognized teratogens associated with optic nerve hypoplasia include alcohol, quinine, anticonvulsants and illicit drugs.

Clinical Assessment

MRI is an important tool for the diagnosis of children with optic nerve hypoplasia. Cerebral hemispheric anomalies are predictive of neurodevelopmental deficits, and neurohypophyseal abnormalities are predictive of endocrinological deficiencies.

Evaluation of the hypothalamic-pituitary axis is imperative in children with optic nerve hypoplasia. Children with endocrinological deficiencies are at risk for impaired growth, hypoglycemia, developmental delay, seizures and death. Early detection of abnormalities and proper hormone replacement may prevent or limit these complications. Parents, pediatricians and neurologists of these children can follow them for clinical signs of hypopituitarism, including monitoring their growth rate.

Treatment

Infants who initially appear blind may have superimposed delayed visual maturation and therefore may have improvement of their vision during the first several months of life. In children with unilateral or asymmetric bilateral optic nerve hypoplasia, a superimposed amblyopia may reduce vision. The amblyopia should be treated with a trial of occlusion therapy. Children with hypopituitarism should be treated with appropriate hormone replacement.

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1 Parker, K. et al. J Pediatr Endocrin Metab 2002;15:697–700.
2 Lehnstein Campbell, C. Optometry 2003; 74:417–426.
3 Phillips, P. H. and M. C. Brodsky. “Congenital Optic Nerve Abnormalities,” in Pediatric Ophthalmology and Strabismus, 2nd edition. Edited by Wright, K. W. and P. H. Spiegel (New York: Springer-Verlag, Inc., 2003), 918–922.
4 Egan, R. A. and J. B. Kerrison. Ophthalmol Clin N Am 2003;16:595–605.

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Dr. Smith is a third-year resident at The Friedenwald Eye Institute at Maryland General Hospital, and Dr. Rismondo is clinical associate professor of ophthalmology at the University of Maryland and assistant professor of ophthalmology at Johns Hopkins Hospital.