Optic nerve hypoplasia.

Optic nerve hypoplasia (ONH) is a congenital anomaly of the optic disc that might result in moderate to severe vision loss in children. With a vast number of cases now being reported, the rarity of ONH is obviously now refuted. The major aspects of ophthalmic evaluation of an infant with possible ONH are visual assessment, fundus examination, and visual electrophysiology. Characteristically, the disc is small, there is a peripapillary double-ring sign, vascular tortuosity, and thinning of the nerve fiber layer. A patient with ONH should be assessed for presence of neurologic, radiologic, and endocrine associations. There may be maternal associations like premature births, fetal alcohol syndrome, maternal diabetes. Systemic associations in the child include endocrine abnormalities, developmental delay, cerebral palsy, and seizures. Besides the hypoplastic optic nerve and chiasm, neuroimaging shows abnormalities in ventricles or white- or gray-matter development, septo-optic dysplasia, hydrocephalus, and corpus callosum abnormalities. There is a greater incidence of clinical neurologic abnormalities in patients with bilateral ONH (65%) than patients with unilateral ONH. We present a review on the available literature on the same to urge caution in our clinical practice when dealing with patients with ONH. Fundus photography, ocular coherence tomography, visual field testing, color vision evaluation, neuroimaging, endocrinology consultation with or without genetic testing are helpful in the diagnosis and management of ONH. (Method of search: MEDLINE, PUBMED).

Introduction

The congenital malformation optic nerve hypoplasia (ONH) is a unilateral or bilateral non-progressive underdevelopment of the optic nerve, accounting for about 15%-25% of infants with serious vision loss.[1] Over the years, the incidence of the disease seems to be rising.[2]

ONH may occur as an isolated defect or in association with other ocular abnormalities (microphthalmos, aniridia, coloboma, nystagmus, and strabismus), cranial abnormalities (agenesis of septum pellucidum, anenephaly, midline abnormalities of brain) or facial anomalies. It may occur as a component of the syndrome of septo-optic dysplasia (de Morsier's syndrome), which includes midline brain malformations and hypopituitarism.

ONH should also be suspected in all infants with signs of hypothalamic dysfunction or vision impairment as adverse outcomes can often be avoided with early intervention.

History

In 1884, Magnus was the first to describe a small pale optic nerve with presence of the retinal vessels unilaterally in a small child. The child had no apparent useful vision in that eye. This case presentation was the first to completely describe all the characteristics of optic nerve hypoplasia[3]

During the next 50 years, isolated additional 15 cases of ONH were reported[4]

In 1941, there was first reported association of ONH and absence of the septum pellucidum in a seven-month-old infant with congenital blindness and otherwise normal development[5]

In 1956, de Mosier described a patient with hypoplasia of the optic nerves and agenesis of the septum pellucidum and defined this as “septo-optic dysplasia.” Within six years, he reported 36 cases of septum pellucidum agensis, nine of which had an associated ONH[67]

Hoyt et al. first described the association of pituitary dwarfism with septo-optic dysplasia in 1970. In 1970, Hoyt and colleagues observed that some cases of septo-optic dysplasia also had hypopituitary dwarfism; hence, the evolution of the expanded term “septo-optic-pituitary dysplasia,” the descriptor most often used now. The term “septo-optic dysplasia” is often used only for the combination of ONH and absent septum pellucidum without hypopituitarism, whereas “septo-optic-pituitary dysplasia” refers to the additional presence of hypopituitarism. In that same year, Kaplan and co-workers described six patients with ONH, midline brain defects, and pituitary dwarfism[8]

Clark and Meyer described characteristic presentation of septo-optic-pituitary dysplasia in infancy with neonatal hypoglycemia and seizures as the chief complaint[9]

The concept of segmental (partial or incomplete) ONH was given in the report by Schwartz in 1915. He described a patient with bilateral ONH and binasal hemianopic field defects[10]

In 1972, Hoyt and colleagues proposed that this represented congenital retrograde axonal degeneration leading to hemihypoplasia of the optic nerves, resulting from damage to the optic tract or radiation or both.[11]

Embryogenesis of optic nerve hypoplasia

ONH occurs due to diminished number of axons in the involved nerve with normal development of supporting tissues and the retinal vascular system. Hotchkiss and Green postulated that ONH may result from an insult suffered by a normally developing system occurring any time between the sixth week and the fourth month of gestation.[12]

The correlation of macular lesions with the segmental involvement of the papilomacular axons is so specific as to suggest that ONH may result from ascending as well as descending neuronal death.

Three major embryogenic theories have evolved. Supporters, who claim ONH to be occurring as an isolated ocular defect, believe that primary failure of the ganglion cells occurs between the 12 and 17-mm stages of embryogenesis.[13]

When ONH occurs in association with CNS anomalies, two other embryogenic theories have been proposed.[14]

Theory of the malformed chiasm: Normally developing ganglion cells that reach a malformed chiasm at the 18-mm stage cannot proceed across the midline into the opposite tracts, and thereafter undergo retrograde degeneration

Hypoplasia results from stretching of the optic nerves due to the abnormal development of the cerebral hemispheres and ventricular system, with retrograde degeneration of the ganglion cells of the retina. It is further proposed that developmental arrest may occur even later in those cases in which mainly uncrossed fibers are affected. The uncrossed fibers normally grow along the optic nerve at a later time than the crossed fibers. In albinism, due to the greater number of uncrossed fibers,[15] there may be a developmental delay and hence the association with albinism: Clinically apparent ONH is found in roughly 10% of patients with aniridia and may occur independently or in association with foveal hypoplasia.[16]

Inheritance

ONH is not an inherited disease. It is usually thought to be sporadic.[17] So, parents of patients may be assured that the siblings are not at an increased risk of the disease. Septo-optic dysplasia, less commonly, has been found to run in families. Most familial cases appear to have an autosomal-recessive pattern of inheritance. In few familial cases, autosomal-dominant pattern of inheritance has been also been noted.[18]

Prenatal risk factors

ONH may occur due to an insult anywhere along the developing visual system from the retinal ganglion cells to the occipital cortex.[19] There may be no obvious underlying etiology, or it may be associated with one of the following two causative factors: (1) a genetic alteration and (2) alteration of the intrauterine environment by maternal metabolic or toxic stress. About 70% of patients with ONH do not have any of the following risk factors.[20]

Genetic risks

The following genes are believed to be involved in ON development - netrin, POUF1, PROP1, SF-1, PITX2, NeuroD1, GATA-2, LHX3, TPIT, SOX3, SOX2, and HESX1.[21] Of these mutations, only HESX1 is reported to affect optic nerve development as well as anterior pituitary gland formation in humans. However, HESX1 mutations were found to be present in less than 1% of cases of ONH. Recent studies have reported association of superoxide dismutase with segmental hypoplasia.[22] Thus, a specific genotype/phenotype correlation has not yet been found to explain the majority of cases of ONH.

Gestational and exposure history

It appears that an insult to the developing optic nerve on or around the 17 mm stage of embryonal development results in ONH. Risk factors include:

Preterm birth

Low birth weight

Intrauterine growth restriction

Twin-twin transfusion syndrome

Young maternal age

Primiparity

Prenatal exposure to smoking, alcohol, recreational drugs, anti-depressants, anti-convulsants, anti-emetic, anti-fungal agents, infertility treatment, and quinine

Prenatal complications

Gestational diabetes

Toxemia

Viral infection (CMV)

Maternal anemia.

Types

ONH is often considered to be a more diffuse syndrome, but was sub-divided into three clinical subtypes.[23]

Type I: Optic Nerve Hypoplasia Simplex

A. Diffuse

B. Segmental

C. Segmental with tilt

Type II: Septo-optic dysplasia

Type III: Septo-optic-pituitary dysplasia.

It was suggested that tilted disc syndrome is a distinct subgroup of ONH without associated CNS defects. Superior segmental ONH (topless disc syndrome) may occur in children of insulin-dependent diabetic mothers.[24]

They have no other systemic abnormalities but only inferior visual field defects. They may have accompanying superior halo, superior neuroretinal thinning or superior disc pallor indicating maternal diabetes. Unilateral hemispheric lesions in the post-chiasmatic part of optic pathway may cause hemioptic homonymous visual field defects and hypoplasia.

Clinical features

Although mostly bilateral, the disease has been reported to be unilateral in 15-25% of cases.[25] The unilateral cases are usually detected at a later age than those bilaterally affected (owing to better vision) unless they present with other problems related to hypothalamic dysfunction. The incidence of ONH in males and females is equal. Asymmetrical as well as severe unilateral ONH commonly presents with concomitant squint.[2326]

Visual acuity

There appears to be little correlation between size of the optic nerve and its visual function. Visual acuity ranges in a wide spectrum from no light perception to near normal. ONH is a stable condition as far as vision is concerned. Visual function does not deteriorate with time. A mild improvement in visual function may occur as the result of maturation of the visual pathways. Patients may have no difficulties in work or other daily activities, the discovery of visual field defects may lead to the late diagnosis of ONH in patients with normal visual acuity.

Pupillary reactions

Careful assessment of the pupillary light reflex is very important as there is usually some degree of afferent pathway defect. This includes cases with normal visual acuity but with extensive field defects. In unilateral or asymmetrical cases, the Marcus-Gunn pupil can be elicited.[27]

Ophthalmoscopy

Diagnosis of ONH is primarily clinical. No current laboratory or radiographic tests establish the diagnosis. The most common mistake is labeling patients of ONH as optic atrophy. Hence, a careful clinical examination is a must.[28] In an infant, examination with sedation or general anesthesia, including fundus photography, may be required to differentiate ONH from optic atrophy.

The diagnosis of ONH is made by ophthalmic confirmation of a small optic disc with the vasculature appearing very large relative to the disc.[29]

The diagnosis of ONH in the extreme case is not usually difficult to make. The disc substance is markedly reduced and usually surrounded by an area of bare, exposed sclera which appears to coincide with the gap between the retinal pigment epithelial border and where a normal-sized disc should have extended. The retinal nerve fiber layer is variably thinned, and the disc itself may appear grayish or even white in color [Figure 1].

Figure 1

Fundus photograph of a patient with severe optic nerve hypoplasia demonstrating anomalous vessel morphology. The patient is a seven-year-old male child, with a small optic disc. The vasculature appears very large relative to the disc. The retinal nerve fiber layer appears thinned. The distance between macula and temporal edge of the disc is 0.4. The macula also appears to have a diminished light reflex

Diagnosis becomes much more difficult when the degree of hypoplasia is less extreme, or even segmental in nature, because clinically hypoplasia becomes difficult to appreciate. The calculated anatomic size of the disc varies from 39% of normal area to 93%. The ratio of disc to macula distance/disc diameter is characteristically increased in eyes with ONH. Ninety-five percent of the normal population has a ratio of 2.94.[26] The disc-macula: Disc diameter ratio as measured from fundus photographs when greater than three indicates milder forms of ONH.[303132] In all normal children, the ratio of the horizontal disc diameter (DD) to the distance between the macula and the temporal edge of the disc (DM) has been greater than 0.35. All eyes with a ratio of the horizontal disk diameter to the disk-macula distance less than. 30 had poor visual acuity.[33] (De Silva et al. found that the average DD/DM ratio of preterm, but otherwise normal, infants was 0.26 at birth; they found out that increased DD/DM ratio occurs with age. Therefore, the age of the patient may need to be considered when measuring DD/DM ratios). The macula may show a flattening of the normal contours and loss of the foveal light reflex. These changes are due to the relative absence of nerve fibers, the paucity of which can be discerned with red-free light[34]

Double ring sign-In cases of ONH, a pigmented ring is seen. It is presumably caused by migration of sensory retina and pigment epithelium from their original margin at the edge of the optic stalk to a new position at the border of the optic nerve that failed to fill, or regressed from, this area

Vascular signs-Tortuous retinal vessels may accompany ONH. This may affect arterioles, venules, or both. Alternatively, the vessels may be uncommonly straight with decreased branching.

Many authors believe that none of these signs is pathognomonic. Frisen and Holmegaard[35] stated that in mild ONH, the disc may be normal in diameter and that the double-ring sign may not be seen. Vascular tortuosity is also an inconsistent feature. Detection of nerve fiber layer thinning is not feasible in the neonatal period. Thus, diagnosis of milder degrees of ONH is problematic, and even more so in the premature neonate.

In another study, MRI of the intracranial visual pathways was compared with ophthalmologic measurements of optic disc size as means of detecting ONH to provide objective diagnostic support when ONH is clinically suspected. Authors found out that MRI of the visual pathways was a better diagnostic tool than measurement of the optic disc size in confirming the diagnosis of ONH.[36] Brodsky and Glasier introduced a classification of ONH based on the results of MRI of the central nervous system, which allowed one to predict in an individual child the risk of neurodevelopmental deficit and endocrinologic deficiency.[37]

Ocular associations

These include microphthalmos, aniridia, coloboma, nystagmus, and strabismus [Table 1].[28] Nystagmus usually develops at 1 to 3 months of age in cases of bilateral ONH. Strabismus (mostly esotropia) is seen in first year of life in unilateral ONH. The affected child may not be aware of people or objects in periphery

Table 1

Ocular associations of optic nerve hypoplasia

Unable to locate objects in space precisely due to lack of depth perception. Depth perception is more severe if vision loss is great

Child may have mild photophobia, avoid light by restricting participation in outdoor activities.

Electrophysiology

Electro-retinograms (ERGs) and electro-oculogram to flash stimuli are typically normal in ONH (due to normal photoreceptors in ONH). The amplitude of the visual evoked response (VER) is commonly reduced. Severe bilateral cases of ONH which present in early infancy may need to be differentiated from conditions such as achromatopsia and Lebers amaurosis. In these cases, the demonstration of a normal ERG response in the presence of an abnormal VER can be of critical diagnostic importance. Abnormalities that have been reported in some cases of ONH may suggest retinal dysfunction distal to the ganglion cell layer.

Systemic associations

ONH may occur as an isolated pathology or along with neurological or hormonal abnormalities. Hormonal problems not apparent in early life may appear later. Hormonal insufficiencies include thyroid, growth hormone (GH), pituitary, adrenal, and anti-diuretic hormone (ADH) deficiency. The risk of hormonal imbalances increases in cases where both eyes are affected, and/or if midline brain defects are present.[46] Hormonal deficiencies, however, may also occur in mild, unilateral cases, with no evidence of brain anomalies. Children with unilateral ONH are at significant risk for hypothalamic/pituitary dysfunction (69%)[47] and developmental delay (39%), although they are at lower risk than those bilaterally affected (81% and 78%, respectively). Behaviors of some children with ONH may be due to associated medical conditions, such as inattentiveness and irritability due to hypoglycemia.

Neurological associations

ONH is seen in 25% of cases of agenesis of the septum pellucidum. Conversely, 27% of patients with ONH had partial or complete absence of the septum pellucidum.[48] This condition is known as septo-optic dysplasia. The neurological features of this condition are mental retardation, spasticity, abnormalities of taste, and impaired smell.[623] Midline anomalies of the brain and other neurological associations: Anencephaly, cerebral atrophy, basal encephalocoeles, hypoplasia of the cerebellar vermis, cystic dilatation of the 4th ventricle, posterior fossa cysts, and anterior visual pathway space occupying lesions including tumors.[495051] Developmental delay often occurs in affected children. A retrospective review of 100 patients with ONH showed developmental delay in 32% and cerebral palsy in 13%. Patients with bilateral ONH and abnormal gray or white matter development had a higher rate of developmental delay (65%) than those without abnormalities (35%).[52] .” This condition was first described in 1956 by the Swiss neurologist De Morsier. In 1970, the American ophthalmologist Hoyt and his co-workers described the association between septo-optic dysplasia and hormonal insufficiency.

Hypothalamic dysfunction

All pituitary hormones can be affected due to defects of the hypothalamus, infundibulum, or the pituitary gland itself. The hormones affected and the associated clinical features are summarized in Table 2.

Table 2

Endocrine associations of optic nerve hypoplasia

Management

Physicians should be vigilant for signs of hypothalamic dysfunction along with any vision problems. Certain clinical features of ONH, its systemic associations, and aspects of their investigation are exclusive to infancy. These include difficulties in the investigation of the ocular features and assessment of visual function, neonatal hypoglycemia, and jaundice. All children with neonatal jaundice and recurrent hypoglycemia should have ophthalmoscopic evaluation, especially if the child has associated temperature instability. In addition, the investigation of cerebral structure is possible in infants by means of real-time ultrasound examination through the anterior fontanelle.[58] An MRI of the brain should be obtained. MRI has been shown to be a more sensitive modality for detecting intracranial abnormalities in patients with ONH.[37] An MRI can rule out treatable conditions such as hydrocephalus and others like developmental delay associated with corpus callosum hypoplasia or other major malformations. As neuroendocrine dysfunction can occur with or without a structural neurological anomaly, Skarf and Hoyt stated that scanning is not indicated unless the child shows clinical evidence of either hormone deficiency or a congenital anomaly.[25]

Endocrinologic work-up should include fasting morning cortisol and glucose, thyroid-stimulating hormone, free T4, IGF-1, IGFBP-3, and prolactin. If the child is less than six months of age, luteinizing hormone, follicle-stimulating hormone, and/or testosterone levels should be checked in order to anticipate delayed sexual development. Children should be monitored at least twice a year for growth. With growth deceleration, thyroid function tests should be repeated and a GH stimulation test should be performed. Free T4 should be rechecked annually for at least four years. If fasting cortisol is low, it should be repeated or provocative testing for cortisol should be done. Children with inadequate cortisol response to provocative tests should be given cortisol for administration during illness or physical stress. Occupational, physical, and/or speech therapy are frequently needed by children with ONH. Attention should especially be given to an early development of oral motor skills and acclimation to textured foods for those children resistant to eating.

Conclusion

The diagnosis of congenital ONH is of great importance because of the genetic and systemic implications. The ophthalmologist has the opportunity of being the first to diagnose an underlying disease or syndrome and referring patients for genetic and pediatric assessment. In children with ONH, vision development may be delayed. This means that they may have been perceived as blind in the first few months of life, but that vision improves to a certain extent up to two years of age. It is recommended that children with bilateral ONH, nystagmus, and poor vision should undergo a thorough neuroradiographic and endocrine examination. Based on the high incidence of structural brain malformations, which may be associated with an increased risk of endocrinopathy and developmental delay, it is advisable that neuroimaging of the brain is advisable in all patients with ONH. CT accurately delineates the altered anatomy of septo-optic dysplasia. The vision of young children with ONH should be monitored at least annually, and any refractive errors should be treated when the visual acuity reaches a functional level. Amblyopia treatment can result in improvement of vision in the worse eye. Early surgical correction of strabismus is needed for children who have symmetrical functional vision in the eyes, and thus have some potential for binocularity. Otherwise, correction of strabismus should be deferred until it is a psychosocial issue.

Although there is no cure or treatment per se, the purpose of early intervention programs and early vision stimulation programs is to minimize the impact of the vision loss on general development in patients of ONH.