Chapter 4

Introduction

Optic atrophy is a morphologic sequel to a multitude of anterior visual pathway insults that culminate in the loss of retinal ganglion cell axons.573,701,753 Histopathologically, it is characterized by a variable reduction of nerve diameter with loss of axons and little or no gliosis. Ophthalmoscopically, the disc retains its normal size and shows diffuse or segmental pallor. The pallor in optic atrophy has been attributed to thinning of the neural tissue of the optic disc and resulting changes in cytoarchitecture and decreased transmission of light, rather than to loss of optic disc capillaries or astrocytic proliferation.700,702 The ophthalmoscopic appearance of the atrophic disc alone occasionally suggests a specific mechanism of injury.872

In adults and older children with optic atrophy, results of the sensory visual examination (visual acuity, color vision, pupillary responses, visual field examination, and optic disc examination) often suggest certain mechanisms of optic nerve injury and definitively rule out others. In infants and toddlers, however, accurate subjective visual testing is often impossible, and clues to the underlying etiology must be sought in the associated systemic, neurological, and neuroimaging findings in addition to the information obtained in the family and medical history.

Infants and children may present with optic atrophy with a known underlying diagnosis (e.g., hydrocephalus, optic glioma) or may require a complete evaluation to establish such diagnosis. Referral may be initiated due to poor vision in one or both eyes or due to the presence of other disorders that require neuro-ophthalmologic consultation as a part of a multidisciplinary workup. A thorough gestational, prenatal, birth, and neonatal history is essential. A history of perinatal head trauma, prematurity, perinatal asphyxia, meningitis, encephalitis, hydrocephalus, and related disorders should be specifically sought. A family history should be obtained, with appropriate examination of family members and pedigree analysis to establish the diagnosis and the mode of transmission of suspected heritable cases.

A thorough ophthalmologic examination should then be undertaken. Attention to the appearance of the optic discs, pupillary examination, visual field testing, color vision performance, and any related physical findings may provide clues to the diagnosis. Long-standing cases with a relatively stable course are often found in children with a history of hypoxia, prematurity, meningoencephalitis, congenital hydrocephalus, microcephaly, craniostenosis, or previous head trauma. The clinical identification of such cases usually obviates the need for further diagnostic workup. In contrast, a previously normal child who develops progressive optic atrophy poses an entirely different diagnostic problem. Such a patient should undergo a thorough neurologic evaluation and, if deemed appropriate, neuroimaging studies with specific views of the anterior visual pathways and posterior fossa should be obtained. Other investigations for neurodegenerative, genetic, and metabolic disorders are customized to fit the overall clinical picture.

Optic atrophy is initially evaluated by observing the color of the discs. The disc appears pale, either in a diffuse or in a segmental pattern, and typically shows fewer than normal fine vessels on its surface. The optic discs of young infants may ordinarily appear gray and slightly pale in appearance, even when excessive pressure on the globe while prying the eyelids open (which may cause vascular blanching and apparent pallor) is avoided.441 The examiner must be cautious when concluding that optic atrophy is present in a young infant and should reconsider the diagnosis if it is incompatible with other clinical findings. Similarly, the finding of normal visual acuity in an older child does not exclude the possibility of optic nerve damage because the degree of optic atrophy is not tightly correlated with visual acuity. Certain parameters may impart a misleading appearance of pallor to a normal disc. These include a large optic disc size, a deep physiologic cup, and axial myopia.

Ophthalmoscopic inspection of the atrophic disc should be accompanied by an attempt to evaluate the peripapillary nerve fiber layer, if examination conditions permit.683 Generalized thinning, sectoral atrophy, wedge-shaped or

slit-like defects, and other patterns of nerve fiber layer dropout may be found in children with optic atrophy who are sufficiently cooperative or sedated. Abnormalities in the peripapillary nerve fiber layer often provide early clues regarding axonal loss in equivocal cases of optic atrophy. For instance, selective dropout of the nasal nerve fiber layer is a critical diagnostic sign of band atrophy. Other ophthalmoscopic correlates of nerve fiber layer loss include a more distinct appearance of the peripapillary retinal vessels, variable attenuation of retinal arterioles,272 loss of Gunn dots, and blunting of the macular reflex in children with optic atrophy.755

Although the appearance of the optic disc is usually unhelpful in localizing the site of visual system injury or defining its mechanism, important exceptions exist. Band atrophy is an important localizing sign in children because it signifies selective injury to axons that decussate in the chiasm to the contralateral hemisphere. Recognition of band atrophy is especially important in infants and young children, who commonly present with congenital suprasellar tumors and in whom accurate visual field testing is often impossible. Band atrophy appears as a horizontal stripe of pallor extending from the nasal to the temporal disc margin. Examination of the peripapillary nerve fiber layer shows selective dropout of the nasal sector. (The temporal sector is also absent; however, because the temporal nerve fiber layer is normally difficult to visualize, it cannot be used as a reliable gauge of nerve fiber dropout). The diagnosis of band atrophy can now be confirmed by optical coherence tomography (OCT).584

Bilateral band atrophy occurs exclusively in the setting of chiasmal injury (usually compression from a suprasellar tumor) and is accompanied by bitemporal hemianopia571 (Fig. 4.1). Unilateral band atrophy usually signifies intrauterine retrogeniculate injury with transsynaptic degeneration,369,376 but it may occasionally reflect a pregeniculate abnormality.539 The most common causes of congenital band atrophy in children are unilateral porencephaly, arteriovenous malformation, and ganglioneuroma, which involve the occipital lobe and lead to transsynaptic degeneration. A congenital optic tract syndrome may be a rare cause of congenital homonymous hemianopia and contralateral band atrophy539 (Fig. 4.2). Acquired band atrophy of one optic disc results from injury to the contralateral optic tract, and is usually accompanied by an afferent pupillary defect in the eye with the band atrophy.61a,504 The histology associated with band atrophy was discussed by Unsold and Hoyt.886 In cases purporting to show bilateral diffuse transsynaptic degeneration of the optic nerves due to bilateral cerebral lesions, coexisting primary damage to the optic nerves should be excluded.748

A congenital lesion involving the optic radiations may produce secondary neuronal loss in the lateral geniculate nucleus through the process of transsynaptic degeneration. This leads to a disorder termed homonymous hemioptic

hypoplasia, which is characterized by homonymous hemianopia, contralateral band atrophy of the optic disc, and corresponding changes in the nerve fiber layer bilaterally (Fig. 4.3). Transsynaptic degeneration of the retinogeniculate pathways is well documented to occur in nonhuman primates when the cerebral lesion occurs even during adulthood.208 In the case of humans, retrograde transsynaptic degeneration of the retinogeniculate pathways has been shown to occur following prenatal or perinatal lesions, but its occurrence after cerebral lesions in adults is considered rare. It is, however, well established that retrograde transsynaptic degeneration affects other neural systems in humans even when the injury occurs during adulthood. Some histopathological evidence points to the possibility of transsynaptic degeneration of the retinogeniculate pathway in humans even when the lesion occurs in adults, but the clinical significance is unknown.58

Congenital optic atrophy is uncommon. In infants, congenital disc anomalies are a much more common cause of optic nerve dysfunction than is optic atrophy.406 Many patients with clearly hypoplastic optic nerves show significant associated disc pallor. Hypoplastic nerves may also be misconstrued as atrophic when a white sector of the lamina cribosa is laid bare. In other cases, the hypoplastic disc can be confused with the optic cup, and the lamina cribosa with the neuroretinal rim. This interpretation is made more difficult when a yellowish rim of the retinal pigment epithelium extends over the border of the normal-sized lamina cribrosa. Prematurity is often associated with a unique form of pseudoglaucomatous cupping, which is probably a form of optic atrophy. Neuroimaging studies of the optic nerves are of limited use in differentiating optic nerve hypoplasia from optic atrophy because the dimensions of the optic nerves are generally reduced in either condition.

Epidemiology

Optic atrophy is a major cause of visual disability in children. In several studies, optic atrophy was found to be the leading cause of severe visual impairment among 2,527 Nordic children, followed by retinopathy of prematurity and amblyopia. It is also probably the leading cause of visual impairment in mentally handicapped children.89 The increasing survival rate of premature children in recent decades has resulted in an increased incidence of both cortical visual impairment and optic atrophy in infants, the latter largely explained by their greater predisposition to hydrocephalus and, to a lesser extent, associated perinatal hypoxiaischemia. Common infectious disorders, such as tuberculous

meningitis, can produce primary optic atrophy.26 Disorders that are rarely encountered in the United States, such as onchocerciasis and intracranial hydatid cysts, may also cause optic atrophy.240

The reported incidence of diseases associated with optic atrophy differs according to series. Referral bias plays an important role, with large neurosurgical referral centers more likely to report higher incidences of compressive or postpapilledema optic atrophy in children who have intracranial tumors or shunt failure and with neurological referral centers more likely to accumulate neurometabolic cases. Not all

cases of optic atrophy in children are readily classifiable. The availability of high-resolution neuroimaging modalities, such as magnetic resonance (MR) imaging, and the increased availability of blood tests to identify genetic mutations and metabolic products of enzymatic defects, have increased the diagnostic yield.564,716 In 1968, Costenbader and O'Rourk176 were able to determine the cause of optic atrophy in a series of children so affected in only 50%, which is in contrast to 89% of children in the series by Repka and Miller.716 In the latter study of 218 children with optic atrophy, the underlying causes included tumors (29%), postinflammatory

(meningitis, optic neuritis) (17%), trauma (11%), undetermined (11%), hereditary (9%), perinatal disease (9%), hydrocephalus (6%), neurodegenerative disease (5%), toxic/ metabolic disease (1%), and miscellaneous (3%). They found that in 13 children less than 1 year of age with optic atrophy, five had a history of intrauterine infection, prematurity, or perinatal trauma; three had tumors, and five had optic atrophy of undetermined etiology.

In the last decade, these authors have found that prematurity and hydrocephalus have become more important causes of optic atrophy.594 In patients without a history of prematurity, perinatal or postnatal trauma, meningitis, optic neuritis, or evidence of familial optic atrophy, the chance of an underlying tumor or hydrocephalus was 45%. The causative tumors included anterior visual pathway gliomas, craniopharyngiomas, other supratentorial tumors, pituitary adenomas, posterior fossa neoplasms, and orbital mass lesions. Rarely, optic atrophy occurs in children with autoimmune and col-

lagen vascular disease.75 Optic atrophy in children is therefore commonly accompanied by other neurological or systemic abnormalities. In this setting, intracranial, genetic, and neurometabolic diseases need to be ruled out. Although mitochondrial mutations account for most hereditary optic neuropathies, mitochondrial abnormalities have not been found in most nonhereditary cases of bilateral symmetrical optic atrophy.88

The natural history of visual loss due to optic atrophy or other causes in children can be difficult to ascertain due to the child's limited ability to provide an accurate history and greater capacity to compensate for handicaps. Children are probably more likely than adults to ignore unilateral visual loss. Many unclassifiable cases of childhood optic atrophy are undoubtedly caused by remote trauma, optic neuritis, neuroretinitis, or other disorders that went unrecognized during the acute phase. Most such cases are unilateral.