Chapter 593. Optic Nerve Disorders

Optic Nerve Hypoplasia

Optic nerve aplasia is extremely rare, and most often the diagnosis represents an extreme example of optic nerve hypoplasia. Optic nerve hypoplasia is characterized by a reduction in the number of axons within the optic nerve. The nerve head is small and often pale. There may be a white or yellow peripapillary halo surrounded by a ring of pigment (double ring sign) corresponding to the size of a normal disc (Fig. 593-1). The normal distance from the temporal disc edge to the macula is 3 to 3.4 disc diameters. If the optic nerve is small, the number of disc diameters increases to greater than 4 disc diameters. The retinal vasculature may be tortuous, and the fovea pit may be underdeveloped. On radiographic study, the optic canal is small. The diagnosis can be difficult if optic nerve hypoplasia is mild. Disc photography and quantitative assessment of optic nerve head features by a nerve head analyzer may be helpful in establishing a diagnosis.

Visual acuity ranges from normal to no light perception but is stable over time. It is difficult to predict vision outcome based on the appearance of the optic nerve head or with neuroimaging. Most cases are sporadic. Familial instances are rare. Optic nerve hypoplasia has been associated with fetal alcohol syndrome; maternal diabetes (usually a hemihypoplasia affecting the upper or lower half of the disc); maternal use of quinine, anticonvulsants, or aminopterin; maternal illicit drug use; in utero cytomegalic infection; toxemia; and adolescent pregnancy. Accompanying ocular disorders may include aniridia, albinism, coloboma, Duane retraction syndrome, high myopia, and numerous neurological and pediatric conditions.

Up to 78% of affected patients have bilateral optic nerve hypoplasia, and 75% have neurodevelopmental problems that accompany bilateral involvement. In bilateral optic nerve hypoplasia, particularly in severe forms, poor vision and nystagmus may be apparent early in life, and there may be associated abnormalities such as mental retardation, delayed development, seizures, deafness, cerebral atrophy, hemiparesis, ventricular defects, porencephalic cyst, hypopituitarism, hypothyroidism, and diabetes insipidus. Sudden death has been reported in response to a viral illness likely due to unrecognized pituitary insufficiency. Septo-optic dysplasia, also known as de Morsier syndrome, is one of the more common bilateral optic nerve hypoplasia syndromes. It is characterized by midline central nervous system abnormalities such as hypothalamic dysfunction, pituitary dysfunction, and agenesis of the septum pellucidum; malformation of the optic chiasm; and agenesis of the corpus callosum. Patients have a characteristic facies with a broad forehead and large anterior fontanelle. Mutations in the autosomal dominant HESX1 gene at 3p21.2-p21.1 may be responsible in many affected patients.1

Because of the high incidence of associated central nervous system anomalies and endocrinologic problems, all patients with optic nerve hypoplasia, particularly if bilateral, need a complete neurological workup, including brain computerized tomography (CT) or magnetic resonance imaging (MRI). An absent infundibulum of the pituitary or an ectopic posterior pituitary bright spot are characteristic MRI findings. Endocrinologic evaluation should include growth hormone, adrenal, and thyroid function. Patients with partial absence of the septum pellucidum have a threefold lower risk of pituitary hormone deficiency than those with complete absence of the septum pellucidum. Abnormalities of the hippocampus correlate with severe neurological problems. Early recognition and treatment of the hormonal imbalance permits prompt endocrinologic management and helps the child achieve normal growth and development.2

In unilateral optic nerve hypoplasia, serious central nervous system abnormalities are present in about 20% of affected individuals. Patients are typically seen because of strabismus and decreased vision. Amblyopia may develop in addition to the organic visual loss and should be treated if the visual impairment directly due to the optic nerve malformation is felt not to be profound. Because it is difficult to predict visual potential based on the appearance of the nerve, patching of the unaffected (or less affected) eye is often indicated. If the hypoplasia is unilateral or asymmetric, there may be an afferent pupillary defect (Marcus Gunn pupil).3

Coloboma

Optic nerve coloboma is due to incomplete closure of the posterior end of the embryonic fissure of the optic cup in the seventh week of gestation. This process is in part driven by the PAX2 transcription gene at 10q25, mutation of which can result in the renal-coloboma syndrome characterized by renal malformations and isolated optic nerve coloboma. Most cases of coloboma are sporadic. Optic nerve coloboma may also be part of an incomplete closure of the rest of the fissure affecting the iris, or choroid (with dysplasia of the overlying retina). Multiple other genes have been implicated in this process.

The colobomatous optic nerve appears as an enlarged, white, excavated nerve head with or without coloboma of the surrounding choroid (Fig. 593-2). Microphthalmia may be present. If large, it may include the macula. Visual acuity can be very good if coloboma is isolated to the nerve. Subarachnoid cerebrospinal fluid around the optic nerve may flow through the defect under the retina, interfering with macular function.

Optic Nerve Pit

Optic nerve pits are a mild form of nerve head coloboma characterized by dark gray oval or slitlike holes in the disc, usually on the inferotemporal side or centrally. They are usually unilateral and most often have no hereditary pattern. A wide variation in visual acuity can occur, and the vision is usually normal. Optic pits are important clinically, because they may produce scotomas, at times associated with serous (caused by fluid under the retina) retinal detachments.4 Although retinal detachment has been seen in children in the first decade, it occurs in up to 50% of the patients at a mean age of 31 years. It is believed that cerebrospinal fluid tracks under the retina, causing the detachment. Attempts to repair the elevated retina with silicone oil injected into the eye have resulted in the silicone oil migrating into the subarachnoid space of the optic nerve.5 Systemic abnormalities are not commonly associated with congenital optic nerve pits.

Morning Glory Disc

This optic disc anomaly can be considered a form of optic nerve coloboma. Most instances are unilateral and nonfamilial. The disc appearance resembles the morning glory flower. The optic nerve is located in the center of an enlarged, excavated disc with central fibroglial tissue (Fig. 593-3). It can be orange or pink in color, with the retinal vessels splayed out at the periphery of the disc. It is twice as common in females as in males, and the right eye is more frequently involved. Visual acuity is usually 20/100 or worse, although it is difficult to predict the visual potential based on the appearance of the anomaly. Patients with vision as good as 20/40 are known. Patching the unaffected eye may be helpful in reversing amblyopia, which complicates the vision loss. High myopia and visual field defects are prominent. Serous retinal detachment is the most serious ocular complication and may occur in up to 38% of the patients. Although usually isolated, association with sphenoidal encephalocele is known and may be suspected if the patient also has a notch in the center of the lip. Morning glory optic nerve has also been reported in trisomy 4q and the PHACE syndrome (posterior fossa malformations; hemangiomas; arterial abnormalities; cardiac defects, especially aortic coarctation; and eye abnormalities).6

Myelinated Nerve Fibers

Myelination of the optic nerve usually ceases at the lamina cribrosa just before birth. Occasionally, it proceeds distally, extending intraocularly to produce a congenital, white, feathery opacification of the neuroretinal rim and peripapillary retina (Fig. 593-4). Visual acuity is usually unaffected unless the myelination extends into the fovea. The blind spot may be enlarged. This condition is bilateral in 20% of patients. Extensive myelinated nerve fibers have been associated with high myopia and amblyopia.7

Persistent Fetal Vasculature

A persistence of the primary vitreous, previously referred to as persistent hyperplastic primary vitreous (PHPV), has been renamed persistent fetal vasculature (PFV). The hyaloid artery and vein normally course from the optic disc to the back of the lens in utero and spontaneously resorb in the late third trimester. At the back of the lens, the hyaloid system is confluent with a dense array of vasculature that envelops the lens, including the tunica vasculosa lentis on the lens surface, and communicates with iris vessels. The manifestations of PFV include abnormalities of pupil size and iris development, which are usually visually insignificant but can appear as a dense cataract with extensive retrolental fibrovascular tissue between the optic nerve and posterior lens. The lens posterior capsule is abnormally vascularized and fibrotic. This may cause the ciliary processes to be pulled in centrally with anterior displacement of the iris-lens diaphragm. Angle-closure glaucoma may result. Occasionally the retina may also be involved. Microphthalmia is common. Visual prognosis is guarded, but satisfactory results can be obtained if the macular retina is not involved and cataract surgery is performed early in infancy followed by aggressive patching of the unaffected eye. The disorder is almost always unilateral, isolated, and sporadic.8

With partial resorption, a thin patent vessel containing blood extends from the optic disc to the posterior lens capsule, usually attaching inferonasally to the optical center. This is usually visually insignificant. A small posterior capsule opacity, called the Mittendorf dot, falls within the spectrum of PFV but is not of any visual concern.

Optic Nerve Drusen

Intrapapillary drusen or hyaline bodies of the optic nerve head are tiny white or yellow translucent masses of hyaline-like material buried within the substance of the optic nerve head anterior to the lamina cribrosa. They occur almost exclusively in Caucasians, with an incidence of 0.3% to 1.0% clinically and 2% histopathologically. They are bilateral in 75% to 80% of cases. In young children, the masses are inconspicuous, but within 1 to 2 decades, they become visible on the surface of the disc as shiny, refractile bodies that glow with indirect light. They may elevate the nerve head, thus simulating papilledema (pseudopapilledema). Drusen of the optic disc can be identified in at least 75% of the instances of pseudopapilledema. Pseudopapilledema and neurological disorders that frequently coexist by coincidence (eg, headache) may lead to unnecessary neuroradiologic and neurosurgical investigations for exclusion of an intracranial process. Because drusen of the optic nerve can be inherited as an autosomal dominant trait, ophthalmoscopic examination of family members may disclose similar lesions and thus help establish the correct diagnosis in a child with pseudopapilledema. Ophthalmoscopy is diagnostic if the drusen are visible. Ultrasonography, CT scan, and intravenous fluorescein angiography may be helpful ancillary tests if the drusen are buried. Visual acuity is usually unaffected, although progressive visual field defects have been reported in adults. Rarely, subretinal neovascular membranes with hemorrhage may compromise central acuity.9

Optic nerve edema is characterized by elevation and congestion of the optic nerve head, blurring of the disc margin, obliteration of the physiological cup, venous congestion, loss of spontaneous venous pulsations, peripapillary splinter hemorrhages, and edema of the peripapillary retina. Optic disc edema has a variety of causes, including increased intracranial pressure, which is called papilledema (Fig. 593-5). Papilledema is almost always bilateral. It may fail to develop in infants with increased intracranial pressure because of open fontanels. Two ocular conditions protect the eye from papilledema: high myopia (5 to 10 diopters) and optic atrophy. Visual acuity, color vision, and pupillary responses are rarely affected in the acute stage of papilledema unless the macula is involved by edema, hemorrhage, or exudates. If optic nerve edema is due to other causes such as ischemia or vasculitis (papillitis), then vision is more likely to be impaired. The blind spot may be enlarged in edema of any cause. Diplopia may occur secondary to sixth cranial nerve palsy when increased intracranial pressure is present. Optic atrophy and poor visual acuity may be the result of chronic papilledema. In general, papilledema is a neurological emergency.

Optic disc edema is differentiated from optic neuritis by the absence of inflammatory cells in the vitreous, the lack of a central scotoma, and the lack of pain on eye movement. Papillitis may be mimicked by pseudopapilledema, glial tissue on the surface of the disc, high hyperopia, or myelinated nerve fibers.10

Pseudotumor Cerebri

Also known as benign intracranial hypertension, pseudotumor cerebri is characterized by papilledema, normal cerebrospinal fluid composition, normal or small ventricular system on radiography, and absence of an intracranial mass. Patients complain of headache, tinnitus, dizziness, blurred vision, and diplopia. After a CT or MRI to rule out intracranial pathology, a spinal tap may reveal an opening pressure of greater than 180 mm H2O in those under 8 years of age. In older patients and those without papilledema, pressures are greater than 250 mm H2O. Although patients are typically obese young women, the condition is seen in children of both sexes. The cause often is unknown but can occur with steroid withdrawal, vitamin A intoxication, ciprofloxacin- and tetracycline-type drug ingestion, growth hormone, all-trans retinoic acid (tretinoin), head trauma or surgery, dural sinus thrombosis, hyperviscosity syndromes, and systemic lupus erythematosus. Children tend to tolerate papilledema better than adults, but visual loss can result especially if the papilledema is severe or chronic. Treatment to reduce cerebrospinal fluid (CSF) pressure and prevent permanent visual loss includes serial lumbar punctures, diuretics, optic nerve sheath decompression, and lumboperitoneal shunt procedures.11

Optic Neuritis

Optic neuritis implies inflammation of the optic nerve. Inflammation of the nerve posterior to the globe is called retrobulbar optic neuritis. Inflammation occurring at the nerve head is called papillitis. In children, papillitis is more common than retrobulbar optic neuritis. The reverse is true of adults. In addition, bilateral involvement is the general rule in children, whereas monocular involvement is typical in adults. Optic neuritis is characterized by profound loss of visual acuity within hours or days, pain on eye movement or globe retrodisplacement, the development of a central scotoma, depressed color vision, and an afferent pupillary defect (Marcus Gunn pupil). Worsening of vision with exercise or fever has been referred to as Uhthoff’s sign and is more frequent in multiple sclerosis.

Fully developed papillitis may be difficult to distinguish from papilledema on ophthalmoscopy. The appearance of inflammatory cells in the vitreous on slit-lamp examination is a helpful distinction. Hemorrhages around the disc are rare.

Pediatric optic neuritis may result from inflammation of contiguous structures or from systemic infection. Optic neuritis secondary to meningoencephalitis is not uncommon. The optic nerves can be involved by spread from orbital abscesses, cellulitis, and foci of infection in the teeth, tonsils, or sinuses. Optic neuritis can develop in the setting of infectious viral diseases such as measles, mumps, chicken pox, poliomyelitis, mononucleosis, and influenza. It has also been reported following vaccination for viral diseases. Optic neuritis usually appears 1 to 2 weeks after the onset of an infectious illness and resolves completely. Even with apparently full recovery, pallor of the disc and nerve fiber layer defects may be seen. Marked loss of vision occasionally results, with partial or complete atrophy of the nerve. Optic neuritis may also occur with syphilis, Guillain-Barré syndrome, Behçet disease, various leukodystrophies, Schilder disease, and Devic disease.12,13

Optic neuritis is less commonly associated with multiple sclerosis (MS) in children than adults. Longitudinal studies in adults have shown a clear association between optic neuritis and MS. The majority of women who have a single episode of optic neuritis eventually develop MS. The conversion rate for men is slightly lower. In contrast, papillitis and retrobulbar optic neuritis in childhood appear to be self-limited with little risk for subsequent central nervous system involvement.

The recent Optic Neuritis Treatment Trial study in adults found that intravenous methylprednisolone (1 g/day for 3 days) followed by oral prednisone (1 mg/kg per day for 11 days) hastened the rate of visual recovery from optic neuritis in adults but did not affect final visual outcome.14 Treatment with oral prednisone alone was no better than placebo. Intravenous methylprednisolone treatment also reduced the 2-year incidence of definite MS (a new neurological deficit occurring at least 4 weeks after the onset of optic neuritis) by more than 50%.15 This data has been generalized to pediatric patients, with some pediatric neuro-ophthalmologists electing to treat children with idiopathic optic neuritis using similar protocols.

Tumors involving the optic nerve produce proptosis and progressive vision loss. Strabismus and an afferent pupillary defect (Marcus Gunn pupil) may also occur.

Optic Nerve Glioma

This tumor is the fourth most common orbital tumor of childhood and is the most common tumor of the optic nerve in childhood. Ninety percent of optic gliomas are seen by the end of the second decade of life. The peak incidence is between ages 2 and 6 years; 75% become apparent before age 10. Between 25% and 50% of patients have neurofibromatosis, and 15% to 25% of patients with neurofibromatosis type 1 have optic nerve gliomas.16

Optic nerve gliomas may arise anywhere along the optic nerve, including the chiasm. Gliomas anterior to the chiasm behave in a benign fashion, whereas those in and posterior to the chiasm may be more aggressive. When the tumor arises in the orbit, ophthalmoscopic findings may include optic disc edema, optic atrophy, and retinal striae from pressure by the tumor on the posterior surface of the globe. Optociliary shunt vessels (vessels that shunt blood from the retinal to the choroidal venous circulation) may be seen on the surface of the optic nerve head. Chiasmal gliomas cause bilateral vision loss and optic atrophy without proptosis. An afferent pupillary defect may develop if one optic nerve is compressed more than the other. If a chiasmal glioma enlarges sufficiently, endocrine dysfunction may ensue from compression of the pituitary gland and hypothalamus. Hydrocephalus, head nodding, and nystagmus (often asymmetric) may develop as a result of compression of the third ventricle. The diagnosis of optic nerve glioma is made by the clinical findings and the typical appearance of the tumor on ultrasonography, CT scan, or MRI. Orbital tumors produce a fusiform enlargement of the optic nerve. Enlargement of the optic foramen and sella turcica have also been observed. Histopathologically, optic nerve gliomas are pilocytic astrocytomas of the juvenile type.

Treatment is controversial. Some authors believe optic nerve gliomas are benign hamartomas and do not require treatment.17 The majority of patients have a paucity of symptoms and signs, if any at all. There are reports of spontaneous involution and a lack of growth.18 Other authors advocate surgical excision or radiotherapy, because some tumors tend to be aggressive.19 If there is minimal visual loss without proptosis, the child may be kept under observation. If there is progressive loss of vision with little or no proptosis, observation may continue or radiotherapy considered, which in some instances stabilizes growth of the tumor and vision.20 Surgical excision is probably not indicated unless disfiguring proptosis develops or there is extension toward the chiasm. Gliomas do not metastasize. When excision is necessary, the globe can usually be spared, even though it is blind. For chiasmal gliomas, surgery is not advised; radiotherapy seems to be the best method of treatment.

Optic Nerve Meningioma

This tumor is seen more often in adulthood, is five times more common in females than males, and is rare in childhood. Presenting signs, symptoms, and ophthalmoscopic findings are the same as for optic nerve glioma. This tumor is also associated with neurofibromatosis. The compressive optic neuropathy produced by optic nerve meningioma may result in blindness, optic atrophy, and the formation of optociliary shunt vessels. Imaging studies may demonstrate a discrete mass or diffuse thickening of the optic nerve. Following contrast injection, the periphery of the nerve enhances, the so-called railroad track sign. Histopathologically, optic nerve meningiomas arise from arachnoid meningoendothelial cells. Treatment is by surgical excision if the tumor causes disfiguring proptosis or if it extends into the optic foramen.21

Optic atrophy is the ultimate result of optic nerve injury, regardless of cause. It is characterized by ganglion cell and axon loss, nerve head pallor (Fig. 593-6), reduced visual acuity, scotoma, poor color vision, and the development of an afferent pupillary defect (Marcus Gunn pupil). The optic nerve head of the normal, healthy infant is paler than that of the adult; therefore, a diagnosis of optic atrophy in the infant should be made only when one is sure of the findings. Attention to the normally prominent macular nerve fiber layer of the retina in children (Mound of Buncic) may be helpful in recognizing when there is a reduction in the number of nerve fibers. Optic nerve hypoplasia and other congenital disc anomalies are much more common than optic atrophy in the first year of life.

When optic atrophy in a child presents a diagnostic dilemma, the investigation should include detailed family history; search for metabolic or toxic factors; careful eye examination; evaluation for vasculitis or infection; imaging studies of the skull, orbits, and optic foramina; and consideration of other ancillary tests such as ultrasonography, neuroimaging, and visual evoked potential. A useful clinical pearl is that children blind from retinal disorders are more likely to rub their eyes (oculodigital phenomena) than children blind from disorders of the optic nerve or cortex.

Autosomal Dominant Hereditary Optic Atrophy

Autosomal dominant optic atrophy (Kjer optic atrophy) is the most common form of hereditary optic atrophy. Mild to moderate reduction in vision with no nystagmus becomes apparent between 4 and 8 years of age. Bilateral vision loss may be slowly progressive throughout life. A scotoma with impaired color vision and normal electroretinogram (ERG) are characteristic. Temporal atrophy of the optic nerve is most prominent. The genetic defect has been linked to 3q28-q29 and 18q12.2-12.3. In the former, mutations in the OPA1 gene Msp1, which encodes for the GTPase protein dynamin, are known to be causative.22

Other Inherited Optic Atrophies

Optic atrophy may be seen in inherited neurological diseases that include Canavan, Charcot-Marie-Tooth, infantile subacute necrotizing encephalomyelopathy, Friedreich ataxia, and familial dysautonomia. These diseases are autosomal recessive with Charcot-Marie-Tooth disease inherited also as an X-linked recessive disorder. Isolated autosomal recessive optic atrophy has been linked to 8q21-22 with another variant due to mutations in the 3-methylglutaconic aciduria III gene at 19q13.2-13.3. Leber optic atrophy is discussed in Chapter 592.