Paraneoplastic syndromes often have an autoimmune basis. Sera from patients with visual paraneoplastic syndromes have been shown to contain immunoglobulins that are reactive with both the tumor and with various retinal elements (e.g., photoreceptors, large ganglion cells, bipolar cells).140

Radiation Optic Neuropathy

Radiation therapy is not infrequently administered for the treatment of various ocular (e.g., retinoblastoma) and intracranial (e.g., craniopharyngioma, dysgerminoma) tumors of childhood. Shielding the globes and the optic nerves from the field of radiation is not always possible. Patients receiving a cumulative dose of radiation of greater than 50–60 Gy or dose fractions greater than 200 cGy/day are particularly at risk of developing radiation retinopathy or optic neuropathy, depending on the path of administered radiation. Early radiation optic neuropathy can occur within several weeks of irradiation and is characterized by acute inflammation leading to optic nerve pallor. In contrast, late radiation optic neuropathy occurs years after treatment and has been characterized by irreversible vasculitis, necrosis, and optic disc pallor.574

Radiation retinopathy reveals findings similar to those seen in diabetes. Radiation optic neuropathy presents 1–6 years (peak: 18 months) after radiotherapy. Acute loss of vision occurs along with visual field changes that localize to various parts of the anterior visual pathways, depending on the site of involvement. Patients are often misdiagnosed as having optic neuritis or a recurrent tumor compressing the visual pathways. MR imaging in the acute phase of visual loss shows intense Gadolinium enhancement of the affected segments of the anterior visual pathway.326 Functional neuroimaging modalities (positron emission tomography, single photon emission computed tomography) may help delineate either metabolically active tumor or inactive necrotic neural tissue.

The primary site of pathogenesis is the vascular endothelium, and the underlying pathologic changes are those of radiation-induced occlusive vascular disease: endothelial proliferation, fibrinoid necrosis, and reactive astrocytosis. Therapeutic trials of corticosteroids and hyperbaric oxygenation have been, with a few exceptions,86 unsuccessful. Treatments for radiation optic neuropathy have included corticosteroids, anticoagulation, and hyperbaric oxygen therapy. The most promising, hyperbaric oxygen therapy, is expensive, difficult to administer, and relatively ineffective.503 However, one adult treated with intravitreal bevacizumab showed improved visual acuity, with dramatic resolution of optic disc edema and hemorrhage without the development of optic atrophy.261

Hydrocephalus

Hydrocephalus is a common cause of optic atrophy in children.171,284,290,542,883 It is difficult to determine with certainty which, if any, of the various types of hydrocephalus is more likely to result in optic atrophy. In contrast to optic atrophy arising from increased intracranial pressure in older patients, the childhood variety may or may not pass through a stage of papilledema. Optic atrophy and/or cortical visual impairment are the usual causes of bilateral visual defects in hydrocephalic children. Andersson and Hellström28 diagnosed optic atrophy in 10 of 69 (14%) children with hydrocephalus. If the optic disc area is significantly smaller in children with hydrocephalus it indicates a prenatal or perinatal disturbance in optic nerve development. The retinal arterioles were also straighter, with fewer branching points as compared to controls.28

The following mechanisms have been proposed as possible causes of optic atrophy in hydrocephalus (1) long-term papilledema or acute severe papilledema with subsequent atrophy. This typically arises after shunt placement with subsequent failure(s) because hydrocephalic infants tend not to develop significant papilledema due to their expansile cranium, (2) stretching of the chiasm and its blood supply as a result of intracranial displacement of the brainstem in an effort to accommodate increasing cerebral volume, (3) optic nerve stretching by an expanding skull. (4) Chiasmal compression by a dilated third ventricle. In such cases, bulging of the third ventricle anteriorly into the sella turcica can be demonstrated on CT or MR imaging (Fig. 4.10). Most cases of optic atrophy associated with hydrocephalus are bilateral although asymmetric and even unilateral cases do occur. Compression of one optic nerve, presumably against the internal carotid artery, with unilateral visual loss, has been reportedinachildwithanobstructedshunt.122 (5)Transsynaptic degeneration of the retinogeniculate pathway after cortical damage. (6) Optic tract damage by shunt placement.284,290,883

The major mechanism appears to be postpapilledema optic atrophy that occurs in children with poorly controlled hydrocephalus and repeated shunt failure. In our experience, children with hydrocephalus secondary to intraventricular hemorrhage are at particularly high risk of developing severe optic atrophy early in life. The specific mechanism of afferent visual system injury in these infants has not been determined.

Hereditary Optic Atrophy

Hereditary optic neuropathies represent a heterogeneous group of disorders that generally manifest with bilateral optic atrophy and evidence of genetic transmission.610 The pathogenetic role of mitochondrial disease in many of the hereditary

Figure 4.10  Chiasmal compression by dilated third ventricle. Dilation of third ventricle in child with hydrocephalus may lead to stretching and ballooning of optic chiasm

optic neuropathies is now well-established. These optic hereditary optic neuropathies are often isolated, but may also occur in the context of more widespread mitochondrial disease, which can result from a mitochondrial or a nuclear gene defect.192 Four types of hereditary optic atrophy (autosomal dominant optic atrophy, autosomal recessive optic neuropathy, Costeff syndrome (Costeff syndrome), Leber hereditary optic neuropathy, and Charcot–Marie– Tooth (CMT2) disease), are now attributed to mitochondrial dysfunction. Many of the mitochondrial disorders produce isolated optic neuropathy without other neurological dysfunction. Other systemic mitochondrial disorders, such as the syndrome of mitochondrial encephalomyelopathy with ragged red fibers (MERRF) syndrome, may optic atrophy may show optic atrophy in the absence of ophthalmoplegia.319

All of these disorders show significant interfamilial and intrafamilial variability. A rare isolated form of X-linked optic atrophy is now recognized.34,430 An increasing number of hereditary neurologic and systemic diseases have been described with optic atrophy as a component.34,207,618,904 A single gene defect need not be responsible for each type of optic neuropathy. Some of these disorders have visual loss as the only clinical manifestation, and others are associated with neurologic or systemic abnormalities. Table 4.1 provides a partial listing of the genetic disorders that have optic atrophy as one of the clinical findings.377

The traditional classification of the hereditary optic neuropathies relies on the recognition of typical clinical characteristics and classic patterns of familial transmission, but genetic analysis now permits diagnosis of some of these disorders even in the absence of family history or in the setting of unusual clinical presentations. Nearly all of the inherited optic neuropathies eventually have symmetric, bilateral, central visual loss.679 In many of these disorders, the papillomacular bundle is affected, with resultant central or cecocentral scotomas. Optic nerve damage is usually permanent and, in many diseases, may be progressive. In classifying the hereditary optic neuropathies, it is important to exclude the primary retinal degenerations that may masquerade as primary optic neuropathies because of the common finding of optic disc pallor. Retinal findings may be subtle, especially among the cone dystrophies, in which optic nerve pallor may be an early finding. Retinal arteriolar attenuation and abnormal electroretinography should help to distinguish these diseases from the primary optic neuropathies. In addition, it is also customary to distinguish disorders in which optic neuropathy is the primary clinical feature, with or without associated neurologic or systemic findings, from neurologic and systemic multisystem diseases in which there may be optic nerve involvement.

Dominant Optic Atrophy (Kjer Type)

Dominant optic atrophy is the most common from of hereditary optic atrophy, with a disease frequency in the range of 1:50,000.458,617 It is transmitted as a dominant Mendelian trait with incomplete penetrance and variable clinical expression.165 The visual loss has an insidious onset within the first decade of life, typically between ages 4 and 8 years. Affected children are often unaware of their visual disorder until it is uncovered during routine visual screening. Visual acuity typically ranges from 20/70 to 20/100, but may be as good as 20/20 or as poor as counting fingers.370,462,611,841 The degree of vision loss varies considerably among members of the same family and may be asymmetric between fellow eyes in an affected individual. A mild degree of photophobia is often present. Affected children usually do not display nystagmus, even when the vision is reduced beyond the 20/200 level. It may thus be inferred that the acuity of such children must have been considerably better during early visual development. A characteristic blue-yellow color vision defect (tritanopia), best elicited with the Farnsworth–Munsell 100-hue test, is often seen,370,455,456,462,642,80 6,807 but is not necessary to make the diagnosis, as other studies have shown a more generalized dyschromatopsia.234,538,908 There is usually no clear correlation between the severity of the dyschromatopsia and the visual acuity. Many patients show

generalized nonspecific dyschromatopsia, and some patients may even show a deutan defect.538,908 Kinetic perimetry is often conspicuous for the absence of any apparent central scotoma. Static perimetry may be necessary to show central, paracentral, or centrocecal scotomas, or bilateral superotemporal hemianopia, which may raise concern about chiasmal compression.537,805,908 An isolated report of “hereditary chiasmal optic neuropathy” may actually represent dominant optic atrophy.685 Because of the tendency toward tritanopia, color visual fields are said to show a characteristic inversion of isopters in the peripheral visual field, being more constructed to blue than to red targets.494 In some patients, there is a mild, slow, insidious progression of visual dysfunction.617

The appearance of the optic disc ranges from mild but definite temporal pallor to complete atrophy.370,462,908 A “characteristic” focal temporal excavation of the disc is seen in some but not all patients (Fig. 4.11). An associated loss of the nerve fiber layer in the papillomacular bundle is present and is frequently dramatic. A few patients may show subtle macular pigmentary changes. The severity of disc pallor does not correlate with visual acuity, fields, or color vision. In patients with remote visual loss, it may be difficult to differentiate dominant optic atrophy from other conditions such as Leber optic neuropathy.403 Differentiation of mild cases of dominant optic atrophy from congenital tritanopia, another autosomal dominant disorder, requires blue cone ERG.578

The visual prognosis is generally good.234 These children function surprisingly well given the degree of their measured visual deficits. Some patients are even unaware of the visual deficit before the initial examination. Rarely do affected children attend schools for the blind. Long-term follow-up reveals either stabilization of visual function after the middle teens or minimal deterioration of vision (by a few lines) that is gradual and often unnoticed by the patient234 Kjer et al459 reported that all of his patients younger than 15 years of age had visual acuity better than 20/200, whereas 20% of patients beyond 45 years of age had acuities reduced to this level.

Visual evoked cortical potentials reveal reduced amplitudes and, in some patients, delayed latencies. The amplitude of the negative component of the pattern ERG is markedly reduced, whereas the positive component is normal.381 In some patients with normal electrophysiological studies, standard visual fields, and color vision (FM 100 hue), static perimetry with blue test spots may show enlarged central scotomas, indicative of subclinical dominant optic atrophy.72

Histopathologic studies have shown primary degeneration of the retinal ganglion cell layer, accompanied by loss of myelin and ascending optic atrophy, with intact cerebral hemispheres.459 Earlier suggestions that there are at least two genetic types of autosomal dominant optic atrophy, one congenital and one manifesting postnatally730 have not been borne out by genetic analysis, which suggest that these two types are probably a result of a single genetic defect, representing the variable expressivity so common in autosomal dominant disorders.670

Most patients with dominant optic atrophy are monosymptomatic. Affected patients are typically entirely healthy, with the exception of sight. Rare exceptions have included the association of mental retardation,417 hearing loss,569 and chronic progressive external ophthalmoplegia.561 Sensorineural hearing loss, which tends to cluster in families, may be congenital and severe or subclinical, requiring audiology for detection. It is unclear whether hearing loss signifies a phenotypic variant of dominant optic atrophy, a genetically distinct disorder, or a genetically heterogenous group of disorders with a similar phenotype.617 Two families with an autosomal dominant optic atrophy, hearing loss, and peripheral neuropathy have been described.334 This triad (optic atrophy +/ – hearing loss +/ – polyneuropathy) has been described as an autosomal dominant, autosomal recessive, and X-linked disorder; the various forms have been compared by Hagemoser et al334 In one remarkable family, in which ophthalmoplegia and ptosis accompanied dominant optic atrophy and hearing loss, a chromosome 3 missense mutation was found, a mutation which, in other pedigrees, resulted solely in nonsyndromic optic atrophy.669

Also, a large family with an autosomal dominant disorder manifesting with progressive optic atrophy, abnormal ERGs without retinal pigmentary changes, and progressive sensori­ neural hearing loss has been reported.870 The disorder appears in the first or second decade of life, followed by the emergence of ptosis, ophthalmoplegia, ataxia, and a nonspecific myopathy in midlife.870 It has recently been found that mutations in the Wolfram’s syndrome gene (WFS1) can produce dominant optic atrophy with hearing loss.229 Table 4.2 lists the various genetic syndromes encompassing the findings of hearing loss and optic atrophy.

Autosomal dominant optic atrophy is genetically heterogenous, with the OPA1 gene on chromosome 3q28 being the most prevalently mutated gene. More than 100 mutations have been described; however, the specific pathogenesis of the visual loss in this condition remains unclear.165 The major locus is OPA1 mapped in 3q28-q29. The penetrance of OPA1 mutations has been estimated at 82.5–98%.165 Additional loci are OPA3,718 OPA4,437 and OPA5,49 located at 10q13.2,18q12.2,and22q12.1-q13.1,respectively.229 Dominant optic atrophy appears to be a primary retinal ganglion cell

degeneration.197,908 The OPA1 gene encodes for a dynaminrelated GTPase that is made in the nucleus and imported into mitochondria, where it appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity,17,197,647 with a mutation leading to a deficit in oxidative phosphorylation.446,514 GTPase activity is particularly critical for retinal ganglion cell development and function.130,197,854 Downregulation of the OPA1 gene leads to fragmentation of the mitochondrial network and dissipation of the mitochondrial membrane potential, with cytochrome c release and caspase-dependent apoptosis.573,647 Certain OPA1 mutations exert a dominant negative effect, resulting in multisystemic disease closely resembling the mitochondrial cytopathies, by a mechanism involving mitochondrial DNA instability.24 The OPA1 gene polymorphism has also been associated with normal-tension glaucoma and high-tension glaucoma.523 Linkage analysis of patients with normal tension glaucoma has shown an association with polymorphisms of the OPA1 gene.38 Mutations in the OPA3 gene have been found to be responsible for the rare syndrome of autosomal dominant optic atrophy and cataract.718