Heredodegenerations and Abiotrophies

Pigmentary Retinopathies

Cone and Cone-Rod Dystrophies

Chorio-retinal Inflammations

Metabolic Storage Disorders

Retinal Arterial Occlusions

Carotid Atheromatous Disease

Other Retinal Arterial Occlusions

Retinal Migraine

Retinal Vasculitis

Uveo-Meningeal Syndromes

Human Immunodeficiency Virus Infection and

AIDS

Toxic Retinopathies

Congenital Hamartoma Syndromes

Tuberous Sclerosis

Neurofibromatosis

To suppose that the eye, with all its inimitable contrivances for adjusting the focus to different distances, for admitting different amounts of light, and for the correction of spherical and chromatic aberration, could have been formed by natural selection, seems, I freely confess, absurd in the highest possible degree.

Charles Darwin

“Organs of extreme perfection and complication”

In The Origin of Species, 1859

Accurate diagnosis of disorders of the visual sensory system is dependent on knowledgeable history taking and competent evaluation of visual function, including acuity, visual fields, and color perception, of pupillary light reactions and of the fundi. There are no valid diagnostic shortcuts; rather, there are guiding principles and axioms that should at least determine a provisional impression and course of investigation, if not provide a conclusive diagnosis. Part I of this chapter is intended to provide a reasonably detailed overview of those retinal disorders and diseases that may confound or otherwise touch on neuro-ophthalmologic diagnosis.

These “hidden” retinal disorders include the following: congenital and hereditary photoreceptor or pigment epithelial abiotrophies and dystrophies; immune-mediated retinopathy associated with distant carcinoma; and an enlarging list of acute zonal occult outer retinopathies, conveniently labeled AZOOR by Gass and associates.^1,2 Previously lumped as the “big blind spot syndrome,” AZOOR now encompasses a variety of heterogeneous, presumably inflammatory, retinopathies to be discussed below. Other lesions such as serous detachment of the macula (central serous choroidopathy) or cone dystrophies may be quite subtle on funduscopic examination alone, even during biomicroscopy with the use of a corneal contact lens or Hruby lens. It is in such situations that auxiliary tests of visual function, including color function, Amsler grid, photostress, ERG, and fluorescein angiography are critical in distinguishing modest lesions involving the choroid and retina from early optic nerve compression and demyelination.

In the assessment of visual function, the role of retinal aging alone is noteworthy. Even as macular photoreceptors are incompletely developed at birth and do not reach maturity until at least 4 years post partum, so virtually every parameter of visual function declines from mid-adulthood onward. Age-related degradations in reading acuity, color perception, and feature recognition (contrast sensitivity) are caused by senescent changes of neuronal elements, and, in fact, over a 70-year life span there is a loss of almost 50% of retinal ganglion cells, some half of which serve the macula.³ After the age of 40 years, there is apparently a linear net loss of cone photoreceptors especially from the fovea, to which is added the non-neural factors of increasing pupillary miosis and decreasing lens transparency.⁴ Other studies dispute an age-related reduction in rod and cone counts.⁵

The temporal profile of monocular visual deficit is often an important clue in differential diagnosis. Abrupt, non-transient visual symptoms usually indicate retinal artery or vein occlusion, infarction of the optic disc, retinal detachment, or hemorrhage into the vitreous. Age-related macular degeneration may suddenly cause hemorrhage beneath the fovea. In addition, on occasion, optic neuritis may run a course that is interpreted by the patient as abrupt, rather than subacute or rapidly progressive. Transient visual events are considered below (see Table 3).

TABLE 3. Transient Obscurations of Vision

  Amaurosis fugax (retinal microembolization or hypoperfusion)
  Papilledema of raised cerebrospinal fluid pressure
  Migraine: retinal, monocular; cortical, hemianopic
  Hyaline bodies of optic nerve
  Hypotension (orthostatic, arrhythmia)
  Refractive errors (myopia)
  Congenital dysplasias of optic disc
  Anemia
  Arteritis
  Polycythemia/thrombocythemia
  Coagulopathies
  Angle-closure glaucoma
  Spontaneous anterior chamber micro-hyphema, especially after lens implantation

PIGMENTARY RETINOPATHIES

Heredodegenerative retinal disorders such as retinitis pigmentosa are almost always separable from “neurologic” causes of visual deficits on the basis of chronicity, bilaterality, and typical funduscopic appearance of pigmentary retinopathy, attenuated arteriolar tree, and waxy disc pallor. “Retinitis pigmentosa” is actually a misnomer twice over: the progressive photoreceptor degeneration is not inflammatory, as “-itis” would imply; and pigmentary changes evolve relatively late and may not be obvious. The term “retinitis pigmentosa sine pigmento” is not a separate entity, but it represents a stage of disorder when the retina appears relatively unaltered but photoreceptor function is defective.

A thorough account of retinal photoreceptor dystrophies is beyond the scope of neuro-ophthalmologic subjects, but A. C. Bird's Jackson Lecture⁶ provides an overview of current concepts of clinical classification, molecular biology, and therapeutic advances. Hereditary transmission may follow autosomal dominant or recessive, or X-linked, patterns, with a spectrum of responsible gene mutations. Indeed, molecular geneticists have now identified numerous mutations in literally dozens of genes that are associated with or cause photoreceptor degeneration, findings suggesting an extraordinary vulnerability of these cells, possible stemming from their high-oxygen-requiring metabolism and physiologic population culling. These detailed genetic elaborations are replacing imprecise, if more classic, clinical descriptions.⁶

In the fully developed disorder, there is usually profound constriction of the fields with relative sparing of the central fixational area, resulting in so-called “gun-barrel” or “tubular” field constriction. End-stage retinitis pigmentosa is actually one of the few organic causes of markedly narrowed visual fields. The causes of such “gun-barrel” field constrictions are listed in Table 1. The retained field function actually mimics a cone (see Volume 2, Chapter 2, Fig. 19), because the central remnant enlarges as the testing distance is increased between the patient and, for example, the tangent screen. The field diameter does not enlarge with increasing testing distances in hysteria or malingering, and, in fact, the diameter of the field may shrink further if this possibility is suggested to the naive patient.

TABLE 1. Constricted Field with Retained Acuity

  Glaucoma, late
  Retinitis pigmentosa
  Post-papilledema optic atrophy
  Hyaline bodies (drusen) of optic disc
  Bilateral occipital infarcts with “macular sparing”
  Malingering or hysteria

Atypical cases of selective pigmentary degeneration of the nasal retinal sectors (Fig. 2) produce field defects that may mimic bitemporal hemianopias. Such preferential involvement of the fundus nasal to the optic disc occurs in at least one-third of patients with sectoral retinitis pigmentosa. Nerve fiber bundle scotomas, somewhat mimicking glaucoma, are also recorded.^7,8

Acuity is reduced when cystic or wrinkling changes occur at the fovea or as the central aperture of field finally darkens. Disc pallor and retinal arteriolar attenuation are not simply the result of ganglion cell death because the ganglion cell and nerve fiber layer of the retina are affected only late in the disease. Unilateral or bilateral disc hyaline bodies (drusen), at times most marked in peripapillary and juxtapapillary locations, occur in some 10% of all genetic subtypes.⁹

Central field defects with acuity loss occur with photoreceptor degeneration that especially affects the macula, so-called retinitis pigmentosa inversa, but this disorder likely represents a separate nosologic class, the cone-rod dystrophies (see below) (Fig. 3). Severe visual defect in early infancy is frequently enough caused by a primary outer segment retinal abiotrophy, Leber's congenital amaurosis, although this is probably not a single clinical entity. This disorder is characterized by the following: severe impairment of vision, present at birth or becoming evident during early to late infancy; a fundus that may initially approach normal, but within years, optic atrophy, diffuse fine pigmentary degeneration, and attenuation of the arteriolar tree are evident; and either an absent or a markedly reduced ERG response. Other variable features include nystagmus, photophobia, digito-ocular maneuver (forceful eye rubbing with sunken globes; “blindisms”), strabismus, cataracts, hyperopia, mental retardation, deafness, renal anomalies, seizures, hydrocephalus, and focal neurologic deficits (e.g., cerebral diplegia). Hereditary transmission is typically autosomal recessive¹⁰ (see Volume 2, Chapter 13).

CONE AND CONE-ROD DYSTROPHIES

As noted above, the macular (“inversa”) form of abiotrophic pigmentary retinopathy is actually a selective loss of cone function, but rod function also is defective. Indeed, retinal dystrophies accompanying many systemic disorders are typically, but not exclusively, this macular form. Of special neuro-ophthalmologic interest is the association of this and other geographic pigmentary patterns with hereditary cerebellar ataxias,^11,12 with olivopontocerebellar and spinocerebellar degenerations,^12–14 and with Friedreich's ataxia.¹⁵ These disorders are usually dominantly inherited, with variable expression of early life onset of progressive spasticity, ataxia, slowed saccades or supranuclear ophthalmoplegia, and chorioretinal macular dystrophy. Trinucleotide gene expansion (point mutation) is incriminated, but not exclusively. In Friedreich's ataxia, the most common inherited, if clinically inhomogeneous, spinocerebellar ataxia, a mitochondrial location of frataxin (Friedreich's ataxia protein) has been identified; this locus on chromosome 9 reflects the relationship with vitamin E deficiency ataxia and certain neuropathies with mutations in nuclear genes.¹⁶

Other subsets of pigmentary retinopathies are due to mitochondrial DNA mutations and are associated with migraine, ataxia, dementia, and Leigh's disease¹⁷; the sporadic or maternally inherited MELAS syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, usually presents in the teens as cognitive regression, headaches, and cerebral lesions causing field defects.^18–20 Even in family members, there is considerable variation of genotypic and phenotypic specificity in metabolic disorders mediated by mitochondrial DNA aberrations, including Kearns-Sayre progressive external ophthalmoplegia (see Volume 2, Chapter 12) and other conglomerations of pigmentary retinopathies. Further identification of gene point mutations will eventually provide a more precise classification.

Progressive cone degenerations present as bilaterally diminished acuity, defective color vision, and aversion to bright lights (photophobia) with “day blindness” (hemeralopia). Central field defects progress, at times showing a fenestrated central scotoma. This widespread loss of cone function usually begins in the first 2 decades of life, but severe cone disease may begin at any age. Heredity is autosomal dominant, but sporadic cases are common, and both severity and rate of progression are variable. The fundus may appear quite normal, a finding that, when coupled with photophobia, provokes an impression of hysteria, but defective pigment epithelium in the form of a “bullseye,” nonspecific mottling, and crystalline deposits are usually enhanced by fluorescein angiography (see also Fig. 1). Mild disc pallor is not unusual. Abnormal single-flash photopic and flicker (i.e., cone-mediated) responses define the disorder by ERG²¹; fluorescein angiography and full-field ERG may be inconclusive, yet focal ERG is abnormal.²² If considered sooner rather than later, full-field or focal ERG should obviate more exhaustive and inappropriate diagnostic studies for optic nerve disease.

Cones may be congenitally absent, as in the case of rod monochromatism, a rare form of “color blindness” with acuity of about 20/200 and reduced visual capacity under bright light situations; that is, these children show a preference for dim illumination. Pendular or mixed jerk-pendular nystagmus patterns are typical, and the fundus foveal reflex may be blunted. ERG shows absent or markedly subnormal photopic (cone) responses, but normal scotopic (rod) responses.

Pigmentary retinopathies, or more typically cone-rod dystrophies, keep company with a large number of other neurodegenerative and metabolic disorders, such as Bassen-Kornzweig syndrome, Refsum's disease, Kearn-Sayre progressive ophthalmoplegia (see Volume 2, Chapter 12), Laurence-Moon-Bardet-Biedl cerebellar ataxia, and sensorineural hearing loss. A complete description of the retinal abiotrophies, dystrophies and degenerations may be found in topical reviews, and pertinent texts. Age-related macular degenerations and other macular dystrophies and abiotrophies without neurologic implications are beyond the scope of this chapter.

Acute multifocal retinitis, another idiopathic inflammation in eyes of healthy young to middle-aged adults, may be associated with optic disc edema and may follow flulike prodromes.²⁴ Mild vitrous reaction and macular exudative stars are characteristic, and a self-limited benign outcome is usual, with no evidence of specific infectious or autoimmune causes. Other relatively acute multifocal chorioretinal inflammations include presumed ocular histoplasmosis, coccidioidomycosis, Pneumocystis carinii infection, cryptococcosis, mycobacterial or syphilitic choroiditis, birdshot (vitiliginous) retinochoroidopathy, punctate inner choroidopathy, and acute multifocal posterior placoid pigment epitheliopathy (AMPPPE). Although specific infectious agents may also be incriminated in meningeal reactions, such as cryptococcosis, AMPPPE is associated with CSF pleocytosis and protein elevation, findings suggesting possible viremia.²⁵ The foregoing discussion has focused on retinal pigmentary and macular disease in relation to neurologic disorders, not simple isolated macular dystrophies, which are considered at length elsewhere.^23,26

The ganglion cell layer of the retina is a principal site of abnormal accumulation of anomalous storage products, such that ophthalmoscopic changes are observable either in the form of retinal “graying” or the well-known cherry-red spot. The ganglion cell layer densely surrounds the thin fovea, which transmits the normal red color of underlying choroid (Fig. 4). The storage disorders with cherry-red spot or macular graying are listed in Table 2.²⁷

TABLE 2. Storage Diseases with Macular Changes

  Sphingolipidoses

  Gm₁ gangliosidosis (“Generalized” gangliosidosis)
  Tay-Sachs disease (Gm₂ gangliosidosis type I)
  Sandhoff's disease (Gm₂ gangliosidosis type II)
  Niemann-Pick disease
  Lactosyl ceramidosis
  Childhood metachromatic leukodystrophy

  Mucoliposaccharidosis (MLS) type I (lipomucopolysaccharidosis)
  Farber's disease
  Sea-blue histiocyte syndrome or chronic Niemann-Pick disease (yellow perifoveal granules)
  Mucolipidosis I (lipomucopolysaccharidosis) (Spranger)

In addition to retinal changes, pallor of the optic disc occurs in numerous storage disorders, the nerve being affected by several mechanisms. Optic atrophy occurs when abnormal glycolipids are stored in retinal ganglion cells with subsequent neuronal death and nerve pallor, such as occurs in Tay-Sachs disease (Gm₂ gangliosidosis), but ophthalmoscopic evidence of optic atrophy is not invariable. Tay-Sachs is an autosomal recessive inherited disease, resulting from mutations of the hexosaminidase (Hex) A gene coding for the alpha-subunit of beta-D-N-acetyl-hexosaminodase. Juvenile and adult Hex A deficiencies are rare, less severe variants. Both infantile and late forms are most prevalent among Ashkenazi (roughly, Middle and Eastern European) Jews, but are reported in non-Jews, in whom clinically benign mutations may occur.^28,29 MRI findings include hyperintensities in basal ganglia and thalamus, with marked brain atrophy and diffuse white matter lesions; these findings likely reflect accumulation of Gm₂ ganglioside.³⁰ Similarly, in Gm₁ gangliosidosis (generalized gangliosidosis; “Tay Sachs disease with visceral involvement”), there is also an abnormal deposition of ganglioside in the retina, with subsequent atrophy of the nerve, but it is a mucopolysaccharide that accumulates in the viscera.

Metachromatic leukodystrophy (sulfide lipidosis) is an autosomal recessive deficiency of arylsulfatase A, with ceramide-galactose sulfate in retinal ganglion and glial cells and macrophages in the optic nerve; a cherry-red spot occurs occasionally. The optic atrophy of Krabbe's disease (formerly considered one of the familial diffuse scleroses) is due to extensive demyelination associated with the accumulation of globoid bodies containing ceramide-galactose resulting from beta-galactosidase deficiency.

The ceroid lipofuscinoses are among the most commonly inherited childhood neurodegenerative disorders. These autosomal recessive syndromes are caused by accumulation of an insoluble, complex lipopigment that demonstrates autofluorescence and appears microscopically as characteristic curvilinear bodies. Histopathologic examination discloses degeneration of rods and cones beginning at the macula, narrowing of retinal vessels, atrophy of pigment epithelium with pigment migration, and curvilinear bodies in ganglion cells. These progressive disorders are not genetically homogeneous and are separable into infantile, late infantile, juvenile, and Finnish variants. These share seizures, motor disturbances, visual impairment, dementia, and autosomal inheritance.³¹

The late infantile type (Bielschowsky-Jansky) is a fatal recessively inherited disorder with genomic defect localized to chromosome 13q22, thus delineating this disease as a separate entity.³² Presentation is with developmental arrest and seizures at 2 to 5 years of age, with motor and visual symptoms thereafter. There is massive tissue accumulation of lysosomal hydrophobic subunit-c protein of the mitochondrial adenosine triphosphate synthase. Ganglion cells are decreased in number, with thinning of the nerve fiber layer and optic atrophy. In addition, there is involvement of the outer segments with degeneration of the rods and cones and pigmentary clumping in the outer retinal layers. On MRI, hyperintense periventricular signals correlate with severe loss of myelin.³³

Juvenile amaurotic idiocy (Batten-Mayou, Vogt-Spielmeyer) presents as visual loss in early adolescence and is characterized by retinal pigmentary changes predominantly at the macula, with late and minimal pallor of the disc. Apoptosis of photoreceptors and brain neurons has been confirmed as the mechanism of cell death.³⁴ At a later stage, motor and mental deficits evolve. The late or adult form of amaurotic idiocy ascribed to Kufs paradoxically is associated neither with amaurosis nor with retardation to the degree of idiocy, but rather, with dementia with cerebellar and extrapyramidal motor signs.

Optic nerve involvement may occur in the mucopolysaccharidoses (MPS), taking the form of optic atrophy or papilledema. Although true papilledema doubtlessly occurs in association with hydrocephalus seen in these disorders, there are other instances of “papilledema” in which fundus descriptions or photographs are not convincing. Goldberg and Duke³⁵ reported the ocular histopathologic findings in a patient with Hunter's syndrome (MPS II), in which premortem examination included the observation of “bilateral chronic papilledema.” On microscopic examination, the optic nerve was normal, despite marked retinal pigmentary degeneration, showing neither consecutive atrophy nor changes compatible with chronic papilledema. Similarly, Kenyon and colleagues³⁶ reviewed the systemic mucopolysaccharidoses and included an instance of a 26-year-old man with Hunter's syndrome (MPS II), whose ophthalmoscopic examination revealed “blurred disc margins in both fundi (without venous congestion, hemorrhages or exudates) compatible with mild chronic papilledema,” but no further comment was made in elucidation of this finding. Hunter's syndrome is an X-linked recessive disorder characterized by facial and skeletal dysmorphism, stiff joints, and mental slowing. Deafness and chronic disc edema occur, without raised intracranial pressure, and mucopolysaccharide deposition in the sclera and optic nerve septa, especially at the lamina cribrosa, is described.³⁷ MRI may disclose large multifocal cystic areas of hypointense or hyperintense signals in white matter, including the corpus callosum, likely reflecting deposition of mucopolysaccharide and increased fluid content.³⁸

Mailer³⁹ reviewed 16 patients with optic atrophy in gargoylism and concluded that communicating hydrocephalus was the most frequent cause. Although hydrocephalus has long been recognized to occur in mucopolysaccharidosis, it is uncovered more frequently at autopsy than clinically. Goldberg and associates⁴⁰ reported a case of Maroteaux-Lamy syndrome (MPS VI) with hydrocephalus and papilledema, treated with a ventriculojugular shunt. Those authors discussed the following possible pathogenetic mechanisms of visual dysfunction due to optic nerve involvement in mucopolysaccharidosis: optic atrophy secondary to glaucoma, retinal pigmentary degeneration, or mucopolysaccharide deposition in the retinal elements; infiltration of the nerve substance or meninges; narrowing of the optic canals; and hydrocephalus, with or without papilledema. Retinal pigmentary dystrophy occurs in MPS I-H (Hurler), MPS III (Sanfilippo), and MPS I-S (Scheie), all resulting from storage of heparan sulfate.

The cherry-red spot myoclonus syndrome is an autosomal recessive oligosaccharidosis due to deficiency of lysosomal acetylneuraminidase. The syndrome is comprised of typical cherry spot macula, resting and intention myoclonus, and preserved intellect. Sogg et al⁴¹ also described flutterlike ocular oscillations attributed to possible cerebellar involvement.

The onset of retinal arterial occlusion rarely goes unnoticed by the patient, but unlike venous thrombosis, arterial occlusions of a minor degree may be difficult to discern ophthalmoscopically, especially if days or weeks pass before the fundus is examined. Muci-Mendoza et al⁴² used fluorescein fundus angiography to demonstrate ophthalmoscopically occult emboli and post-embolic endothelial damage after episodes of amaurosis fugax (see below, Carotid Atheromatous Disease).

With acute infarction, the retina becomes opaque and takes on a creamy or gray appearance. Atheromatous material in the form of “bright plaques” of cholesterol or other microemboli may be seen, especially lodged at arterial bifurcations (Fig. 5). Segmental arteriolar mural opacification (see Fig. 5D) may follow retinal microembolization by weeks to months, and such sheathing may be as useful as the recognition of the cholesterol embolus itself.⁴³ ERG may show diminished B-wave amplitude, a finding indicating inner retinal ischemia. Weeks following retinal infarction, the optic disc becomes pale, and the arterial tree becomes narrowed in the sector corresponding to the arterial occlusion.

The visual field defects with arterial occlusion are variable, but they usually take the form of arcuate scotomas or “altitudinal hemianopias” of the superior or inferior half fields (Fig. 6). These altitudinal or pseudo-quadrantic defects are dense and are easily discovered by hand- or finger-counting confrontation techniques. The localizing value of the position of the “vertex” of quadrantic and wedge-shaped defects was pointed out by Alfred Kestenbaum. When the wedge originates at or points toward the blind spot, the defect is due to a retinal arterial occlusion or a lesion at the edge of the optic disc (including the arcuate defects seen in glaucoma). The differential diagnosis of arcuate scotomas, that is, with radial borders originating at the blind spot (see Fig. 6, right field), includes glaucoma, ischemic optic neuropathy, branch retinal artery occlusion, hyaline bodies of optic disc, congenital optic pit, juxtapapillary inflammation, and, rarely, chiasmal interference (see Volume 2, Chapter 6, Fig. 1F).

CAROTID ATHEROMATOUS DISEASE

The pathogenesis of embolic retinal arterial occlusions is diverse, but most are associated with atheromatous degeneration of the cervical carotid arteries. Since the observations by Fisher⁴⁴ of mobile intravascular material during episodes of transient retinal ischemic episodes (amaurosis fugax), an embolic source is commonly invoked, especially when any material is detected ophthalmoscopically within the retinal circulation. Such retinal emboli have been examined histopathologically and may consist of cholesterol crystals,⁴⁵ platelet aggregates,⁴⁶ fibrin and blood cells,⁴⁷ and neutral fat.⁴⁸ A study of the prevalence of asymptomatic retinal emboli among 3654 persons aged 49 years or older disclosed photographic evidence in 1.4%, the majority being judged as cholesterol; risk for subsequent stroke is not yet calculated.⁴⁹ On the other hand, the incidence of visible emboli in retinal arterial occlusion is estimated at about 20%.⁵⁰ Wilson and coworkers⁵¹ compared the incidence of carotid and cardiac disease in 103 patients with retinal artery occlusions and reported cardiac valve abnormalities in 28; of 62 carotid arteriograms, 35% were normal, 13% were occluded, and the remainder showed irregularity or significant stenosis. In a small group of 41 patients with transient monocular visual loss or retinal artery occlusion, no cardiac or carotid source was uncovered in two-thirds of subjects, ipsilateral carotid disease was seen in 11 (27%) cases, and a cardiac source was noted in a single patient.⁵²

Even in those patients without ophthalmoscopically visible emboli, it is possible that the embolus either has lodged in the retro-laminar portion of the optic disc or has disintegrated and passed to the retinal periphery. Primary thrombosis in the retinal arterial circulation, beyond evidence of frank vasculitis or hypercoagulable states, is considered obsolete. Vasospasm, on the other hand, is an unlikely candidate to explain arterial occlusion, although rare instances of otherwise unexplained transient visual loss are reported.⁵³ Other noncarotid sources of emboli, including cardiogenic, are discussed below.

Transient ischemic episodes involving the retinal arterial tree produce the well-known symptom of amaurosis fugax (“fleeting darkness, or blindness”; ocular transient ischemic episode). This phenomenon may be defined as a painless unilateral, transient loss of vision that usually progresses from the periphery toward the center of the field. Often, the visual deficit takes the pattern of a dark curtain descending from above or ascending from below. Complete or subtotal blindness follows in seconds and lasts from 1 to 5 minutes (rarely longer). Vision returns to normal within 10 to 20 minutes, at times by reversal of the pattern of progression. Incomplete variations produce less distinctive sensations such as “looking through a fog … through raindrops … through haze.” By convention, the term amaurosis fugax is reserved for the ocular symptoms as described, which are usually distinguishable from other episodic visual disturbances (see Volume 2, Chapter 1), and it implies transient ischemia in retinal arterial circulation. Those conditions with principally monocular transient visual loss are listed in Table 3.⁵⁴

It is likely that microembolic material in the form of fibrin-platelet aggregates momentarily occludes retinal vessels, then fragments and passes into the retinal periphery. If disaggregation with reconstitution of blood flow does not take place within several minutes, ischemic damage to inner retinal layers may be irreversible, and permanent visual defects may ensue. Most evidence indicates that the major source of retinal microemboli is the extracranial internal carotid artery, specifically an ulcerating atheromatous lesion at the level of the bifurcation.⁵⁵ The incidence of carotid atheromatous disease in patients with retinal strokes or amaurosis fugax, as noted above, ranges from a low of 27%⁵² to an estimated high from 57 to 67%.⁵⁶ Moreover, retinal ischemic events may be more frequent when carotid stenosis is greater than 50% to 70% or in the presence of ulcerative atheromatous plaques.^57,58 The diagnosis of amaurosis fugax and the implied underlying carotid atheromatous disease may usually be made on the basis of signs and symptoms (Table 4).

TABLE 4. Symptoms and Signs of Carotid Atheromatous Disease

  Transient symptoms

  Amaurosis fugax
  Photopsias
  Orbital and ocular pain

  Arteriosclerotic retinopathy
  Hypertensive retinopathy
  Bright plaques
  Occluded arteries
  Optic atrophy

  Dilated episcleral veins
  Edematous cornea
  Anterior chamber reaction
  Rubeosis and iris atrophy
  Synechiae
  Cataract
  Glaucoma (or hypotony)
  Retinal venous dilation
  Microaneurysms, hemorrhages
  Neovascularization
  Arterial occlusions

The presence of a carotid bruit is suggestive evidence of turbulent flow, but, however practical, auscultation and tender palpation of the carotid arteries and performance of ophthalmodynamometry or ocular plethysmography no longer suffice. At any rate, in the patient with amaurosis fugax, in whom carotid disease must be evaluated, further technical procedures are mandatory. Such tests of carotid morphology and hemodynamics assume two distinct forms: arteriographic, requiring intraluminal contrast opacification of arteries; and nonarteriographic (“noninvasive”), using ultrasound, Doppler imaging, and, most recently, MRI (magnetic resonance angiography or MRA). Noninvasive panels are commonly employed for preliminary assessment, with the advantages of risk-free, outpatient application. Carotid duplex scanning combines simultaneous real-time B-mode ultrasonography with gated, pulsed Doppler ultrasonography. These studies provide color-coded images of the degree of stenosis and plaque morphology, although not without limitations and artifactual data.⁵⁹ MRA imaging of carotid vessels is currently an evolving field, but preliminary drawbacks include overestimation of stenosis and perturbation by signal voids related to turbulant flow. MRA images are useful in combination with duplex ultrasonography, especially when the carotid bifurcation is involved.⁵⁸

The general consensus⁵⁸ is that there is a sharp decline in the risk of stroke and in benefit from endarterectomy as the degree of angiographically defined stenosis diminishes from 99% to 70%, and this critical point underscores the importance of precise measurement of stenosis. Whereas modern techniques of angiography carry a 0.09% to 0.3% stroke rate risk, it is generally recognized that duplex ultrasonography be used as a screening tool to exclude patients with no detectable carotid disease from further testing, but patients suspected of harboring carotid disease, who are otherwise suitable candidates for endarterectomy, should undergo confirmatory contrast angiography. Ultrasonography may also be applied to monitor for progression of stenosis. Therefore, the elimination of conventional carotid angiography in favor of combined Doppler and MRA, to assess for stroke risk or determination of proper therapy, is premature, cost-containment strategies notwithstanding.

In contrast to transient symptoms and signs of retinal microembolic episodes, a condition of chronic ocular hypoxia (ocular ischemic syndrome) occurs less frequently, resulting from diffuse vascular occlusive disease of the aortic arch or common carotid artery. Acute or chronic occlusion with insufficient collateralization produces an ischemic pseudo-inflammatory uveitis, which variably includes an injected painful globe, corneal edema, aqueous flare and cells, a mid-dilated fixed pupil, rubeosis and iris atrophy, rapidly advancing cataract, either hypotony or elevated intraocular pressure (“neovascular glaucoma”), retinal microaneurysms and new vessel formation, posterior pole and mid-peripheral blot hemorrhages, macular edema, venous dilation and “sausaging,” cytoid infarcts (cotton-wool spots) of the nerve fiber layer, and arterial occlusions (Fig. 7; see Table 4). The hypoxemic fundus changes constitute a picture of venous stasis (low-pressure) retinopathy, perhaps the commonest ocular sign of chronic carotid obstruction.

Ischemic photoreceptor metabolism accounts for subjective afterimages following exposure to bright light, including a positive photostress test⁶⁰ (see Volume 2, Chapter 2). Low retinal arterial pressure may be detected by observing pulsation or collapse of the disc arterioles with even slight fingertip pressure exerted on the globe. Such borderline perfusion associated with carotid stenosis and retinopathy may be heralded by postprandial visual loss.⁶¹ In the situation of chronic, subacute, or rapidly progressive ischemic oculopathy, giant cell arteritis must be considered in the differential diagnosis, and chronic venous obstruction or diabetic retinopathy may produce similar fundus appearance.

From a series of 32 patients⁶² with ocular ischemic syndrome manifested by anterior segment neovascularization, the following data were accrued: mean age 68 ± 8 years; visual symptoms presented as amaurosis fugax, 15%, gradual, 28%, or sudden, 41% loss; initial visual acuity less than or equal to 20/400 in 64%, and in 77% at final follow-up; iris neovascularization, 87%; iridocorneal angle neovascularization, 59%; disc pallor, 40%, or cupped, 19%, or edematous, 8%; retinal circulatory stasis, 21%; retinal hemorrhages, 24%. Intraocular pressures ranged widely from 4 mmHg to 60 mmHg. Ipsilateral carotid occlusion or severe stenosis (80% to 99%) was found in 74%, but endarterectomy in 7 patients did not influence visual outcome, which was poor at onset. Other significantly associated systemic diseases included diabetes (56%), arterial hypertension (50%), coronary artery disease (38%), and previous stroke or transient ischemic attack (TIA) (30%).

Visual outcome in such ischemic globes is guarded, but endarterectomy may prevent progressive infarction of ocular tissues and may alleviate pain (ocular “angina”). Improvement or stabilization of vision and some resolution of retinopathy are reported, especially if carotid reconstruction is performed before irreversible neovascular glaucoma.⁶³ A vasospastic form of ocular ischemia is reported, with improvement with the calcium channel blocker verapamil.⁶⁴

It is exceedingly difficult to predict which patients with amaurosis fugax will develop permanent visual loss or suffer a hemispheral vascular accident, and it is not yet clear that patients with asymptomatic carotid stenosis benefit from arterial surgery. From the exacting North American Symptomatic Carotid Endarterectomy Trial (NASCET),⁶⁵ in patients with 70% or greater stenosis and cerebral TIAs within the past 4 months, stroke risk is estimated at up to 25% per year; with first-time amaurosis fugax and high-grade stenosis, the risk is 8.5% per year, but apparently with less severe stoke deficits.⁶⁶ These risks are compared with surgical complication rate of carotid endarterectomy, with a perioperative stroke or death rate of 5.8% in the NASCET study, but as much as 8.5% even in academic centers,⁶⁷ and the surgical morbidity/mortality figures may be greater outside major vascular surgery facilities.

Regarding the Asymptomatic Carotid Atherosclerosis Study (ACAS),⁶⁸ in 1662 patients with greater than 60% stenosis but no symptoms, after 4465 cumulative patient-years, aggregate risk of stroke or death was 4.8% among surgical patients and 10.6% among patients who did not have surgery; both groups received aspirin and attempts at reduction of risk factors; perioperative morbidity/mortality risk was 3%, but patients were selected to avoid those with confounding factors to avoid excessive surgical risk. Interestingly, patients with 80% stenosis or greater had a lower subsequent events rate than those with less stenosis.

To reiterate, carotid endarterectomy may be recommended for properly selected asymptomatic patients with stenosis of 80% to 90% by modern contrast angiography and when angiography and surgery can be performed with a combined stroke or death rate of less than 3%. In patients with asymptomatic carotid stenosis who are prepared to undergo coronary artery bypass grafting for symptomatic coronary artery disease, there are no data suggesting benefit from prophylactic endarterectomy.⁶⁹

In a British study,⁷⁰ retinal infarction was believed to have some prognostic value, the presence of retinal emboli being associated with increased mortality rate of 8% per year. It was emphasized that the most deaths in such patients were related to cardiac infarctions.

In recent years, aspirin, in daily low doses of 75 mg to 325 mg, has been used as a platelet antiaggregant. A collaborative overview⁷¹ summarizing data from 173 randomized trials of antiplatelet therapy in patients at high risk for occlusive vascular disease showed a definite protective value for myocardial infarction, nonfatal stroke, and vascular death, with respective risk reductions of one-third, one-third, and one-sixth. Other previous analyses showed stroke reduction rates as high as 42% in both men and women; dipyridamole (Persantine) has no established role in stroke prophylaxis.⁷² Most interestingly, an analysis of published randomized studies of the medical treatment (chronic anticoagulation or platelet inhibitors, versus no treatment or placebo) of TIAs showed that neither treatment modality significantly reduced mortality rates.⁷³ Failure to prevent cardiac complications appears independent of therapeutic effectiveness in reducing the incidence of cerebral strokes in patients with TIAs.

Not without controversy, there is general agreement with the following management recommendations regarding indications for endarterectomy, as modified from Trobe.⁷⁴ Patients for whom carotid endarterectomy is indicated: cerebral hemispheric ischemic symptoms within the carotid artery distribution occurring within the past 6 months; ipsilateral stenosis of 70% or greater, without intraluminal thrombosis or substantial syphon stenosis (i.e., distal intracranial segment stenosis does not exceed cervical segment stenosis); age less than 75 years; no evidence of significant disease (organ failure) of kidney, liver, lung; no severe disabling stroke or progressing neurologic dysfunction; no recent myocardial infarct, unstable angina pectoris, or a cardiac valvular or rhythm disorder that could be a source of embolic symptoms; no uncontrolled hypertension; life expectancy of at least 2 years and adequate quality of life. Patients with acute ocular ischemia (amaurosis fugax, recent retinal infarction, ischemic optic neuropathy) do not qualify. Again, it is imperative that a proficient vascular surgical team with a perioperative stroke and death rate less than 2% to 4% should be available. It also must be reiterarated that atherosclerotic disease is multifocal, and most patients succumb to myocardial infarcts, not stroke.

Other nonatheromatous carotid diseases may manifest as transient visual obscurations. Fibromuscular dysplasia, most common in younger women, is also a likely source of recurrent microembolization, requiring angiography for confirmation, and surgical intraluminal dilation may be required.⁷⁵ Spontaneous dissection of the cervical segment of the internal carotid artery is increasingly recognized as a cause of stroke, with a mean age of 45 years (range, 16 to 76 years), and an estimated annual incidence of 2.5 to 3.5 per 100,000.⁷⁶ Symptoms of dissection frequently include headache, neck and jaw pain, dysphagia, metallic dysgeusia, Horner's syndrome, and amaurosis fugax. According to Biousse and colleagues,^76a nearly two-thirds of patients have ocular signs or symptoms, 5,270 at presentation; almost half have a painful Horner's syndrome, one-third with transient monocular vision loss, and rarely ischemic optic neuropathy occurs. Trivial trauma or exertion such as weight-lifting may be inapparent contributing factors, but predisposing conditions include fibromuscular dysplasia, Marfan's or Ehler-Danlos syndrome, and cystic medial necrosis.⁷⁷ Diagnosis is made on angiography, which shows irregular narrowing, and MRI discloses hyperintense signal of mural hematoma. Duplex echography demonstrates arterial enlargement due to mural hematoma and stenosis distal to the point of dissection. Recanalization is the anticipated outcome, but antithrombotic therapy such as heparin is usually used to prevent subsequent embolization.

Pulseless disease (Takayasu's arteritis), suggested by the inability to obtain peripheral pulses in the arms and confirmed by aortic arch angiography,⁷⁸ is also associated with transient obscurations of vision and chronic retinal ischemic changes. This disorder is an idiopathic chronic inflammation of the aorta and proximal segments of its major branches, producing progressive stenosis and end-organ hypoperfusion. Although there is a predilection for Asians and for women, pulseless disease has been described in all racial groups. Ophthalmologic signs and symptoms are considered late manifestations, and visual loss may be noted when the patient assumes an erect posture. Ischemic retinopathy, iris neovascularization, cataract, vitreous hemorrhage, and anterior segment ischemia are chief ophthalmic findings.

Color Doppler ultrasound imaging is a relatively recent noninvasive technique to assess blood flow dynamics in the eye and orbit, although the accuracy and applicabilities are not yet fully explored. Nonetheless, preliminary investigations suggest effective application in retinal arterial occlusions, cranial arteritis, ischemic neuropathies, and carotid artery disease.⁷⁹ In a study of 24 persons with greater than 75% carotid stenosis,⁸⁰ all patients showed lower mean peak systolic velocities in the central retinal, posterior ciliary, and ophthalmic arteries, with improvement after endarterectomy.

OTHER RETINAL ARTERIAL OCCLUSIONS

Although atherosclerotic disease of the extracranial carotid system is by far the most common source of emboli to the retina and brain, other sites should be considered. Embolic material may originate from damaged endocardium following myocardial infarction, a significant difference being noted between observed and expected probabilities of stroke at 1 and 2 months.⁸¹ Rheumatic or atherosclerotic aortic and mitral valvular disease may serve as a nidus for recurrent embolus formation. Patent foramen ovale is found in one-third of normal hearts at autopsy, as well as other septal defects (right-to-left shunts), and atrial fibrillation, are all potential sources of retinal and cerebral microemboli. In recent years, mucoid degeneration of the mitral valve and chordae tendineae (“prolapsing mitral valve”; Barlow's syndrome) has been recognized as a source for ocular and cerebral stroke and transient ischemic events.^82,83 In 59 patients with mitral prolapse, Lesser and colleagues⁸³ found an incidence of 22% with amaurosis fugax. This syndrome should come to mind especially in nonhypertensive patients younger than the sixth decade; both men and women may be affected, and most patients with native valve endocarditis have mitral valve prolapse.⁸⁴ This condition is suggested by chest pain, dyspnea and cardiac arrhythmias, and mid-systolic click or murmur. The diagnosis is confirmed by echocardiography and angiocardiography. Otherwise, endocarditis of native or prosthetic valves is rarely unaccompanied by systemic manifestations of malaise, fever, petechiae, and heart murmur. Other ocular manifestations include conjunctival petechiae, Roth's spots, choroidal septic emboli with subretinal vascularization, embolic retinitis, and endophthalmitis.⁸⁵

Retinal arterial obstructions in children and young adults are only rarely the result of embolization in the absence of detectable cardiac disease. Of 27 patients with retinal artery occlusions occurring before the age of 30 years, Brown and colleagues⁸⁶ found a history of migraine headaches in 8 patients, but no instance of a previous history of “retinal migraine” attacks (see below), and emboli were detected in only 7%. In a similar series of retinal arterial occlusions in 27 eyes of 21 persons aged 22 to 33 years, 67% of whom were women, Greven and coworkers⁸⁷ found identifiable emboli in 7 (33%) patients and cardiac valvular disease (atrial myxoma, bacterial endocarditis, mitral valve lesions) in only 4; hypercoagulable or embolic factors included various admixtures of oral contraceptives, cigarette use, pregnancy, obesity, and migraine; 2 patients with either anticardiolipin antibody elevation or protein S deficiency were both pregnant, and no patient in the series had typical migrainous symptoms at the time of retinal arterial occlusion. The role of transesophageal echocardiography is stressed, especially in young patients with unaccountable arterial occlusions, with or without visible emboli.⁸⁸ In a retrospective review⁸⁹ of 16 patients with idiopathic recurrent branch arterial occlusions and no particular common risk factor, the long-term visual, neurologic, and systemic prognosis remained favorable after a mean follow-up of 9 years, with no systemic thromboembolic events.

Coagulation studies (e.g., prothrombin and partial thromboplastin times, total platelet count) are generally unrevealing unless specific thrombophilic (coagulants and fibrinolytics) factors are evaluated, such as lupus anticoagulants, other immunoglobulins against phospholipids, proteins C and S (inhibit clotting cascade), antithrombin III, and homocysteine.^90,91 The antiphospholipid antibody syndrome accounts for both venous and arterial occlusions. Antibodies to negatively charged phospholipid include anticardiolipin antibodies, lupus anticoagulant, and those responsible for biologic false-positive Venereal Disease Research Laboratory tests. Antiphospholipid antibodies are detectable in 2% of healthy persons, but in 35% to 50% of patients with lupus erythematosus and in 25% to 50% of young patients with stroke.⁹² However, in a prospective study⁹³ of 75 patients with retinal vascular occlusions, mostly venous, no increased prevalence of antiphospholipid antibodies was found. With regard to homocysteine, there is unequivocal evidence that hyperhomocysteinemia is a risk factor in carotid artery stenosis,⁹⁴ likely related to impaired production of endothelium-derived relaxing factor, to stimulated proliferation of smooth muscle cells that play a key role in atherogenesis and affecting the expression of thrombomodulin and activation of protein C.

Among young patients with stroke, 17% exhibit a deficiency of natural anticoagulants, with protein S deficiency in 12%, protein C deficiency in 2%, and antithrombin III deficiency in 2%. However, 5 to 10 times more common than these conditions is functional resistance to activated protein C (APC), especially in youthful patients with venous thrombosis, and it is prevalent in the general population in 2% to 5% of individuals. APC, also known as factor V Leiden, is due to a single point mutation altering coding for residue 506 from arginine to glycine and is dominantly inherited.⁹²

Branch arterial occlusion is documented in association with Lyme disease,⁹⁵ and arterial and venous retinal vascular disease is rarely associated with Crohn's ulcerative colitis.⁹⁶ Other systemic (“collagen”) vasculitides such as lupus erythematosus, polyarteritis nodosa,⁹⁷ and dermatomyositis are also infrequent causes of retinal arterial occlusions, but they must be suspected especially in young women. Serum complement (C3, C4) and antinuclear antibody (ANA) levels, erythrocyte sedimentation rate (ESR), and other rheumatologic evaluations are mandatory.

The single and multiple influences of some risk factors remain speculative. For example, the previously described mitral valve prolapse syndrome, with or without “sticky platelets,” occurs in some 20% of otherwise healthy women, migraine affects at least 10% (other estimates run as high a prevalence as 20% in men and 30% in women) of the population, and millions of women regularly use oral anovulatory agents.

It bears emphasizing that the origin of transient, monotonously stereotyped visual obscurations in healthy young persons often proves elusive, but fortunately most of these attacks are self-limited and benign, with neither identifiable risk factors nor need for therapy. Of course, echocardiography should be considered. Extrapolating from general stroke data,⁹⁸ there is no consensus that low-dose oral contraceptives increase the risk of retinal vascular occlusions. However, other reviews⁹⁹ suggest that the presence of complex or prolonged migraine aura, or of additional stroke risk factors (increased age, smoking, hypertension), likely increases the ischemic stroke risk further in patients with migraine when oral contraceptives are added. Otherwise, intra-ocular pressure, occult vasculitis, and hemoglobinopathies should be considered in patients with retinal arterial occlusions, as well as the multiple causes considered here, and judiciously selective laboratory assessments should be applied. That is not to say that definitive diagnosis is forthcoming, nor do abnormal laboratory data necessarily imply cause and effect; for example, antiphospholipid antibodies are found in healthy persons. Optimal, or even minimal, therapy remains controversial, and only basic regimens currently suffice: systemic corticosteroids to suppress antibody production; anticoagulants to block thrombosis; and antiplatelet agents. In the acute period, perhaps hours after occlusion, ocular massage may lower intraocular tension, and microcatheter infusion of urokinase or tissue plasminogen activator is advocated,¹⁰⁰ but there is little evidence to support anterior chamber paracentesis or other medical therapies.⁸⁵

Retinal vein occlusion has far fewer neuro-ophthalmologic implications than do arterial retinal infarctions. Significant associations are found with hypertension, diabetes, glaucoma, cardiovascular disease, and increased ESR in women, but not with estrogen use, alcohol consumption, or physical activity.¹⁰¹ Vein occlusion is reported in association with hyperhomocysteinemia,¹⁰² and with antiphospholipid antibody syndrome,¹⁰³ although in larger series⁹⁴ no direct relationship with anti-cardiolipin antibodies or lupus anticoagulant is found. However, in patients younger than 45 years, dominantly inherited APC resistance (see above) is a distinct risk factor.¹⁰⁴ Venous stasis retinopathy may be found in instances of arteriovenous shunts or fistulas, as discussed in Volume 2, Chapter 17. The general problem of venous occlusions is reviewed elsewhere.¹⁰⁵

RETINAL MIGRAINE

Retinal migraine implies stereotypical transient monocular loss of vision of rapid onset, usually followed by ipsilateral headache, in persons usually with other migrainous symptoms, including typical common migraine headaches. The following case history is exemplary:

A 22 year-old male medical student complained of “blackouts” in the left eye, lasting between 10 and 20 minutes, often followed by mild diffuse headache localized to the left side of the head. Cephalgia usually began as the visual deficit was clearing. These episodes began at age 16, at first occurring once or twice per year, but currently every 4 weeks for the past 6 months, especially at “exam time.” The patient had no other particular headache pattern, and the family history was negative. Standard cardiac echography was unremarkable.

The retinal variety may be admixed in a person who suffers the more conventional attacks of migraine. It is presumed that vasospasm in the retinal circulation determines transient hypoxia, perhaps somewhat similar to the visual cortical event. On rare occasions, the fundus has been examined during typical retinal migraine episodes, and arterial constriction has been described. Wolter and Burchfield¹⁰⁶ photographically documented such an episode and demonstrated mild “retinal edema”; vessel narrowing is also evident (Fig. 8). Fortunately, permanent complications of retinal migraine are rare. These may take the form of central retinal artery occlusion or ischemic papillopathy (see Volume 2, Chapter 16); nerve fiber bundle visual field defects may be demonstrated (Fig. 9).

When disc swelling seems disproportionate to other hemorrhagic features, the vague term “papillophlebitis” is clinically applied, admittedly with little or no evidence of actual inflammatory disease. Although the course may be protracted (up to 18 months), the outcome is benign and apparently is unaltered by corticosteroid therapy. In a series of 40 patients with this diagnostic rubric,¹⁰⁷ some 7 cases of mitral valve prolapse were found, and 8 of 23 patients studied hematologically showed an increase in platelet coagulant activity concerned with the initiation of early stages of intrinsic coagulation. Nine patients had macular edema that contributed to lowered acuity, at times worse than 20/200, and “all patients had a fluorescein angiogram that was consistent with a central retinal vein occlusion of the nonischemic type.” So-called papillophlebitis may be associated with retinal arterial occlusions and may possibly represent a form of idiopathic vasculitis or a coagulation defect of pregnancy.¹⁰⁸

In contrast to this benign form of papillary or retinal “vasculitis,” Cogan¹⁰⁹ documented a “severe vasculitis” category, including cases of periarteritis nodosa, Behçet's disease, multiple sclerosis, and granulomatous vasculitis. The cause in patients without systemic disease is speculative, but Cogan demonstrated in his patients with “severe vasculitis” that there was round cell infiltration of the venular walls.

The question of retinal arteritis, vasculitis, and autoimmune mechanisms was admirably reviewed by M. D. Sanders,¹¹⁰ who presented clinical information on 150 cases examined at St. Thomas' Hospital, London. Retinal vasculitis should be considered when inflammatory changes (focal or extensive sheathing or occlusion of vessels; retinal infiltrates and hemorrhages; cellular debris in vitreous; vascular leakage of fluorescein) occur in relation to retinal vessels. Diagnostic categories include the following: infectious (tuberculosis, syphilis, herpes simplex, cytomegalovirus [CMV]); multiple sclerosis with phlebitis; polyarteritis nodosa, lupus erythematosus, Wegener's and Goodpasture's syndromes, sarcoidosis, Behçet's disease; autoimmune vasculitis without systemic disease, polymyositis, dermatomyositis, polyarteritis nodosa, Whipple's disease, and ulcerative colitis. Despite these purported associations, in well patients with primary retinal vasculitis and no medical history suggestive of underlying systemic disease, results of diagnostic batteries are meager, and follow-up data do not suggest subsequent manifestations of specific causes.¹¹¹ Although it is admittedly unrewarding, minimal evaluation would include complete blood count, ESR, urinalysis, fluorescent treponemal antibody absorption test, rapid plasma reagent, and chest roentgenogram.¹¹¹

Retinal vasculitis exceptionally is associated with CNS vasculitis (angiitis). In 1882, Eales described a variety of retinal periphlebitis characterized by “retinal hemorrhage associated with epistaxis and constipation” seen in young men in southern England. Patients present with recurrent, usually monocular, vitreous hemorrhages that may persist for years and ultimately involve the second eye. Neurologic complications must be rare, but subacute myelopathies, chronic lymphocytic meningitis, and middle cerebral artery stroke have been reported.¹¹² Distinction from the retinal vasculitides discussed above is problematic, and “Eales' disease” remains a diagnosis of exclusion.

Microangiopathy of the brain, retina, and inner ear (Susac's syndrome) is a rare disorder predominantly affecting women of child-bearing age, but without a specific origin or systemic manifestations. An immune or coagulopathic background is unproved. Patients present with the following: vision loss due to branch retinal arteriolar occlusions with vessel hyperfluorescence on fluorescein angiography, and delayed leakage; hearing loss; multiple CNS infarctions.¹¹³ Efficacy of treatment with corticosteroids and immunosuppressive agents is uncertain, but hyperbaric oxygenation has been beneficial in a single case, with rapid visual improvement.¹¹⁴

Other infrequent causes of multifocal segmental retinal vasculitis, co-mingled with neuroretinitis and choroiditis, include Lyme disease,¹¹⁵ Rochalimaea infection (cat-scratch disease),¹¹⁶ and intraocular lymphoma.¹¹⁷ Without neurologic or systemic implications, a syndrome of retinal vasculitis, with aneurysmal dilatation of arterioles, capillary nonperfusion, and exudative neuroretinitis with marked decrease in acuity, has been described, with an age range of 9 to 49 years and a female preponderance; oral corticosteroids had no beneficial effects.¹¹⁸ Ten patients with isolated retinal vasculitis with family history of multiple sclerosis, or positive HLA-B7 typing, underwent MRI, which showed white matter lesions resembling those of multiple sclerosis in 3 instances, suggesting a causative relationship.¹¹⁹

Ureitis, including periphlebitis (“venous sheathing”), and pars planitis, is infrequently discovered in association with multiple sclerosis. Delay between onset of neurologic and ocular symptoms occurs, and the possibility of a shared genetic factor is raised.^120a

Zonal outer retinopathies (AZOOR, see above) can show choroidal changes and are reported with CSF pleocytosis, cervical myelopathy, and periventricular white matter lesions on MRI, abnormal ERG, perivenous sheathing, and retinal pigment migration.¹²¹ Posterior placoid pigment epitheliopathy (APMPPE, see above) also is reported to occur in association with headaches, CSF aseptic cellular reaction, TIAs, inner ear symptoms, and multiple strokes, requiring immunosuppressive agents for presumed cerebral vasculitis.¹²² The classification found in Table 5 highlights the difficult diagnostic dilemma posed by these diverse disorders.

TABLE 5. Uveo-meningeal Syndromes

  Infections

  Syphilis, Lyme borreliosis, tuberculosis, fungal infections
  Cytomegalovirus, herpes simplex, herpes zoster, rubeola, subacute sclerosing panencephalitis
  Toxoplasmosis, Whipple's disease

  Sarcoidosis
  Vogt-Koyanagi-Harada syndrome
   Behçet's syndrome
  Lupus erythematosus

  Reticulum cell sarcoma
  Lymphomas: B or T cell
  Metastatic carcinoma

  Acute posterior pigment epitheliopathy
  Acute zonal occult outer retinopathy
  Sympathetic ophthalmia
  Inflammatory bowel disease

Opportunistic infections, particularly CMV retinitis, are major causes of severe visual loss and blindness; CMV retinitis is estimated to occur in 37% of patients with AIDS.¹²⁶ CMV retinitis is a relatively late manifestation of the basic disease and is associated with CD4 T-cell counts of less than 0.10 × 10⁹/L. Other tissues are affected, including the brain, lungs, and gastrointestinal tract. CMV retinitis presents as patches of opaque retina with intraretinal hemorrhages and exudative borders of advancing necrosis, which may eventuate in retinal detachment. Intravenous or intraocular ganciclovir and intravenous foscarnet are effective in controlling (viro-static) CMV retinitis, but they do not eliminate the virus.¹²⁶

Other opportunistic fundus infections include the following: toxoplasmosis (retinochoroiditis, at times also involving optic nerve¹²⁷), frequently accompanied by toxoplasmic encephalitis, the most common cause of focal CNS dysfunction in AIDS; varicella-zoster virus, producing acute retinal necrosis¹²⁸; herpes simplex; and Pneumocystis carinii choroidopathy. Central retinal vein occlusions are documented, with pathologic examination disclosing no histologic evidence of HIV, a finding suggesting other hemorheologic factors.¹²⁹ The protean manifestations of AIDS are exemplified by a case of sudden blindness in a 50-year-old man who showed, at autopsy, simultaneous CMV infection of the retina, herpes simplex in the optic nerve, and nonHodgkin's lymphoma of the optic tract.¹³⁰

Ocular symptoms of the cardiac glycosides have been recognized since the time of Withering, who wrote on “foxglove” in 1785. Visual anomalies include blurring, peri-central scotoma, abnormal dark adaptation, xanthopsia (“yellow vision”), a peculiar sensation of whitish glare described at times as “frosting,” and other aberrations of color perception. Symptoms may be continuous or intermittent and are reversible with diminished dosage levels, although other systemic signs of digitalis toxicity may be absent, and, indeed, serum levels may be well within the normal therapeutic range.¹³² Although this condition is classically attributed to optic nerve dysfunction, evidence provided by ERG and color vision data implicate a cone dysfunction syndrome, likely related to inhibition of adenosine triphosphate in rod outer segments, or ganglion cell intoxication.¹³² Pain on eye movement is also reported.¹³³ Fisher¹³⁴ recorded visual disturbances in five elderly patients who were receiving quinidine therapy, disturbances that were at first attributed to transient ischemic episodes, consisting of temporary dark shadows or bright afterimages noted only on awakening, and lasting a few minutes to less than 1 hour. Four of these patients were also receiving digoxin, and a synergistic effect cannot be dismissed. Although the long-term effect of quinine on retinal ganglion cells is well known, causing severe visual field contraction, optic atrophy, and narrowing of retinal arteries, Fisher considered these morning scotomas to be symptoms of transient failure of retinal light adaptation.

The oral antiestrogen agent tamoxifen, used for breast cancer, even at high daily doses has infrequent ocular side effects, including the deposition of fine crystalline deposits in the retina and occasional macular edema,¹³⁵ and intra-arterial cisplatin for glioblastoma may produce severe retinotoxic effects.¹³⁶ Interferon produces retinopathy characterized by hemorrhages and cotton-wool spots.¹³⁷ In patients undergoing renal transplantation, to prevent organ rejection, a murine monoclonal antibody, OKT3, is used and is associated with profound and irreversible visual loss at the retinal level.¹³⁸

Most dramatically, temporary blindness occurs following transuretheral prostate resection (TURP), during which a nonelectrolyte, nonconducting irrigating fluid (glycine) is absorbed through prostatic venous sinuses into the systemic circulation.¹³⁹ The TURP syndrome consists of confusion, bradycardia, nausea, hypertension, convulsions, and visual disturbance (even to no light perception) lasting minutes to several hours, and it may be related to hyponatremia, glycine retinal toxicity, or cortical edema. Retinol (vitamin A) is fat soluble, absorbed in the small intestine, and stored in the liver; deficiency occurs in malnutritional situations, liver dysfunction, and malabsorption states,¹⁴⁰ including mastocytosis,¹⁴¹ and it is characterized by night blindness, visual loss, and abnormal ERG findings.

Along with other remote effects of carcinoma on the nervous system must be included an immune-mediated retinal photoreceptor degeneration, cancer-associated retinopathy (CAR). Described initially, and most commonly, with small cell carcinoma of the lung, visual disturbances include usually subacute loss of acuity and field depression, color anomalies, narrowed arterioles, pigment epithelial disturbances, and vitreous cells. The ERG is severely diminished, and pathologic examination discloses loss of rods and cones and thinning of the outer nuclear layer of the retina, but only mild disruption of inner retinal layers. Antiretina antibodies have been isolated in sera from patients with CAR syndrome, and rising titers of CAR antigen prove useful in identifying this disorder.¹⁴² Acute night blindness and sensations of shimmering lights have been reported as paraneoplastic effects of melanoma (MAR), with ERG and other psychophysical responses consistent with interruption of bipolar rod function and selective disruption of magnocelluler neurons.¹⁴³ Thirkill¹⁴⁴ provided a review of the CAR syndrome and noted the evidence of elaboration of autoantibodies reactive with the 23 kDa retinal CAR antigen, located within the photoreceptors. Although paraneoplasia antibodies can be reduced by plasmapheresis and immunosuppressants, only questionable results are reported, and controversy persists over consequences of reducing the immune competence of cancer patients. Intravenous immunoglobulin is an alternative treatment option.^144a In the setting of cancer, especially with rapid visual loss and normal ERG, the likelihood of carcinomatous meningitis should be considered, as well as the possibility of complications of chemotherapy. Autoimmune retinopathy may occur without evidence of cancer, but with typical photopsias, field depression, ERG abnormality, and sera containing antiretinal antibodies directed against inner plexiform layer, as opposed to CAR.¹⁴⁵

A hamartoma is a tumor of anomalous origin composed of elements normally present in the tissue in which it originates and with a limited capacity for proliferation. The following tumors may be classified as hamartomas: (1) in neurofibromatosis: optic gliomas (see Chapter 6), neurofibromas, and ganglioneuromas; (2) in tuberous sclerosis: retinal and cerebral astrocytomas, cutaneous angiofibromas (“adenoma sebaceum”), rhabdomyomas, and leiomyomas; (3) in von Hippel-Lindau disease: hemangioblastomas of the cerebellum and retina (including optic nerve head) and renal hypernephromas or cysts; (4) in Sturge-Weber disease: facial and choroidal cavernous hemangiomas and meningeal angiomatous malformations; and (5) in Klippel-Trenaunay-Weber syndrome: cutaneous nevi, visceral and limb hemangiomas, and orbitofacial venous varices.

If all disorders with neurocutaneous manifestations are considered, the term phakomatoses (Greek, phakos, “spot,” “birthmark”) is appropriate, and the catalog of “related” disorders becomes cumbersome. “The Phakomatoses,” Volume 14 of Vinken and Bruyn's Handbook of Clinical Neurology, is extraordinarily complete and serves as a source of detailed clinical descriptions of these diseases.¹⁴⁶ Syndromes characterized by vascular hamartomas, that is, retinal-cerebellar angiomatosis (von Hippel-Lindau), and other angiomatous malformations, are discussed in Volume 2, Chapter 17.

TUBEROUS SCLEROSIS

Tuberous sclerosis, so-called because of cerebral tubers (potatoes), is a multiorgan complex that often shows the stigmata of retinal astrocytic hamartomas in epipapillary and parapapillary locations, as well as in the retinal periphery (Fig. 10; see Color Plate 5-1B). These characteristic lesions appear as elevated semitransparent domes in the nerve fiber layer of the retina and may undergo calcification as the patient ages. The calcified hamartomas, when on or near the optic disc, have been termed “giant drusen.” These tumors should not be confused with the much more common drusen (hyaline bodies; see Part II of this chapter, Optic Nerve) within the substance of the nerve head, which are nonhamartomatous lesions and are not characterized by astrocytic hyperplasia. There is no evidence to support the suggestion that hyaline bodies of the optic disc are minor manifestations of tuberous sclerosis.

The retinal hamartomas are said to occur in approximately half of patients with tuberous sclerosis. Though rarely symptomatic themselves, they are of great help in establishing diagnosis in the setting of seizures, facial angiofibromas and variable mental retardation. Seizures and EEG abnormalities are present in 80% to 90%, adenoma sebaceum in 80%, mental retardation in 60%, intracranial calcifications in 50%, as well as cardiac rhabdomyomas or hamartomas.¹⁴⁷ Because of ventricular obstruction by giant cell astrocytomas, papilledema may develop and consequently visual loss.¹⁴⁸ On rare occasions abnormal capillaries on optic disc astrocytomas may abruptly alter vision because of intravitreal hemorrhage.¹⁴⁹ Familial occurrence in first-degree relatives should be sought, but some 60% of cases arise as new mutations.

Neuroimaging in tuberous sclerosis demonstrates subependymal (periventricular) nodules, calcifications, and parenchymal hamartomas (cortical tubers); although calcifications are difficult to discern, MRI is considered a better screening procedure.¹⁵⁰

NEUROFIBROMATOSIS

Neurofibromatosis embraces at least two disease entities. General neurofibromatosis (NF-1; von Recklinghausen's disease) is characterized by café-au-lait skin lesions, neurofibromas, schwannomas, optic-chiasmatic gliomas, and Lisch's nodules on the iris. NF-1 is the most commonly inherited CNS disorder, with an estimated prevalence of 1 in 3000 in Western countries, with gene locus at chromosome region 17q11.2. Lesions of the fundus are rare in neurofibromatosis, although some authors believe that the astrocytic hamartomas typical of tuberous sclerosis also occur in patients with neurofibromatosis. Although there is said to be an increased incidence of medullated retinal nerve fibers, no convincing evidence exists. Multiple gray-brown to yellow, placoid choroidal nevi may be seen at the posterior pole,¹⁵¹ representing a proliferation of Schwann's cells and occurring in 50% of patients with neurofibromatosis.¹⁵² Other stigmata include neurofibroma and neurilemmoma of the orbit and lid, neuronal hamartomas of the iris (Lisch's nodules) and trabecular meshwork, congenital glaucoma, and sphenoid wing dysplasia with pulsating enophthalmos or exophthalmos.

Neurofibromatosis-2 (NF-2) is an autosomal dominant trait characterized by bilateral acoustic schwannomas associated with other neurofibromas, gliomas, and schwannomas. NF-2 is caused by a mutation in the chromosome region 22q12, with a prevalence rate of only 0.1 in 100,000.¹⁴⁷ Cutaneous lesions such as café-au-lait spots and neurofibromas are also found in NF-2. Various cataracts, posterior subcapsular or cortical, are described, as well as small tuberous sclerosis-type retinal nerve fiber and pigment epithelial hamartomas and macular epiretinal membranes, but not Lisch's iris nodules, as found in NF-1.¹⁵³ A limited study¹⁵⁴ of the behavior of optic nerve gliomas in NF-1 versus those in NF-2 suggests that there is better survival rate with less likelihood of tumor progression in NF-1. In addition, in NF-1 tumors are located more anteriorly, that is, in the orbit and chiasm, than in the optic tract or hypothalamus. Optic gliomas are discussed in Part II of this chapter.

Nerve Hypoplasia

Colobomas and Pits

Dysversions and Crescents

Anomalous Disc Elevations: Pseudo-papilledema and Hyaline Bodies

Heredodegenerative Optic Atrophies

Recessive Optic Atrophy

Simple

Complicated

Wolfram's Syndrome and Juvenile Diabetes

Dominant (Juvenile) Optic Atrophy

Leber's Disease

Neurodegenerative Syndromes

Acquired Optic Nerve Disease: An Overview

Clinical Characteristics

Neuroimaging Techniques

The “Swollen Disc”: Differential Diagnosis

Papilledema with Raised Intracranial Pressure

Pseudotumor Cerebri Syndrome

Primary: Idiopathic Intracranial Hypertension

Secondary Pseudotumor Cerebri Syndrome

Inflammatory Optic Neuropathies: Optic Neuritis

Demyelinative Disease

Immunemediated and Atypical Optic Neuritides

Infective Neuropathies

Slowly Progressive and “Chronic” Optic Neuritis

Contiguous Inflammations

Ischemic Optic Neuropathies

Common (Arteriosclerotic, Non-arteritic) Ischemic Optic Neuropathy

Cranial (Giant Cell) Arteritis

Diabetes Mellitus Papillopathy

Infrequently Associated Disorders

Glaucoma and Pseudoglaucoma

Neoplasms and Related Conditions

Masses of the Optic Disc

Optic Gliomas

Perioptic Meningiomas

Secondary Neoplasms: Carcinoma and Lymphomas

Paranasal Sinus Disease

Orbitopathies: Graves' Disease

Vascular Compression: Aneurysms

Nutritional and Toxic Optic Neuropathies

Vitamin Deficiencies and “Tobacco-Alcohol Amblyopia”

Drugs and Toxins

Central Scotoma Syndromes

Traumatic Optic Neuropathies

Orbito-cranial Injuries

Radiation and Thermal Burns

My lad asked me to look up a word in the French Dictionary and I could not make out the letters because of the bouncing grey dots. The next day I could see peripheral colours but the central zone of vision was covered with what seemed like a grey asbestos mat that occluded all light. The next day saw a further deterioration, loss of colour and general darkening…. In three days all visual response had been lost.

High on the right of my circle of vision, through the murk, I could make out my fingers fluttering after two weeks of blackness. “Hello, Cobalt Blue!” Response to the ophthalmoscope. Strong white light was blue….

It was a thrill to see the cloud and identify its shape at such distance even though that mid-grey was as near as I could get to white…. A friend brought me a plant with red flowers…. “You may have difficulty with reds.” … Another pot of flowers but what fascinated me was the pointilist-like disintegration of each detail … At home. The grey flicks are still there but … I add this ironic homage … “You won't notice any difference but a doctor could tell.”

Artist Peter MacKarell went blind in one eye and then recovered, no doubt due to optic neuritis.

New Scientist, February, 1982

The optic nerve, roughly the diameter of thick spaghetti, is subject to a staggering variety of congenital anomalies and acquired disorders. Or perhaps it is even more remarkable that most persons are born without and remain free of optic nerve disease over a long lifetime. From simple myopia, optic neuritis, glaucoma, infarcts, and even its unfavorable location in the crowded skull base, the second numbered cranial nerve is victim to the widest spectrum of developmental malformations and disease processes. Consider the gross anatomic relationships (Fig. 11): at the nerve head, the peculiarities of vascular supply and ocular tissue tension (intraocular pressure) are unique; in the orbit, the nerve may be compromised by muscle enlargement or soft tissue tumors; the optic canal is flimsy protection from fractures or sinus inflammations; and the neighborhood relationship with the pituitary gland and arterial circle is clearly an evolutionary disadvantage. Indeed, malfunctions of the optic nerves and chiasm, taken together as the anterior visual pathways, constitute a large portion of all neuro-ophthalmologic diagnostic and management challenges.

Among those benign conditions mistaken for new disease is aberrant myelination of the retinal nerve fiber layer on and around the disc, which presents a funduscopic picture of intensely white patches with feathered edges (see Color Plate 5-1A). Said to occur in less than 1% of ophthalmologic patients, slightly more common in men, and bilateral in 20%, such myelination is anecdotally linked to numerous conditions, but it may be associated with the triad of amblyopia, strabismus, and myopia.¹

NERVE HYPOPLASIA

Hypoplasia of the optic disc may be unilateral or bilateral, marked or minimal (see Color Plate 1C), and associated with good or poor visual function. The condition may occur in isolation or may accompany other ocular or forebrain malformations. This anomaly has alternately been termed micropapilla, partial aplasia, or, incorrectly, aplasia. Literature related to optic disc hypoplasia has been for years almost exclusively composed of isolated case reports, but recognition of associated endocrine and central nervous system (CNS) anomalies and the relative ease of magnetic resonance imaging (MRI) have provoked considerable rewakened interest. This is especially true when optic hypoplasia is not simply part of gross ocular maldevelopment, but rather is discovered as a cause of diminished vision, strabismus, nystagmus, or growth retardation, in various combinations. Some authors^2,3 contend that increased abuse of alcohol and drugs has contributed to an increased prevalence of optic nerve hypoplasia (ONH), but surely also there is heightened awareness of this funduscopic anomaly and its systemic ramifications.

When hyperplasia is bilateral and is accompanied by poor vision and nystagmus, most patients harbor other developmental abnormalities, but such defects occur in only about 20% of unilateral or segmental cases of hypoplasia.⁴ When the nerve head is slightly or segmentally reduced, especially in the presence of normal acuity, fundus diagnosis may be supported by careful side-by-side comparison of disc photographs (Fig. 12), or calculation from photographs of the ratio of the disc center-to-fovea distance (DM), to disc diameter (DD); this ratio (DM/DD) is significantly higher in hypoplasia than in normal fundi, a ratio greater than 3.0 being considered diagnostic.⁵ Otherwise, optic disc dimensions may be assessed using the Goldmann three-mirror contact lens and adjustable slit-lamp beam to measure vertical and horizontal disc diameters and applying the formula for area of an ellipse, according to the method of Jonas and colleagues.⁶ In eyes with minimal spherical refractive error, Zeki and associates⁷ found that a ratio of disc-to-macula to DD of 2.94 provides an 95% population upper limit, whereas disc hypoplasia has a mean ratio of 3.57.

Field defects with ONH are variable and include central depressions, nasal and temporal wedges and hemianopias, inferior “altitudinal” loss, and generalized constrictions.^8,9 Disc hypoplasia need not be accompanied by severe diminution of visual acuity, but, as a rule, the smaller the disc, the worse is the vision. The size of the optic disc may also be diminished in albinism, aniridia, and in other disc anomalies such as inferior scleral crescents and in the “crowded” elevated discs of pseudopapilledema (see below).

Maternal diabetes has been implicated in simple ONH, but especially in segmental hypoplasia of the superior portion of the nerve head.¹⁰ Otherwise incriminated as teratogenic are a variety of toxic agents, including phenytoin, quinine, alcohol, lysergic acid,² and cocaine.¹¹

ONH may be the result of a spectrum of malformations occurring at several sites along the developing visual system, from the retinal ganglion cells and nerve head through the chiasm to occipital cortex.¹² Hoyt et al¹³ described “bow-tie” hypoplasia (homonymous hemioptic hypoplasia) in eyes opposite congenital cerebral hemisphere lesions, with simple ONH in the homolateral fundus, resulting from transsynaptic retrograde axonal degeneration.

The congenital syndrome of septo-optic dysplasia (de Morsier's syndrome) may be recognized by the clinical triad of short stature, nystagmus, and optic disc hypoplasia. Neuroimaging demonstrates a single anterior ventricle (holoprosencephaly) without a midline partition; that is, the septum pellucidum is absent (Fig. 13). Other important but variable aspects include the following: neonatal hypotonia, seizures, and prolonged bilirubinemia; growth hormone, corticotropin, and antidiuretic hormone deficiencies; and mental retardation. Brodsky and colleagues¹⁴ reported sudden death in patients with corticotropin deficiency, diabetes insipidus, and thermoregulatory disturbances, aggravated by fever and dehydration. The forebrain dysplasia is important to recognize because accompanying growth hormone deficiency (and often diabetes insipidus) may be corrected, resulting in resumption of normal skeletal growth patterns.¹⁵ Septo-optic dysplasia is not necessarily a strictly separate entity, and various radiologic findings and endocrine deficiencies carry specific prognostic clinical implications. MRI¹⁶ is essential in identifying several clinical subgroups of ONH, as follows: isolated ONH; absence of septum pellucidum; posterior pituitary ectopia (posterior pituitary bright spot absent or ectopic hyperintense focus in tuber cinereum, absence of infundibulum, and especially growth hormone deficiency and diabetes insipidus); hemispheric migration anomalies (schizencephaly, cortical heterotopia); and intrauterine or perinatal hemispheric injuries (e.g., periventricular leukomalacia).

Dysplastic disc development may accompany congenital tumors that involve the anterior visual pathways, such as optic glioma and craniopharyngioma, such nerve heads being described as hypoplastic, truncated, or irregularly oval.¹⁷ Other investigators¹⁸ have reported enlarged discs with optic glioma.

It seems rational that patients with bilateral ONH should undergo neuroradiologic imaging, preferably MRI, and endocrinologic assessment, and that patients with unilateral ONH, or with segmental disc hypoplasia, in whom growth and development are normal, should undergo regular ophthalmologic and pediatric examinations. Children with unilateral ONH and reduced vision may undergo a trial of occlusion therapy to discover the additional role of amblyopia.

True aplasia of the optic nerves is an exceedingly rare condition, only some 30 cases reported in the world literature, with no evidence of a hereditary tendency or consistent environmental factors.¹⁹ In an otherwise healthy infant, bilateral aplasia of optic nerves, chiasm, and tracts is documented.²⁰

COLOBOMAS AND PITS

Optic nerve colobomas (Greek, meaning mutilation or curtailment) or pits are congenital malformations that enlarge or distort the nerve head circumference and assume several forms (Fig. 14; see also Volume 2, Chapter 13, Fig. 4): enlarged discs with deep excavation; enlarged, relatively round disc filled with retained embryonic glial and vascular remnants, at times projecting forward as a funnel (“morning glory syndrome” of Kindler); discs posteriorly displaced within excavated peripapillary staphylomas; dysplastic, excavated, vertically oblong discs contiguous with retinochoroidal colobomas, located especially inferiorly; and slightly enlarged, irregular discs containing pits within the borders of the nerve head (see below). In most instances, the expanded peripapillary area is irregularly pigmented and is crossed by numerous anomalous vessels (Fig. 14A). These conditions probably represent different degrees of dysplasia in the spectrum of optic nerve malformations possibly related to faulty closure of the embryonic ventral (fetal) fissure of the optic stalk and cup.²¹ Rare instances of coloboma show momentary dynamic changes in the surrounding peripapillary staphyloma, described as “contractile” or “pulsatile,” and possibly related to mesodermal fat or smooth muscle replacing the optic meninges.^22,23

Savell and Cook²⁴ recorded a family with 15 members affected by bilateral colobomas and a pattern of autosomal dominant inheritance, but most colobomatous dysplasias are unilateral and sporadic, especially the morning glory type.^3,22 Gopal and coworkers²⁵ categorized several variants of disc position and morphology in the spectrum of coloboma, the majority of discs being included in the retinochoroidal defect itself. Simple disc colobomas may be accompanied by a variety of systemic disorders,³ including Aicardi's syndrome, CHARGE association (congenital heart disease, choanal atresia), oculo-auricular dysplasia (Goldenhar), linear sebaceous nevus, and orbital cyst. Bilateral disc coloboma is reported in association with bilateral retro-bulbar arachnoid cysts,²⁶ and with Dandy-Walker cyst²⁷; unilateral coloboma is recorded with basal vascular system lesions that include carotid occlusions, moya-moya collateralization with dolichoectasia, and absent ophthalmic artery.²⁸

Of great clinical importance is the association of disc malformations, especially morning glory,²⁹ and congenital forebrain anomalies, including basal encephaloceles. Herniated brain tissue may present as pulsating exophthalmos (spheno-orbital encephalocele, most commonly in neurofibromatosis), hypertelorism with a pulsatile nasopharyngeal mass (transsphenoidal encephalocele), or a frontonasal mass, with or without hypertelorism (fronto-ethmoidal encephalocele) or other mid-facial malformation. The physical findings of transsphenoidal or transethmoidal basal encephalocele are listed below:

  Midline facial anomalies

  Broad nasal root
  Hypertelorism
  Midline lip defect
  Wide bitemporal skull diameter
  Cleft palate

  Midline pharyngeal space
  Pulsatile
  Symptoms of nasal obstruction
  “Nasal polyp” (true polyp rare in infancy)
  Hypopituitarism/dwarfism
  Ocular

  Chiasmal field defects, poor vision
  Exotropia

Neuroimaging of the skull base, the chiasm, and the inferoanterior brain structures affirms the diagnosis. Biopsy or attempted resection of posterior nasopharyngeal masses should be vigorously deprecated because these “masses” invariably are encephalomeningoceles, and surgical manipulation may result in meningitis with tragic outcome. Patients with congenital disc malformations may complain of transient obscurations of vision lasting seconds to minutes, but the mechanism of visual disturbance is unknown (Figs. 14D and 15).

Pits of the optic disc are usually definable ophthalmoscopically as intrapapillary pearly gray dimples or slits containing filmy pale glial material, located typically just within the scleral rim of the disc margin, extending about 2 clock hours or one-third of the disc diameter. The disc border is frequently distorted and may be highlighted by contiguous mild pigment epithelial changes (see Fig. 14C), and cilioretinal vessels may traverse the depression.³⁰ Pits usually occur singly in a temporal location, less frequently centrally, or in an inferior, superior, or nasal quadrant, but they may be multiple and bilateral in perhaps some 15% of patients. They are rarely familial, but an autosomal dominant inheritance pattern is possible. Indeed, Ragge and colleagues³¹ suggested that there is evidence that cavitary anomalies of the disc form a spectrum ranging from pits to colobomas, and the existence of persons with pits in one eye and contralateral coloboma implies that these anomalies are variations of the same genetic or environmental insult; moreover, pedigrees are reported that contain the various phenotypic expressions of the cavitary anomalies, some related to mutations of the PAX2 gene.

The association of temporal pits with serous detachment of the macula, and consequent diminished acuity, is well known, with an incidence perhaps in some 50%³² of patients and presenting in young adulthood. Otherwise, stable visual field changes take the form of dense nerve fiber bundle defects that extend from the blind spot, especially toward fixation in the papillomacular zone.³³ In contrast to congenital disc pits, acquired pits are part of the spectrum of glaucomatous excavation, perhaps more frequent with normal ocular tension, typically with dense field depressions in the central portion of the visual field.³⁴ Pulsatile communication of fluid between the vitreous cavity and a retro-bulbar cyst via an optic pit has been demonstrated.³⁵

DYSVERSIONS AND CRESCENTS

Field defects associated with congenital dysversions of the optic disc (“tilted discs,” situs inversus) and accompanying depigmented peripapillary crescents may be confused with the bitemporal hemianopia of acquired chiasmal lesions. The most common variety of crescent is that located inferiorly (inferior conus, Fuchs' coloboma), first described by Fuchs in 1882 (see Fig. 14E). Not only is the disc hypoplastic, ovoid, and vertically truncated, but also the fundus in the sector contiguous to the crescent takes on a semialbinotic or tigroid appearance because of hypopigmentation of pigment epithelium and choroid. Because the inferonasal retinal quadrant is involved most frequently, relative superior temporal field defects are found (Fig. 16), and they may simulate bitemporal hemianopia.³⁶ As a rule, inferior crescents are associated with moderate myopia with astigmatism (usually manifest in the same axis as the dysversion of the disc, that is, between 90° and 110° in right eyes and between 90° and 70° in left eyes), slightly reduced corrected visual acuity, and abnormal foveal reflex. During field testing, failure to properly correct for optical anomalies enhances the refractive scotoma that is most profound at and above the area of the blind spot. Riise³⁷ provided an excellent monograph on this entity. Disc abnormalities in craniofacial disorders, including hypertelorism, Crouzon's and Apert's syndromes, show a spectrum of forms: simple pallor, tilt and inferior conus, and coloboma, some with widespread fundus hypopigmentation.³⁸

ANOMALOUS DISC ELEVATIONS: PSEUDOPAPILLEDEMA AND HYALINE BODIES

Anomalous elevation of the optic nerve head, with or without ophthalmoscopically detectable hyaline bodies, is a major cause of unnecessary alarm and misdirected diagnostic procedures. Because this funduscopic appearance somewhat resembles acquired disc swelling, including papilledema of raised intracranial pressure, in previous decades patients were subjected to cerebral arteriography, pneumoencephalography, and even craniotomy for innocent headaches, vertigo, or more trivial symptoms. Nowhere in neuro-ophthalmology is funduscopic differentiation more critical, for once a pronouncement of “papilledema” is made, a course of neurodiagnostic procedures becomes inevitable, and the patient, usually a child or young adult, as well as family members, endure the suspicion of brain tumor.

Congenitally elevated discs have been termed pseudopapilledema or pseudoneuritis, but, when possible, more specific funduscopic characteristics should be described (e.g., intrapapillary hyaline bodies, simple hyperopia, persistent hyaloid tissue). It is likely that most cases of anomalous elevation are associated with hyaline bodies of the nerve head (alternately, drusen; because the term “drusen” is more frequently applied to the common multiple punctate pigment epithelial, subretinal lesions at the posterior pole, perhaps the term “hyaline bodies” is less confusing, histopathologic tinctorial niceties aside).

Disc hyaline bodies are acellular laminated concretions of unknown source, often partially calcified, and possibly related to accumulation of axoplasmic derivatives of degenerating retinal nerve fibers, in which orthograde axoplasmic flow is obstipated at an abnormally narrow scleral canal.^39,40 Hyaline bodies slowly become (more) visible as they enlarge toward the disc surface and margins, but the overlying retinal nerve fibers also becomes progressively thinner. Anomalously elevated discs in children usually do not show ophthalmoscopically detectable hyaline bodies (said to be “buried”), which insidiously emerge by the early teens. Hoover et al⁴¹ reported first evidence in one or both eyes at a mean age of 12.1 years in 40 children, and other series included a low age range of 6 years.⁴²

The occurrence of overt hyaline bodies in parents of children with anomalously elevated discs, but without apparent hyaline bodies, attests to both the progressive and the heredofamilial nature of this disorder. Indeed, some family members have visible hyaline bodies, whereas others have only elevated discs (see Color Plate 5-1E). Examination of family members is ideal when the distinction between true papilledema and pseudopapilledema is in doubt.

According to the genetic analysis of Lorentzen,⁴³ disc hyaline bodies are inherited as an autosomal irregular dominant trait. Additionally, there appears to be a distinct tendency for occurrence in fair Caucasians.^42,44

Although one disc may be more elevated than the other, both with or without apparent hyaline bodies, there is a tendency toward some degree of bilaterality. Lorentzen's⁴³ figure for bilaterality in ophthalmoscopically visible hyaline bodies is 73%, and that of Rosenberg and colleagues⁴⁴ is 69%. Mustonen⁴⁵ studied 184 patients and found hyaline bodies to occur bilaterally in 66.9%, strictly unilateral in 25.5%, and with the contralateral eye showing disc elevation without hyaline bodies in 7.6%. There is no significant relationship between hyaline bodies and refractive error,^44,45 a factor further minimized in light of unilateral occurrence. With the infrequent exception of retinitis pigmentosa,⁴⁶ and angioid streaks (with and without pseudoxanthoma elasticum),⁴⁷ there appears to be no statistically significant association of hyaline bodies with the numerous and diverse ocular and neurologic disorders (including tuberous sclerosis) with which they have been described.^44,45

Hyaline bodies may become symptomatic by virtue of either insidious field loss or spontaneous hemorrhage, at times associated with choroidal neovascular membrane formation, even in children.^41,48 Field defects usually take the form of blind spot enlargement, arcuate or other nerve fiber bundle patterns, or irregular peripheral contraction^49,50 (Fig. 17). These deficits typically progress exceedingly slowly, with a predilection to involve the inferior nasal quadrant. Because enlarged blind spots occur in both pseudopapilledema and true papilledema, this finding is of no differential diagnostic significance. Loss of central field, that is, diminished acuity, should not usually be attributed to disc drusen unless it is due to hemorrhagic complications such as bleeding from submacular fibrovascular membranes (Color Plate 5-2D), arterial occlusions, or ischemic disc infarction^51,52 or is associated with profound loss of peripheral field, which may occur rarely without obvious additional fundus findings.⁵³

It is not uncommon to elicit a history of transient obscurations of vision in patients with hyaline bodies,⁴³ and this symptom may further serve to confuse the clinical differentiation from true papilledema. These episodes may last seconds to hours, and vision may be profoundly affected during the episode.⁵⁴ Sarkies and Sanders⁵⁵ have documented the extraordinary history of 26 years of recurrent episodic visual loss associated with ischemic disc swelling, perhaps related to anomalous vasculature.

Pseudopapilledema, with or without visible intrapapillary hyaline bodies, is not an uncommon condition. Friedman et al⁵⁶ cited the following figures for incidence of hyaline bodies: in Lorentzen's clinical study, 3.4/1000; in histologic series, 10 and 20.4/1000 (the latter figure indicating a frequency of 6 times that of the clinical diagnosis). Therefore, it should not be surprising that other ophthalmoscopic changes occur, but they need not be statistically related. I have seen a 54-year-old woman with long-standing bilateral hyaline bodies who developed mild but distinct disc swelling associated with a massive right hemispheral glioblastoma. In addition, a 15-year-old girl presented with bilateral pseudopapilledema and typical unilateral papillitis that recovered spontaneously.

Ophthalmoscopic criteria that distinguish between true and pseudopapilledema are listed below and are elaborated in Color Plates 5-1E and F and Color Plates 5-2A, B, and C.

1. The central cup is absent; the disc diameter tends toward small.
   
2. Vessels arise from the central apex of the disc.
   
3. Anomalous branching of vessels occurs; an increased number of major disc vessels is noted; venous pulsation is present.
   
4. The disc may be transilluminated with a focal light source of the ophthalmoscope or slit beam, with a glow of hyaline bodies when present.
   
5. The disc margins are irregular with derangement of peripapillary retinal pigment epithelium.
   
6. Superficial capillary telangiectasia is absent.
   
7. No hemorrhages (rare exceptions) are seen.
   
8. No exudates or cotton-wool spots are present.
   

If difficulty in fundus diagnosis persists, the following rules may prove valuable: a spontaneous venous pulsation militates strongly against papilledema of increased cerebrospinal fluid (CSF) pressure; if the patient is otherwise thriving, it is probably not papilledema; computed tomography (CT) scan⁵⁷ and ultrasonography can reveal buried hyaline bodies (Fig. 18).

Simple or complicated optic atrophies occur in various patterns of transmission and with graded symptomatology, such that a vast and heterogenous literature has accrued. Table 6 is an attempt at pragmatic clinical classification.

TABLE 6. Heredofamilial Optic Atrophies

RECESSIVE OPTIC ATROPHY

Simple

Isolated optic atrophy of recessive inheritance must represent a relatively rare entity, the very existence of which has been called into question.⁵⁸ In older literature citations, most such instances were not clinically well documented, where consanguineous parentage was roughly coupled with congenital or early childhood optic atrophy, and most cases were reported without electroretinography (ERG) recording, much less modern techniques that assess mitochondrial genome mutations. Those cases originally described by Behr in 1909 as complicated optic atrophy (see below) seem too heterogeneous for analysis, and citation search of the Index Medicus and Medline since 1968 reveals no clearly documented cases.⁵⁸

Complicated

The previous reservations notwithstanding, instances are described of a form of complicated optic atrophy, also called infantile recessive atrophy, or Behr's syndrome. In 1909, Behr described six boys in whom optic atrophy was associated with mild mental deficiency, spasticity, hypertonia, and ataxia. Subsequent reports have indicated no sex predilection, although all of Behr's original patients were male. The disorder purportedly has its onset in childhood (1 to 9 years) and stabilizes after a variable period of progression. Pallor of the disc tends to be temporal; nystagmus is present in one-half the patients and strabismus in two-thirds, according to Francois.⁵⁹ It is generally thought that Behr's infantile complicated optic atrophy may represent a transitional form between simple hereditary optic atrophy and the hereditary cerebellar ataxias of the Marie type. Two sisters with Behr's syndrome have been reported,⁶⁰ including the autopsy findings of atrophy of the optic nerves, tracts and lateral geniculate, and mild changes in visual radiations and cortex. Also consistent with Behr's syndrome, a constellation of recessively inherited infantile optic atrophy, ataxia, extrapyramidal dysfunction (choreiform movements), variable cognitive function, and juvenile spastic paresis is reported among Iraqi Jews with elevated urinary excretion of 3-methylglutaconic acid.⁶¹

Axonal motor and sensory neuropathy is also documented in association with optic atrophy, with presumed autosomal inheritance.⁶² Occurring almost exclusively in the Finnish population is the PEHO syndrome (progressive encephalopathy, subcutaneous limb edema, hypsarrhythmia, and optic atrophy), presenting as intractable seizures, and infantile hypotonia, attributed to an autosomal recessive infantile cerebello-optic atrophy.⁶³ Optic atrophy is also reported in autosomal recessive familial dysautonomia.⁶⁴

WOLFRAM'S SYNDROME AND JUVENILE DIABETES

The association of early childhood-onset optic atrophy with diminished vision usually in the 20/200 range and juvenile diabetes is known as Wolfram's syndrome, and is recalled by the mnemonic DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness).⁶⁵ The disc pallor is not directly related to degree of diabetic retinopathy and, indeed, is found even without background retinopathy. Lessell and Rosman⁶⁶ reported an experience of 9 cases that included other associated manifestations, including ptosis, ataxia, nystagmus, seizures, mental retardation, abnormal ERG, elevated spinal fluid protein and cells, and small stature. Other systemic anomalies include ureterohydronephosis and neurogenic bladder. In the United Kingdom, the prevalence rate is 1/770,000, with median age at presentation of diabetes at 6 years and optic atrophy at 11 years; cerebellar ataxia and myoclonus tend to evolve in the fourth decade, and median age at death is 30 years (range, 25 to 49 years).⁶⁷

Neuropathologic examination⁶⁸ has disclosed the following: atrophy of olfactory bulbs and tracts, optic nerves, and chiasm; loss of neurons in small cell layers of the lateral geniculate; atrophy of the superior colliculus; fiber loss in the cochlear nerve and cochlear nuclei; olivopontocerebellar atrophy; and pyramidal tract demyelination. Other neurologic features include central apnea and respiratory failure, startle myoclonus, axial rigidity, and Parinaud's syndrome.⁶⁹ MRI may show striking brain stem atrophy, especially of the pons and midbrain (Fig. 19).

The possibility of a mitochondrial defect has been raised, with rare patients that present with Leber-type visual loss (see below) and 11778 DNA mutation,⁷⁰ and other studies demonstrate heteroplasmic 8.5-kb deletion in mitochondrial DNA⁷¹ and clusters of nucleotide exchanges at positions 4216 (similar to Leber-type optic atrophy), but with other distinct haplotype exchange variants.⁷² For these reasons, the Wolfram genotype may not be homogeneous.

To reiterate, the simple autosomal recessive optic atrophies are not common, and patients previously categorized as having recessive congenital or infantile optic atrophy may indeed have suffered from retinal dysplasias or other unrecognized hereditary patterns. Of the more complicated situations in which optic atrophy is associated with clinical manifestations in organs unrelated functionally or embryologically, the possibility of mitochondrial defects is now strongly implicated.

DOMINANT (JUVENILE) OPTIC ATROPHY

The monograph on dominant optic atrophy by Poul Kjer⁷³ published in 1959 was an important milestone in nosologic analysis of the heritable optic atrophies, defining the clinical parameters and providing further evidence for distinction from Leber's hereditary optic atrophy, with which it had previously been confused. Kjer distinguished two dominant forms, separated primarily by the presence of nystagmus. Damien Smith⁷⁴ provided an additional admirable review of dominant optic atrophy and defined diagnostic criteria and clinical variants, emended here with data from a study of 21 families from the Genetic Clinic of Moorfields Hospital⁷⁵: (1) dominant autosomal inheritance; (2) insidious onset between the ages of 4 and 8 years; (3) moderately reduced visual acuity, from 20/30 to 20/70, but rarely so poor as 20/200, with some considerable asymmetry of acuities possible, and modest deterioration with age; (4) temporal pallor of optic discs, at times with temporal sectoral excavation, and striking thinning in the papillomacular nerve fiber layer (Fig. 20); other discs show diffuse atrophy; (5) centrocecal enlargement of the blind spot or mid-zonal temporal depressions, at times mimicking temporal central hemianopia (Figs. 21 and 22); (6) full peripheral fields but elevated threshold for motion detection; (7) acquired blue-yellow dyschromatopsia, which is pathognomonic when present (about 8%), but also with nonspecific or mixed color-confusion axes; and (8) reduced amplitude and delayed evoked potentials and reduced N95 component of pattern ERG.

Kjer⁷³ and others⁷⁵ have noted that many patients are ignorant of the familial nature of their disease and, indeed, had themselves not been aware of visual defects. Frequently, no special schooling is required for these patients, nor are vocations regularly limited. These phenomena attest to the insidious onset in childhood, mildly progressive course, and usual mild degree of visual dysfunction. From Kjer's data (and those of the Moorfields Hospital study), there is some evidence of disease progression, because patients less than 15 years of age did not show vision worse than 20/200, whereas 10% of patients 15 to 44 years old, and 25% of patients 45 years and older, had visual function less than 20/200; none of Kjer's patients had vision reduced to hand-motion or light-perception levels, although the Moorfields data do include such low levels. Other familial studies^76,77 also suggest a less sanguine visual outcome, with many patients experiencing insidious visual decline even to levels of legal blindness by middle age. In a three-generation Danish analysis,⁷⁸ over a mean follow-up of 14 years (range, 1 to 38 years), one-third of patients showed no progression, whereas in two-thirds, visual deterioration occurred, at times quickly; presenting visual acuities in offspring were not worse than in parents, nor was there a gender difference. Genomic DNA linkage mapping has identified a genetic homogeneity at chromosome region 3q27–3q28.^76–78

Regarding nystagmus, interestingly, none of Kjer's patients was unequivocally demonstrated to have the combination of optic atrophy and nystagmus. However, C.S. Hoyt⁷⁹ reported nystagmus with sensorineural hearing loss in 2 families, and Grehn and colleagues⁸⁰ carefully documented autosomal dominant optic atrophy of severe degree, hearing loss with mutism, deuteranomalous color defects, no nystagmus, and normal ERG when this test was conducted. Twenty-three members of a large kindred⁸¹ demonstrated progressive optic atrophy, acuity of 20/30 to 20/400, variable a- and b-wave ERG amplitude reductions (without pigmentary retinopathy), ptosis and moderate gaze palsies, hearing loss beginning in the second decade, and ataxia; CT scan and CSF results were normal. Other associated syndromes include a dominant form of relatively asymptomatic hereditary motor and sensory neuropathy (HMSN type IV) with optic atrophy.⁸² Thus, there is an obvious spectrum of dominantly inherited optic atrophies not encompassed by the relatively benign Kjer type.

Johnston and associates⁸³ described a pathologic study, including diffuse atrophy of the retinal ganglion cell layer, normal inner and outer nuclear layers, and thinning of the papillomacular nerve fiber bundle; the optic nerves showed noninflammatory demyelination and loss of temporal disc substance. In addition, in a pathologic study of one of Kjer's original patients,⁸⁴ there was ganglion cell loss in retina and geniculate body, normal cortex, and some axonal loss in both vestibulo-auditory nerves. These authors concluded that evidence pointed to primary retinal ganglion cell degeneration.

Sufficient case material has accrued to indicate that dominant (juvenile-onset) optic atrophy is the most common heredofamilial simple (monosymptomatic) optic atrophy. Visual dysfunction in this disorder is considerably milder than in either Leber's hereditary optic neuropathy (LHON) or any form of recessive optic atrophy. As a rule, progression is minimal, and prognosis good, but, in some instances, relatively rapid deterioration may occur, even after years of stable visual function.

LEBER'S DISEASE

In 1871, Leber described a nosologically distinct hereditary form of optic neuropathy that now bears his name. Leber's hereditary optic neuropathy (LHON) is characterized by sudden and severe loss of visual acuity associated with large, dense central scotomas, sequentially bilateral, occurring mostly in the second and third decades of life, affecting young males primarily. The disorder is inherited strictly in the maternal line (Fig. 23), but with incomplete penetrance, and affected males do not transmit the trait. Although most patients with LHON are otherwise healthy, some show cardiac conduction defects, and also well documented^85,86 are major and minor neurologic abnormalities including dystonia, spasticity, ataxia, encephalopathic episodes and psychiatric disturbances, and a syndrome mimicking multiple sclerosis (MS). The degree of symmetry, high rate of failure to remit, mostly painless onset, and typical disc appearance serve to distinguish most cases of Leber's optic neuropathy from the retro-bulbar neuritis of MS. Nonetheless, MRI should be considered to rule out demyelinative disease, for which therapeutic trials are now available (see below). T2-weighted fast spin echo MRI does not show signal changes in the optic nerves in the acute stage of LHON.⁸⁷

During the acute phase of visual loss, the nerve head usually appears hyperemic and swollen, as do the dense arcuate retinal nerve fiber bundles above and below the disc, accompanied by tortuousity of large and small peripapillary vessels (see Color Plate 2F). Variable arteriolo-venular shunting is best demonstrated by fundus fluorescein angiography (Fig. 24). Nikoskelainen et al^88,89 demonstrated that this characteristic peripapillary microangiopathy occurs also in the presymptomatic phase of involved eyes and in a high number of asymptomatic offspring in the female line. Increased peripapillary capillary shunting and disc hyperemia herald the acute phase of visual loss; slowly, marked disc pallor evolves. Peripapillary and subhyaloid hemorrhage is quite rare. Thus, telangiectatic microangiopathy is a hereditary “marker” and signifies increased risk of acute optic neuropathy, with a phase of visual loss triggered by as yet unclear environmental or metabolic factors.

The strict maternal transmission is determined by inheritance of defective cytoplasmic mitochondrial DNA from the mother, that is, a nucleotide mutation that substitutes adenine for guanine, affecting the organelle's capacity to manufacture adenosine triphosphate.⁹⁰ Mitochondrial mutations at nucleotide position 11778 (Wallace mutation) account for an estimated 50% to 76% of LHON probands, the 3460 point mutation for 7% to 30%, and at point 14484 for about 10% to 31%, with some ethnic variability.⁸⁸ In the series of Newman et al,⁹¹ 82% of patients with the 11778 mutation were males, but in a large British series,⁹² male-to-female ratios were as follows: for mtDNA mutation 11778, 2.5:1; for 3460, 2:1; and for 14484, 5.7:1. Apparently, patients with the 14484 mutation may show a greater tendency for spontaneous recuperation of vision,^92,93 which correlates also with younger age onset, especially less than age 15 years⁸⁸; other analyses suggest that final acuity may be most favorable with the 3460 mutation.⁸⁸ Although the disc remains diffusely pale, remarkable visual recovery includes recuperation from finger-counting levels to eventual 20/20 acuity. It is suggested that women with the 11778 mutation may suffer particularly severe visual loss, even to levels of only light perception, and that an MS-like illness may be observed in a large proportion in this group.⁹²

Instances of apparently nonfamilial cases (“singleton”) are not rare, and the relative ease and accessibility of mitochondrial testing may disclose occult cases of LHON among otherwise undiagnosed chronic or acute, but bilateral, optic neuropathies. False-positive results for the 11778 mutation may occur and can be verified by concomitant loss of restriction endonuclease SfNI and MaeIII marker sites.⁹⁴ Otherwise, point mutations at 11778, 3460, and 14480 have not been detected in normal control subjects.

Combined data indicate age at onset to be usually in the second or third decade, typically in the late teens to middle twenties, but ranging from 5 years well into the sixth and even seventh decades. In the analysis by Riordan-Eva and coworkers,⁹² visual loss developed between ages 11 and 30 years in 69%, with no significant differences between point mutation groups or gender. There are data⁸⁸ that marginally support a slightly later age-onset incidence in females, but variable age of onset in some families contrasts with remarkably constant age of onset for other sibships. Asymmetry of onset is difficult to assess because of patient subjectivity, but some interval of weeks to a few months would appear to be the rule. According to Nikoskelainen and colleagues,⁸⁸ 40% of patients are unsure of the interval between eyes, but second eye onset was less than 2 months in 23%, from 2 to 6 months in 32%, and more than 6 months in only 6%. Newman et al⁹¹ reported simultaneous onset in 55% of patients with 11778 mutation and an inter-eye interval of 1.8 months, whereas in the British study,⁹² visual loss was simultaneous in 22% and sequential in 78%, with a median inter-eye delay of 8 weeks. Individual variations in severity and tempo may be confusing, but entirely unilateral cases are distinctly rare^88,91,92; one case with the 11778 mutation was considered unilateral for 16 years.⁸⁸ Of interest, monozygotic (“identical”) twins homoplastic for mitochondrial mutations 4216, 13708, and 11778 are reported, one with typical visual loss at age 34 years, the second with normal visual function and unremarkable optic discs after more than 6 years of observation.⁹⁵

There are no known effective therapeutic measures, medical or surgical, although succinate and co-enzyme Q, co-factors for normal mitochondrial function, may be easily used. The role of endogenous and external epigenetic “trigger” factors has been questioned. It is reasonable to counsel individuals at risk to at least guard against potential toxins such as tobacco and alcohol. An entire issue of Clinical Neuroscience (Volume 2, 1994) is given over to LHON and is a rich source of additional specific information.

NEURODEGENERATIVE SYNDROMES

There is considerable overlapping of syndromes variously combining progressive degeneration of cerebellar and pyramidal systems, deafness, and optic atrophy. To add to the nosologic confusion, familial progressive polyneuropathies of the Charcot-Marie-Tooth type have occasionally been associated with optic atrophy⁹⁶ or abnormal visual-evoked potentials.⁹⁷ The association of optic atrophy with spinocerebellar degenerations, familial bulbospinal neuronopathy,⁹⁸ cerebellar ataxia with sensorineural deafness (CAPOS syndrome),⁹⁹ and familial dysautonomia^64,100 is also well established. Optic nerve dysfunction, though not necessarily symptomatic, is documented in Friedreich-type and hereditary spastic ataxia.¹⁰¹ As previously noted, optic atrophy associated with neurologic signs may take the form of an acute optic neuritis, at least superficially resembling Leber's disease, or may occur as a recessive optic atrophy in childhood, associated with ataxia (Behr's syndrome). Other ocular findings associated with cerebellar ataxia include ophthalmoplegia with slow saccades, retinal pigmentary degenerations with primary or consecutive optic atrophy.

This frequent intermingling of spinocerebellar degenerations, heredoataxias, motor and sensory neuropathies, deafness, and optic atrophy strongly suggests a complex genetic continuum in which finite distinctions are not yet possible (Fig. 25). Transmission may be dominant, as in Charcot-Marie-Tooth polyneuropathy, some cases of Friedreich's ataxia, and in CAPOS syndrome, recessive, as in most cases of Marie's disease, or may not conform to strict mendelian rules, or as yet disclosed mitochondrial mutations.

CLINICAL CHARACTERISTICS

The typical and characteristic symptomatic deficits of visual function with optic nerve disease may be summarized as follows:

1. Monocular deficits are the rule unless, of course, both optic nerves are involved. Hereditary atrophies and toxic-nutritional neuropathies are bilateral, but they may be asymmetric. Optic neuritis is occasionally bilateral and simultaneous, most frequently in childhood.
   
2. Defects in central field function include diminished acuity, desaturation of color perception, a sense of reduced brightness, and sluggish direct pupillary light reaction.
   
3. Field defects include central depression and nerve fiber bundle defects. Altitudinal defects are more usually vascular in origin. Optic disc disease (e.g., glaucoma, ischemic neuropathy, hyaline bodies) typically shows inferior nasal predilection.
   
4. The appearance of disc pallor depends on the nature of the offending lesion, the time interval, the degree of axonal attrition, and, to some extent, the distance of the lesion from the optic nerve head. Disc swelling is discussed below.
   

Acquired optic nerve disease is usually heralded by acute, or subacute progressive, dimming of central vision. Abrupt onset of monocular visual dysfunction in the age group up to the fifth decade, with a normal-appearing optic disc, is highly suggestive of retro-bulbar neuritis, especially if accompanied by dull orbital pain or discomfort of the globe itself. Otherwise, pain is not generally a symptom of optic neuropathies. In the older age group, the single most common optic nerve disease that presents as apoplectic loss of vision is ischemic infarct of the disc, almost always with disc swelling during the acute phase, for which reason the term anterior ischemic optic neuropathy (anterior ION) has been popularly applied. Retro-bulbar disease producing abrupt to subacute loss in the elderly includes cranial arteritis (CA) and meningeal metastases. Slowly progressive monocular visual loss over many months, in neuro-ophthalmologic context, typifies chronic tumoral compression of the optic nerve in its prechiasmal portion.

Insidious bilateral, but not necessarily symmetric, central, or cecocentral scotomas are hallmarks of intrinsic optic nerve disease, resulting from nutritional deficiencies, intake of toxins, or heredofamilial atrophies. Rarely, demyelinative disease runs such a slowly progressive course.

When a central field defect is found in one eye, careful search of the temporal field of the contralateral eye is mandatory to rule out the possibility of junctional (nerve and chiasm) compression (see Volume 2, Chapter 6, Fig. 1A and C). Most prechiasmal optic neuropathies are due to inflammatory or vascular disease, whereas practically all chiasmal syndromes are due to pituitary adenomas, other neoplasms, or aneurysm compression.

Visual loss may be subjectively misinterpreted as sudden under circumstances in which the better eye is momentarily closed or obstructed, or when the involved eye is used unaccustomarily for monocular viewing (e.g., microscope, telescope, gunsight).

Optic atrophy, with few exceptions, is generally a nonspecific clinical observation, and ophthalmoscopic criteria that permit a retrospective etiologic diagnosis, without other clinical clues, may include arterial attenuation in vascular causes. However, Frisen and Claesson¹⁰² quantitatively demonstrated a reduction in central retinal artery caliber of 17% to 24% in nonischemic descending (retro-bulbar nerve, chiasm lesions) optic atrophy. Likewise, focal narrowing of retinal vessels correlates best with age and may be seen with a wide variety of optic nerve diseases, including glaucoma.¹⁰³

NEUROIMAGING TECHNIQUES

With the exception of lesions or fractures of skull bones, MRI has supplanted CT in the elucidation of occult optic nerve disease. By clinical criteria, suspicion may fall on a particular segment of the nerve, such as intraorbital, intracanalicular, or prechiasmal (intracranial), and special anatomic attention should be addressed accordingly. Standard “brain” studies may provide few sections of orbital or basal skull structures. Therefore, the clinician should provide precise and specific instructions to the radiologist or technician. Relatively thin-section techniques (e.g., 3 mm) are required especially for adequate visualization of the optic canal, paraclinoidal and prechiasmatic portions of optic nerves, with and without gadolinium enhancement. Ideally, high-resolution (1 to 1.5 Tesla unit magnet systems) T1- and T2-weighted views should include axial, coronal, and sagittal sections; oblique views aligned with the long axis of the optic nerve (oblique sagittal) are of dubious value. The fat tissue of the orbit permits excellent contrast because fat appears bright (hyperintense) on T1-weighted images, whereas muscles, vessels, and nerves are darker (hypointense). Moreover, the optic nerve shares MRI characteristics with myelinated white matter of the brain. Blood vessels appear dark because of proton “flow voids.”¹⁰⁴ Protocols that delineate optic nerves from orbital fat and minimize eye movement artifacts, such as fat-suppression fast spin-echo,¹⁰⁵ are more effective than conventional T1- or T2-weighted images (see Volume 2, Chapter 14, Figs. 19 and 20). Subsequent illustrations of specific studies follow; a more exhaustive discussion of technical details is beyond the scope of this work, and the reader is referred to available comprehensive reviews.¹⁰⁶

Ultrasonography (echography) is a practical, noninvasive adjunct to evaluate anatomic characteristics of optic nerve morphology. Standardized echography is useful in disclosing the presence of perineural fluid, highly suggestive of inflammatory optic neuritis. In addition, perineural fluid accumulation in papilledema may be confirmed and monitored.¹⁰⁷

TABLE 7. Etiology of the “Swollen” Disc

  Congenital

  Anomalous elevation
  Hyaline bodies (drusen)
  Gliotic dysplasia

  Uveitis
  Hypotony
  Vein occlusion

  Papillitis
  Neuroretinitis
  ? Papillophlebitis

  Lymphoma
  Reticuoendothelial

  Anemia
  Hypoxemia
  Hypertension
  Uremia

  Hemangioma
  Glioma
  Metastatic

  Ischemic neuropathy
  Arteritis, cranial
  Arteritis, collagen
  Juvenile diabetes
  Proliferative retinopathies

  Perioptic meningioma
  Glioma
  Sheath “cysts”
  Retrobulbar mass

  Elevated intracranial pressure
  Mass lesion
  Pseudotumor cerebri

The distinction of congenitally elevated discs, that is, pseudopapilledema, from papilledema has already been elaborated. It should be recalled that true papilledema, even in the fully developed form, does not reduce acuity (unless the macula is encroached), nor does it present with field defects other than enlarged blind spots. Therefore, confusion should not arise in distinguishing papilledema from inflammatory papillitis or from ION (Table 8), two common causes of disc edema that regularly are associated with acute loss of acuity or field and diminished direct light reaction of the ipsilateral pupil.

TABLE 8. Clinical Characteristics of Optic Neuritis, Papilledema, and Ischemic Optic Neuropathy

Disc edema accompanying local ocular diseases, including uveitis, central retinal vein occlusion, or postoperative hypotony, should represent no diagnostic problem. Even simple posterior vitreous detachment¹⁰⁸ may be associated with disc and peripapillary hemorrhage and edema.¹⁰⁹ Primary nerve head tumors (melanocytoma, glioma, astrocytic hamartoma, hemangioma) are rare and usually are definable by ophthalmoscopy. Metastatic disc tumors, other than those arising in the adjacent choroid and retina, are extremely infrequent and are characterized by massive hemorrhagic elevation of the disc and peripapillary retina and drastic reduction of vision. Occasionally, the optic nerve head may be infiltrated by leukemia or similar hematologic process, usually with rapidly progressive visual loss.

Orbital mass lesions characteristically produce proptosis, but they may present as chronic, unilateral disc edema with insidiously advancing field loss. As a general rule, unilateral disc swelling should be considered a local vascular or inflammatory disorder of the nerve head or the result of a chronic perioptic mass lesion in the orbit (e.g., nerve sheath meningioma). On rare occasions, papilledema from increased intracranial pressure, including pseudotumor cerebri,¹¹⁰ may be remarkably asymmetric or even strictly unilateral. When any diagnostic dilemma arises, enhanced CT scan or MRI of brain and orbital optic nerves is mandatory and should be performed sooner rather than later, but obviously after thorough history-taking and meticulous examination.

As noted, thin-section (ideally 1.5 mm) contrast-enhanced CT scan or especially fat-suppression MRI displays fine details of optic nerve anatomy on both axial and coronal views, and increase or distortion of nerve diameter is regularly detected. Standardized A-scan ultrasonography¹⁰⁷ also defines the morphologic characteristics (normal vs. enlarged, solid vs. sheath fluid) of various optic neuropathies; this technique can effectively distinguish among causes of chronic optic neuropathy (perioptic tumor mass vs. remote neuropathy) and disc edema (tumor vs. inflammatory neuritis vs. ischemic neuropathy). Conditions that enlarge the optic nerves include optic neuritis, papilledema of raised CSF pressure, Graves' orbitopathy, direct or indirect trauma, perioptic inflammatory pseudotumor and sarcoid, optic glioma, perioptic meningioma, and infrequent infiltrations.

The pathogenesis of papilledema is a confused and controversial issue. Elevation of intracranial pressure in acute and chronic experiments have provided variable results and conclusions, but it seems reasonable that raised pressure is transmitted in the vaginal sheaths of the optic nerves¹¹¹ with resultant (or attendant?) stagnation of the venous return from the retina and nerve head. That nerve sheath pressure is critical has been demonstrated by Hayreh, who showed reversal of disc swelling by opening the nerve sheath, and subsequently Tso and Hayreh¹¹² established that there is stasis of both fast and slow axoplasm flow at the lamina cribrosa of the nerve head. In essence, optic nerve fibers are compressed in the subarachnoid space of the intraorbital portion of the optic nerve because of an elevation of CSF pressure. The subsequent obstipation of intra-axonal fluid mechanics results in leakage of water, protein, and other axoplasmic contents into the extracellular space of the prelaminar region of the optic disc. This protein-rich fluid adds to the osmotic pressure of the extracellular space of the disc substance. Venous obstruction and dilation, and nerve fiber hypoxia and vascular telangiectasis of the disc, are secondary events. Therefore, it is likely that papilledema is primarily a mechanical rather than a vascular phenomenon. It has been suggested¹¹³ that the distal retro-bulbar portion of the optic nerve sheath is bulbous and distensible, and that movement of the globe in the orbit normally milks sheath fluid posteriorly, thus reversing flow and completing the circulation of CSF into the intracranial subarachnoid space. Therefore, perturbation of this pumping mechanism may also play a role in the evolution of papilledema.

No simple mechanistic explanation serves to include other circumstances in which papilledema develops. Patients with cyanotic congenital heart disease may show papilledema with markedly tortuous retinal vessels, in the absence of elevated CSF pressure.¹¹⁴ Decreased arterial oxygen saturation and polycythemia are believed to be etiologic factors, which similarly may play a role in the production of papilledema in sleep apnea.¹¹⁵ Other conditions include spinal cord tumors (with and without elevated CSF protein),¹¹⁶ thoracic disc herniation,¹¹⁷ syringomyelia without hydocephalus,¹¹⁸ inflammatory polyneuritis,¹¹⁹ thyrotoxicosis,¹²⁰ and neurocysticercosis.¹²¹

The various underlying mechanisms that raise CSF pressure may be summarized as follows: intracranial mass lesions; increased CSF production (e.g., choroid plexus papilloma); decreased CSF absorption, the presumed cause of pseudotumor cerebri; high protein content or cellular debris that obstructs CSF absorption at arachnoidal granulations; obstructive hydrocephalus; increased cerebral blood volume (arteriovenous shunts and malformations^122,123); and obstruction of cranial venous outflow (venous sinus thrombosis,¹²⁴ neck surgery,¹²⁵ and jugular vein compression¹²⁶).

The clinical picture of chronic unilateral disc swelling most commonly results from obstruction of the sub-arachnoid space of the ipsilateral nerve by an intraorbital process such as sheath meningioma (with modest visual loss in the early stage and normal CSF pressure). As noted, on rare occasions, true unilateral papilledema does evolve from increased CSF pressure, including in the pseudotumor cerebri syndrome¹²⁷; with respect to intracranial mass lesions, unilateral papilledema has no consistent lateralizing value. Previous optic atrophy may prevent disc swelling of one side, with papilledema developing on the other (the so-called Foster Kennedy syndrome, attributed to subfrontal masses). It is also speculated that a congenital nerve sheath anomaly may obstruct transmission of pressure such that the disc remains flat despite elevated intracranial pressure. However, Muci-Mendoza and colleagues¹²⁸ demonstrated by CT scan bilateral optic nerve sheath distention in two cases of pseudotumor cerebri, with unilateral papilledema, thus raising the question of mechanisms at the distal portion of the optic nerve.

Although usually associated with slow-growing or subacute mass lesions, papilledema may develop within hours from subarachnoid or intracerebral hemorrhage,¹²⁹ but curiously, papilledema seemingly is relatively rare in acute elevation of pressure that is due to spontaneous intracranial hemorrhage or craniocerebral trauma.¹³⁰ Once the intracranial space is decompressed, venous congestion of the disc diminishes rapidly, but disc edema, hemorrhages, and exudates resolve more slowly. Well-developed papilledema resulting from mass lesions takes 6 to 10 weeks to regress after lowering of intracranial pressure.

Early, and even well-developed, papilledema may not be symptomatic. Neither visual field nor acuity is affected unless retinal hemorrhage, edema, or exudate involves the macular area. Enlargement of the blind spot is of no help in early diagnosis because ophthalmoscopically overt disc swelling precedes, and actually accounts for, this typical field change. The major clinical concept that separates papilledema of intracranial origin from other forms of acquired disc swelling is that visual acuity, field, and pupillary reactions are typically normal, whereas visual function (acuity, field, pupillary reaction) is almost always defective with papillitis (neuritis) or ION. When papilledema has existed for many weeks or months, nerve fiber attrition results in progressive field loss in the form of irregular peripheral contraction and nerve fiber bundle defects (as in Fig. 17). This is the atrophic stage of chronic papilledema, which can ultimately lead to severe visual loss and even blindness (Fig. 26).

Patients with well-developed papilledema experience brief transient obscurations of vision. “Gray-outs,” “black-outs,” or other momentary dimming of vision may involve one or both eyes at a time, last seconds, and clear completely. Sudden changes in posture may precipitate such obscurations, or they can occur spontaneously. The cause of these visual disturbances is unknown, but it is probably related to transient fluctuations in nerve head perfusion as determined by the influence of increased intracranial pressure on cerebral blood flow mechanisms. Obscurations are unrelated to the location or nature of space-occupying lesions and occur with great regularity in the pseudotumor cerebri syndrome. The frequency of obscurations appears to be most closely correlated with high intracranial pressure (at least at the moment of the obscurations) and advanced degree of disc swelling. Transient obscurations without papilledema, but resolved by relief of intracranial pressure, are reported.¹³¹ It is problematic that a prognosis of ultimate visual function is related to the frequency or intensity of these episodes.

Other signs and symptoms associated with papilledema are related to the underlying pathologic processes that produce the increased intracranial pressure. Headache, nausea and vomiting, and diplopia resulting from lateral recti weakness are typical but nonspecific symptoms of raised CSF pressure, whereas hemiparesis, hemianopias or other field defects, seizures, or specific ocular motility disturbances all have localizing value.

It is helpful ophthalmoscopically to “stage” papilledema, which on occasion has considerable clinical value. As suggested by Jackson in 1871, papilledema may be classified into four temporal types: early, fully developed, chronic, and atrophic. The early phase of papilledema refers to the incipient disc changes that occur before the development of obvious disc swelling. Blurring of the nerve fiber layer and obscuration of the superior and inferior disc margins are early changes that may actually precede venous engorgement (see Color Plate 5-1F and Color Plates 5-4A and B). The use of red-free light (green filter) in the ophthalmoscopic may further delineate early nerve fiber layer changes in incipient papilledema. The veins of the retina ultimately become engorged, tortuous, and dusky, but usually not until disc swelling is well under way.

Spontaneous pulsation of major disc veins is anticipated in approximately 80% of eyes, and its presence militates against the possibility of raised CSF pressure. It is estimated that spontaneous venous pulsation ceases when intracranial pressure exceeds 200 ± 25 mm H₂O, but the absence or presence of pulsation is not a consistently useful sign.¹³²

The occurrence of splinter hemorrhages in the nerve fiber layer at or just beyond the disc margin is a major confirmatory finding, especially in the course of repeated fundus observations. However, as noted previously, hemorrhages may infrequently occur with intrapapillary hyaline bodies or in chronic glaucoma, posterior vitreous separation, or for no apparent reason in the elderly.

In early papilledema, as well as in the more fully developed stage, the optic cup is retained. In fact, absence of the central cup is much more likely to be seen in pseudopapilledema than in incipient disc swelling. In the more chronic stage of papilledema, the central cup is likely to be slowly obliterated.

As edema progresses, the surface of the disc becomes elevated above the plane of the retina. Nerve fiber layer opacification obscures the scleral disc margins, and minor or major vessels are buried as they course off the disc. At this stage, that is, fully developed papilledema, disc elevation is consistently accompanied by multiple flame hemorrhages, nerve fiber layer infarcts (“cotton-wool” spots), serpentine tortuosity of veins, and marked disc hyperemia and hypervascularity attributable to telangiectatic dilatation of the superficial capillary bed of the disc surface (see Color Plates 5-4C and D). Swelling of the nerve fiber layer extends laterally into the retina, so that the area of the nerve head appears enlarged. The retina is raised up from pigment epithelium, and circumferential retinal folds (Paton's lines) may be seen around the swollen disc, representing the concentric lateral displacement of retina; these may extend even to the macula. Rarely, retinal exudates radiate spoke-like from the fovea in the form of a star (or half-star between the disc and fovea), with the apex toward the fovea (see Color Plate 5-1D). If intracranial pressure remains elevated, the acute hemorrhagic and exudative components resolve, and the disc progressively takes on the appearance of the dome of a champagne cork (see Color Plates 5-1F and 4E). The central cup remains obliterated, but peripapillary retinal edema resorbs. Small, round glistening “hard exudates” (axoplasm or protein remnants?) on the surface of the disc may simulate hyaline bodies. This stage of chronic papilledema indicates that disc swelling has been present for months. Nerve fiber attrition is predictable, leading to progressive field loss (see Fig. 26). As the disc detumesces, pallor slowly emerges, with apparent “sheathing” of vessels but no real loss of disc substance. Although the disc usually has a milky gray appearance (“secondary optic atrophy”) (see Color Plate 5-4E), at times it appears remarkably crisp and white. Even with fairly rapid detumescence of pre-atrophic papilledema, retinal exudates, changes in the foveal pigment epithelium secondary to edema or subretinal hemorrhage may permanently reduce central acuity.¹³³

Choroidal folds, with and without acquired hyperopia, are described in association with papilledema, with neuroimaging that strongly suggests that these striae are likely related to distention of the most distal patulous portion of the optic nerve sheath, which flattens and foreshortens the posterior wall of the globe. It is reported¹³⁴ that such folds may precede actually disc swelling.

The appearance of the optic discs, sequence of funduscopic changes, and ultimate visual outcome are dependent on variations of intracranial pathology, surgical interventions, and obscure hemodynamic events involving both the disc and the retro-bulbar visual pathways. Acute and drastic visual loss in the form of ischemic infarction of the disc is documented,¹³⁵ as well as central retinal artery occlusion.¹³⁶ In the presence of well-developed, usually chronic, papilledema, cranial decompression, including shunt procedures or ventriculography, is followed by visual loss that is abrupt or progressive over weeks. Such tragic outcome is neither understood nor predictable, and it may not be prevented even if shunting procedures precede decompression of the primary mass. This event may be related to arterial hypotension provoked by intracranial decompression, especially with the patient in a seated position (e.g., for posterior craniectomy), or to an increase in CSF pressure precipitated by anesthesia. A question of perfusion insufficiency of the distal optic nerve has been raised,¹³⁷ but the precise mechanism(s) remain elusive.

Although much has been written regarding the use of fluorescein angiography in the diagnosis of papilledema, in instances of ophthalmoscopically definable papilledema, fluorescein fundus angiography is usually superfluous. In eyes in which disc changes are truly debatable, fluorescein angiography may be inconclusive and should not be considered the single indication for further complicated diagnostic studies. Thin-section CT views and fast spin-echo MRI,¹³⁸ as well as standardized A-scan ultrasonography,¹⁰⁷ are useful in confirming distended perioptic meninges, and the latter provides a convenient technique to monitor the effects of therapy on nerve sheath size.

For the ophthalmologist or neurologist, the finding of bilateral papilledema is, of course, an indication for immediate action. Following adequate history-taking, including queries regarding the use of pharmaceuticals associated with pseudotumor cerebri (see below), and otherwise competent neuro-ophthalmologic assessment including blood pressure evaluation, CT scan or MRI is mandatory to determine the state of the ventricular system and the potential presence of a mass lesion.

PSEUDOTUMOR CEREBRI SYNDROME

Pragmatically, ophthalmologists may distinguish perhaps three major clinical types of pseudotumor cerebri syndrome: purely idiopathic intracranial hypertension (IIH); a condition in which venous sinus thrombosis is demonstrable; and a condition in which other identifiable toxic or mechanical mechanisms secondarily cause raised intracranial pressure.

Primary: Idiopathic Intracranial Hypertension

IIH without discernable origin, perhaps somewhat inaccurately equated with a more general syndrome of “pseudotumor cerebri,” is strictly a diagnosis of exclusion, although in obese female patients it is a frequently anticipated cause of well-developed, often florid papilledema (see Color Plate 5-4C) and headaches. Other neurologic deficits, with the exception of nonspecific signs of raised CSF pressure (see below), are inconsistent with this diagnosis or, at least, occur so infrequently that a thorough investigation beyond simple contrast-enhanced neuroimaging is essential.

Although various factors (Table 9) are implicated in the production IIH, most cases reveal no clearly identifiable underlying cause, although there is a distinct female preponderance from the teens through the fifth decade, that is, the hormonally active, child-bearing years. In fact, there is no apparent gender difference for IIH in children or a tendency to obesity.^139,140 Otherwise, these indisputable characterizations strongly imply an “endocrine connection,” although studies of hormonal function in IIH, including patients with radiologic empty sella or with long-standing raised CSF pressure, do not show significant abnormalities of the anterior or posterior pituitary or of the peripheral target glands.¹⁴¹

TABLE 9. Conditions Associated with Papilledema and Increased Intracranial Pressure (Excluding Space-Occupying Lesions)

  Renal diseases

  Chronic uremia

  Syringomyelia
  Craniostenosis
  Aquaductal stenosis (adult type)

  Heavy-metal poisoning:

  Lead, arsenic

  Serum sickness
  Allergies

  Bacterial

  Subacute bacterial endocarditis
  Meningitis
  Chronic mastoiditis (lateral-sinus thrombosis)
  Brucellosis

  Viral diseases
  Poliomyelitis
  Acute lymphocyte meningitis
  Coxsackie B virus encephalitis
  Inclusion-body encephalitis
  Recurrent polyneuritis
  Guillain-Barré syndrome

  Sandfly fever
  Trypanosomiasis
  Torulosis
  Neurocysticercosis

  Eclampsia
  Hypoparathyroidism
  Addison's disease
  Scurvy
  Oral progestational agents
  Diabetic ketoacidosis
  Menarche
  Obesity
  Menstrual abnormalities
  Pregnancy
  Thyrotoxicosis

  Schilder's disease
  Muscular dystrophy

  Gastrointestinal hemorrhage
  Lupus erythematosus
  Sarcoidosis
  Syphilis
  Subarachnoid hemorrhage
  Status epilepticus
  Paget's disease
  Opticochiasmatic arachnoiditis

  Carcinomatous “meningitis”
  Leukemia
  Spinal-cord tumors

  Infectious mononucleosis
  Idiopathic thrombocytopenic purpura
  Pernicious anemia
  Polycythemia
  Iron-deficiency anemia
  Hemophilia

  Congestive heart failure
  Mediastinal neoplasm
  Congenital cardiac cyanosis
  Hypertensive encephalopathy
  Pulmonary emphysema
  Dural-sinus thrombosis
  Chronic pulmonary hypoventilation
  Sleep apnea

IIH affects about 1 to 2/100,000 in the general population, but 19 to 21/100,000 of obese women of reproductive age.¹⁴² The relative percentage of men with pseudotumor ranges from 17% to 35% in large series, with the Iowa study citing 16% in male patients older than 16 years of age,¹⁴³ and including obesity and hypertension as risk factors, but discounting the roles of tetracyclines, steroids, vitamin A, or head trauma. More recently, the antiarrhythmic drug amiodarone¹⁴⁴ and the androgen danazol¹⁴⁵ were reported to induce pseudotumor cerebri, joining the classic list of steroid usage or withdrawal, nalidixic acid, hypervitaminosis A, tetracyclines, the insecticide chlordecone (Kepone),¹⁴⁶ and lithium.¹⁴⁷ The association with anovulatory agents (especially Norplant) may be fortuitous, these being so commonly used in the population at risk. Ironically, IIH has been reported without elevated CSF pressure,¹⁴⁸ but in a typical obese, hypersomnolent young woman, with papilledema and headaches, normal MRI, and responding to standard therapy.

General symptoms and signs of increased CSF pressure include the following: daily diffuse or frontal headache; transient visual obscurations (“black-outs”) associated with usually florid bilateral papilledema (rarely unilateral¹²⁷); neck stiffness; shoulder, arm, or leg pain, likely representing transmission of CSF pressure to dural sleeves of radicular spinal nerve roots; pulsatile tinnitus, related to transmitted increased pressure in the scala tympani of the inner ear; and diplopia due to sixth nerve palsy. Unusual ocular motor disturbances are infrequently encountered, including internuclear ophthalmoplegia, external ophthalmoplegia, vertical gaze palsies, and supranuclear palsies.¹⁴⁹

Neuroimages of the brain are categorically normal, their role being to exclude other causes of raised CSF pressure: CT or MRI shows undisplaced normal or small ventricles and no signs of mass lesions. Dural venous sinuses may show evidence of thrombosis or slowed flow in an unknown proportion of otherwise idiopathic cases, but otherwise neither CT nor MRI has revealed much evidence in regard to pathogenesis; rarely, increase in brain white matter signal, representing a prolongation of the T2 relaxation time, indicates a general increased water content,¹⁵⁰ consistent with previous theories of intracellular and extracellular edema.

Authoritative consensus dictates that lumbar puncture is vital in affirming a diagnosis of IIH, the only supportive finding being raised CSF pressure, but without abnormalities in protein level or cell count. Curiously, low-pressure pseudotumor is reported,¹⁴⁸ as is IIH without papilledema.¹⁵¹ CSF pleocytosis or increased protein content suggests chronic inflammatory meningitis or encephalitis, or lupus arteritis. Corbett^151a provided the figure 200 to 250 mm H₂O for the upper limit of normal for CSF opening pressure, especially in the obese patient (Fig. 27).

Although headaches may easily be controlled, the possibility of visual loss is real and demands regular monitoring, in children¹⁴⁰ as in adults.¹⁵² Visual field defects relate to progressive nerve fiber atrophy consecutive to chronic papilledema, with fundus evidence of special predilection for thinning in the superior temporal arcuate nerve fiber bundles.¹⁵³ Field defects take the form of blind spot enlargement, generalized field depression, arcuate nerve fiber bundle defects, and nasal contraction (see Fig. 26A). There is histopathologic evidence of axonal loss, especially in the peripheral rather than axial portions of the optic nerves, which may be as extensive as 80% to 90% attrition.¹⁵⁴ Automated field strategies¹⁵² within the central 30° and along the nasal horizontal meridian disclose visual loss in more than 75% of involved eyes. Ultimately, the potential for visual loss is the single most serious complication of IIH, and proper management demands meticulous ophthalmologic surveillance.

That IIH is a self-limited disorder, with brief and transient manifestations, must be in considerable doubt. The precise pathophysiologic mechanism is not yet clarified, but various theoretical considerations include the following¹⁴²: increased resistance to CSF outflow; vasogenic brain edema; and increased intracranial blood volume. Noteworthy is the relative rarity of IIH beyond middle age, suggesting either an endocrine transition or the mitigating effect of age-related brain atrophy. Whereas pathogenesis is confused, the efficacy of medical management is well established. Therapy commonly begins with the carbonic anhydrase inhibitor acetazolamide (Diamox), 500 mg twice daily; side effects include perioral and hand paresthesias, anorexia, metallic taste, and rarely renal stones or aplastic anemia and transient myopia with choroidal detachments.¹⁵⁵ Furosemide (Lasix), 2 mg/kg three times daily, or thiazide diuretics are alternatives. It is not clear whether diuretics are effective by decreasing central plasma volume or by suppressing CSF production. Corticosteroids may be less useful considering the side effects of fluid retention, hypertension, and elevation of intraocular tension. However, in instances of relatively acute visual loss associated with florid papilledema, high-dose intravenous methyprednisolone may quickly reduce edema and may rapidly improve vision.¹⁵⁶ The importance of a weight-reduction program bears emphasis; Johnson et al¹⁵⁷ have suggested that as little as 6% weight loss may be critical to the success of standard acetazolamide therapy. Multiple lumber punctures may be effective but painful, and patient compliance is understandably tenuous. Therapeutic success is determined by relief of headaches, diminished frequency of transient visual obscurations, regression of papilledema, stability or improvement of field defects, and weight reduction.

When various optimum medical therapies fail, and disc swelling with field loss is progressing, operative decompressions are necessary. Lumbar-peritoneal shunts are undertaken frequently and are successful in acutely lowering intracranial pressure, but accumulated data¹⁵⁸ indicate a high rate of shunt failure requiring multiple revisions. Shunting usually relieves headaches, but it may paradoxically produce headaches related to low CSF pressure. More importantly, delayed shunt failure may go undetected with recrudescence of intracranial hypertension and insidious papilledema with slow or sudden visual loss.¹⁵⁹ Peculiarly, shunt failure may present with visual loss without papilledema.¹⁶⁰

Direct fenestration of the optic nerve sheaths via medial or lateral orbitotomy has evolved as an effective and relatively simple procedure for relief of papilledema and stabilization of visual function.^161,162 Nonetheless, such surgical manipulation may worsen vision through vascular events¹⁶³ or neural damage.¹⁶⁴ Interestingly, bilateral disc detumescence may follow unilateral optic sheath opening, and headache may be relieved, but to what extent the intracranial subarachnoid compartment is decompressed is debatable (see Volume 2, Chapter 14, Part II).

The co-existence of IIH with pregnancy is likely fortuitous, but perinatal hypercoagulable states are known to play a role in cerebral, pelvic, and deep vein thromboses. Although teratogenicity is debatable, acetazolamide may be safely used after 20 weeks, that is, beyond the critical teratogenic period. Peculiarly, some unknown proportion of patients with chronic daily headaches, without papilledema and with normal neuroimaging, may show elevated CSF pressures (range, 230 mm to 450 mm H₂O); when treated with acetazolamide or furosemide, headache control improves.^151,165 Of extraordinary interest is familial idiopathic pseudotumor, of which more than a dozen cases have been reported, including in siblings, but also in successive generations, strongly suggesting a hereditary disposition.¹⁶⁶

Secondary Pseudotumor Cerebri Syndromes

With the advent of MRI, cerebral dural venous sinus thrombosis or venous outflow obstruction is demonstrated with increasing frequency. Such cases of dural sinus hypertension include surgical neck dissection, ligation of sigmoid sinus, thrombosed central intravenous catheters, tumoral compression or invasion of dural sinuses, and arteriovenous malformations.¹⁶⁷ Indeed, it may be that elevated intracranial venous pressure is a universal mechanism in pseudotumor cerebri of various causes.¹²⁴ The importance of otitis media, mastoiditis, and lateral sinus thrombosis in childhood pseudotumor is, of course, well known.¹³⁹ Purvin et al¹⁶⁸ have characterized the neuro-ophthalmic manifestations of cerebral venous obstruction, listing cases of noncompressive ( Behçet's disease, mastoiditis, thrombogenic factors), compressive (dural sinus meningioma, glomus tumor, cervical masses), and iatrogenic surgical ligation of dural sinuses or during neck surgery. Other underlying risks for hypercoagulable states include paroxysmal nocturnal hemoglobinuria.¹⁶⁹

Various toxic or mechanical factors are incriminated in the pseudotumor syndrome (see Table 9), some of which are unsubstantiated; that is, association does not necessarily imply cause. Oral contraceptives are reported as a likely risk factor for migraine and vascular disease in the child-bearing population, and purportedly for venous thrombosis and pseudotumor cerebri, but in the absence of other risk factors (smoking, diabetes, hypertension obesity, hyperlipidemia), no substantial evidence exits.^170,171 In children or young adults, growth hormone replacement,¹⁷² Addison's disease (primary hypoadrenalism),¹⁷³ long-term corticosteroid use or withdrawal,^139,174 vitamin A intoxication,¹⁷⁵ nalidixic acid, minocycline,^175a and thyroid replacement¹³⁹ all seem to be genuine determinants. Chronic pulmonary insufficiency with pickwickian syndrome (obesity, hypoventilation, and somnolence) produces hypercapnia, increased cerebral blood flow, and increased CSF pressure.¹⁷⁶

Skull growth anomalies such as achondroplasia¹⁷⁷ or with craniosynostosis¹⁷⁸ may be associated with insidious and severe visual failure related to chronic raised intracranial pressure and papilledema. In addition, many different abnormalities in CSF composition, as in the infections cryptococcosis, cysticercosis, and neurosarcoidosis, or in residual subarachnoid blood, may serve to obstruct absorption of CSF by arachnoidal villi, producing a secondary form of pseudotumor cerebri.¹⁷⁹

When the optic nerve is damaged by vascular, compressive, or unknown mechanisms, the more general term “optic neuropathy” is preferable. “Papillitis” refers to the intraocular form of optic neuritis in which disc swelling of variable degree is observed. The clinical distinction among “papilledema,” that is, passive disc edema associated with increased intracranial pressure, papillitis, and ischemic neuropathy with disc edema is summarized in Table 8.

The general clinical characteristics of noninfective optic neuritis may be summarized as follows:

1. Relatively acute impairment of vision, progressing rapidly for hours or days; visual function usually reaches its lowest level by 1 to 2 weeks after onset, but it may actually be improving by that time.
   
2. The typical episode involves one eye only, although in children especially it is not unusual for bilateral neuritis (with disc swelling) to follow viral illnesses, including measles, mumps, and chickenpox.
   
3. Tenderness of the globe and deep orbital or brow pain, especially with eye movements, may precede or coincide with visual impairment.
   
4. Visual function is depressed over the entire field, but most markedly involves the central 20°, with variable diminution of acuity, color sense, and contrast sensitivity; normal or near-normal acuity may be preserved.
   
5. Perimetric findings include admixtures of central and cecocentral scotomas, nerve fiber bundle and altitudinal defects, and general constrictions (Fig. 28).
   

   Fig. 28. Optic neuritis. A. Central scotoma pattern with finger-counting vision. B. Inferior altitudinal (nerve fiber bundle) pattern, sparing the fixational area with acuity of 20/20. C. Complete loss of temporal field, 4/200 acuity. Peripheral field returned completely within 2 months, but central function remained diminished to 20/40.

6. In the majority of cases, especially in demyelinating disease, visual function begins to improve in the second or third week, and many patients enjoy normal or near-normal vision by the fourth to fifth week; in others, following a fairly rapid improvement to modest levels of acuity (20/60 to 20/40), vision slowly but steadily improves over several months.
   
7. In a small percentage of cases, vision does not improve to functional levels, and, even more rarely, vision does not improve at all after the initial precipitous loss.
   

Visual symptomatology in optic neuritis is related to the nature of neural conduction defects, which may be subjectively approximated by viewing through a neutral density filter or dark lens before the eye. In addition to diminished central acuity and field loss, the following symptoms are typical: drabness (desaturation) of colored objects, although specialized color vision testing¹⁸⁰ suggests mixed types of dyschromatopsia without correlation with acuity, and fluctuations over time; apparent dimness of light intensities (e.g., room lighting appears reduced when viewed with affected eye); impairment of binocular depth perception (stereo-illusion), especially with moving objects (Pulfrich's phenomenon¹⁸¹), attributed to inter-eye disparity of light sense or retinal illumination; and increase in visual deficit with exercise (Uhthoff's symptom¹⁸²) or other elevations of body temperature, typically noticed in the chronic or recovered phase. These visual defects may persist after return of reading acuity to normal levels, and thus patients continue to be visually symptomatic in spite of good acuity and field.

From the Optic Neuritis Treatment Trial (ONTT),¹⁸³ visual field defects included the following: diffuse depression occurred in about 48%, and especially vertical altitudinal half and quadrant localized defects; strictly central or cecocentral scotomas constituted less than 10%; various single or double arcuate defects were reported; and unilateral nasal or temporal hemianopias were recorded, as well as chiasmal and retro-chiasmal patterns. At ONTT entry, field defects were found in two-thirds of fellow (non-acute) eyes.

In the common retro-bulbar form of optic neuritis, the fundus is unchanged during the acute episode, and subsequent pallor may range from profound to imperceptible. Papillitis, that is, disc swelling caused by local inflammatory processes of the nerve head, may be thought of as an intraocular form of optic neuritis, although etiologic considerations are not parallel. In children, papillitis is the common presentation of optic neuritis. In the Kennedy-Carroll series,¹⁸⁴ 22 of 26 children less than 15 years of age showed acute disc swelling. In addition, simultaneous bilateral neuritis is by far more common in children than adults. This latter point may be attributable to two factors: children with unilateral visual loss are less likely to complain than those with bilateral visual loss; the incidence of viral diseases (mumps, chickenpox, nonspecific fevers, and upper respiratory infections) is high in childhood, and these systemic disorders may be more prone to provoke symmetric optic neuritis than other demyelinative or inflammatory causes.

The role of vaccination and infections preceding optic neuritis in childhood was noted in a Scandinavian study,¹⁸⁵ in which 8 of 11 children had bilateral nerve involvement; in this series, 10 patients eventually developed definite MS, implying that associated immune mechanisms may be risk factors for MS. From the Mayo Clinic study¹⁸⁶ of 79 children less than 16 years old with isolated optic neuritis (39% unilateral, 57% bilateral, 3% recurrent), 13% had clinical MS by 10 years of follow-up, and 26% by 40 years; gender, age of onset, fundus findings, or acuity level had no predictive value, but the presence of bilateral sequential or recurrent optic neuritis increased the risk of MS, whereas the presence of infection within the 2 preceding weeks decreased the risk. It is likely that some degree of parainfectious encephalomyelitis (acute disseminated encephalomyelitis) exists in a subset of children with optic neuritis, as evidenced by the frequency of headache, nausea and vomiting, spinal fluid lymphocytosis, and some MRI abnormalities are indeed reported.¹⁸⁷

Papillitis is frequently accompanied by cells in the vitreous especially just anterior to the disc, and deep retinal exudates may form a star figure at the macula, or half-star between the disc and fovea, termed Leber's stellate maculopathy (Fig. 29). When edema spreads to the peripapillary nerve fiber layer, the term neuro-retinitis is applied. This fundus appearance is not likely to be associated with subsequent disseminated sclerosis (see below). In certain patients, especially following febrile illnesses, a viral agent may be suspected. We have seen three instances of children with unilateral papillitis, with temporally related mumps in siblings. Otherwise, even recurrent neuroretinitis with mixed visual outcome, and no discoverable systemic cause, is not a harbinger of MS.¹⁸⁸

Visual prognosis with papillitis or uncomplicated neuroretinitis is surprisingly good, even in the presence of massive disc edema and hemorrhages or with initial severe loss of visual function. However, progressive atrophy may ensue regardless of therapeutic intervention, and good visual outcome is not guaranteed. In hopes of favorably influencing visual outcome, corticosteroids are used orally, but, as with retro-bulbar neuritis, there is no substantive evidence that eventual visual function is affected by therapy. In patients with neuroretinal edema or cellular debris in the vitreous, a short-term course of steroids seems reasonable.

Discussed previously (Part I of this chapter), but noted in passing here, optic neuritis, expressed in variable degrees of disc swelling, may accompany inflammation primarily of the uvea, retina, or sclera. The ocular signs and symptoms, cellular debris in the vitreous, and fundus characteristics are sufficient to establish a local, if nonspecific, cause of the neuritis. In such cases, reduced central vision may be due to cystoid macular edema rather than the papillitis, or a combination of both.

In clinical practice, the largest proportions of cases of optic neuritis present as a monosymptomatic event without clinically obvious cause. By history or physical examination alone, only rarely is a specific cause deduced (Table 10). History-taking should include the following points: symptoms of a preceding viral illness (e.g., upper respiratory or gastrointestinal infection, febrile illness); subjective sinus disease; previous or co-existing neurologic signs and symptoms (e.g., paresthesias, clumsiness of limbs, ataxia, diplopia, urinary incontinence); and concurrent viral illness in the family (especially children) or other close contacts. The presence of painful eye movement is an especially useful symptom, occurring in more than 90% of patients with optic neuritis.¹⁸⁹ The minute details of disc swelling in some instances may be helpful in the distinction of optic neuritis from anterior ION (see below), the presence of altitudinal or pallid edema, hemorrhages, or arterial attenuation suggesting the latter diagnosis,¹⁹⁰ but of course pain and younger age of onset favor neuritis.

TABLE 10. Causes of Optic Neuritis

  Unknown origin
  Multiple sclerosis
  Viral infections of childhood (measles, mumps, chicken pox) with or without encephalitis
  Postviral, paraviral infections
  Infectious mononucleosis
  Herpes zoster
  Contiguous inflammation of meninges, orbit, sinuses
  Granulomatous inflammations (syphilis, tuberculosis, cryptococcosis, sarcoidosis)
  Intraocular inflammations

The standard workup of patients with monosymptomatic optic neuritis, who are otherwise in good health and with an unremarkable medical history, is controversial. Unfortunately, many instances of isolated optic neuritis represent the clinical onset, or forme fruste, of disseminated demyelinating disease, that is, MS (see below). Even in a seemingly typical case of optic neuritis, neuroimaging studies, specifically MRI, are no longer considered superfluous, not only to rule out potential occult structural defects, but to detect brain white matter lesions. These most commonly take the form of discrete or confluent lesions contiguous with the ventricles (periventricular) (Fig. 30), but also in the anterior and posterior forceps, subcortical white matter, internal capsule, temporal lobes, and pons. On entry in the ONTT, fully 49% of patients had abnormal brain MRIs. With fat-suppression MRI techniques (Fig. 31), increased signal intensities in optic nerves may be found in 80% to 100% of patients with optic neuritis.¹⁹¹ Dunker and Wiegand,¹⁹² using short-time inversion recovery MRI technique suggested that optic nerve lesions greater than 17.5 mm in length, or lesions involving the intracanalicular segment, are more likely associated with incomplete or partial visual recovery.

Vision rapidly regains acuity levels of 20/20 to 20/40 often within a few weeks and in 75% of cases by 6 months; recovery is only marginally influenced by corticosteroid treatment during the first 2 weeks, but without significant therapeutic effect on all parameters of visual function at 1 year.¹⁸⁹ Paradoxically, in the ONNT, the regimen of oral steroids alone not only proved without benefit, but it was associated with an increased rate of new attacks (30%, compared with 14% in the group treated with intravenous methylprednisolone, and 16% recurrence rate in the group receiving placebo). The only predictor of poor visual outcome was very low vision at ONTT study entry, with 8 of 160 patients with acuity of 20/200 or worse still at that level at 6 months; remarkably, of 30 patients with initial vision of only light perception or worse, 20 (67%) nonetheless recovered to 20/40 or better.

Of great interest are the results of applying the same visual testing procedures to clinically unaffected eyes contralateral to acute optic neuritis¹⁹³: 14% show diminished acuity, 15% abnormalities of contrast sensitivity, 22% dyschromatopsia, and 48% field defects. Intuitively, these phenomena infer the presence of bilateral optic neuropathy and the likelihood of disseminated demyelinative lesions, although in patients without subjective history of previous optic neuritis, this conclusion is debatable. (The details of tests of visual function, including color sense, contrast sensitivity, and evoked potentials are described in Volume 2, Chapter 2).

In spite of recovery to good levels of reading acuity, and failure to uncover specific defects by standardized techniques,¹⁹⁴ loss of contrast at medium spatial frequencies and disordered depth and motion perception (see above, Pulfrich's stereo-illusion phenomenon) best correlate with subjective symptoms. Extraordinary complaints include phosphenes, photopsias, and subjectively better vision under dim (scotopic) levels of illumination.^195,196

DEMYELINATIVE DISEASE

As noted above, the association of optic neuritis, usually of the retro-bulbar type, with demyelinating disease is well recognized. In fact, optic neuritis, internuclear ophthalmoplegia, and various nystagmus patterns are the most common ocular complications of MS. In the individual patient with a first episode of monosymptomatic optic neuritis and a normal MRI study, it is not yet possible to predict with precision the future development of MS. According to the ONTT,¹⁹⁷ of 388 patients with acute optic neuritis, but without probable or definite MS, 5-year cumulative probability of definite MS was 30%, and it did not differ by treatment group. Neurologic impairment was generally mild. In 89 patients with 3 or more MRI abnormal white matter signals, 51% developed definite MS; 35% of patients with one or 2 lesions developed MS, as did 16% of 202 patients even with normal baseline MRI. Another study analysis¹⁹⁸ showed 42 of 74 patients (57%) with isolated monosymptomatic optic neuritis to have multiple white matter changes on MRI, but all clinically asymptomatic lesions; during 5.6 years mean follow-up, 28% developed MS (of which 76% had initially abnormal MRIs); of 53 patients who did not develop clinically symptomatic MS, 26 (49%) had initially abnormal MRIs; this study found that abnormal CSF immunoglobulin G levels correlated more strongly than did abnormal MRIs with subsequent clinically definite MS. According to the ONTT,¹⁸⁹ additional tests, including laboratory studies for lupus or syphilis, chest radiography, and lumbar puncture, proved of no diagnostic or prognostic value; white patients predominated, 77% of patients were women, and mean age was 32 years.

From the British experience at Moorfields Eye Hospital,¹⁹⁹ after a mean follow-up of nearly 12 years, it was found that 57% of 101 patients presenting with optic neuritis had developed MS, almost all with clinically “definite” disease. With life-table analysis, the probability of developing MS was 75%, 15 years after initial optic neuritis, and the presence of HLA-DR2 or DR3 increased the overall risk. In a population-based study²⁰⁰ of 116 patients with monosymptomatic optic neuritis (80% women), 55% had 3 or more lesions on MRI (all with at least 1 periventricular white matter locus), 9% had 1 to 2 lesions, and 35% had normal imaging; of 143 patients, oligoclonal immunoglobulin G bands were demonstrated in the CSF of 72%; and of 146 patients, 47% carried the DR15,DQ6,Dw2 haplotype; laboratory screening for syphilis and Borrelia were entirely unproductive. Only 4 patients with strongly positive MRI findings were negative for oligoclonal bands. (In the absence of oligoclonal bands so typical of MS, some clinicians caution that another diagnosis must be considered.) During the study period (mean follow-up, 2.2 years), 36% developed definite MS, but there was no significantly higher risk among women, supporting the lack of gender risk in evolution of MS as in the ONTT.¹⁹⁷

Retinal venous sheathing (periphlebitis retinae) accompanying optic neuritis may serve as an additional “marker” for MS, as well as providing some pathophysiologic insight. Lightman and colleagues²⁰¹ found retinal vascular abnormalities in 14 of 50 patients with optic neuritis; MS developed in 8 of these 14 and in 5 of 32 patients without retinal vasculitis. The occurrence of perivenular sheathing or fluorescein leakage in tissues free of myelin and oligodendrocytes provides evidence that vascular changes may be the primary event in the formation of new demyelinative lesions. A Danish study²⁰² found 27 instances of retinal periphlebitis among 135 cases of MS, and those patients with such fundus findings suffered a more severe neurologic course. Of note is the association of MS with uveitis, usually mild “pars planitis,”²⁰³ and also of positive MRI in a minority of patients with retinal vasculitis with a positive family history of MS.²⁰⁴ Other granulomatous inflammations such as syphilis, sarcoid, tuberculosis, and Behçet's disease must be considered as causes of uveitis and CNS disorders (see Chapter 5, Part I, Ureomeningeal Syndromes).

It is apparent that the longer the follow-up of patients with optic neuritis, the greater the incidence of subsequent demyelinative signs and symptoms, and MRI is a major predictor of such development. Identification of risk factors, especially MRI white matter lesions and presence of oligoclonal bands in CSF, provides guidelines for therapy. For example, patients receiving a course of intravenous corticosteroids show a slower rate of progression to MS; that is, there is a distinct 2-year delaying influence on subsequent signs and symptoms,¹⁸⁹ and, arguably, even in patients with isolated first-event optic neuritis, this treatment should be considered when MRI shows diagnostic changes. In acute optic neuritis, CSF changes, with the exception of oligoclonal banding, do not predict development of MS independently of baseline MRI characteristics.²⁰⁵

The early and accurate identification of patients with occult MS is vital. The long-term treatment of MS is evolving, with clinical trials of naturally occurring and recombinant interferons (antiviral proteins from T lymphocytes), co-polymers, oral myelin, and other immune-stimulating and immune-suppressing agents.

Neuromyelitis optica (Devic's disease) is a curious variant of demyelinative disease of indeterminate nosology. This syndrome is characterized by rapid or subacute, severe unilateral or bilateral visual loss accompanied by transverse myelitis and paraplegia. MRI lesions are more rare in the brain than in MS, and there is a propensity for necrotizing myelopathy of the cervical and upper thoracic spinal cord associated with thickened blood vessels.²⁰⁶ Organ-specific antibodies may be detected, spinal cord lesions extend beyond one segment by MRI, and remissions are much less likely than in MS.²⁰⁷

IMMUNE-MEDIATED AND ATYPICAL OPTIC NEURITIDES

Many different inflammatory conditions afflict the optic nerves, confounding nonchalant differential considerations beyond simple MS. These causes embrace an exhausting range of possibilities (see Table 10) that tax determinations of specific clinical diagnosis. However, some physical features may prove useful. For example, optic disc edema may eventuate in fundus patterns of precipitates radially arranged in the macula, pointing toward the fovea (see Fig. 29) and termed a “macular star.” As noted previously, this is a nonspecific retinal feature found even in diabetes and hypertension, less frequently in papilledema of raised intracranial pressure, and rarely in ION. It does suggest inflammation of the disc itself (papillitis, neuroretinitis), including causes such as various viruses, cat-scratch disease, spirochetal disease, and even sarcoidosis.²⁰⁸ However, the presence of macular exudates militates strongly against MS.

Acute disseminated encephalomyelitis may follow viral infections, including measles, mononucleosis, mumps, varicella, and pertussis. Acute disseminated encephalomyelitis mimics experimental acute encephalitis induced by sensitization to myelin basic protein. Especially in childhood, this disorder may cause bilateral optic neuropathy, with headache, seizures, or meningeal signs, including CSF lymphocytosis and raised CSF pressure.²⁰⁹ Encephalitis with optic neuritis may develop subsequent to vaccination for polio, measles-mumps-rubella, hepatitis, or diphtheria-tetanus-pertussis, for example.^185,187,210

Of special interest are reports of optic neuritis after influenza vaccination,^211,212 attributed to allergic cross-reaction to viral antigens or to immune-mediated vasculitis. Other acute inflammatory demyelinating polyneuropathies, such as Guillain-Barré syndrome, follow immune upsets, but optic neuropathy with Guillain-Barré syndrome must be rare (as well as auditory neuritis), extraordinary case reports,^213,214 notwithstanding.

Optic neuropathies following chickenpox,²¹⁵ rubella, rubeola, mumps, herpes zoster, and mononucleosis²¹⁶ may be formes frustes of acute disseminated encephalomyelitis or are referred to as parainfectious, as opposed to direct tissue infiltration by microbiologic agents. Indeed, an undoubtedly immune-mediated form of bilateral optic neuritis is reported following bee sting.²¹⁷ In such instances, visual loss is typically bilateral and severe, occurring 10 days to 2 weeks after dermatologic signs (or envenomization), such delay suggesting an autoimmune cascade mechanism. In general, complete visual recovery is anticipated, although corticosteroid therapy may be indicated.^209,210

The association of optic neuritis with systemic lupus erythematosus and other autoimmune states (e.g., mixed connective tissue disease, Sjögren's syndrome) is well-known, if relatively rare. The principal pathologic process is one of inflammation and necrosis of blood vessel walls and, as such, is best classified as a variety of ION, discussed subsequently. Without the necessary criteria for classification as systemic lupus erythematosus, a small subset of patients are considered to suffer from a form of “autoimmune optic neuritis,” which is roughly characterized by more severe visual loss and resistance to corticosteroid therapy than is typical of idiopathic or demyelinative types. At times, diagnostic criteria are circuitous and, in the absence of substantial clinical or laboratory support (hematuria, serum antinuclear antibodies, erythrocyte sedimentation rate [ESR], abnormal complement levels), a vague relationship with immune-mediated processes is insinuated, especially in young women (see below).

INFECTIVE NEUROPATHIES

Of those optic neuritides in which infectious agents are more readily apparent, the impact of human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) has most palpably altered the modern etiologic spectrum. HIV-associated optic nerve disease may be related to tumoral compression, infiltrations such as lymphoma, vasculitides, inflammations, and especially secondary infections. As noted in Chapter 5, Part I, opportunistic infectious agents regularly invade the retina, optic nerve, meninges, and brain, and co-existing multiple infections further confound diagnosis and management. Neurologic symptoms are said to occur in 40% of cases, CNS pathologic findings in 70% to 80%, ocular manifestations in 50% to 70%, and neuro-ophthalmologic signs in at least 3% to 8%.^218,219 Optic nerve complications of immunodeficiency are included in Table 11.

TABLE 11. Optic Neuropathies in Immunodeficiency

  Papilledema (raised cerebrospinal fluid pressure)

  Cryptococcal meningitis
  Toxoplasmosis
  Lymphoma

  Cryptococcosis
  Syphilis (perineuritis form)
  Cytomegalovirus
  Pneumocystis carinii
  Human immunodeficiency virus ?
  Histoplasmosis
  Varicella

AIDS-related optic neuropathies generally reflect direct infestations of viral, spirochetal, or fungal organisms, but grossly diminished axonal counts may indicate a primary AIDS optic neuropathy.²²⁰ Otherwise, cytomegalovirus retinitis with spread to the nerve, or as an initial papillitis, is associated with poor visual outcome even with therapy.²²¹ Likewise, cryptococcosis (Fig. 34) may be associated with chronic optic meningitis, with insidious or rapid vision loss related to fulminant nerve necrosis.²²² Optic nerve sheath decompression for raised CSF pressure in cryptococcal meningitis has been reported to improve function.²²³ Other infectious agents include Toxoplasma gondii,²²⁴ varicella-zoster,^225,226 and Histoplasma capsulatum.²²⁷

The role of HIV itself as an etiologic agent in optic nerve disease is imprecise, but the virus has been isolated from all ocular tissues, it is neurotropic, and is implicated in cases of meningitis (including with Cryptococcus), encephalitis, and peripheral neuropathies.²²⁸ Indeed, HIV-seropositive patients are reported with recoverable bilateral optic neuropathies without other infectious or neoplastic processes, suggesting a primary role of HIV infection.²²⁹ Berger and associates²²⁸ described a neurologic disease clinically indistinguishable from MS, including mostly bilateral optic neuritis, occurring with HIV; indeed, histopathologic features of the CNS were consistent with MS.

By 1990, the incidence of primary and secondary syphilis in the United States increased 34% to 18.7/100,000 persons, and serologic testing is indicated in many cases of optic neuropathy without other clearly discernable cause, but especially in patients with, or at risk for, AIDS. Co-infection alters the natural history and increases the propensity for a more aggressive course and rapidly evolving neurosyphilis. Moreover, even in biopsy-confirmed syphilis, treponemal and nontreponemal tests may be negative in HIV infection.²¹⁹ Corticosteroids, so frequently used in optic neuritis, are contraindicated until infectious causes are ruled out, including CSF assessment, especially when HIV is suspected. Empiric penicillin treatment for neurosyphilis may be considered.²²⁹ Modern laboratory tests include the fluorescent treponemal antibody absorption (FTA-ABS) test and microhemagglutination assay.

Syphilitic neuroretinitis, papillitis, and “perineuritis” are clinical manifestations of secondary stage and neurorecurrence, whereas slowly progressive atrophy evolves in the tertiary stage; simple papilledema of raised pressure may herald meningoencephalitis.²³⁰ Uncomplicated “retro-bulbar” neuritis, so common otherwise, must be extremely rare in syphilis, although Zambrano²³¹ reported bilateral overnight blindness in association with AIDS. Optic “perineuritis” purportedly inflames primarily the optic meninges, with relative sparing of the central core of the nerve and preservation of central field function, including acuity; disc swelling is characteristic, but papilledema of increased pressure and meningitis are ruled out by lumbar puncture. Color vision and evoked potentials may be normal.²³² Late “descending” optic atrophy is a sign of tertiary neurosyphilis, classically seen in taboparesis.

Arruga and colleagues²³³ reviewed neuroretinitis in acquired, secondary syphilis, with funduscopically evident clouding of the central retina, vasculitis, hemorrhages, pigment epithelial disarray, and disc swelling; most cases are bilateral, and vitreous cellular debris is present.

Lyme borreliosis must be an uncommon cause of optic neuropathies, or of any other ocular manifestation, according to authoritative reviews²³⁴ of neurologic manifestations of the disease. In the early disease, a nonspecific follicular conjunctivitis occurs in about 10% of patients, and flu-like symptoms are common along with the typical erythema migrans rash, itself noted in only 60% to 80% of cases. Uveitis is extremely rare, as is neuroretinitis. Schmutzhard and associates²³⁵ included two young women with “optic neuritis,” and Pachner and Steere²³⁶ cited no optic nerve involvement among 38 cases of Lyme meningitis. The case report of Wu and coworkers²³⁷ of “optic disc edema” seemingly occurred in the setting of a 7-year-old boy with stiff neck and CSF pleocytosis. Strominger and colleagues²³⁸ reported worsening of Lyme neuroborreliosis, including optic neuritis, following ceftriaxone therapy. In the early disseminated phase, aseptic meningitis, cranial neuropathies (facial palsy being the most common), and radiculoneuritis occur. Indirect immunofluorescence antibody (IFA) and enzyme-linked immunosorbent assays (ELISA) are used to detect antibodies, but even for patients with the pathognomonic cutaneous manifestation of erythema migrans, in a Connecticut study the overall sensitivity of serology was 30% to 45% by IFA and 24% to 32% for ELISA.²³⁹ At present, serpositivity alone does not distinguish between past exposure and active infection, and false-positive results are common. Polymerase chain reaction techniques are currently being evaluated.²³⁵ In the early stages, doxycycline or penicillins are used, and ceftriaxone is used for neurologic or ophthalmic disease.²³⁵

Cat-scratch disease is an infection caused by Bartonella (Rochalimaea) henselae and R. quintana, gram-negative bacilli implicated in subacute regional lymphadenitis, conjunctivitis (at times with pre-auricular adenopathy), intermediate uveitis, retinal vasculitis, serous retinal detachment (see also Part I of this chapter), papillitis with retinal exudates, and aseptic meningitis.^240,241 Disease evolves days to weeks after cat scratch or bite, and it is thought that almost 50% of domestic cats, and their fleas, are the persistent reservoir of these organisms. Visual acuity is variable, and papillitis may be bilateral. IFA of serum is positive in the majority of patients, but serologic assays are also positive in some 3% of the healthy population. Although cat-scratch disease is considered a self-limited and relatively benign infectious disorder, and no optimal therapy is yet defined, various antibiotics are usually administered to maximize visual outcome.²⁴¹ Reed and colleagues²⁴² suggested the use of doxycycline and rifampin.

Toxacara canis²⁴³ is also documented to cause inflammatory papillitis with vitreous cellular reaction. Toxoplasma gondii (the agent of toxoplasmosis), a relatively frequent cause of posterior uveitis in the United States, with characteristic pigmented chorioretinal scars, is an uncommon but eradicable agent that can produce neuroretinitis characterized by retinal edema with macular star exudates. Serologic tests include IFA titers and ELISA, and sulfamethoxazole, sulfadiazine, or clindamycin therapy is indicated, usually coupled with corticosteroids.²⁴⁴ Familial Mediterranean fever (recurrent poly-serositis), an autosomal recessive disorder, is reported to produce uveitis, retinal detachment, or optic neuritis.²⁴⁵

SLOWLY PROGRESSIVE AND “CHRONIC” OPTIC NEURITIS

Although it is undoubtedly true that certain inflammatory conditions such as sarcoidosis, syphilis, tuberculosis, or other chronic meniningitides may be responsible for insidiously progressive loss of vision, the diagnosis of “chronic optic neuritis” is otherwise only rarely applicable. Most such clinical enigmas are eventually disclosed as compressive lesions such as meningiomas (intracanalicular or tuberculum sellae), pituitary tumors, or paraclinoid aneurysms. Moreover, because it is uncommon for demyelinative optic neuritis to run a relentless course, this clinical rubric demands precise neuroimaging procedures (MRI) and spinal fluid investigations. A salutary visual response to systemic corticosteroids may not be interpreted as positive evidence of inflammatory causes because vision may also be improved when mass lesions actually exist (see Volume 2, Chapter 6).

Covert visual loss, both unilateral and bilateral, that progresses at a slow uniform rate is documented in MS,²⁴⁶ and indeed it may be the presenting symptom. Insidious depression of visual acuity is the rule, although central scotoma patterns may be indiscernible in severe field loss. Such chronic central or cecocentral scotomas must be considered extremely rare in compressive lesions (see Volume 2, Chapter 6). Other associated neurologic signs and symptoms, CSF protein abnormalities, and typical white matter signals with MRI provide evidence in favor of a demyelinative cause.

Eidelberg and coworkers²⁴⁷ studied the clinical, electrophysiologic, and MRI features of 20 patients 12 to 77 years of age with chronic unilateral progressive visual failure lasting a minimum of 6 months. Extrinsic mass lesions were disclosed in 8 patients, intrinsic nerve or sheath tumors in 5; in 7 patients, short-time inversion recovery MRI sequences revealed altered signals in symptomatic nerves, and T2-weighted sequences showed periventricular white matter lesions.

Perineuritis, an idiopathic inflammatory cuffing of the orbital and intracranial optic nerve, does occur,²⁴⁸ with or without pain or other orbital signs, and it may radiologically mimic nerve sheath meningioma.²⁴⁹ Bilateral instances are recorded,²⁵⁰ and other features include nerve enlargement and retinal vascular occlusions.²⁵¹ Such instances of perineuritis may be caused by syphilis.²⁵²

Sarcoidosis frequently involves the nervous system and can present as abrupt or chronic visual loss, with or without disc changes. The cranial nerves, most commonly the facial and optic, the meninges, hypothalamus, and pituitary gland are frequent sites. In a series of 11 patients with sarcoidosis of the optic nerve,²⁵³ ranging in age from 16 to 48 years, only 2 patients were previously known to have the disorder. Four patients showed disc granulomas, 4 had optic nerve granulomas, and 3 mimicked retro-bulbar neuritis. Chest film findings were characteristic in 8 of 11, but only one-third of these cases had elevated serum angiotensin-converting enzyme levels.

Sarcoid granulomas may elevate the optic disc or may inflame retro-bulbar nerves and chiasm, presenting as optic atrophy. Chorioretinopathy, uveitis, and perivascular infiltrates (“candle-wax spots”) are well-recognized fundal signs of sarcoid.²⁵⁴ Leptomeningeal sarcoid may present as secondary pseudotumor cerebri resulting from dural sinus thrombosis.²⁵⁵ Modern MRI now regularly discloses enlarged anterior visual pathway sites, and lymph node or, more rarely, optic nerve or chiasm, biopsy provides histologic affirmation. Therapy is based on corticosteroids and immunosuppressives such as methotrexate. Current inclusive reviews are available elsewhere.^256,257

Other causes of optic meningeal or nerve enlargement and chronic visual loss include perioptic meningioma, optic glioma, perioptic idiopathic inflammation, and Wegener's granulomatosis²⁵⁸ (see below). The cautionary comment of David Cogan again bears repetition: “Probably no branch of neuro-ophthalmology has to its discredit the abundance of erroneous diagnoses as has optic neuritis.”

CONTIGUOUS INFLAMMATIONS

The optic nerve may be secondarily involved by various inflammatory lesions of adjacent tissues, including the orbit, paranasal sinuses, and intracranial meninges. With orbital cellulitis or nonspecific inflammatory pseudotumor, it is not clear whether true optic neuritis is present or visual deficits are caused by pressure effect. In orbital inflammatory pseudotumor, especially in the subacute or chronic forms, visual loss may be accompanied by variable degrees of disc swelling, a finding suggesting actual optic neuritis or perineuritis, as noted above. Rarely is visual impairment an initial symptom, and other clinical signs (proptosis, diplopia, conjunctival chemosis) usually have evolved before vision is disturbed. Systemic steroids are frequently beneficial.

Decades ago, many instances of optic neuritis were attributed to acute or chronic sinusitis. This popular concept was not farfetched, especially when the close anatomic relationship of the optic nerve with the ethmoid and sphenoid sinuses is considered (see Volume 2, Chapter 4, Fig. 5 and Fig. 11). The pendulum has now swung far in the other direction, and indeed rarely can the paranasal sinuses be directly incriminated in cases of optic neuritis.

Acute, severe, and irreversible visible loss may occur from spheno-ethmoiditis and contiguous cellulitis at the orbital apex.²⁵⁹ Visual loss occurs before, and often out of proportion to, overt signs of orbital inflammation. To be ruled out are Wegener's granulomatosis (see below), opportunistic fungal infections, and acute compression by mucopyocele.

Mucoceles of the sphenoid sinus may be associated with chronic progressive visual loss and ocular motor nerve palsies. However, on rare occasions, a clinical picture consistent with optic neuritis may be encountered, as exemplified by the following case:

A 16-year-old boy complained of progressive loss of central vision of 6 weeks' duration. For 6 months, the patient had noted mucopurulent nasal discharge, pain, and tenderness of the brows, and for 3 weeks, deep orbital ache increased on eye movement. Examination revealed corrected acuities of 20/40, right, and 20/70, left. Fields demonstrated a central scotoma in the left eye and a similar defect with superior extension in the right field (Fig. 33). The nerve heads showed mild but distinct hyperemia and edema. Frontal tomography demonstrated massive enlargement of the sphenoid sinuses. Following transnasal evacuation of a chronic pyomucocele, vision and discs returned to normal.

Optic neuritis may accompany acute or chronic meningitis in children or adults. Purulent leptomeningitis spreads to involve the optic nerve sheaths, primarily in the optic canal, or the substance of the nerve itself. Disc swelling may be present. Optic atrophy can follow severe neuritis, but as a rule, vision returns to functional levels, even after several months. In cases complicated by hydrocephalus or opticochiasmatic arachnoiditis, field loss may be progressive.

The optic nerves may also be involved in focal basal granulomas²⁶⁰ or diffuse granulomatous or infectious meningitis, including fungal infections such as cryptococcosis,²⁶¹ syphilis, and tuberculosis (Fig. 34). The therapy is that of the primary infectious process, but ultimate visual outcome is guarded.

As noted, optic neuritis is not rare in the viral disorders of childhood, which may be associated with symptomatic or asymptomatic meningoencephalitis. As a rule, bilateral disc swelling is seen, resulting from either papilledema or optic neuritis. Both viral and bacterial meningitis may cause visual complications that fall into three anatomic categories: (1) papillitis, retro-bulbar interstitial, or perineuritis (leptomeningitis); (2) cortical blindness (usually with cortical venous thromboses); and (3) progressive optic atrophy as a result of opticochiasmatic arachnoiditis or hydrocephalus.

On rare occasions, herpes zoster ophthalmicus, the trigeminal dermatologic reactivation of varicella-zoster virus (human herpes virus-3), may be associated with optic neuritis, either in the retro-bulbar form or with a severe ischemic papillitis. In immune-compromised patients, varicella-zoster optic neuropathy may precede retinal necrosis,²⁶² or it is more usually delayed.²⁶³ The efficacy of acyclovir and corticosteroids is variable. With perineuritis and perivasculitis as pathologic substrate, poor visual outcome is the rule, from which the following case is an extraordinary exception:

A 7-year-old boy experienced right earache followed by vesiculation in the cutaneous distribution of the ophthalmic trigeminal nerve (Fig. 35). Vision was recorded as “light perception only,” and corticosteroids were injected into the right orbit. Ultimate visual outcome while the patient received systemic steroids was 20/25, within 2 weeks. Within 9 days of onset, two siblings developed chickenpox.

Histopathologically, zoster involves the optic nerve as an inflammatory arteritis with associated mild leptomeningitis. With these lesions in mind, it was believed that the recovery of vision in the patient in the above case was directly attributable to intraorbital and systemic steroids.

Diffuse idiopathic perioptic meningeal thickening (cranial fibrosclerosis; hypertrophic pachymeningitis) is a relatively rare cause of progressive visual loss, with or without associated systemic multifocal fibrosclerosis.²⁶⁴ Signs and symptoms include chronic headaches, optic disc atrophy or edema, meningeal thickening on MRI (Fig. 36), CSF pleocytosis and protein elevation, dural sinus thrombosis, and cranial nerve palsies producing ophthalmoplegia, hearing loss, and facial palsies. Other causes of pachymeningitis must be ruled out, including sarcoidosis, tuberculosis, syphilis, rheumatoid arthritis, dural carcinomatosis, meningioma-en-plaque, and plasmacytoma. These conditions may be distinguished by accompanying clinical findings and definitive meningeal biopsy. Corticosteroid and immunosuppressive agents are undoubtedly useful.

A brief anatomic review of the vascular supply of the optic nerve may be summarized. The nerve fiber layer at the surface of the disc is supplied by small papillary capillaries of the central retinal artery branches, whereas the major prelaminar disc substance is nourished by peripapillary choroidal arterioles from the elliptic anastomotic annulus formed from the short posterior ciliary arteries (see Volume 2, Chapter 4, Fig. 4).^265,266 The perforated lamina cribrosa of the scleral wall, and this section of the optic nerve, is also supplied by centripetal arterioles of the partial arterial circle (Zinn-Haller) formed by branches of the posterior choroidal arteries. Consensus dictates that the central retinal artery does not contribute in any significant way to these anterior portions of the nerve. The immediate retro-laminar segment is supplied by recurrent pial arterioles of the peripapillary circulation, and pial capillaries of the central retinal artery running in the fibrous supportive septa of the nerve. Venous drainage is principally via the central retinal vein and variable peripapillary optociliary collaterals. These latter vessels may enlarge in conditions of chronic nerve sleeve obstruction, such as papilledema and meningeal infiltration, forming ophthalmoscopically visible shunts at the disc perimeter (see Color Plate 5-4F). The orbital and canalicular segments of the optic nerve are supplied by penetrating capillaries of the peripheral pial plexus of the ophthalmic artery and, to some extent, by the intra-axial central retinal artery circulation. The likely influence of these vascular patterns is discussed below.

COMMON (ARTERIOSCLEROTIC, NON-ARTERITIC) ISCHEMIC OPTIC NEUROPATHY

In contrast to inflammatory or demyelinative retro-bulbar optic neuritis, ION characteristically involves the prelaminar portion of the optic nerve with a constant ophthalmoscopic appearance of disc swelling (thus, the alternate term “anterior” ION) (Fig. 37 and Color Plate 5-3A). In fact, the absence of disc swelling with acute monocular loss of vision makes a diagnosis of “simple” ischemic infarction untenable. The rare exception to this rule is retro-bulbar ION associated with cranial arteritis (see below). Otherwise, abrupt visual loss in the elderly patient with a normal optic disc should bring to mind the possibility of other lesions, including rapidly expanding basal tumors or carcinomatous infiltration of the optic nerve sheaths.

Common ION may be generally characterized as follows:^267–269 age- and sex-adjusted incidence rate as high as 10/100,000; slight male predominance (about 62%) and extremely uncommon in black persons; peak median age 66²⁶⁸ or 72 years,²⁶⁷ but on rare occasions ION may occur in the late forties; hypertension in more than 40% to 50% and diabetes in 25%, these risk factors being of greater importance with onset in the slightly younger subset; many, perhaps most, patients noting visual symptoms on awakening; sudden onset of altitudinal^267,270 or other field defects (see Fig. 6), usually, but not invariably, involving the central fixational area and producing reduced acuity, ranging from 20/20 to no light perception, with one-half of patients seeing better than 20/60, and one-third seeing 20/200 or worse; visual deficits typically maximal at onset, but deterioration may progress for a few days to several weeks^270,271; recurrent disc infarcts in the same eye are considered relatively rare.²⁷²

Results of the Ischemic Optic Neuropathy Decompression Trial²⁷¹ indicate that untreated eyes show a spontaneous improvement rate of three or more optotype lines in 43%, and visual deterioration in 12%; other studies²⁷³ provide variable results (see below). Unlike infarction with cranial arteritis, premonitory ocular symptoms do not occur, and significant eye or brow discomfort, or headache, is exceptional, perhaps in about 10%, unlike optic neuritis, in which orbital ache or pain on eye movement is a prominent symptom (see above).

The optic disc is swollen to some degree (see Fig. 37), usually in a sector with small flame hemorrhages, and edema typically extends only a short distance beyond the border of the disc. It has been suggested that altitudinal swelling, pallor, arterial attenuation, and hemorrhage are found more commonly in anterior ION than in optic neuritis.¹⁹⁰ In addition, a presymptomatic phase of disc swelling may be observed²⁷⁴; for example, a patient presents with characteristic ION with visual loss in one eye, and disc edema with good visual function surprisingly is found in the contralateral fundus; after a brief delay, disc edema progresses, and vision usually declines. Perhaps this odd situation is related to chronic or subacute nerve ischemia with obstipation of axoplasm flow, but without significant nerve fiber infarction.

Clinical and experimental studies²⁷⁵ indicate that ION is precipitated by insufficiency in posterior ciliary artery circulation, more likely resulting from a reduction in critical perfusion pressure than from embolism or thrombosis, and that branches of the peripapillary choroidal arterial system become ischemic, with consequent infarction of retinal nerve fiber bundles in the disc substance anterior to the lamina cribrosa. Olver and associates²⁷⁶ studied the morphology of the microvasculature of the retro-laminar area of the human optic nerve and described an elliptic anastomosis (“circle of Zinn-Haller”) of branches of the medial and lateral para-optic short posterior ciliary arteries. This ellipse is divided into superior and inferior portions by the entry points of these branches into the eye, providing potential superior and inferior “altitudinal” blood supplies to the retro-laminar optic nerve that may play a role in the pathogenesis of the upper- or lower-half patterns of visual field defects frequently found in ION. Fundus fluorescein angiography in 41 instances of nonarteritic ION, less than 3 weeks after onset, showed delay in prelaminar optic disc capillary dye filling, but neither onset nor completion of filling of peripapillary choroid was delayed when compared with control subjects; frequency of delayed filling within peripapillary choroidal watershed zones was also not increased, nor was there consistent correlation by quadrant between disc filling delay, choroidal filling delay, optic disc swelling or hyperfluorescence, and visual field defect.²⁷⁷ The role of carotid embolic or occlusive disease is considered below.

Although some small case series imply that chronic raised intraocular tension may play a role in ION, in larger series,²⁷⁸ no evidence was found to support this hypothesis. Pre-existing chronic glaucoma in the involved or fellow eye must be considered a rare condition. Hayreh and colleagues²⁷⁹ emphasized the role of nocturnal hypotension and failure of disc autoregulatory mechanisms, predisposed by hypotensive medications often taken at bedtime. Again, the early morning subjective symptoms support this hypoperfusion hypothesis; indeed, Hayreh believed that more than 70% of patients note the new visual symptoms on awakening or shortly thereafter, and that ION develops more often in summer than in winter months.

The visual field defects in ION vary but usually take the form of arcuate scotomas or “altitudinal hemianopias” of the superior or inferior half-fields (see Fig. 6). These altitudinal or nasal pseudo-quadrantic defects are dense and are easily discovered by hand or finger-counting confrontational field techniques. The localizing value of the position of the “vertex” of quadrantic and wedge-shaped defects has been emphasized by Kestenbaum: when the wedge originates at, or points toward, the blind spot, the defect is due to disease at the nerve head or just behind it. The differential diagnosis of such arcuate scotomas (i.e., with curvilinear or radial borders originating at the blind spot) includes branch retinal artery occlusion, glaucoma, ION, optic neuritis, hyaline bodies (drusen) of the optic disc, congenital optic pit, juxtapapillary inflammation, and, very rarely, chiasmal interference. Central scotomas are the predominant field defects in about one-sixth to one-fourth²⁸⁰ of cases of common ION.

Optic atrophy ensues as disc edema resolves (see Fig. 37 and Color Plate 3B), and some small loss of disc tissue may be evident; increase in cup size is observed, but rarely is glaucomatous excavation mimicked.²⁸¹ The ophthalmoscopic criteria that permit a retrospective diagnosis of optic atrophy of ischemic origin include arterial attenuation,²⁸² although Frisen and Claesson²⁸³ have quantitatively demonstrated a reduction in central retinal artery caliber of 17% to 24% in nonischemic, descending (retro-bulbar nerve, chiasm lesions) optic atrophy.

Following ischemic infarction of one disc, there is great likelihood of second eye involvement, generally believed to sequentially occur in approximately 30% to 40%. Beri and associates²⁸⁴ provided the following figures for 10-year cumulative incidence rates: for patients 45 to 64 years of age, 55.3%; for patients 65 years old or older, 34.4%; for patients younger than age 45, 75.9%; for patients with diabetes mellitus, 72.2%; for patients with arterial hypertension, 42.2%; for patients with diabetes and hypertension, 60.6%. When ION occurs in the second eye, there is no consistent agreement on correlation of final visual function outcomes.^285,286

In common ION simultaneous bilateral disc infarction is practically unknown, and an underlying systemic disease such as cranial arteritis or severe renovascular hypertension must be suspected. The occurrence of consecutive disc infarction with fresh disc swelling in one eye, when combined with contralateral previous optic atrophy, mimics the ophthalmoscopic combination popularized as the “Foster Kennedy syndrome,”²⁸⁷ but there are obvious functional differences that separate acute disc infarction from papilledema of raised pressure (see Table 8). Ironically, then, the celebrated “diagnostic sign” of Foster Kennedy is most typical of alternating, consecutive ION and is exceedingly infrequent as a sign of intracranial frontal fossa masses with raised intracranial pressure.

Although the precise roles of diabetes and hypertension are not known, certainly the prevalence of these systemic disorders is significantly greater in patients with ION than in comparable age-matched groups^268,269; as noted, correlations with these systemic risk factors seem to be greater in patients less than 45 years old. Likewise, the association of cerebral and cardiac vascular disease seems to be circumstantial, and that simple ION, uncomplicated by chronic diabetes or hypertension, may be taken for a harbinger of future vascular events is moot. Although ipsilateral carotid disease does not seem to be a risk factor for ION,²⁸⁸ analysis of MRI of the brain in a small series of patients with ION (8 of 13 with hypertension) suggests an increased number (mean, 4.0 vs. 1.4 in age-matched controls) of ischemic white matter lesions.²⁸⁹ Giuffre²⁹⁰ reported that serum cholesterol, triglycerides, and glucose are elevated in ION, and other investigators have found a correlation of elevated concentrations of immunoglobulin G anticardiolipin antibody in patients with arteritic ION, but not in common ION.²⁹¹ Various coagulopathic states have been implicated, including activated protein C resistance, as well as antithrombin III and antiphospholipid antibody syndromes.²⁹² Smoking, elevated cholesterol, and serum fibrinogen >3.6 g/l are also risk factors.²⁹³

A series of funduscopic analyses addressed the question of the cup-to-disc ratio as a possible morphologic factor in the pathogenesis of common ION, culminating in the article by Beck and associates.²⁹⁴ By observing the disc appearance of the normal fellow eyes of patients with ION, it is apparent that the optic cup is small or absent at a significant rate in common ION (but not in arteritic ION). Furthermore, one study²⁹⁵ suggested that both the horizontal disc diameter and disc area are smaller in fellow eyes with ION than in controls (p < .05), and there is evidence²⁹⁶ of a modest protective role of myopia versus hyperopia. Possibly, ischemic axons in the “crowded” setting of a small scleral canal are predisposed to infarction. However, because patients with common ION may have variably sized contralateral physiologic cups, and patients with arteritic ION may show contralateral cupless discs, no strong diagnostic distinction should be placed on the state of fellow eye cup-to-disc ratio.

No medical therapies have proved to be effective in restoring vision in acute ION, although systemic corticosteroid usage could theoretically reduce the focal impact of edema and free radical production; therefore, short-term therapeutic trials are not unreasonable. The untoward effects of corticosteroids on diabetes, hypertension, intraocular tension, and general well-being must be taken into account. Hyperbaric oxygen is considered ineffective,²⁹⁷ and levodopa/carbidopa²⁹⁸ is under investigation. Regarding aspirin (ASA), in a retrospective study of 431 patients²⁹⁹ (153 treated with ASA), the 2-year cumulative probability of ION in second eye was 7% in the ASA-treated group and 15% in the untreated; 5-year cumulative rates were 17% and 20%, respectively, thereby suggesting at least a short-term advantage, but the total 5-year cumulative risk of only 19% in this study seems lower than most reported incidences of fellow eye occurrence. Kupersmith and colleagues³⁰⁰ suggest that ASA taken two or more times per week decreases the risk of second eye involvement, regardless of other risk factors.

As noted, spontaneous significant recovery of vision after ION indeed occurs. Movsas and associates²⁷¹ documented that, of 116 eyes with acuity of 20/60 or worse, 21% improved by 3 or more lines, and of 126 eyes with acuity better than 20/60, 23% improved by 3 or more lines. In a small series,²⁷³ 5 of 21 eyes improved acuity, even from 10/400 to 20/30.

Optic nerve sheath fenestration for drainage of perineural subarachnoid CSF has been systematically investigated by the Ischemic Optic Neuropathy Decompression Trial³⁰¹ in a large series of patients with both progressive and stable common (non-arteritic) ION: whereas visual function worsened spontaneously in 12% of 125 eyes, vision worsened in 24% of 119 eyes subjected to decompressive surgery. These results were in keeping with the poor surgical outcomes in the University of Miami study³⁰² of 47 eyes, and Indiana University study³⁰³ of 18 operated eyes; indeed, in the latter series, 23 of 71 eyes without surgery had increased acuity of 2 or more optotype lines.

Although intense interest in therapies for common ION continues, the actual incidence of this disorder is imprecise. Two limited surveys suggest an age-adjusted annual incidence in the white population 50 years old and older of 2.77³⁰⁴ and 10.2²⁶⁷ per 100,000 individuals; by extrapolation, it is estimated that 5700 new cases would occur each year in the white population of the United States. Tobacco usage has also been implicated³⁰⁵ in ION, especially in the slightly younger subset of patients. After onset of common ION, patients with both hypertension and diabetes show higher rates of subsequent cerebrovascular disease.

CRANIAL (GIANT CELL) ARTERITIS

The most common vasculitis responsible for neuro-ophthalmologic symptoms and signs is cranial arteritis, and the frequent presentation is a usually severe form of ION, occurring in a slightly older age group than common ION, and usually with devastating visual loss (Table 12). Even a tentative diagnosis must be treated as a true ophthalmologic emergency. Arteritis may result in a retro-bulbar form of nerve infarction in about 7% of patients with ocular symptoms, according to Hayreh et al,³⁰⁶ or it may produce a picture of central or branch retinal artery occlusion (about 14%); these authors also noted an appreciable incidence of fleeting premonitory visual symptoms (31%), similar to amaurosis fugax from carotid atheromatous emboli. Such episodes may be precipitated by changes from the supine to upright head position and suggest impending nerve infarction; bed rest with lowering of the head to flat or dependent levels is an important maneuver, of course, along with hospitalization for intensive corticosteroid therapy (see below).

TABLE 12. Ischemic Optical Neuropathy

Common: Arteriosclerotic		Cranial Arteritis
Age peak	60–65 yr	70–80 yr
Visual dysfunction	Minimal-severe	Usually severe
Second eye*	40%	75%
Fundus, acute	Swollen disc, often segmental	Swollen, normal disc, or central artery occlusion
Systemic manifestations	Hypertension 50%	Malaise, weight loss, fever, polymyalgia, head pain
ESR (mm/h)	40	Usually high (50–120)
Response to steroids	None	Systemic symptoms + ; return of vision ±

Few cases of biopsy-proved CA occur in patients younger than age 50 years, and instances of “juvenile temporal arteritis” represent focal and benign lesions limited to branches of the external carotid artery,³⁰⁷ without the systemic implications of CA in the aging population. The precise origin of CA is not clear, but reports of presence in first-degree relatives, a distinct predilection for occurrence in whites, and an association with HLA-DR1 all suggest a genetic link.³⁰⁸ Apparently, in response to antigens residing in arterial walls, helper T lymphocytes infiltrate and proliferate in situ, and interferon gamma produced by T cells is the key cytokine in the inflammatory cascade, including macrophage activation.³⁰⁹

In the population age 50 years or older, annual incidence rates for CA are estimated at as high as 15 to 30/100,000³¹⁰; age-specific prevalence rate between ages 60 and 69 years is 33/100,000, and more than age 80 years, 844/100,000.³¹¹ Most large series report a female-to-male preponderance of about 3 to 4:1, and this disorder is most prevalent in the white population of European origin.

The nosologic relationship of CA (temporal or giant cell) with polymyalgia rheumatica (PMR) is unsettled, although differences are more quantitative than qualitative, with the important exception of the perceived risk of visual loss, varying widely in the literature between 6% and 70%.³⁰⁶ Certainly, both syndromes share clinical features, laboratory abnormalities, arterial histopathologic features, and potential for serious adverse outcomes.³¹² Perhaps CA and PMR represent a spectrum of the same basic disease, but patients with simple PMR seem successfully managed without the high-dose steroid therapy usually justified in instances of CA, in which blindness is considered more likely. Interestingly, Turnbull³¹² suggested that the yearly incidence of both CA and PMR has increased because of diagnostic awareness, but that the incidence of severe visual loss has decreased (for the same reason), resulting in a spurious amelioration of disease severity.

Visual loss with arteritic ION tends to be more profound than with common ION³¹³; levels of finger-counting to no perception of light are not uncommon. At times, the optic disc is characterized by a milk-pale edema that may extend into the retina,³⁰⁶ some considerable distance away from the optic nerve (see Fig. 37D and Color Plate 5-3D), and central retinal artery occlusion with “cherry-red spot” also occurs. As mentioned, bilateral simultaneous ION is suggestive of CA, and both therapy and laboratory investigations are bent toward that diagnosis. In 50 cases of arteritic ION,³¹⁴ 19 of the 20 patients who had bilateral vision loss had both eyes involved by the time of initial visits; in the Iowa series,³⁰⁶ of 27 patients with bilateral loss, 17% were simultaneous, and second eye loss was delayed 1 to 7 days in 46%, 8 to 14 days in 8%, 15 to 30 days in 8%, and more than 6 months in 8%. Therefore, when second eye infarction occurs in CA, it usually does so within days to weeks, longer intervals being exceptional. The general prognostic value of this point bears emphasis: if the second eye is not yet involved, and patients are under adequate systemic corticosteroid therapy, the likelihood of bilateral visual loss becomes more remote (though not assured) with each passing week.

Other signs of orbital hypoxia include evidence of anterior segment ischemia: hyperemia of the conjunctival and episcleral vessels, mild-to-moderate corneal edema, lowered intraocular tension, anterior chamber cellular reaction, iris rubeosis, and rapidly progressive cataract. Irregular streaks and patches of chorioretinal pigmentary disturbances secondary to choroidal ischemia may appear weeks after visual loss (see Color Plate 5-3E), and considerable disc cupping may rapidly ensue, at times mimicking extensive cupping of glaucoma.^306,315 Mild visual symptoms associated with punctate retinal infarcts (“cotton-wool spots”) may herald the onset of ocular ischemia,³¹⁶ and in a series of seven such cases (six biopsy-positive), the authors concluded that prompt corticosteroid therapy led to preservation of vision in all. Diplopia is infrequent, less than 6% in the Iowa series,³⁰⁶ probably reflecting diffuse ischemia of extraocular muscles,³¹⁷ but preceding symptomatic ophthalmoplegia of any degree may be obscured by the more dramatic occurrence of severe visual loss.

Ocular pneumotonography, which measures the ocular pulsation induced by perfusion pressure in choroidal (posterior ciliary) and ophthalmic arteries, has been used³¹⁸ to distinguish common ION from arteritic ION. In patients with arteritic ION, ocular pulse amplitude was only 4% of pulse amplitude of patients with arteritis but without ION and only 6% of pulse amplitude of patients with nonarteritic ION. Moreover, half the patients with arteritic ION showed pulsation loss in the noninfarcted contralateral eye. Return of pulse amplitudes to a normal range can occur rapidly with systemic corticosteroid therapy, although in some cases the pulse does not revert to normal levels. Bosley and associates³¹⁹ suggested that ocular pneumoplethysmography, measuring ocular pulse amplitude that reflects the volume changes in the globe with each cardiac cycle, provides a diagnostic accuracy of 94% for CA, rivaling the accuracy of ESR determination or even of temporal artery biopsy.

Fluorescein fundus angiography has proved helpful in distinguishing between the common and arteritic forms of ION. Siatkowski and colleagues³²⁰ demonstrated that delayed retinal arterial appearance of dye beyond 15 seconds after arm injection, or without full choroidal dye filling (i.e., choroidal nonperfusion) by 18 seconds (Fig. 38), is highly suggestive of the diffuse orbital and choroidal circulation involvement associated with arteritic, but not with common ION, in which mean retinal arterial appearance time was 11.29 seconds, and mean choroidal filling time was 12.9 seconds. Slavin and associates³²¹ reported visual loss in three patients caused by choroidal ischemia, established by fluorescein angiography, preceding anterior ION in giant cell arteritis. Color Doppler ultrasound hemodynamics are also demonstrably altered in CA, including reduced central retinal and short posterior ciliary artery mean flow velocities and increased vascular resistance values.³²² Most recently, color duplex ultrasonography of temporal arteries demonstrated a typical hypoechoic dark halo around the perfused lumen of stenotic or thrombosed temporal arteries; this halo was said to be reversible following corticosteroid therapy.³²³ These adjunctive clinical studies are especially helpful when systemic signs and symptoms are minimal or absent and the ESR is nonpathologic, when CA is occult or atypical.

Other ophthalmic manifestations of CA include the following³¹⁰: anterior segment ischemia with corneal edema, aqueous cells and protein flare, hypotony, and rapidly advancing cataract; retinal central and branch artery occlusion, retinal infarcts (“cotton-wool spots” or “cherry-red spot”), choroidal infarcts; orbital cellulitis and facial swelling. Rare instances of posterior ION in arteritis, with infarction occurring in retro-laminar portions of the optic nerve,^306,310 show no fundus abnormalities during the acute phase. This clinical possibility is always a diagnosis of exclusion, and a search for nonvascular causes must be conducted, including exquisite neuroimages of the anterior visual pathways and cranial meninges, for example.

It is critical to discover, when possible, instances of ION due to CA because prompt steroid therapy may be effective in restoring some degree of vision (see below), averting similar visual deficit in the other eye, and potentially improving long-term systemic morbidity and mortality, although several analyses showed no statistically significant effect of arteritis on survivorship rates.^312,324 Patients with CA/PMR may complain of weakness, weight loss, and fever. Myalgia of the large muscle masses of the shoulders, neck, thighs, and buttocks is variable, and, indeed, these symptoms constitute PMR (previously believed to represent a variant of rheumatoid arthritis, but more properly termed polymyalgia arteritica, as in some Scandinavian countries). PMR and CA are best viewed as facets of a common disease spectrum with variable risk outcome, with PMR often responding to lower doses of steroids, whereas fear of blindness dictates the use of higher doses in CA.³¹² Other common complaints include chronic suboccipital headache (frequently mistakenly attributed to cervical osteoarthritis, so common in this age group), and pain or tenderness of the scalp of the forehead or temples. A palpable, often nonpulsatile, temporal artery should be sought as a likely biopsy site.

Pain in the jaw muscles precipitated by eating or talking (masseter or jaw “claudication”) is apparently an extraordinarily specific symptom, noted in 55% of patients with visual loss in the Mayo series³²⁵ and 53% in the Bascom Palmer series.³²⁶ Remarkably, according to the Iowa study³²⁷ of 363 patients undergoing temporal artery biopsy, the odds of a positive biopsy are increased by 9-fold in the presence of jaw claudication, by 3.4 times with neck pain, by 3.2 times with C-reactive protein (CRP) levels greater than 2.45 mg/dl, and only by a factor of 2 for elevated ESR of 47 mm to 107 mm per hour. To reiterate, jaw, tongue, and swallowing claudication are highly specific and sensitive symptoms of CA.

The Westergren ESR has been considered the most consistently helpful laboratory test in the confirmation of the diagnosis of arteritis. Cullen,³²⁸ in comparing arteritic versus “arteriosclerotic” (common, idiopathic) ION, found only 3 of 19 patients in the latter group with ESR greater than 30 mm per hour (mean, 26 mm), whereas only 3 of 25 patients with biopsy-positive arteritis had ESRs of 50 mm and less (mean, 84 mm; 70 mm or more in 80%). In the Iowa study³²⁷ mean ESR was 84.9 ± 33.4 mm per hour (range, 4 mm to 140 mm) in 106 biopsy-positive patients, and 14 ± 10.7 (range, 1 to 59) in age-matched controls; CRP mean was 6.6 ± 6.7 mg/dl (range, 0.5 to 34.7) in biopsy-positive, and <0.5 ± 0.5 (range, <0.5 to 3.3) in controls.

It is clear that ESR increases with age and is “elevated” (i.e., greater than 20 mm/hour) in apparently healthy elderly subjects. Miller and Green³²⁹ provide the following rule for calculation of the maximum normal ESR at a given age: in men, (age in years)/2; in women, (age in years plus 10)/2. We agree with the aforementioned authors and personally use 35 mm to 40 mm/hour (Westergren) as the upper limit of normal for the ESR in the elderly. Hayreh et al³²⁷ contribute data that suggest cutoff criteria of 33 mm/hour in men and 35 in women, providing a sensitivity of 92% and specificity of 92%. The ESR reflects red cell aggregation, which is fostered by plasma fibrinogen or globulins (“acute-phase reactants” of inflammatory or infectious states), and may be elevated in diabetes, nephrotic syndrome, connective tissue disorders, and neoplasm.³³⁰

As noted above, CRP may be more specific. From the Iowa study,³²⁷ it is clear that CRP is elevated along with ESR in patients with CA, but not in control subjects with elevated ESR. The specificity and sensitivity of CRP in detecting CA were 100% and 83% in men and 100% and 79% in women, respectively. The authors therefore found CRP to be highly useful for both diagnosis and for monitoring therapy.

The affirmation provided by a positive artery biopsy is obviously helpful when instituting long-term corticosteroid therapy in an elderly patient. However, Klein and associates established the presence of “skip lesions” in temporal artery biopsies from patients with unequivocal CA.³³¹ They also pointed out that a temporal artery that is normal to palpation may show histologic signs of inflammation and that patients with “skip lesions” do not have a more benign form of the disease. Biopsy is usually performed on a frontal branch of the superficial temporal artery ipsilateral to head pain or visual loss, and the specimen should be of maximal length; bilateral biopsies increase the diagnostic yield.³¹⁰ Given the implications of long-term therapy, multiple biopsies may be considered, especially in the “occult” form of CA, with no systemic signs or symptoms and normal or minimally elevated ESR; Hayreh and associates³⁰⁶ estimated this occult variant to represent some 20% of cases of giant cell arteritis. With the phenomenon of skip lesions in mind, a negative biopsy does not militate strongly against a diagnosis of arteritis. Therefore, it may be argued that arterial biopsy is often superfluous because diagnosis or treatment is not altered by the results, especially in the full-blown case of CA accompanied by significant ESR elevation, with or without symptoms of PMR. Other typically involved sites may be considered for biopsy, such as the suboccipital arteries. Wegener's granulomatosis is reported rarely to show temporal vasculitis,³³² and focal noncaseating granuloma of sarcoid is documented.³³³

In the appropriately aged patient with systemic or cranial signs or symptoms, and normal or (usually) elevated ESR, systemic corticosteroid therapy (e.g., oral prednisone 80 to 100 mg/day, or intravenous methylprednisolone 250 mg every 6 hours) should be instituted immediately on presumed diagnosis. To reiterate: When arteritis is suspected, therapy should not be delayed for results of ESR, other laboratory investigations or biopsy. Although reversal of visual loss is not predictable, the general symptomatic response to steroids may be dramatic within 24 hours, with relief of headache, myalgias, and malaise.

No precise information may be deduced regarding the risk of visual loss in CA/PMR, with values ranging from as little as 7% to as high as 60% (average 36%), and rates of simultaneous or consecutive bilaterality loss from one-third to three-fourths.^325,326,334 ION is the single most frequent clinical presentation, reflecting the predilection for diffuse inflammation of orbital arteries, and especially of posterior ciliary circulation.³³⁵ Although recovery of vision is considered rare, sanguine outcomes are substantiated,^{310,325,326,334} some examples being the following: from finger-counting and 20/400-100 levels, to as good as 20/240 following steroid therapy; these recovery rates range from 15% to 34%, with some support for intensive intravenous therapy as opposed to smaller oral dosage schedules.³²⁶ On the other hand, unfortunately some visual deteroration may continue while patients are receiving apparently adequate therapeutic doses.³³⁶ It is difficult to be more (or less) dogmatic about route of administration or level of steroid dosage, no strictly controlled trials being yet available. In the elderly patient, however, hospitalization is justifiable, especially to monitor the untoward effects of large steroid doses on blood glucose, serum potassium, and blood pressure and to maintain a lowered head position. Most patients experience greater or lesser side effects of steroid medication and, indeed, sudden death, cardiac arrhythmia, and anaphylaxis are reported.³³⁷

Prolonged therapy should be dictated by symptomatic response to steroids and anticipated depression of the ESR. It is suggested that high oral dosage be maintained for approximately 4 to 8 weeks, then tapered so long as the patient remains symptom free and the ESR is less than 40 mm per hour (see above). Complications of prolonged steroid usage are well known and include gastric ulcers, hyperglycemia, osteoporosis, hypo-adrenalism, and recrudescence of tuberculosis. Corticosteroids in this age group can produce severe and rapid myopathy, including proximal muscle weakness and myalgia, which may be mistakenly construed as continuing or worsening symptoms of PMR, paradoxically suggesting that dosage should be increased. Again, after initial presentation and commencement of therapy, it should be recalled that the risk of delayed visual loss,³⁰⁶ or benefit to general well-being, may be overestimated.³¹² In most patients, about 88%,³³⁸ the disease is clinically inactive at a mean follow-up of more than 7 years.

Biopsy specimens of temporal arteries from patients with CA/PMR with ongoing or recurrent manifestations may show pathologic changes regardless of steroid dosage or duration; that is, biopsy positivity rate is not directly related to prior therapy, the resolution of vessel inflammation being governed by incompletely understood factors. As an alternative to corticosteroid therapy, or when side effects are intolerable, methotrexate (7.5 to 20.0 mg/week) is of limited effect, as are other immunosuppressive agents.³¹⁰ In a randomized, double-blind study,³³⁹ patients begun on prednisone and then randomized to receive methotrexate or placebo showed no effect on remissions or relapses; that is, there was no demonstrable steroid-sparing effect of weekly methotrexate. Dapsone has been suggested, but with considerable side effects, including agranulocytosis.³⁴⁰

DIABETES MELLITUS PAPILLOPATHY

It is currently unclear whether a direct relationship exists between diabetes and acquired optic neuropathies, other than as an apparent risk factor for common ION, especially in the slightly younger age group. As previously discussed (see above), a genetically determined progressive optic atrophy may be associated with juvenile diabetes (Wolfram's syndrome), but the incidence in diabetes of inflammatory retro-bulbar neuritis or papillitis is probably no higher than in the nondiabetic population. Skillern and Lockhart³⁴¹ collected 14 cases of “optic neuritis” in patients with poorly controlled diabetes. Apparently, slowly progressive loss of vision was a common symptom (as opposed to the frequently apoplectic onset of ION), and visual fields showed central scotomas or peripheral contraction. No mention was made of altitudinal defects, and only 2 patients demonstrated diabetic retinopathy. Of greater importance is the report by Lubow and Makley³⁴² of teenage patients with long-standing juvenile diabetes who presented with hemorrhagic swelling of one or both optic discs, mimicking papilledema of increased intracranial pressure (Fig. 39 and Color Plate 5-3G).

Barr and colleagues³⁴³ reported a series of 21 eyes in 12 patients with juvenile diabetes and outlined a clinical profile consisting of symptoms of slightly blurred vision, minimal acuity and field deficits, general salutary outcome, and no consistent correlation with clinical control of hyperglycemia; diabetic retinopathy is usually of modest degree, and prognosis for proliferative retinopathy is uncertain. Neurodiagnostic studies are not indicated, and corticosteroid administration upsets diabetic control without providing any known therapeutic effect. A study³⁴⁴ of 27 eyes in 19 diabetic patients showed an age range of 17 to 79 years (mean, 50 years), two-thirds of patients with type II diabetes, disc swelling resolving slowly (average, 3.7 months), macular edema in 70% of eyes, with only 4 eyes with final acuity less than 20/50 (these all with prominent macular edema); acute visual fields showed enlarged blind spots or general depression, but not altitudinal defects. Widespread retinal capillary nonperfusion was found in 52% of eyes studied with fluorescein angiography, yet with a conspicuous lack of progressive diabetic retinopathy.

The transient nature, frequent bilaterality, benign outcome, and low incidence of subsequent disc atrophy are all features that leave unanswered the question of precise pathophysiology, despite evidence of retinal hypoperfusion. Although likely related to hypoxia of the prepapillary capillaries or unidentified metabolic substances, “diabetic papillopathy” enjoys a much better visual prognosis than do most other types of ION. This form of bilateral disc edema, with normal acuity and minimal field change, may be confused with papilledema of raised intracranial pressure, however.

INFREQUENTLY ASSOCIATED CONDITIONS

In 1973, Carroll originally called attention to a form of ischemic optic papillopathy occurring after uncomplicated cataract extraction, with sudden visual loss from 4 weeks to 15 months postoperatively.³⁴⁵ In Carroll's series, about half the patients with initial eye affected had visual loss following operation on the second eye; three patients were in their fifties, and the disc infarction occurred with either retro-bulbar or general anesthesia; no patient experienced a loss of vision in a second eye unless subjected to cataract extraction; neither corticosteroids nor anticoagulants are effective therapies.

Sufficient data fail to incriminate simple postoperative rise in ocular tension, although discs with marginal perfusion could be vulnerable. Hayreh's suggestion of lowering ocular tension when second eyes are at risk seems reasonable.³⁴⁶ This subtype of optic neuropathy following cataract extraction represents a distinct variant characterized by a circumscribed onset time course and high incidence of consecutive bilaterality, to the point of predictability, when the second eye is operated on (even in the fifth and sixth decades).³⁴⁷

Acute disc edema with visual loss, in patients not yet old enough to be included in what may comfortably be called the “vasculopathic” age group, and without compelling risk factors of diabetes or severe hypertension, falls into categories in which collagen vascular or autoimmune arteritis are suspected (see below) or in which inflammatory neuritis may not be ruled out clinically. This rare, idiopathic ION of the “young” tends to be bilateral and recurrent.³⁴⁸ The question of retinal arterial vasospasm or thrombophilic states is unanswered, and, indeed, both unilateral and sequential bilateral disc infarctions have been reported in migraine^349,350 and during cluster headache.³⁵¹ On the other hand, migraine is an extremely common disorder, and any association with optic neuropathies may be fortuitous.

Other varieties of ischemic disc swelling occur following marked or recurrent blood loss,³⁵² most frequently from the gastrointestinal tract, but with visual symptoms peculiarly delayed by days to weeks. Williams et al³⁵³ provided a complete overview (for anesthesiologists) of the subject of visual loss following nonophthalmic surgical procedures. These intraoperative or postoperative visual events occurred in 77 cases culled from the literature, of which 27 were related to occipital cortical strokes, in 22 instances following cardiopulmonary bypass (CPB) or cardiac valve surgery. Anterior ION occurred in 19 cases, 14 of which followed CPB; posterior ION occurred in 17 cases, 4 following CPB, 5 after neck dissections; other procedures followed by anterior or posterior ION included rhinoplasty, sinus surgery, abdominal and thoracic resections, and other common procedures. Likewise, ION has occurred after lengthy spinal procedures without evidence of intra-operative globe compression related to head support in the prone position (the “head-rest syndrome” of Hollenhorst,³⁵⁴ originally described in neurosurgical procedures), but instead attributed to prolonged anesthesia, deliberate or incidental hypotension, and relative anemia due to blood loss.³⁵⁵ In my experience, prolonged globe compression produces variable degrees of choroidal infarction, which eventually causes widespread reaction of pigment epithelium distinguishable by funduscopy from optic nerve ischemia alone. Delayed and, at times, progressive ION may follow CPB or other general surgical procedures in which continuous postoperative red blood cell destruction decrementally drops hemoglobin levels³⁵⁶; visual loss has been reversed apparently by blood replacement.

Frequently enough, both eyes are involved, and bilateral retro-bulbar infarcts with mild disc edema have been documented histologically.³⁵⁷ Risk factors apparently include systemic hypertension, diabetes, coronary artery disease, pre-existing anemia, and occasionally renal failure with uremia. In three cases of acute nonsurgical hypotensive episodes, including unduly rapid correction of malignant hypertension, and during renal dialysis, five eyes had anterior ION with partial recovery on immediate reversal of hypotension; pre-existing anemia was present (hematocrit range of 23% to 28%).³⁵⁸ Prolonged CPB and low perioperative hematocrits³⁵⁹ during open heart surgery are well-documented causes of ION. Cardiac arrest has also precipitated ION.³⁶⁰ One may conclude that intraoperative hypotension, usually coupled with low hematocrit, is the single most common cause of genuine posterior ION.

Knox and associates³⁶¹ reported a variety of uremic optic neuropathy characterized by bilateral visual loss with disc swelling in patients with severe renal disease manifested by uremia, anemia, and hypertension. Improvement followed hemodialysis, except in one case of actual cryptococcal meningitis. However, Hamed and associates³⁶² contended that “uremic optic neuropathy” does not constitute a single pathophysiologic entity, but rather a heterogeneity of pathophysiologic processes that include complications of raised CSF pressure, severe consecutive anterior ION, and adverse reaction to hemodialysis itself. Bilateral ION was reported in a young woman with optic disc drusen and chronic hypotension while she was undergoing renal dialysis.³⁶³ These risk factors, that is, pre-existing hypertension, anemia, and uremia, taken collectively likely interfere with vital autoregulation of arterial perfusion at the disc or retro-bulbar nerve in ways not yet completely understood.

Carotid artery disease does not seem to play any regular role in ION; in fact, retinal arterial embolization and ION are mutually exclusive findings, except in the rarest of situations. Waybright and associates³⁶⁴ documented 3 instances of typical ION with ipsilateral carotid occlusions, with retrograde filling of the ophthalmic artery by external carotid branches, perhaps indicating hypoperfusion of the nerve head, and Brown³⁶⁵ reported a single case of abrupt visual loss at first with a normal disc, then with pale edema, in an eye with chronic hypoxia from complete carotid occlusion. From a series of 612 patients with acute ischemic hemispheric strokes resulting from internal carotid occlusions with “reversed flow in the ophthalmic artery,” only 3 cases of simultaneous optic nerve infarction were uncovered.³⁶⁶ Pulseless disease (Takayasu's disease) has been complicated by ION.^367,368 In addition, in a patient with atrial fibrillation,³⁶⁹ emboli were found in the posterior ciliary arteries at autopsy, and Tomsak³⁷⁰ recorded 3 patients with ION accompanied by retinal emboli, following coronary artery bypass surgery and cardiac catheterization.

Acute disc swelling attributed to ION has occurred in eclampsia,³⁷¹ porphyria,³⁷² and pseudoxanthoma elasticum with platelet hyperaggregability.³⁷³ Sickle cell disease is reported rarely to cause anterior³⁷⁴ and posterior ION,³⁷⁵ in single case documentations.

Although cranial (giant cell) arteritis is clearly the most commonly encountered vasculitis of neuro-ophthalmic importance, other arteritides do involve the anterior pathways with some regularity, with disc swelling, retro-bulbar neuropathy, or chiasmal inflammation. MRI of vasculitis-induced retro-bulbar ischemia in lupus arteritis, rheumatoid arthritis, and Sjögren's syndrome has demonstrated³⁷⁶ enlargement and gadolinium enhancement of orbital and prechiasmal segments of optic nerves, and especially of the chiasm (Fig. 40). Childhood lupus is reported as a cause of bilateral, simultaneous optic neuropathy.³⁷⁷ When lupus is suspected, assay of antinuclear antibody and anti-double-stranded DNA antibody titers are diagnostic clues, and there is evidence that antiphospholipid antibodies are associated with neurologic and ophthalmic complications of lupus.³⁷⁸ In addition, Sjögren's syndrome is recognized as an autoimmune-mediated cause of dysfunction of salivary gland (xerostomia) and lacrimal gland (xerophthalmia), and rarely with extraglandular manifestations, including optic neuropathy and CNS disease.³⁷⁹ Primary Sjögren's syndrome is characterized by female preponderance, pulmonary fibrosis, glomerulonephritis, thyroiditis, presence of high titers of antinuclear antibody, anti-SSA(Ro), and anti-SSB(La); this disorder should be distinguished from MS, lupus, and antiphospholipid syndrome, for which labial salivary gland biopsy is essential. Otherwise, polyarteritis nodosa³⁸⁰ and relapsing polychondritis³⁸¹ are rare vasculitic causes of ION, as is Takayasu's arteritis^378,382 (see also the discussion on retinal arterial occlusions).

As ION with disc swelling (i.e., anterior) does not constitute a single nosologic disorder, neither does retro-bulbar (i.e., posterior) optic nerve ischemia connote a distinctive origin, but it represents a rare consequence of various diseases. This “posterior” ION variant consists of abrupt unilateral, rarely bilateral, visual loss without disc edema; other compressive, inflammatory, toxic, traumatic, or infiltrative causes must be rigorously excluded. Isayama and associates³⁸³ reported 14 patients with posterior ION, aged 20 to 73 years (6 less than 54 years), with hypertension, diabetes, and infrequent carotid stenosis, and also documented is an instance of acute internal artery occlusion.³⁸⁴

When other specific mechanisms of ischemic damage to the retro-bulbar optic nerves are evident, for example, as a delayed complication of radiation therapy, the term posterior ION may be only loosely applied, although no doubt vasculitic ischemia plays a role. In those subsets of ION in which a degree of inflammation is implicated, the use of systemic corticosteroid therapy seems reasonable.

Conversely, progressive visual defects may be attributed to “glaucoma” when no such condition exists. Here, the interpretation of visual field defects is critical, and the judicious use of radiologic studies is mandatory. Greenfield et al³⁸⁸ found that only 2 of 31 patients diagnosed initially with glaucoma had neuroradiologic evidence of mass lesions, and in both instances other neuro-ophthalmic signs had been overlooked, including optic disc neural rim pallor. Defects that preferentially involve the nasal field, but without a hemianopic character (aligned on the vertical meridian) are most likely due to glaucoma or ION. Bilateral nasal field defects that are truly hemianopic must be extraordinarily rare. Otherwise, binasal defects may be associated with chronic papilledema or hyaline bodies of the nerve head, either of which should be discernible by ophthalmoscopy.

MASSES OF THE OPTIC DISC

These often fascinating lesions provoke controversy related to funduscopic and fluorescein angiographic differential characteristics, but the neuro-ophthalmic dilemma is reduced from “Where?” to “What?” Congenital elevations (pseudopapilledema and hyaline bodies), epipapillary astrocytomas, and acquired disc swelling are discussed previously, to which is added mention of glial and vascular remnants of the primitive embryonic hyaloid system that take the form of thinly curved membranes or gray pearl-like nodules attached to the disc face. Vascular hamartomas include the capillary and cavernous hemangiomas and the racemose malformations of the Wyburn-Mason syndrome (see Volume 2, Chapter 17). Melanocytomas are deeply pigmented disc tumors with limited growth potential, not to be confused with juxtapapillary choroidal melanomas that extend into the disc. Retinoblastomas may also secondarily invade the optic nerve, but with a characteristic fundus appearance.

Metastatic carcinoma, lymphoblastic and myeloblastic leukemic infiltrates, and sarcoid granulomas may present at the disc, usually with severe and sudden loss of vision. Indeed, in general, secondary tumors are more common than all primary optic nerve tumors. Brown and Shields³⁹⁰ have provided an excellent one-stop monograph, Tumors of the Optic Nerve Head.

OPTIC GLIOMAS

Primary astrocytic tumors of the anterior visual pathways assume two major clinical forms: the relatively benign gliomas (hamartomas) of childhood and the rare malignant glioblastoma of adulthood. With the exception of visual loss and anatomic location, these two lesions have little in common, and the assumption that the progressive malignant form stems from the static childhood form is untenable. The major clinical characteristics of these tumors are contrasted in Chapter 6.

Optic gliomas represent almost 20% of orbital tumors of childhood and 65% of all intrinsic optic nerve tumors; about 25% of optic gliomas involve the nerve alone, in which case there may be a small female preponderance.³⁹¹ It is estimated that as many as 70% of childhood optic pathway gliomas are associated with neurofibromatosis-1 (NF-1), an autosomal dominant disorder, and that such lesions may be uncovered incidentally in this disease.³⁹² Optic nerve gliomas may also occur sporadically and do occur with neurofibromatosis-2 more rarely. These NF-1 low-grade neoplasms are best termed “pilocytic astrocytoma of the optic pathway” and are essentially indistinguishable from hypothalamic or thalamic diencephalic glioma; invasive and aggressive behavior is rare. The incidence of symptomatic optic glioma in NF-1 is 2% to 8%, although neuroimaging studies imply a higher incidence.³⁹² Typically, most childhood optic gliomas present in the first 6 years, median age being 4.9 years, and some 90% before age 20 years.

With childhood optic glioma, clinical presentation is predicated on location and extent of tumor. Optic gliomas account for only a small percentage of children presenting with proptosis, but they present as insidious proptosis of variable degree, and, although vision is usually diminished, remarkably good visual function is not uncommon.³⁹² Strabismus, disc pallor, or disc swelling may be observed. Progressive proptosis, even if abrupt, or increased visual deficit does not imply aggressive activity of the tumor, hemorrhage, or necrosis. In a patient with such rapid increase in proptosis and concurrent loss of vision, Anderson and Spencer³⁹³ elucidated the following histopathologic features: (1) microcystic areas of tumor are neither necrotic nor degenerated but composed of highly differentiated glial cells; (2) the “microcysts” are extracellular accumulations of periodic acid-Schiff-positive mucosubstance, presumably synthesized by tumor cells; (3) the space around axons is distended by mucosubstance, with a tendency to collect in central areas of the glioma; and (4) the hydrophilic property of mucosubstance may contribute to rapid expansion of the glioma (simulating “growth”), with concurrent loss of visual function or increase in proptosis. Vision may fluctuate, abruptly worsen, or even spontaneously improve.³⁹¹

The optic disc may appear normal, pale, or swollen, and congenital enlargement is described, as well as vein occlusion.^391,394 Approximately 70% of orbital gliomas involve the anterior aspect of the optic canal, best appreciated by bone-window settings on CT or by thin-section MRI (Fig. 42). Paradoxically, canal enlargement does not categorically imply gliomatous change in the nerve but may represent arachnoidal proliferation. Regarding the concept of “extension” of orbital gliomas to involve the intracranial visual pathway or aggressive orbital and transcranial surgery to prevent such “extension,” the following points must be made: (1) incomplete resection of gliomas leads to no recurrence (although rarely arachnoidal hyperplasia may mimic regrowth of tumor), and such patients do spectacularly well over long periods of observation; (2) incomplete excision is not accompanied by malignant transformation, nor has it ever been documented that childhood gliomas undergo malignant degeneration; (3) documented instances³⁹⁵ wherein a previously normal optic canal subsequently enlarged must be extremely rare³⁹² (large canals likely represent congenital bony change in concord with congenital large optic nerve); and (4) subsequent visual symptoms in the opposite eye, or of a chiasmal nature, do not necessarily imply “extension” because many gliomas initially reside in one nerve plus chiasm or chiasm plus both intracranial nerves.

Of course, modern MRI is prerequisite for baseline staging of all cases, and regular follow-up is indicated, but it is clear from accumulated data³⁹² that only a small minority of children with isolated orbital gliomas and NF-1 will exhibit tumor progression 5 to 10 years after diagnosis. It is suggested that physical examination and sequential MRI be performed 3 months after initial detection of orbital gliomas and yearly thereafter, and radiation therapy should be reserved primarily for patients with useful residual vision, but with evidence of visual deterioration or radiographic progression; there is no evidence to support the efficacy of chemotherapy for isolated optic nerve gliomas.³⁹²

MRIs of optic nerve gliomas in NF-1 show typical double-intensity tubular thickening characteristic of perineural arachnoidal gliomatosis (the perineural layer with signal characteristics similar to water or CSF), elongation of the nerves, and vertical kinking in the mid-orbit.^396,397 Precise MRI studies, echography (regular, homogeneous, low to medium reflectivity³⁹⁸), and the constellation of clinical signs and symptoms obviate the question of routine lateral orbital exploration for histologic confirmation, although orbital meningiomas in the first 2 decades of life may behave as aggressive lesions, and collateral hyperplasia of the nerve sheath may be mistaken for meningioma. Because gliomas do not erode through dura, whereas meningiomas do, extradural tumor extension should raise the suspicion of meningioma, and such tissue may undergo biopsy for diagnostic purposes. Ganglioglioma, an extremely rare CNS tumor, may mimic a rapidly expanding orbital glioma.³⁹⁹

If proptosis of a blind or near-blind eye is cosmetically unacceptable, frontal resection of the tumor from the globe to the orbital apex, and judicious canal unroofing, seems to be logical. Care should be taken not to injure the motor nerves at the apex or the posterior ciliary nerves at the globe. Enucleation and exenteration are categorically not indicated, nor is complete excision if such a procedure injures the globe or ocular motor mechanism. The efficacy of radiation therapy for orbital glioma is variable,^392,400 and conservativism cannot be faulted. Chiasmal and hypothalamic gliomas of childhood and malignant optic glioma of adulthood are discussed in Volume 2, Chapter 6.

PERIOPTIC MENINGIOMAS

Meningiomas arise from meningothelial cells of the arachnoid, at multiple intracranial sites, in the optic canals, and from the intradural tissue that invests the optic nerves in the orbit. Meningiomas of the anterior and middle cranial fossae, and those of the perineural orbital portion and optic canal, are of major neuro-ophthalmologic interest because of the progressive signs and symptoms, typically insidious visual deterioration, and some degree of proptosis. There is a distinct female predilection for meningiomas (60% to 75%), and the intracranial variety occurs predominantly in middle-aged and elderly adults.

Although most meningiomas that involve the orbit derive from the adjacent posterior position of the sphenoid bone, or within the optic canal, intraorbital perioptic meningiomas, arising from the nerve sheath, account for only 1% to 2% of all meningiomas, but for one-third of primary optic nerve tumors.⁴⁰¹ In this location, perioptic meningiomas tend to occur at a younger age, perhaps because of earlier onset of visual symptoms. Karp and associates⁴⁰² noted that 10 of 25 primary intraorbital meningiomas occurred in patients less than 20 years of age, and 6 patients were in the first decade. Dutton⁴⁰¹ reported a mean age at presentation of 40.8 years (range, 2.5 to 78 years), and bilateral (multifocal vs. contiguous?) cases are documented. Meningiomas presenting in youth may be associated with neurofibromatosis.⁴⁰¹ Orbital meningiomas that do not arise from the nerve sheath, that is, “ectopic” tumors, must be extremely rare.

The optic nerves may be involved via several mechanisms, as follows. Intraorbital meningiomas arising from the nerve sheath produce slowly progressive axial proptosis or loss of vision. The retro-bulbar mass may further manifest by increasing hyperopia and the appearance on ophthalmoscopy of retinochoroidal striae. At first, the disc may appear normal, but optic atrophy or chronic disc swelling ensues (Fig. 43). The clinical triad of the presence of optociliary venous shunts on the disc, when accompanied by diffuse disc edema (eventually replaced slowly by pallor), and insidious visual loss, is highly suggestive of indolent nerve sheath meningiomas, even in those patients without proptosis or when the posterior aspect of the optic canal may be principally involved. Pain is distinctly rare, but transient visual obscurations may occur, and ocular motor defects imply extension to the orbital apex or dural penetration with invasion of orbital soft tissues.

Radiologic signs include narrow fusiform or irregular tubular enlargement of the optic nerve (see Fig. 43), at times with calcification detectable by CT or ultrasonography¹⁰⁷; the central neural tissue may be outlined by parallel perioptic thickening, giving the appearance of railroad (“tram”) tracking. Similar “tracking” has been reported in isolated optic nerve sarcoid.⁴⁰³ Unless the posterior aspect of the tumor involves the orbital apex or optic canal, no bony abnormalities are seen. Gadolinium-enhanced T1-weighted MRI usually shows marked enhancement of intracanalicular and intracranial meningiomas, but in the orbit, the tumor signal is less distinct from adjacent fat; fat-suppression protocols resolve this physical obstacle.^401,404,405

In adults, delay in diagnosis is the rule, and, although inexorable blindness is an unsettling prospect, any surgical procedure is ineffective and all too frequently ruins what vision remains. Therefore, with radiologically indolent tumors, there may be no advantage to any form of surgical intervention, either by an orbital approach or by transfrontal craniotomy, although disfiguring proptosis or prevention of intracranial extension may force a decision for judicious frontal craniotomy. Radiation therapy is believed by some to delay recurrence after resection, and precision primary, fractional (5400 cGy at 180 cGy/day) irradiation does show some promise.^401,406,407

Intracanalicular meningiomas usually represent either extensions of posterior orbital tumors or invasion into the canal by periforaminal meningiomas arising in the area of the anterior clinoids or tuberculum sellae. Posterior periforaminal, clinoidal, and tuberculum sellae meningiomas comprise the majority of meningiomas that produce prechiasmal (optic nerve) visual deficits. The monotonous presentation is a complaint of slowly progressive monocular loss of vision, with all the signs and symptoms of an optic nerve conduction defect. With suprasellar extension, these tumors produce chiasmal interference, with variations on a bitemporal theme (see Volume 2, Chapter 6). Pallor of the disc is usually less than that anticipated in view of the visual deficit. It is with posterior periforaminal and tuberculum meningiomas that thin-section gadolinium-enhanced MRI techniques are especially productive.

Meningiomas of the sphenoidal wing present as proptosis and reactive hyperostosis evident on CT or MRI. These slow-growing tumors may eventually involve the optic nerve, early in their course if medially located, and as a relatively late complication if the mass predominantly involves the lateral aspect of the sphenoid ridge and middle cranial fossa (pterional meningioma).

The higher incidence of meningiomas in women, increased growth rate during pregnancy, and possible association with breast carcinoma all suggest an influence of female sex hormones. The presence of progesterone-receptor staining suggests a more favorable prognosis, but effective medical therapy is unproved.⁴⁰⁸

SECONDARY NEOPLASMS: CARCINOMAS AND LYMPHOMAS

As noted, the optic nerves are more frequently involved by exogenous tumors and malignant infiltrations than by primary neural neoplasms. These secondary causes include contiguous spread of intraocular melanoma and retinoblastoma, hematologic malignancies, leptomeningeal infiltration, and direct invasion by metastatic systemic cancer. Of course, orbital, sinus, and skull base masses may compromise the anterior visual pathways, and these do so with some frequency. Aside from extrinsic basal masses, such as pituitary adenomas, meningiomas, and paraclinoidal carotid aneurysms, other lesions are relatively uncommon yet present as “retro-bulbar neuritis” with a normal fundus appearance.

When a systemic malignancy is previously diagnosed, abrupt visual loss not attributable to fundus lesions is prima facie evidence of meningeal carcinomatosis. In two reviews of carcinomatosis,^409,410 the incidence of ocular symptoms was striking; either as the presenting complaint or as a subsequent development, visual loss or double vision comprised the largest group of symptomatic cranial nerve deficits. Rapidly consecutive contralateral visual loss, other cranial nerve palsies, including facial, spinal root symptoms, and headache are also ominous features. Adenocarcinoma of the breast and lung are the most frequent tumors to metastasize diffusely to the leptomeninges and subarachnoid space. Lymphoma, including reticulum cell sarcoma, and melanoma are also relatively common sources of meningeal seeding.⁴¹¹ McFadzean and colleagues⁴¹² have suggested that the combination of headaches, rapidly progressive visual loss, sluggish pupil reactions, and normal optic discs (or at least delayed pallor), with usually normal neuroimages, should bring to mind the diagnosis of leptomeningeal carcinomatosis.

Leptomeningeal deposits are not easily uncovered by radiologic techniques. In a comparative study of CT and MRI, enhanced CT detected meningeal tumor in only 39% of 23 cases with positive CSF cytology and focal CNS defects, and nonenhanced MRI detected the tumor in only 23%; furthermore, MRI failed to show discernable signal changes in areas abnormal by enhanced CT criteria.⁴¹³ Multiple CSF fluid samples may be required and cytocentrifuge technique applied to acquire cytologic confirmation.

The pathophysiologic mechanisms of visual loss with meningeal carcinomatosis include “tumor cuffing” in the perioptic meninges accompanied by localized demyelination, direct tumor infiltration into the substance of the nerve, and demyelination out of proportion to sparse tumor cell infiltrate. With regard to the concept of optic myelopathy as a remote complication of distant malignancy, paraneoplastic syndrome with optic neuropathy has been associated with anti-CV2 antibodies, with resolution following excision of primary small cell carcinoma of the lung.^413a

The outcome of carcinomatosis of the meninges is uniformly grim, with death ensuing within months. However, a substantiated diagnosis precludes unnecessary and uncomfortable neurodiagnostic studies.

The optic nerves may be involved by diffuse infiltrative lesions of diverse origin, including the lymphoma-reticuloendothelioses,^414–416 the histiocytoses, plasmacytomas,⁴¹⁷ and others. Infiltrative disorders more or less share a common clinical profile of subacute or rapid visual loss in one or both eyes. Disc swelling is seen on occasion, indicating infiltration of the nerve head itself. It should be recalled that chronic granulomas, such as sarcoid (see above), may mimic neoplasia.

Leukemia may produce disc swelling via several mechanisms. These include meningeal infiltrate or intracranial hemorrhagic diathesis resulting in obstruction of CSF and increased intracranial pressure, pseudotumor cerebri syndrome associated with prolonged corticosteroid therapy, disc edema associated with severe anemic retinopathy, and actual leukemic permeation of disc tissue; pallid disc edema may be due to massive infiltrates,⁴¹⁸ and prompt irradiation may reverse visual loss.⁴¹⁹ Although chronic lymphocytic leukemia is said only infrequently to cause neurologic symptoms, meningitis, confusional states, cranial nerve abnormalities, cerebellar dysfunction, and optic neuropathy are all reported.⁴²⁰

Although lymphoma may represent up to 10% of orbital malignancies, direct involvement of the optic disc or retina is rare. Of intraocular lymphoma, reticulum cell (histiocytic lymphoma, microgliomatosis) is most frequent, and this malignancy has been reported to involve the intracranial optic nerve.⁴²¹ The syndrome of posterior uveitis associated with reticulum cell sarcoma (microgliomatosis) of the brain has become well established.⁴²² I have personally seen two middle-aged men with myocosis fungoides whose systemic lymphoma was heralded by a picture of acute optic neuritis with disc swelling and severe acute visual loss.

Visual loss in leukemia and lymphoma may also be due to opportunistic infections of the CNS, including cryptococcosis, toxoplasmosis, or herpes zoster infection. Chemotherapeutic agents such as vincristine may be implicated, and the optic nerve complications of cisplatin, carboplatin in combination with cyclophosphamide, carmustine, and bone marrow transplant are well recognized.^423–424 In patients with noncarcinomatous (e.g., leukemia, lymphoma, myeloma) neoplastic infiltration of the optic nerves, radiation therapy often results in rapid return of vision to useful levels,⁴¹⁹ whereas treatment directed at the systemic disorder may have little effect on visual function.

Enlargement of the orbital segment of the optic nerve may be the result of a wide spectrum of pathologic processes (Table 13), which at least may be anatomically localized as the focal cause of visual loss, specific radiologic characteristics (some pathognomonic) and accompanying clinical signs and symptoms, aside. It goes without saying that historical medical data, review of systemic diseases and of previous surgical procedures, physical findings, precise neuroimaging of the orbits and skull base, laboratory investigations, and at times CSF examination and tissue biopsy procedures must all be part of a judiciously considered differential diagnosis.

TABLE 13. Enlargement of the Optic Nerve

PARANASAL SINUS DISEASE

Diseases of the paranasal sinuses, although perhaps disproportionately invoked in years past, are not to be overlooked as a cause of visual loss, proptosis, diplopia, or headache. Ocular motor disturbances with nasopharyngeal tumors and sphenoidal mucoceles are discussed in Volume 2, Chapter 12. This discussion considers the visual complications of inflammatory disorders, mucoceles, and carcinoma of the paranasal sinuses.

The anatomic relationships with the posterior ethmoid and sphenoidal paranasal sinuses (see Fig. 11) place the optic nerves in peculiarly disadvantageous positions, not only in regard to neighboring lesions, but also in harm's way of endoscopic surgical manipulations. Anatomic variability notwithstanding, studies of fine bony details provided by thin-section coronal CT views⁴²⁵ show that the course of the optic canal is directly adjacent to the posterior ethmoid wall in 3%, the majority being in the lateral or superior wall of the sphenoid sinus, 15% indenting the sinus wall, and 6% passing through the sinus cavity; bone dehiscence of the optic canal is found in fully 25%, directly exposing the nerves to thin sinus mucosa. Buss and colleagues⁴²⁶ reported instances of ophthalmic complications of sinus surgery, including blindness resulting from orbital hematoma and optic nerve transection, nor is the chiasm itself entirely safe during endoscopic procedures.⁴²⁷

Mucoceles are cystic bony expansions of the paranasal sinuses that contain mucoid and epithelial debris as a result of obstruction of normal drainage through ostia. These arise in the frontal, ethmoidal, or sphenoidal sinuses and present as effects of mass lesions. With sphenoidal mucocele (posterior ethmoidosphenoidal), the optic nerves are liable to damage as the mass enlarges laterally to involve the optic canals; actually, inflammation alone without bony distortion may result in irreversible blindness.²⁵⁹ Visual loss is usually monocular and slowly progressive, and optic atrophy attests to chronicity. Field defects take the form of central scotomas, with or without peripheral depressions, but chiasmal syndromes (e.g., monocular blindness plus contralateral temporal hemianopia) are infrequent.⁴²⁸ Rapid unilateral or bilateral visual loss with severe headache may mimic pituitary apoplexy.

The radiologic findings with sphenoidal mucocele include expansion of the sphenoid sinus (Fig. 44), elevation of the tuberculum sellae and chiasmatic sulcus, obliteration of optic canal and superior orbital fissure, and lateral displacement of medial orbital walls. An anterior clinoid variant of sphenoidal mucocele has been described, with visual loss mimicking retro-bulbar neuritis.⁴²⁹ In general, the presence of anterior clinoid pneumatization is associated with bone dehiscence and exposure of the optic nerve.⁴²⁵ For mucocele, rhinologic surgery is the treatment of choice, usually by endonasal decompression, and some return of vision may be anticipated unless optic atrophy is advanced.

Indolent fungal infections with minimal sinusitis may present as orbital apex syndrome, including rapidly advancing or chronic, progressive optic neuropathy. Of these, mucormycosis⁴³⁰ (with or without diabetes) and aspergillosis⁴³¹ are most frequent, at times mimicking cranial arteritis, with facial pain, retinal vascular occlusions, or ophthalmoplegia, for which aggressive corticosteroid therapy may prove disastrous. Early transnasal endoscopic exploration for biopsy is vital.

Wegener's granulomatosis (“lethal midline granuloma”) is a necrotizing vasculitis with a predilection for the upper respiratory tracts, at times heralded by nasal and sinus congestion and discharge, and destruction of midline nasal cartilage. Pulmonary nodules or infiltrates and glomerulonephritis with hematuria fulfill the other clinical criteria, and orbital inflammation is common. Isolated retro-bulbar neuropathy has been documented,²⁵⁸ and ocular signs may signal this disorder in up to 17% of cases.⁴³² Ophthalmic complications include the following: episcleritis and scleritis; corneal ulceration; uveitis; retinal vasculitis and optic neuropathy; and granulomatous inflammation of lacrimal glands, salivary glands, orbital soft tissue, and paranasal sinuses. Meningocerebral inflammation, a form of pachymeningitis detectable by enhanced MRI, produces headache, seizures, and cranial neuropathies.⁴³³ Antineutrophilic cytoplasmic antibody (c-ANCA) assay provides highly specific laboratory confirmation, but absence does not rule out this disorder, and biopsy of nasal or sinus tissues commonly shows typical vasculitic, granulomatous inflammation.⁴²² Corticosteroids and immunosuppressants such as methotrexate are the usual therapies. Intranasal cocaine abuse can produce a type of chronic ischemic mucoperichondritis and osteolytic sinusitis, at times with nasoseptal perforation, and variably associated with signs of orbital inflammation and contiguous inflammatory optic neuropathy.⁴³⁴

Tumors of the nasopharynx and paranasal sinuses rarely present primarily as visual loss, but may eventually involve the optic nerve when the posterior ethmoidal or sphenoidal sinus is invaded. Occurring predominantly in men at least in the sixth decade of life, squamous cell carcinoma is the most common type, typically in the maxillary sinus, less frequently the ethmoid complex, and rarely the frontal or sphenoid sinuses. From the excellent review of Harbison and associates,⁴³⁵ in sphenoidal malignancies, headache and diplopia (cranial nerves III, IV, VI, and V) are more usual complaints than visual loss, which involved only 5 of 42 patients in the Harbison series. Visual loss is subacute or rapidly progressive to blindness. Other signs and symptoms, that is, facial pain or anesthesia, radiologic findings, and biopsy usually confirm the diagnosis. Esthesioneuroblastoma, a malignant neuroectodermal tumor originating in olfactory nasal mucosa, is reported to produce rapidly progressive visual loss,⁴³⁶ although presenting symptoms more commonly include nasal obstruction, epistaxis, facial numbness, diplopia, and proptosis. In patients subjected to radiation therapy for malignant nasopharyngeal tumors, loss of vision months after therapy may be attributable to delayed radionecrosis of the optic nerve (see below), but recurrence and spread of tumor must be considered.

ORBITOPATHIES: GRAVES' DISEASE

A variety of orbital disease, including inflammations, trauma, and tumor, may produce optic nerve dysfunction. The ophthalmopathy of Graves' disease is not only a frequently overlooked cause of spontaneous diplopia, but visual loss due to orbital congestion may be mistakenly attributed to corneal exposure and tear film problems (see Volume 2, Chapter 14). By mechanisms not yet entirely elucidated, the optic nerve may participate in the orbitopathy associated with dysthyroid states or even in apparent euthyroidism. Extraocular muscles are enlarged by endomysial fibrosis, mucopolysaccharide deposition, and perivascular lymphocyte and plasmacyte infiltration. Morphologically, the optic nerves are encroached on by swollen muscles at the tight orbital apex,^437,438 and on the basis of ultrasonography and CT, or MRI, it is indeed likely that the optic nerve is compressed by the confluence of enlarged recti muscles in the posterior orbit, but prolapse of orbital fat through the superior orbital fissure is also a possible mechanism.⁴³⁹ There is a loss of large-type axons in the proximal segment of the orbital portion of the optic nerves, associated with mild astrocyte increase, but the nerve and meninges are not inflamed.⁴⁴⁰ It is estimated that optic nerve dysfunction occurs in some 6% of patients with Graves' orbitopathy.⁴⁴¹

As a rule, at the onset of optic neuropathy, many patients are clinically euthyroid, having been treated previously for hyperthyroidism. Middle-aged patients with otherwise well-developed, but not necessarily severe, ophthalmopathy present with usually insidious loss of central vision in one or both eyes. Ocular motility is frequently restricted at this stage, and corneal exposure may be minimal. Care should be taken not to attribute a disproportionate visual loss to minor corneal complications and ignore the potentially blinding optic neuropathy, the tests for which have been outlined (see Volume 2, Chapter 2).

Acuity may be as poor as finger-counting or only minimally diminished, but color sense is uniformly faulty. Visual fields demonstrate central scotomas, often combined with inferior nerve fiber bundle defects (Fig. 45). The latter defects may be confused with those of glaucoma, especially if intraocular pressure is spuriously elevated by restrictive myopathy (see Volume 2, Chapter 14). The ocular fundus may be entirely normal, or various degrees of disc swelling may be observed (Fig. 46), but, apart from profound atrophy, the state of the disc has little prognostic correlation with eventual visual outcome.⁴⁴²

The natural course of dysthyroid optic neuropathy is not entirely benign. In a subject review,⁴⁴² it was noted that more than 20% of cases documented in the literature had eventual acuity of 20/100 or less, including vision of finger-counting and worse. Initial therapy consists of systemic corticosteroids in large doses, orbital decompressive procedures, and irradiation. For example, medical therapy may commence with 80 mg prednisone per day orally, and if no response (acuity, fields) is demonstrable within 2 weeks, the dosage is increased or delivered by intravenous pulse (e.g., methylprednisolone 250 mg every 6 hours) over 3 to 5 days of hospitalization. As a rule, patients do not tolerate well such high levels of corticosteroids, and few care to continue this regimen beyond 6 to 8 weeks. If visual function is severely impaired or is worsening despite medical therapy, radiation therapy or surgical orbital decompression is indicated. The use of intraorbital steroid injections has not been effective, and there is little reason to recommend this route of administration otherwise.

Radiation therapy (e.g., 2000 cGy delivered by posteriorly angled apposed lateral ports, 200 cGy/session)⁴⁴³ for dysthyroid optic neuropathy is generally effective, even as an initial form of treatment. Indeed, in patients refractory to large doses of corticosteroids, dramatic recovery of vision has followed administration of 1500 to 2000 rads.⁴⁴² Regarding orbital decompressive surgery, it would seem that the transantral, inferior septal, medial, and lateral approaches are variably successful, as long as there is adequate decompression of the posterior aspect of the orbit floor (see Volume 2, Chapter 14). It is problematic whether massive doses of corticosteroids, surgical orbital decompression, or modest doses of radiation are least harmful to the individual patient, and, at times, all three approaches may be necessary. Other orbital processes that involve the optic nerve are discussed in Volume 2, Chapter 14.

VASCULAR COMPRESSION: ANEURYSMS

As the intracranial portion of the optic nerve ascends from the canal to the chiasm, it lies immediately above the initial supracavernous segment of the internal carotid artery (Volume 2, Chapter 4, Fig. 1 and Chapter 12, Fig. 20). The anterior cerebral artery passes dorsal to the nerve, often in direct contact, then turns rostrally in the prechiasmatic notch, where it is joined to the opposite anterior cerebral artery via the anterior communicating artery. Thus, the prechiasmal portion of the optic nerve and the anterior angle of the chiasm are intimately related to the major arteries that form the anterior aspect of the basal circle of Willis. These vessels become tortuous and dilated with increasing age and on infrequent occasions may be responsible for progressive visual loss.

Ectatic dilation (“fusiform aneurysm”) of the intracranial segment of the internal carotid artery may compress the optic nerve from below, elevating it against the unyielding periforaminal dura, anterior clinoid, and anterior cerebral artery. Jacobson and coworkers⁴⁴⁴ demonstrated by MRI that contact between the supraclinoid portion of the carotid artery and one or both optic nerve occurs in 70% of asymptomatic patients, depending also on the diameter of the vessel and with advancing age. Therefore, it is problematic to attribute occult optic neuropathy (e.g., normal tension glaucoma) simply to the intimate anatomic relationship of the carotid artery and the adjacent optic nerves. Pathologically, arterial grooving does occur and may result in atrophy of contiguous axons,⁴⁴⁵ to which the evolution of slowly progressive central, nasal, and arcuate field defects may be attributed (Fig. 47).⁴⁴⁶ Interestingly, a 34-year-old woman with progressive, painless monocular visual loss was reported⁴⁴⁷ with compression of the ipsilateral nerve by a dolichoectatic carotid artery, with recovery within 1 month of craniotomy for optic canal decompression. Of course, a diagnosis of ischemic nerve or chiasm compression by dolichoectatic arteries may be entertained only after mass lesions or other pathologic causes are categorically excluded.

Aneurysms at the skull base, in proximity to the optic nerve, also may present as insidious or rapid visual loss mimicking retro-bulbar neuritis, as exemplified by the patient reported by Miller and colleagues,⁴⁴⁸ underscoring three vital points: (1) even if it is true that a carotid-ophthalmic aneurysm must be 10 mm in diameter before it causes visual symptoms, such an aneurysm nevertheless may not be detected by MRI, and if aneurysms less than 10 mm can in fact cause visual symptoms, there is even a greater probability that such an aneurysm would be undetected by MRI; (2) rather than presenting as dramatic subarachnoid hemorrhage, the sacculation of unruptured cranial aneurysms may grow by thrombus organization, intimal proliferation, and ischemia of the aneurysm wall with subsequent thickening and scar formation; and (3) an atypical clinical course, including progression of monocular visual loss, or evolving chiasmal syndrome, demands reinvestigation.

The common anterior communicating artery aneurysm does not usually present with neuro-ophthalmic signs, but on rare occasions may produce acute monocular blindness by downward compression from above, adherence to, and eventual hemorrhage into the optic nerve.⁴⁴⁹ Aneurysmal compression of the chiasm is considered in Volume 2, Chapter 6.

1. Deficiency states
   1. Thiamine (“tobacco-alcohol amblyopia”)
      
   2. Vitamin B₁₂ (pernicious anemia; ? “tobacco amblyopia”)
      
   
   
2. Drugs/toxins
   1. Ethambutol
      
   2. Chloramphenicol
      
   3. Streptomycin
      
   4. Isoniazid
      
   5. Chlorpropamide
      
   6. Digitalis
      
   7. Chloroquine
      
   8. Vigabatrin
      
   9. Disulfiram
      
   10. Heavy metals
       
   11. Yohimbine
       
   
   
3. Hereditary optic atrophies
   1. Dominant (juvenile)
      
   2. Leber's
      
   3. Associated with heredodegenerative neurologic syndromes
      
   4. Recessive, associated with juvenile diabetes
      
   
   
4. Demyelinative
   
5. Graves' orbitopathy
   
6. Atypical glaucoma
   
7. Macular dystrophies and degenerations
   

VITAMIN DEFICIENCIES AND “TOBACCO-ALCOHOL AMBLYOPIA”

Regarding the origin of nutritional neuropathies, the great weight of clinical evidence overwhelmingly favors a dietary deficiency of B-complex vitamins (predominantly thiamine) rather than the direct toxic effects of tobacco or chronic alcoholism. Even when “tobacco amblyopia” is touted as the common variety of abuse-related optic neuropathy, multiple factors seem to converge: patients are often elderly men with diets poor in protein and B vitamins; vitamin B₁₂ absorption may be defective; alcoholic consumption is variable; rough grades of pipe tobacco are smoked.

Of greater practical importance, there are no clinical differences among “tobacco amblyopia,” and “tobacco-alcohol amblyopia,” optic neuropathy in chronic alcoholism, or malnutrition optic neuropathy. It appears that dietary deficiency is the common denominator, and thiamine improves the condition in spite of continuing abuse of alcohol or tobacco.⁴⁵⁰

It goes without saying that alcoholic patients tend not to disclose accurate daily consumption figures, and history-taking from relatives and friends may be more reliable, including details of diet. Although the patient may staunchly deny alcohol abuse, at the slit lamp, the examiner may be only too acutely aware of the odor of alcoholic breath. Normal body weight, much less obesity, is uncommon in this group. Bankers, lawyers, and even physicians are not immune, although the following case history is more common:

A 72-year-old widower presented with visual complaints related to reading and driving of 2 to 3 months' duration. Acuity was 20/200 and 20/60, and bilateral central scotomas were elicited (Fig. 48); the fundi were normal. The patient drank half a pint whiskey each day and smoked 10 to 12 cigars. He lived alone in a mobile home and “didn't bother cooking for myself.” Daily meals usually consisted of peanut butter and jelly sandwiches for breakfast, no lunch, and “some crackers” for supper. This menu had not changed for well over a year. Serum vitamin B₁₂, folate, and lead levels were all normal. Brewer's yeast tablets and the preparation of meals by a neighbor resulted in improvement of vision to 20/40 and 20/30 within 2 months and disappearance of demonstrable field defects.

Bilateral, relatively symmetric centrocecal scotomas, with preservation of the peripheral field, are the characteristic field defects encountered in nutritional-toxic neuropathy. Although minor variations in the scotomas have been said to distinguish between “alcohol” and “tobacco” amblyopia, no real distinctions may be made between central and cecocentral depressions; precise threshold techniques tend to disclose patches of defective field between the blind spot and the fixational area. The defects are characterized by “soft” margins that are difficult to define for white stimuli, but are larger and easier to plot for colored targets, especially red, on the tangent screen. A dense “nucleus” may at times be found between the blind spot and the fixational area, but nerve fiber bundle defects do not occur. Visual acuity is usually reduced to 20/200 levels but may be surprisingly good despite a symptomatic central defect, in which case the scotoma may be demonstrable with red targets only.

On occasion, bilateral cecocentral scotomas may mimic the bitemporal depression of chiasmal interference. The following features should distinguish the field of nutritional neuropathies from that of chiasmal interference: visual acuity is diminished; the defects extend across the vertical meridian, especially demonstrable with red targets; there is no peripheral hemianopic depression; and as the defects progress, they appear more cecocentral and less hemianopic.

As a rule, the fundus appears perfectly normal, but a small percentage of patients may show splinter retinal hemorrhages on or off the disc (Fig. 49) or minimal disc edema. Frisen⁴⁵¹ described bilateral evanescent dilation and tortuousity of small capillaries in the arcuate nerve fiber bundles. With the retinal hemorrhages, these changes imply a retinal ganglion cell disorder (in addition to neuropathy), as suggested by evoked potential studies.⁴⁵²

A case of severe visual loss with bilateral disc edema and retinal hemorrhages was reported,⁴⁵³ in a patient with ulcerative colitis, reversed by subcutaneous thiamine injections. Also documented is vitamin B₁₂ deficiency from malabsorption with initial hematologic manifestations reversed by folic acid, and then cecocentral scotomas that cleared with vitamin B₁₂ administration.⁴⁵⁴

In elderly patients especially, the possibility of vitamin B₁₂ or folate deficiency should not be overlooked. Central scotoma disease may precede the classic neurologic syndrome of subacute dysfunction of the dorsal and lateral spinal columns, and, in fact, optic nerve and neurologic deficits may be well established before macrocytic anemia is present. Hematologic consultation, including elucidation of vitamin B₁₂ absorption, is warranted in the investigation of cases of bilateral progressive central scotomas, especially in the presence of normal hematocrit. The field defects of pernicious or pre-pernicious anemia are identical to those of the other toxic-nutritional optic neuropathies, and evoked potential abnormalities may be found in pernicious anemia even without visual symptoms.⁴⁵⁵

The inter-relationships of nutritional deficiency, vitamin B₁₂ malabsorption, serum cyanide-thiocyanate level (from cigar and pipe smoking), and therapeutic response to hydroxocobalamin are controversial issues.⁴⁵⁶ To confound the inter-relationship of malnutrition and extrinsic factors further, in 1991 to 1993, it was reported in Cuba that some 50,000 persons, mostly men, were affected by epidemic bilateral optic neuropathy, variable sensory neuropathy, and sensorineural hearing loss. Tobacco use was considered an associated risk, and recovery occurred following parenteral and oral B-complex vitamins.⁴⁵⁷ This experience may be contrasted with that in the 1969 Nigeria civil war, and in Mozambique in 1981, when diets consisting of cassava roots and leaves caused a syndrome of bilateral optic neuropathy, nerve deafness, and sensory ataxia, associated with a rise in serum cyanocobalamin levels.⁴⁵⁸

For uncomplicated cases of nutritional deficiencies, prognosis for recovery of vision is excellent for all but the most chronic cases. Treatment consists of a well-balanced diet and B-complex vitamin supplement. Among the least expensive preparations is baking yeast, either in powder form (e.g., Fleischmann's Dried Yeast) or tablets (500 mg, 20 tablets per day; Squibb). Intramuscular thiamine may also be used.

Methanol intoxication is quite a different story, causing severe metabolic acidosis, progressive cerebral dysfunction, and variable visual loss associated with disc edema, at times with cystoid macular edema.⁴⁵⁹ The four cases studied histopathologically by Sharpe et al⁴⁶⁰ demonstrated myelin damage with axonal preservation in the retro-laminar portion of the optic nerve, probably caused by histotoxic anoxia. Acute treatment consists of intravenous bicarbonate and ethyl alcohol.

A most peculiar relatively rapid, bilateral optic atrophy termed “Jamaican optic neuropathy” afflicts young West Indian blacks. This paradoxical disorder defies characterization in terms of an infective, hereditary, toxic, or nutritional origin. Vision is reduced to 20/200 levels, and dense central scotomas are demonstrable. I have seen this syndrome in young Bahamians, Haitians, Cubans, Puerto Ricans, and Jamaicans who have lived in the United States for years preceding loss of sight. They are well nourished, nonintoxicated, and nonreactive on syphilis serologic tests (FTA-ABS), with inconsequential family histories. A British series⁴⁶¹ included West African as well as Caribbean immigrants, and, thus, a genetic factor seems rational. No form of therapy affords relief.

DRUGS AND TOXINS

Insidiously progressive or subacute onset of central field defects may occur as complications of medical therapy or of exposure to specific toxins. The catalog of potentially neurotoxic substances of ophthalmologic significance compiled in Grant's Toxicology of the Eye⁴⁶² should be consulted for more complete indices, but certain agents deserve emphasis here. The antituberculous agents isoniazid and ethambutol hydrochloride (Myambutol) have been clearly incriminated in dose-dependent insidious or subacute optic neuropathies, usually reversible over many months, but not always so.⁴⁶³ Incidence in patients receiving 15 to 25 mg/kg/day is estimated at 2% to 15%.⁴⁶⁴ After several months, acuity fails and field defects are typically cecocentral, but occasional bitemporal hemianopic depression infers also a chiasmal interference (Fig. 50). The relative influences of age, renal function, and serum zinc levels are unclear. Electrophysiologic studies suggest that both retina and optic nerve are involved (ERG and visual-evoked potentials); visual-evoked potentials, color vision tests, and contrast sensitivity measurements⁴⁶⁵ have proved helpful in detecting subclinical effects, and are more sensitive than simple acuity. Other antituberculous agents such as isoniazid and streptomycin are also rarely associated causes of optic neuropathy.⁴⁶⁴

Extensive clinical and epidemiologic evidence, primarily from Japan, has linked a neurologic syndrome that includes optic atrophy (subacute myelo-optic neuropathy) with the halogenated hydroxyquinolines.⁴⁶⁶ These preparations include iodochlorhydroxyquin (Entero-Vioform), iodoquinol (Diodoquin), and clioquinol, the use of which should probably be reserved for acrodermatitis enteropathica or asymptomatic amebiasis. Certainly, the use of these agents is to be deprecated in inflammatory bowel disease or nonspecific diarrhea, especially in children.⁴⁶⁷

Other potentially optic neurotoxic agents include chloramphenicol, especially in children with cystic fibrosis,⁴⁶⁸ D-penicillamine,⁴⁶⁹ toluene from glue sniffing,⁴⁷⁰ 5-fluorouracil,⁴⁷¹ intracarotid BCNU (carmustine),⁴⁷² hexachlorophene,⁴⁷³ and cyclosporine.⁴⁷⁴ The antianginal antiarrhythmic amiodarone has been associated with disc edema that mimics ION or papilledema of raised intracranial pressure.^475,476 Toxic effects of chemotherapeutic agents (e.g., cisplatin, cyclophosphamide⁴²³) are discussed above. Interferon-alpha has been reported to cause abrupt visual loss with disc edema.^423a Digitalis and quinine effects are discussed in Chapter 5, Part II.

CENTRAL SCOTOMA SYNDROMES

It is with the greatest of care and attention that the physician must probe for factors possibly related to the onset of what constitutes a bilateral central scotoma syndrome. As well as drug intake and family history, the patient should be carefully questioned regarding exposure to toxins (heavy metals, fumes, solvents). In the absence of any identifiable specific origin, the investigation of bilateral central scotomas, excluding maculopathies (which may require fluorescein angiography and focal foveal cone ERG⁴⁷⁷) should include the following:

1. Family history.
   
2. Medical history.
   
3. Drug history.
   
4. Diet history.
   
5. Work history; exposure to toxins.
   
6. Serum: vitamin B₁₂, folate.
   
7. Serum lead.
   
8. Hemogram, including mean corpuscular volume.
   
9. Hematology consult; B₁₂ absorption tests.
   
10. Contrast-enhanced CT or MRI; thin sections of anterior visual pathways.
    

When possible, all previous medications should be discontinued; the patient should be placed on a high-protein diet with supplemental B-complex vitamins. If pernicious anemia is suspected, the aid of a competent hematologist should be sought before any parenteral medications are administered.

ORBITO-CRANIAL INJURIES

Penetrating injuries of the orbit, accidental or the result of altercations, may result in transection or contusion of the nerve. When possible, it is imperative that visual function, including pupillary reactions (direct and consensual), and the fundus be evaluated before any surgical procedures are undertaken. For example, therapy directed primarily at repair of an orbital floor fracture is ill advised in the presence of severely impaired vision likely resulting from insult to the optic nerve. Medicolegal implications are obvious. Radiologic studies for orbito-cranial fractures or ocular and orbital foreign bodies are mandatory, but evidence of a retained foreign body alone is not an indication for surgical intervention. Neuroimaging should establish whether penetrating transorbital injuries violate the intracranium through the superior orbital fissure or orbital roof; thin-section CT scans with bone-window techniques are usually considered superior for disclosing bone fractures, and they may reveal vital optic canal fracture sites. In closed-head trauma or when penetrating injuries are suspected, baseline neurologic assessment is essential.

Blunt trauma to the eye and adnexa may result in severe visual loss, not accounted for by visible injury to the globe; when trauma is trivial, the cause of stable or progressive optic atrophy, at times with loss of disc substance, may be puzzling. Seemingly insignificant eye or lid injury can result in disproportionate optic nerve damage, and meticulous search for any evidence of lid or conjunctival penetration should be made. The mechanism of neural damage in many instances is speculative, but direct contusion necrosis or compressive ischemia of retro-bulbar axons is likely, and visual recovery is guarded; as yet, there is no convincing form of therapy (see below).⁴⁷⁸ Hemorrhage within the nerve substance or sheaths may be disclosed by enhanced CT scanning or by standardized A-scan ultrasonography,^107,479 and evulsion of the distal end of the nerve usually assumes a typical fundus picture of peripapillary hemorrhage and disruption of the choroid. Protracted post-traumatic disc swelling with slowly increasing vision is described.⁴⁸⁰ Optic atrophy is not immediately apparent because descending degeneration, even with complete transection, takes 3 to 6 weeks, as evidenced by progressive disc pallor.⁴⁸¹

Loss of vision following orbital surgery is a well-documented tragedy, likely related to intraoperative or postoperative orbital hemorrhage, tight pressure dressings, or manipulation of the nerve itself; preoperative anemia or intraoperative hypotension may play a role (see the discussion of ION after surgical procedures). Visual loss may follow repair of orbital floor fractures using subperiosteal implants or after simple rhinoplasty.⁴⁸² Callahan⁴⁸³ reviewed 68 cases of visual loss following simple blepharoplasty and concluded that intraoperative or postoperative orbital hemorrhage is the universal cause. Of course, the indications for cosmetic surgical procedures should be carefully weighed, especially in the elderly hypertensive patient. Postoperatively, the physician and nursing staff should be alerted for the complaint of acute severe pain, which may herald the onset of orbital hemorrhage. Pressure bandages should be avoided because they add to orbital tissue tension, they obscure lid and conjunctival signs of retro-bulbar bleeding, and pupillary reactions cannot be monitored.

Needle positioning during standard retro-bulbar anesthesia may injure the optic nerve, directly or by perineural or orbital hemorrhaging, usually producing immediate decreased vision discovered in the postoperative interval, with an afferent pupil reaction and usually normal fundus. Such nerve lesions may be confirmed by MRI⁴⁸⁴; in one instance, MRI confirmed an enlarged nerve, but sheath fenestration with release of hemorrhagic distention failed to reverse severe visual loss.⁴⁸⁵ Liu et al⁴⁸⁶ demonstrated, in an elegant and precise MRI analysis of the optic nerve configuration and location in extremes of gaze, that the standard Atkinson position (the eye directed upward and nasally) places the optic nerve in close proximity to the needle path, and that a downward and inward gaze position is optimal. Recall that the orbital segment of optic nerve takes a sinuous course, its length being 25 mm to 30 mm, whereas the orbit is relatively shallow, with a long axis of only 18 mm. The present practice of subtenon (peribulbar) injection techniques may prove less hazardous.

During orthopedic or neurosurgical procedures with the patient in a face-down position, such as for cervical laminectomy or posterior craniectomy, malposition of the face on the headrest may inadvertently tamponade the globe, on which the entire weight of the head is supported for hours at a time.⁴⁸⁷ Resulting retinochoroidal infarction with severe visual deficit is noted on recovery from anesthesia; facial or lid edema may be present, and other signs of secondary ocular ischemia such as iridocyclitis and prolonged ocular hypotony have also been reported.⁴⁸⁸

During orbitofacial or closed-head trauma, the optic nerve is subjected to a variety of forces. In the orbit, as noted above, the nerve is redundant and is cushioned by orbital fat, for which reasons it is less liable to indirect injury. However, the nerve is strongly tethered to bone at the orbital opening of the optic canal, in the canal itself, and at the intracranial entrance of the canal. Moreover, the optic canal has a mean subdural cross-sectional space of only 1.84 mm², through which traverses an extremely delicate vasculature.⁴⁸⁹ Thus, even small amounts of bleeding or edema may infarct the nerve, and how much more so an actual fracture with bone displacement. At both ends of the canal, the nerve is also subjected to shearing forces, because the brain and orbital contents are free to move, but the intracanalicular portion of the nerve is not.

As a rule, indirect injury to the optic nerve follows anterofrontal impact with rapid deceleration of the head, such as occurs in automobile accidents, falls from bicycles, motorcycles, skateboarding, or other frontal trauma. The visual deficits are usually instantaneous and of a marked degree. Lessell⁴⁹⁰ noted that the severity of visual loss does not correlate well with level of consciousness or presence of craniofacial fractures.

The management of indirect optic nerve injuries is controversial, with no clear consensus. Documented outcomes include spontaneous recovery and improvement with corticosteroids, and after a variety of sugical decompressions, but irreversible severe visual loss is the rule.⁴⁷⁸ The use of intravenous dexamethasone in high doses (e.g., more than 1 mg/kg/day), either as an alternative or as an adjunct to surgery, is based on acute spinal cord injury studies, and no carefully controlled prospective data are yet conclusive.^478,491 Extracranial techniques using either transethmoidal or transsphenoidal approaches are rational and may prove advantageous, considering the demonstrated pathologic changes in the intracanalicular segment of optic nerves. When perineural fluid collection is demonstrable in the orbital segment, sheath decompression may be considered, and subperiosteal or intraorbital hemorrhages associated with optic neuropathy are relative indications for surgical evacuation, especially if vision is worsening.

RADIATION AND THERMAL BURNS

The optic nerves are subject to direct effects of ionizing radiation, usually secondary to conventional radiation therapy of malignant lesions of the paranasal sinuses or of pituitary tumors, and of stereotactic radiosurgery of perichiasmal tumors. Despite the large number of patients undergoing therapeutic irradiation, the clinical incidence of radionecrosis of the nervous system is small. Visual loss attributed at first to tumor recurrence is now clearly radiologically distinguishable from radiation effects to the nerves and chiasm. Radionecrosis of the orbital optic nerve has been confirmed histologically,⁴⁹² consisting of proliferation of endothelial cells and thickening of vessel walls with fibrinoid necrosis, obliterated vessel lumina, and necrosis of retro-laminar nerve substance with reactive astrocytosis. Shukovsky and Fletcher⁴⁹³ reported three instances of progressive visual loss with optic atrophy occurring between 4 and 5 years, following megavoltage radiation to the ethmoidal sinuses and nasal cavity. Delayed radionecrosis of the optic nerves and chiasm and potential therapies are discussed at length in Volume 2, Chapter 6.

A rare and peculiar delayed type of optic neuropathy has occurred following thermal burns of the body. Salz and Donin⁴⁹⁴ reported such a case and reviewed the literature. Neither septicemia nor circulatory failure appears to play a role in the pathogenesis, and bilaterality of the disorder in all patients suggests a “burn neurotoxin,” which may be elaborated 2 to 3 weeks after initial thermal injury. The burns need not be extensive. All reported patients have been infants, children, or young adults. Otherwise, visual loss may be an early complication of burns, attributed to diffuse cerebral edema and hypoxia and accompanied by other signs and symptoms of encephalopathy.

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