Chapter 13. Disturbances of Vision

The importance of the visual system is attested by the magnitude of its representation in the central nervous system (CNS). A large part of the cerebrum is committed to vision, including the visual control of movement and the perception of printed words, and the form and color of objects. The optic nerve, which is a CNS structure, contains more than a million fibers (compared to 50,000 in the auditory nerve). The visual system also has special significance in that study of this system has greatly advanced our knowledge of both the organization of all sensory neuronal systems and the relation of perception to cognition. Indeed, we know more about vision than about any other sensory function. Furthermore, the eyes, because of their diverse composition of epithelial, vascular, neural, and pigmentary tissues, are virtually a medical microcosm, susceptible to many diseases, and its tissues are available for inspection through a transparent medium.

Impairment of visual function, expressed as defects in acuity and alterations of visual fields, obviously stands as the most important symptom of eye disease. A number of terms are commonly used to describe visual loss. Amaurosis is a general term that refers to partial or complete loss of sight. Amblyopia refers to any monocular deficit in vision that occurs in the presence of normal ocular structures. A major cause of amblyopia is the suppression by the brain of vision from one eye during early childhood caused by either strabismus, anisometropia (a significant difference in refractive error), or by media opacities. Nyctalopia is the term for poor twilight or night vision and is associated with extreme myopia, cataracts, vitamin A deficiency, retinitis pigmentosa, and, often, color blindness. There are also a number of positive visual symptoms (phosphenes, migrainous scintillations, visual illusions, and hallucinations), but they are generally less significant than symptoms of visual loss. Irritation, redness, photophobia, pain, diplopia and strabismus, changes in pupillary size, and drooping or closure of the eyelids are other major ocular symptoms and signs. Impairment of vision may be unilateral or bilateral, sudden or gradual, episodic or enduring.

The common causes of failing eyesight vary with age. In infancy, congenital defects, retinopathy of prematurity, severe myopia, hypoplasia of the optic nerve, optic pits, and coloboma are the main causes. In childhood and adolescence, nearsightedness or myopia, and amblyopia as a result of strabismus are the usual causes (see Chap. 14), although a pigmentary retinopathy or a retinal, optic nerve, or suprasellar tumor may also begin at this age. In middle age, usually beginning in the fifth decade, a progressive loss of accommodation (presbyopia) is almost invariable (at this age, half or more of the amplitude of accommodative power is lost and must be replaced by plus lenses). Still later in life, cataracts, glaucoma, retinal vascular occlusion and detachments, macular degeneration, and tumor, unilateral or bilateral, are the most frequent causes of visual impairment.

As a rule, episodic visual loss in early adult life, often hemianopic, is the result of migraine. The other important cause of transient (weeks) monocular visual loss in this age period is optic neuritis, often a harbinger of multiple sclerosis. Amaurosis in the child or young adult may also be caused by systemic lupus erythematosus and the related antiphospholipid syndrome, or by migraine, or there may be no discernible cause. Later in life, transient monocular blindness, or amaurosis fugax, lasting minutes to hours is more common; it is caused by vascular disease, particularly stenosis of the ipsilateral carotid artery. Table 13-1 lists the main causes of episodic monocular visual loss. Of course, at any age, diseases of the retina and of other components of the ocular apparatus are important causes of progressive visual loss, and the problem may at first be transient.

In the investigation of a disturbance of vision, one inquires as to what the patient means when he claims that he cannot see properly, for the disturbance in question may vary from near- or farsightedness to diplopia, partial syncope, dizziness, or a hemianopia. Fortunately, the patient's statement can be checked by the measurement of visual acuity, which is the single most important part of the ocular examination. Inspection of the refractive media and the optic fundi—especially the macular region—the testing of pupillary reflexes, color vision, and the plotting of visual fields complete this part of the examination. Examination of the eye movements is also essential, particularly if amblyopia predicated on an early life strabismus is suspected, as discussed in Chap. 14.

In the measurement of distance visual acuity the Snellen chart, which contains letters (or numbers or pictures) arranged in rows of decreasing size, is used (Fig. 13-1A). Each eye is tested separately and, if glasses are required, glasses for distance, not reading glasses, should be worn. The letter at the top of the chart subtends 5 min of an arc at a distance of 200 ft (or roughly 60 m). The patient follows rows of letters that can normally be read at lesser distances. Acuity is reported as a nonmathematical fraction that represents the patient's ability compared to that of a person with normal distance vision. Thus, if the patient can read only the top letter, which would be normally be visible at 200 feet, the acuity is expressed as 20/200, or if the distance is measured in meters rather than feet, as 6/60. If the patient's eyesight is normal, the visual acuity will equal 20/20, or 6/6, corresponding to the eighth line on most charts. Many persons, especially during youth, can read at 20 ft the line that can normally be read at 15 ft from the chart (20/15) and hence have better than "normal" vision.

For bedside testing, a "near card" or newsprint held 14 in from the eyes can be used, and the results expressed in a distance equivalent as if a distance chart had been used (Fig. 13-1B). Here, the Jaeger system is used (J1 is "normal" vision, corresponding to the line 20/25 on a Snellen chart, J5 to 20/50, J10 to 20/100, J16 to 20/200, and so on). In young children, acuity can be estimated by having them mimic the examiner's finger movements at varying distances or having them recognize and pick up objects of different sizes from varying distances. The Teller acuity cards test a child's preference (and hence ability) to view cards with increasingly fine stripes. In most jurisdictions, a corrected acuity of 20/40 or better in one eye is required to obtain and retain a driver's license.

If the visual acuity (with glasses) is less than 20/20, either the refractive error has not been properly corrected or there is some other reason for diminished acuity. The possibility of a nonrefractive error can usually be ruled out if the patient can read the 20/20 line (not the near card) through a pinhole in a cardboard held in front of the eye. The pinhole permits a narrow shaft of light to fall on the fovea (the area of greatest visual acuity) without distortion by the curvature of the lens; this eliminates the eye's optical system, thereby testing the macula alone, and should give an acuity of 20/20 if the structures of the ocular media (cornea, lens, aqueous and vitreous humors) are clear.

Light entering the eye is focused by the biconvex lens onto the outer layer of the retina. Consequently, the cornea, fluid of the anterior chamber, lens, vitreous, and retina itself must be transparent. The clarity of these media can be determined ophthalmoscopically, and a complete examination requires that the pupil be dilated to at least 6 mm in diameter. This is accomplished by instilling two drops of 2.5 percent phenylephrine and/or 0.5 to 1.0 percent tropicamide in each eye after the visual acuity has been measured, the pupillary response recorded, and the intraocular pressure estimated. In elderly persons, lower concentrations of these mydriatics should be used. The mydriatic action of phenylephrine lasts for 3 to 6 h. Rarely, an attack of angle-closure glaucoma (manifesting itself by diminished vision, ocular pain, nausea, and vomiting) may be precipitated by pharmacologic pupillary dilatation; this requires the administration of pilocarpine to the eye and the immediate attention of an ophthalmologist. It is advisable to have access to pilocarpine if the pupils are to be dilated.

By looking through a high-plus lens of the direct ophthalmoscope from a distance of 6 to 12 in, the examiner can visualize opacities in the refractive media; by adjusting the lenses from a high-plus to a zero or minus setting, it is possible to "depth-focus" from the cornea to the retina. Depending on the refractive error of the examiner, lenticular opacities are best seen within the range of +20 to +12. The retina comes into focus with +1 to -1 lenses. The illuminated pupil appears as a red circular structure (red reflex), the color being provided by blood in the capillaries of the choroid layer. If all the refractile media are clear, reduced vision that is uncorrectable by glasses is caused by a defect in the macula, the optic nerve, or parts of the brain with which they are connected. The main limit of direct ophthalmoscopy is its inability to visualize lesions in the retina that lie anterior to the equator of the globe; these are seen only by the indirect method.

It is hardly possible within the confines of this chapter to describe all the causes of opacification of the refractive media. Those with the most important medical or neurologic implications are briefly commented upon. Although changes in the refractive media do not involve neural tissue primarily, certain ones assume importance because they are associated with neurologic disease and provide clues to its presence.

In the cornea, the most common abnormality that reduces vision is scarring caused by trauma and infection. Ulceration and subsequent fibrosis may occur following recurrent herpes simplex, herpes zoster, and trachomatous infections of the cornea, or with certain mucocutaneous-ocular syndromes (Stevens-Johnson, Reiter). Hypercalcemia secondary to sarcoidosis, hyperparathyroidism, and vitamin D intoxication or milk-alkali syndrome may give rise to precipitates of calcium phosphate and carbonate beneath the corneal epithelium, primarily in a plane corresponding to the interpalpebral fissure—so-called band keratopathy. Other causes of corneal opacity include chronic uveitis, interstitial keratitis, corneal edema, lattice corneal dystrophy (amyloid deposition), and long-standing glaucoma. Polysaccharides are deposited in the corneas in some of the mucopolysaccharidoses (see Chap. 37), and copper is deposited in the Descemet membrane in hepatolenticular degeneration (Kayser-Fleischer ring). Crystal deposits may be observed in multiple myeloma and cryoglobulinemia. The corneas are also diffusely clouded in certain lysosomal storage diseases (see Chap. 37). Arcus senilis occurring at an early age (because of hyperlipidemia), sometimes combined with yellow lipid deposits in the eyelids and periorbital skin (xanthelasma), serves as a marker of atheromatous vascular disease.

In the anterior chamber of the eye, a common problem is impediment to the outflow of aqueous fluid, associated with excavation of the optic disc and visual loss, i.e., glaucoma. In more than 90 percent of cases (of the open-angle type), the cause of this syndrome is unknown and a genetic factor is suspected. The drainage channels in this type appear normal. In approximately 5 percent of cases, the angle between iris and the peripheral cornea is narrow and blocked when the pupil is dilated (angle-closure glaucoma). In the remaining cases, the condition is a result of some disease process that blocks outflow channels—inflammatory debris of uveitis, red blood cells from hemorrhage in the anterior chamber (hyphema), new formation of vessels and connective tissue on the surface of the iris (rubeosis iridis), a relatively infrequent complication of ocular ischemia secondary to diabetes mellitus, retinal vein occlusion, or carotid artery occlusion. The visual loss is gradual in open-angle glaucoma and the eye looks normal, unlike the red, painful eye of angle-closure glaucoma that was described above in reference to pharmacologic dilation of the pupil to facilitate fundoscopy. However, some cases of open-angle glaucoma may progress to rapid loss of vision.

Intraocular pressures that are persistently above 20 mm Hg may damage the optic nerve over time. This may be manifest first as an arcuate defect in the upper or lower nasal field or as a paracentral field defect, which, if untreated, may proceed to blindness. The classic finding in glaucoma is the Bjerrum field defect, consisting of an arcuate scotoma extending from the blind spot and sweeping around the macula to end in a horizontal line at the nasal equator. Other characteristic glaucomatous field patterns are winged extensions from the blind spot (Seidel scotoma) and a narrowing of the superior nasal quadrant that may progress to a horizontal edge, corresponding to the horizontal raphe of the retina (nasal step). The damage is at the optic nerve head, the optic disc appearing excavated and any pallor that is present extends only to the rim of the disc and not beyond, thus distinguishing it from other optic neuropathies. Elongation of the optic cup in the vertical axis is typical. It is now appreciated that elevated intraocular pressure is only a concurrent finding and a risk factor for glaucoma and that optic damage may be seen in patients with near normal pressure. This represents a major revision of the previous view that pressure was the elemental cause of damage in glaucoma.

In the lens, cataract formation is the most common and mundane abnormality. The cause of the common type in the elderly is unknown. The "sugar cataract" of diabetes mellitus is the result of sustained high levels of blood glucose, which is changed in the lens to sorbitol, the accumulation of which leads to a high osmotic gradient with swelling and disruption of the lens fibers. Galactosemia is a much rarer cause, but the mechanism of cataract formation is similar, i.e., the accumulation of dulcitol in the lens. In hypoparathyroidism, lowering of the concentration of calcium in the aqueous humor is in some way responsible for the opacification of newly forming superficial lens fibers. Prolonged high doses of corticosteroids, as well as radiation therapy, induce lenticular opacities in some patients. Down syndrome and oculocerebrorenal syndrome (see Chap. 38), spinocerebellar ataxia with oligophrenia (see Chap. 39), and certain dermatologic syndromes (atopic dermatitis, congenital ichthyosis, incontinentia pigmenti) are also accompanied by lenticular opacities. Myotonic dystrophy (see Chap. 48) and, rarely, Wilson disease (see Chap. 37) are associated with special types of cataract. Subluxation of the lens, the result of weakening of its zonular ligaments, occurs in syphilis, Marfan syndrome (upward displacement), and homocystinuria (downward displacement).

In the vitreous humor, hemorrhage may occur from rupture of a ciliary or retinal vessel. On ophthalmoscopic examination, the hemorrhage appears as a diffuse haziness of part or all of the vitreous or, if the blood is between the retina and the vitreous and displaces the latter rather than mixing with it, takes the form of a sharply defined clot. The common cause is rupture of newly formed vessels of proliferative retinopathy in patients with diabetes mellitus, but there are many others including orbital or cranial trauma, rupture of an intracranial aneurysm or arteriovenous malformation with high intracranial pressure, retinal vein occlusion, sickle cell disease, age-related macular degeneration (ARMD), and retinal tears, in which the hemorrhage breaks through the internal limiting membrane of the retina. The most common vitreous opacities are benign "floaters" caused by the condensation of vitreous collagen fibers, which appear as darting gray flecks or threads with changes in the position of the eyes; they may be annoying or even alarming until the person stops looking for them.

A sudden burst of flashing lights associated with an increase in floaters may mark the onset of retinal detachment. Patients complaining of bright flashes and spots in vision should be examined with the indirect ophthalmoscope to rule out tears, holes, or detachments of the vitreous or retina. Another common occurrence with advancing age is shrinkage of the vitreous humor and retraction from the retina, causing persistent streaks of light, usually in the periphery of the visual field. These phosphenes, also known as Moore lightning streaks, had been thought to be quite benign, but they may at times, indicate incipient retinal or vitreous tears or detachment, and their first appearance requires prompt evaluation by an ophthalmologist. They are most prominent on movement of the globe, on closure of the eyelids, at the moment of accommodation, with saccadic eye movements, and with sudden exposure to dark. The vitreous may also be infiltrated by lymphoma originating in the brain; biopsy by planar vitrectomy may be used to establish the diagnosis in those rare instances where the lymphoma is restricted to the eye; its presence can be inferred when there is vitreous cellular infiltration and also a brain lymphoma.

The term uveitis refers to an infective or noninfective inflammatory disease that affects any of the uveal structures (iris, ciliary body, and choroid). According to Bienfang and colleagues, uveitis accounts for 10 percent of all cases of legal blindness in the United States. Infective causes of posterior uveitis (choroidal) are toxoplasmal and cytomegalic inclusion disease, occurring mainly in patients with AIDS and other forms of reduced immune function. Noninfective autoimmune types are also common in the adult. The inflammation may be in the anterior part of the eye or in the posterior part, behind the iris and extending to the retina and choroid. Anterior uveitis is sometimes linked to ankylosing spondylitis and the human leukocyte antigen (HLA) B-27 marker, sarcoidosis, and recurrent meningitis (Vogt-Koyanagi-Harada disease); the posterior forms are associated with sarcoidosis, Behçet disease, and lymphoma.

Retinal diseases, particularly ARMD and diabetic retinopathy, are a more common cause of blindness than are neurologic diseases, as discussed further on, under "Other Diseases of the Retina."

Certain anatomic and physiologic facts are required for an interpretation of the neurologic lesions that affect vision. Visual stimuli entering the eye traverse the inner layers of the retina to reach its outer (posterior) layer, which contains two classes of photoreceptor cells: the flask-shaped cones and the slender rods. The photoreceptors rest on a single layer of pigmented epithelial cells, which form the outermost surface of the retina. The rods and cones and pigmentary epithelium receive their blood supply from the capillaries of the choroid and, to a smaller extent, from the retinal arterioles. The rod cells contain rhodopsin, a conjugated protein in which the chromophore group is a carotenoid akin to vitamin A. The rods function in the perception of visual stimuli in subdued light (twilight or scotopic vision), and the cones are responsible for color discrimination and the perception of stimuli in bright light (photopic vision). Most of the cones are concentrated in the macular region, particularly in its central part, the fovea, and are responsible for the highest level of visual acuity. Traquair described the rapid fall-off of acuity as the distance from the fovea increases as "an island of vision in a sea of blindness." Specialized pigments in the rods and cones absorb light energy and transform it into electrical signals, which are transmitted to the bipolar cells of the retina and then, in turn, to the superficially (anteriorly) placed neurons, or ganglion cells (Fig. 13-2). There are no ganglion cells in the fovea.

The axons of the retinal ganglion cells, as they stream across the inner surface of the retina, pursue an arcuate course. Being unmyelinated, they are not visible, although fluorescein retinography shows a trace of their outlines; an experienced examiner, using a bright light and deep green filter, can visualize them through direct ophthalmoscopy. The axons of ganglion cells are collected in the optic discs and then pass uninterruptedly through the optic nerves, optic chiasm, and optic tracts to synapse in the lateral geniculate nuclei, the superior colliculi, the midbrain pretectum and the suprachiasmatic nucleus of the hypothalamus (Figs. 13-2 and 13-3). The fibers derived from macular cells form a discrete bundle that first occupies the temporal side of the disc and optic nerve and then assumes a more central position within the nerve (papillomacular bundle). These fibers are of smaller caliber than the peripheral optic nerve fibers and appear to be especially sensitive to toxic and metabolic injury. Damage to the papillomacular bundle produces the "cecocentral" scotoma (extending from fixation to the blind spot). It is important to keep in mind that the retinal ganglion cells and their axon extensions are, properly speaking, an exteriorized part of the brain and that their pathologic reactions are the same as in other parts of the CNS.

In the optic chiasm, the fibers derived from the nasal half of each retina decussate and continue in the optic tract with the uncrossed temporal fibers of the other eye (Figs. 13-3 and 13-4). Thus, interruption of the left optic tract causes a right hemianopic defect in each eye, i.e., a homonymous (left nasal and right temporal) field defect (Fig. 13-3D). In partial tract lesions, the visual defects in the two eyes may not be exactly congruent, as the tract fibers are not evenly admixed. Lesions at the junction of the optic nerve and chiasm, generally compressive in nature, may cause a small contralateral superotemporal quadrantic defect in addition to the expected central scotoma in the ipsilateral eye ("junctional scotoma," Fig. 13-3B). The finding is explained by the compression of the tract and the nerve on the same side. It had been thought for many decades to result from compression of Wilbrand's knee, a bundle of fibers that turn back into the contralateral optic nerve before crossing in the chiasm, but it has since been related by Horton that the very existence of the bundle is merely an artifact of fixation in experimental material. We are uncertain if the explanation of this particular configuration of visual field abnormality has a better explanation than the existence of Wilbrand's knee and are reluctant to discard it.

The optic chiasm lies just above the pituitary gland and also forms part of the anterior wall of the third ventricle; hence the crossing fibers may be compressed from below by a pituitary tumor, a meningioma of the tuberculum sellae, or an aneurysm, and from above by a dilated third ventricle or craniopharyngioma. The resulting field defect is bitemporal ("bitemporal hemianopia"; Fig. 13-3C); if the lesion has an anterior extension to the junction with one optic nerve there is a loss of full-field vision in that eye and a partial loss in the other ("functional scotoma"). Optic tract lesions, in comparison with chiasmatic and optic nerve lesions, are relatively rare and cause a full contralateral hemianopia. In albinism, there is an abnormality of chiasmatic decussation, in which a majority of the fibers cross to the other side. How this relates to the global albinic defect in pigmented epithelium is not known.

Approximately 80 percent of the fibers of the optic tract terminate in the lateral geniculate body, a thalamic nucleus, and synapse with the six laminae of its neurons. Three of these laminae (1, 4, 6), which constitute the large dorsal nucleus, receive crossed (nasal) fibers from the contralateral eye, and three (2, 3, 5) receive uncrossed (temporal) fibers from the ipsilateral eye. Selective occlusion of either component of the dual blood supply to the lateral geniculate, consisting of the anterior and posterior choroidal arteries, is infrequent but when it does occur, produces a characteristic "multiple sectoral field defect"; a quadruple sectoranopia, meaning homonymous sectoral defects in the upper and lower quadrants of both eyes due to occlusion of the anterior choroidal artery, and two horizontal sectoranopias with occlusion of the posterior (lateral) choroidal artery. The geniculate cells project to the visual (striate) cortex of the occipital lobe, also called area 17 (Brodmann classification) or V1 (Figs. 13-4 and 13-5).

Other optic tract fibers terminate in the pretectum and innervate both Edinger-Westphal nuclei, which subserve pupillary constriction and accommodation (see Fig. 14-8). A small group of fibers terminate in the suprachiasmatic nuclei in animals and presumably also in humans. These anatomic details explain several useful clinical signs. If there is a lesion in one optic nerve, a light stimulus to the affected eye will have no effect on the pupil of either eye, although the ipsilateral pupil will still constrict consensually, i.e., in response to a light stimulus from the normal eye. This phenomenon is termed an afferent pupillary defect.

In their course through the temporal lobes, the fibers from the lower and upper quadrants of each retina diverge. The lower ones arch around the anterior pole of the temporal horn of the lateral ventricle before turning posteriorly; the upper ones follow a more direct path through the white matter of the uppermost part of the temporal lobe (Fig. 13-4), and probably of the adjacent interior parietal lobe. Both groups of fibers merge posteriorly at the internal sagittal stratum. For these reasons, incomplete lesions of the geniculocalcarine pathways (optic radiations) cause visual field defects that are partial and often not fully congruent (Fig. 13-3E and F).

It is in Brodmann area 17, embedded in the medial lip of the occipital pole, that cortical processing of the retinogeniculate projections occurs. The receptive neurons are arranged in columns, some of which are activated by edges and forms and others by moving stimuli or by color. The neurons for each eye are grouped together and have concentric, center-surround receptive fields. The deep neurons of area 17 project to the secondary and tertiary visual areas of the occipitotemporal cortex of the same and opposite cerebral hemispheres and also to other multisensory parietal and temporal cortices. Several of these extrastriate connections are just now being identified. Separate visual systems are utilized in the perception of motion, color, stereopsis, contour, and depth perception. Conceptually, the flow of secondary visual processing can be divided into a ventral stream, which carries predominantly spatial information to the parietal lobe ("the where") and a dorsal stream, which carries shape and color information to the temporal lobe ("the what") as articulated by Levine and colleagues. The classic studies of Hubel and Wiesel have elucidated much of this visual cortical anatomy and physiology and their papers, for which they were awarded the Nobel Prize, should be consulted for a fuller appreciation of the organization of the visual cortex.

The normal development of the connections described above requires that the visual system be activated at each of several critical periods of development. The early deprivation of vision in one eye causes a failure of development of the geniculate and cortical receptive fields of that eye. Moreover, in this circumstance the cortical receptive fields of the seeing eye become abnormally large and usurps the monocular dominance columns of the blind eye (Hubel and Wiesel). In children with a congenital cataract, the eye will remain amblyopic if the opacity is removed after a critical period of development. A severe strabismus in early life, especially an esotropia, will have the same effect (amblyopia ex anopsia).

The vascular supply of the eye is through the ophthalmic branch of the internal carotid artery that supplies the retina, posterior (uveal) coats of the eye, and optic nerve head. This artery gives origin to the posterior ciliary arteries; the latter form a rich circumferential plexus of vessels (arterial circle of Zinn-Haller) located deep to the lamina cribrosa. The lamina cribrosa is a sieve-like scleral (dural) structure through which the axons of the central and nasal part of the disc run. This arterial circle supplies the optic disc and adjacent part of the distal optic nerve, the choroid, and the ciliary body; it anastomoses with the pial arterial plexus that surrounds the optic nerve. The other major branch of the ophthalmic artery is the central retinal artery. It supplies the inner retinal layers and issues from the optic disc, where it divides into four branches, each of which supplies a quadrant of the retina; it is these vessels and their branches that are visible by ophthalmoscopy. A short distance from the disc, these vessels lose their internal elastic lamina and the media (muscularis) becomes thin; they are properly classed as arterioles. The inner layers of the retina, including the ganglion and bipolar cells, receive their blood supply from these arterioles and their capillaries, whereas the deeper photoreceptor elements and the fovea are nourished by the underlying choroidal vascular bed, by diffusion through the retinal pigmented cells and the semipermeable Bruch membrane upon which they rest. In up to a third of the population, a small cilioretinal artery may arise from either the choroidal circulation or from the circle of Zinn-Haller and supply the macula. In the case of a central retinal artery occlusion, the presence of this cilioretinal artery leads to the preservation of central acuity.

Abnormalities of the Retina

As indicated above, the thin (100- to 350-mm) retinal sheet and the optic nerve head, into which all visual information flows, are exteriorized parts of the CNS and the only part of the nervous system that can be inspected directly. A common limitation in the funduscopic examination in cases of visual loss is failure to carefully inspect the macular zone (which is located 3 to 4 mm lateral to the optic disc and provides for 95 percent of visual acuity). There are variations in the appearance of the normal macula and optic disc, and these may prove difficult to distinguish from disease. A normal macula may be called abnormal because of a slight aberration of the retinal pigment epithelium, a few drusen, or a deep optic cup (see further on). With experience, the examiner can visualize the unmyelinated nerve-fiber layer of the retina by using bright-green (red-free) illumination. This is most often helpful in detecting demyelinative lesions of the optic nerve, which produce a loss of discrete bundles of the radially arranged and arching bundles of retinal fibers as they converge to the disc.

The absence of receptive elements in the optic disc accounts for the normal blind spot. The normal optic disc varies in color, being paler in infants and in blond individuals. The ganglion cell axons normally acquire their myelin sheaths after penetration of the lamina cribrosa, but they sometimes do so in their intraretinal course, as they approach the disc. These myelinated fibers adjacent to the disc appear as white patches with fine-feathered edges and are a normal variant, not to be confused with exudates.

In evaluating the retinal vessels, one must remember that these are arterioles and not arteries. Since the walls of retinal arterioles are transparent, what is observed with the ophthalmoscope is a column of blood within them. The central light streak of normal arterioles is thought to represent the reflection of light as it strikes the interface of the column of blood and the concave vascular wall. In arteriolosclerosis (usually coexistent with hypertension), the lumina of the vessels are segmentally narrowed because of fibrous tissue replacement of the media and thickening of the basement membrane. Straightening of the arterioles and venous compression by arterioles are other signs of hypertension and arteriolosclerosis. In this circumstance the vein is compressed by the thickened arteriole within the adventitial envelope shared by both vessels at the site of crossing. Progressive arteriolar disease, to the point of occlusion of the lumen, results in a narrow, white ("silver-wire") vessel with no visible blood column. This change is associated most often with severe hypertension but may follow other types of occlusion of the central retinal artery or its branches (see descriptions and retinal illustrations further on). Sheathing of the venules, probably representing focal leakage of cells from the vessels, is reportedly observed in up to 25 percent of patients with the optic neuritis of multiple sclerosis, but we have only rarely been able to detect it. Arterial and venule sheathing are also seen in leukemia, sarcoid, Behçet disease, and other forms of vasculitis.

In malignant, or accelerated, hypertension there are, in addition to swelling of the optic nerve head and the retinal arteriolar changes noted above, a number of extravascular lesions: the so-called soft exudates or cotton-wool patches, sharply marginated and glistening "hard" exudates, and retinal hemorrhages. In many patients who show these retinal changes, analogous lesions are found in the brain (necrotizing arteriolitis and microinfarcts) and underlie hypertensive encephalopathy.

Microaneurysms of retinal vessels appear as small, discrete red dots and are located in largest number in the paracentral region. They are most often a sign of diabetes mellitus, sometimes appearing before the usual clinical manifestations of that disease. The use of the red-free (green) light on the ophthalmoscope helps to pick out microaneurysms from the background. Microscopically, the aneurysms take the form of small (20- to 90-mm) saccular outpouchings from the walls of capillaries, venules, or arterioles. The vessels of origin of the aneurysms are invariably abnormal, being either acellular branches of occluded vessels or themselves occluded by fat or fibrin.

The ophthalmoscopic appearance of retinal hemorrhage is determined by the structure of the particular tissue in which it occurs. In the superficial layer of the retina, they are linear or flame-shaped ("splinter" hemorrhages) because of their confinement by the horizontally coursing nerve fibers in that layer. These hemorrhages usually overlie and obscure the retinal vessels. Round or oval ("dot-and-blot") hemorrhages lie behind the vessels, in the outer plexiform layer of the retina (synaptic layer between bipolar cells and nuclei of rods and cones—Fig. 13-2); in this layer, blood accumulates in the form of a cylinder between vertically oriented nerve fibers and appears round or oval when viewed end-on with the ophthalmoscope. Rupture of arterioles on the inner surface of the retina—as occurs with ruptured intracranial saccular aneurysms, arteriovenous malformations, and other conditions causing sudden severe elevation of intracranial pressure—permits the accumulation of a sharply outlined lake of blood between the internal limiting membrane of the retina and the vitreous or hyaloid membrane (the condensed gel at the periphery of the vitreous body); this is the subhyaloid or preretinal hemorrhage, termed Terson syndrome. Either the small superficial or deep retinal hemorrhage may show a central or eccentric pale (Roth) spot, which is caused by an accumulation of white blood cells, fibrin, histiocytes, or amorphous material between the vessel and the hemorrhage. This lesion is said to be characteristic of bacterial endocarditis, but it is also seen in leukemia and occasionally in embolic retinopathy caused by carotid disease.

Cotton-wool patches, or soft exudates, like splinter hemorrhages, overlie and tend to obscure the retinal blood vessels. These patches, even large ones, rarely cause serious disturbances of vision unless they involve the macula. Soft exudates are in reality infarcts of the nerve-fiber layer, caused by occlusion of precapillary arterioles; they are composed of clusters of ovoid structures called cytoid bodies, representing the terminal swellings of interrupted axons. Hard exudates appear as punctate white or yellow bodies; they lie in the outer plexiform layer, behind the retinal vessels, like the punctate hemorrhages. If present in the macular region, they are arranged in lines radiating toward the fovea (macular star). Hard exudates consist of lipid and other serum precipitants as a result of abnormal vascular permeability of a type that is not completely understood. They are observed most often in cases of diabetes mellitus and chronic hypertension.

Drusen in the retina (colloid bodies) appear ophthalmoscopically as pale yellow spots and are difficult to distinguish from hard exudates except when they occur alone; as a rule, hard exudates are accompanied by other funduscopic abnormalities. Although retinal drusen may be a benign finding, in many cases they reflect an ARMD and their accumulation in the macula eventually leads to significant visual loss. The source of retinal drusen is uncertain, but they may result from chronic inflammation generated by degeneration of the retinal pigment epithelium. Hyaline bodies located on or near the optic disc, are also referred to as drusen but must be distinguished from those occurring peripherally. In contrast to peripheral retinal drusen, drusen of the optic discs are probably mineralized residues of dead axons and can be seen on CT in some cases. Their main significance for neurologists is that drusen that are buried under the disc ("buried drusen") are often associated with anomalous elevation of the disc that can be mistaken for papilledema (see further on) but they are for the most part, benign.

The periphery of the retina may harbor a hemangioblastoma, which may appear during adolescence, before the more characteristic cerebellar lesion. A large retinal artery may be seen leading to it and there may be a large draining vein. Occasionally, retinal examination discloses the presence of a vascular malformation that may be coextensive with a much larger malformation of the optic nerve and basilar portions of the brain.

Ischemic Lesions of the Retina

Transient Monocular Blindness

Transient ischemic attacks of visual loss involving all or part of the field of vision of one eye are referred to as amaurosis fugax or transient monocular blindness (TMB). They are common manifestations of atherosclerotic carotid stenosis but have other causes. An altitudinal horizontal border, or "shade", is often, but not invariably, an aspect of the visual loss. The shade may rise or fall at the onset or cessation of the spell and occasionally remains throughout the episode. Fortuitous inspection of the retina during an attack may show segments of arteries that are filled with white material that migrate distally over many minutes. There can be stagnation of arterial and venous blood flow, which returns within seconds or minutes as vision is restored (Fisher). One interpretation of these observations is that an embolus had occurred to the central retinal artery and had broken up and moved distally. Fisher went on to discredit the theory of the time that transient monocular blindness was due to vasospasm of the retinal arteries.

One or dozens of attacks may precede infarction of a cerebral hemisphere, or as often, they may abate without adverse consequence. In one series of 80 patients followed by Marshall and Meadows for 4 years, in an era prior to modern treatment of atherosclerosis, 16 percent developed permanent unilateral blindness, a completed hemispheral stroke, or both. Chapter 34 discusses this subject further.

Occlusion of the internal carotid artery usually causes no disturbance of vision whatsoever, provided that there are adequate anastomotic branches from the external carotid artery or other sources to the ophthalmic artery. Occasionally, occlusion of the proximal internal carotid artery is marked by an episode of transient monocular blindness on the same side, just as a hemispheral transient ischemic attack may indicate recent acute carotid occlusion. Chronic carotid occlusion with inadequate collateralization is associated with an ischemic oculopathy, which may predominantly affect the anterior or posterior segment or both. In this case, insufficient circulation to the anterior segment of the globe is manifest by scleral vascular congestion, cloudiness of the cornea, anterior chamber flare, and low intraocular pressure, or sometimes high intraocular pressure if neovascularization of the iris (rubeosis iridis) occurs and compromises the outflow of aqueous humor. Ischemia of the posterior segment of the eye is manifest by circulatory changes in the optic nerve or by venous stasis. Other signs of carotid disease may be present, for example, a local bruit over the carotid bifurcation.

Central Retinal Artery Occlusion

Most often, ischemia of the retina can be traced to occlusion of the central retinal artery or its branches by thrombi or emboli—central retinal artery occlusion (abbreviated CRAO). Occlusion is attended by sudden painless blindness. The retina becomes opaque and has a gray-yellow appearance; the arterioles are narrowed, with segmentation of columns of blood and a cherry-red appearance of the fovea (Fig. 13-6). With occlusions of smaller branches of the central retinal artery by emboli, one may be able to see the occluding material. Most frequently observed are Hollenhorst plaques—glistening, white-yellow atheromatous particles (Fig. 13-7) seen in 40 of 70 cases of retinal embolism in the series of Arruga and Sanders but are as often an asymptomatic manifestation of carotid or aortic atherosclerosis. The particles may alternatively have the appearance white calcium from calcified aortic or mitral valves or atheroma of the great vessels, and red or white fibrin-platelet emboli from a number of sources, mostly undefined, or perhaps from the heart or its valves. Emboli to retinal artery branches may be difficult to see without fluorescein retinography; furthermore, most of these emboli soon disappear. Central retinal artery occlusion also occurs as a consequence of giant cell arteritis; patients who are in their 50s or older should be screened for this condition.

It has become routine in some centers to treat acute central retinal artery occlusion in an urgent manner with a number of methods in the hope that the embolus or thrombus will be propelled into more distal vessels. These treatments are generally aimed at lowering intraocular pressure (acetazolamide, inhalation of carbon dioxide; paracentesis of the anterior chamber, ballottement), to dilate the vessels, and reestablish flow. We can only offer the impression that these procedures have often not been successful, but some case series have suggested that local thrombolysis with intraarterial agents may be useful. A multicenter controlled trial of thrombolysis (Eagle Study cited under Schumacher and colleagues) was halted early because of safety concerns so this is not likely to remain an option for treatment.

Retinal Venous Occlusion

Because the central retinal artery and vein share a common adventitial sheath, atheromatous plaques in the artery are said to be associated with thrombosis of the retinal vein. This results in a spectacular display of retinal lesions that differs from the picture of central retinal artery occlusion. The veins are engorged and tortuous, and there are multiple diffuse "dot-and-blot" and streaky linear retinal hemorrhages (Fig. 13-8). Retinal vein thrombosis is observed most frequently with diabetes mellitus, hypertension, and leukemia; less frequently with sickle cell disease; and rarely with multiple myeloma, and Waldenstrom macroglobulinemia in relation to the hyperviscosity that these two diseases cause. Sometimes, no associated systemic disease can be identified, in which case the possibility of an orbital mass (e.g., optic nerve glioma) should always be considered. In retinal vein thrombosis, visual loss is variable and there may be recovery of useful vision. In cases where macular edema ensues, recovery may be enhanced by laser photocoagulation.

Other Causes of Transient Monocular Blindness

In addition to the typical ischemic cause of this syndrome, transitory retinal ischemia is observed occasionally as a manifestation of migraine; it has also occurred in polycythemia, hyperglobulinemia, antiphospholipid syndrome, hyperviscosity of any type, and sickle cell anemia. In younger persons, transient monocular blindness is relatively uncommon and the cause is often not immediately apparent. Ischemia related to the antiphospholipid antibody or "retinal migraine" is presumed to be responsible for many cases. Rarely, vasospasm of the central retinal artery may be implicated as a cause of transient monocular blindness, in which case the episodes may cease with the introduction of a calcium channel blocker, as reported by Winterkorn and colleagues.

A common and critical cause of sudden monocular blindness, especially in elderly persons, is anterior ischemic optic neuropathy (AION), essentially an infarction of the nerve head. It is caused by disease of posterior ciliary vessels that supply the optic nerve and is considered further on in the discussion of diseases of the optic nerve. The retinal vessels in this condition usually have a normal appearance, but the disc is swollen. The arteritic form of this process is discussed in more detail in Chap. 34, but most cases are related to occlusion of small vessels as occurs typically in diabetes.

In summary, sudden, painless, monocular loss of vision should raise the question of either retinal ischemia, caused by occlusive disease of the central retinal artery or vein, or of ischemic optic neuropathy from disease of the ciliary vessels. Detachment of the retina, and macular and vitreous hemorrhages are relatively obvious causes as noted below.

Other Diseases of the Retina

Aside from vascular lesions, tears and detachments of the retina may impair vision acutely. The most common form of detachment is an intraretinal one caused by separation of the pigment epithelium layer from the sensory retina with fluid accumulation through a tear or hole in the retina. In so-called traction detachment—observed in cases of premature birth or proliferative retinopathy secondary to diabetes or other vascular disease—contracting fibrous tissue pulls the retina from the choroid.

Serous retinopathy, a cause of monocular visual disturbance in young or middle-aged males, may be associated with the use of corticosteroids. The entire perimacular zone is elevated by edema fluid. The condition may arise acutely or slowly. Metamorphopsia (distortion of vision) in one eye is a common presentation, but acuity is not much impaired. The optic disc remains normal. The retinal change (leakage of vascular fluid into the subretinal space) causes a loss of visualization of the detail of the choroid and is demonstrated by fluorescein angiography or by optical coherence tomography (OCT). The condition tends to resolve over several months and is treated by laser to seal the sites of leakage.

Chorioretinitis, generally the result of an infectious process, may cause difficulty in diagnosis. In many patients the initial diagnosis had been retrobulbar neuritis. One cannot depend upon the appearance of a macular star (see above) for diagnosis.

A large number of patients with HIV-AIDS develop retinal lesions of various types. Infarcts of the nerve-fiber layer (cotton-wool patches), hemorrhages, and perivascular sheathing are the usual findings. Toxoplasmosis is the most common infective lesion, followed in frequency by cytomegalovirus (CMV), but histoplasmosis, Pneumocystis carinii, herpes zoster, syphilis, and tuberculosis are well documented. CMV may cause a particularly severe necrotizing retinitis and permanent impairment of vision. Both the retina and choroid may be involved by these diseases, in which case the ophthalmoscopic picture is characteristic, showing the destruction of the "punched-out" lesions that exposes the whitish sclera, and deposits of black pigment. The choroid may also be the site of viral and noninfective inflammatory reactions, often in association with painful recurrent iridocyclitis and lacrimal inflammation.

Degenerations of the retina are important causes of chronic progressive visual loss. The retinal degenerations assume several forms and many are associated with progressive conditions of the brain or other organs. The most frequent in youth and middle age is retinitis pigmentosa, a hereditary disease of the outer photoreceptor layer and subjacent pigment epithelium. The retina is thin, and there are fine deposits of black pigment in the shape of bone corpuscles, more in the periphery; later the optic discs become pale. The disorder is marked by constriction of the visual fields with relative sparing of central vision ("gun-barrel" vision), metamorphopsia (distorted vision), delayed recovery from glare, and nyctalopia (reduced twilight vision). The causes of retinitis pigmentosa and related retinal degenerations are diverse, too numerous to list here. Furthermore, the condition has been linked to deficits in more than 75 different genes. In one form of isolated retinitis pigmentosa, which follows an autosomal dominant pattern of inheritance, the gene for rhodopsin (a combination of vitamin A and the rod-cell protein opsin) produces a defective opsin, resulting in a diminution of rhodopsin, diminished response to light, and eventual degeneration of the rod cells (Dryja et al). Retinitis pigmentosa is associated with the Laurence-Moon-Biedl syndrome, with certain mitochondrial diseases (Kearns-Sayre syndrome, Chap. 38), and with a number of degenerative and metabolic diseases (e.g., Refsum disease) of the nervous system. Another early life hereditary retinal degeneration, characterized by massive central retinal lesions, is the autosomal recessive Stargardt form of juvenile tapetoretinal degeneration. Like retinitis pigmentosa, Stargardt disease may be accompanied by progressive spastic paraparesis or ataxia. Nonpigmentary retinal degeneration is a familiar feature of a number of rare syndromes and diseases, such as neuronal ceroid lipofuscinosis, Bassen-Kornzweig disease, Batten-Mayou disease, and others (see Chap. 37).

Medications have emerged as a cause of retinal damage. Phenothiazine derivatives, less often used in practice than they had been, may conjugate with the melanin of the pigment layer, resulting in degeneration of the outer layers of the retina and a characteristic "bull's-eye retinopathy" observed by fluorescein angiography. If these drugs are administered in high dosages for protracted periods, the patient should be tested for defects in visual fields and color vision. Among drugs used to treat neurologic disease, the antiepileptic drug vigabatrin is notable for causing retinal degeneration and a concentric restriction of the visual fields in almost half of exposed patients. Elevated levels of gamma-aminobutyric acid (GABA) in the retina are presumably the cause of toxicity. High-dose tamoxifen has caused toxicity in the retina, characterized by the deposition of refractile opacities and in more severe cases, by macular edema.

A cancer-associated retinopathy (CAR) has been described in patients with an oat-cell carcinoma of the lung as a paraneoplastic illness (see Chap. 31). The typical presentation is of positive visual phenomenon and rapid bilateral visual loss. Antibodies against the recoverin protein, which modulates rhodopsin kinase, have been demonstrated in the serum of affected patients (Grunwald et al; Kornguth et al; Jacobson et al). More recently, a melanoma-associated retinopathy (MAR) that affects only rods has been described. These paraneoplastic processes are further described in Chap. 31.

Certain lysosomal diseases of infancy and early childhood are characterized by an abnormal accumulation of undegraded proteins, polysaccharides, and lipids in cerebral neurons, as well as in the macula and other parts of the retina (hence the terms storage diseases and cerebromacular degenerations). Corneal clouding, cherry-red spot and graying of the retina, and later optic atrophy are the observed ocular abnormalities. Chapter 37 discusses these diseases.

In some of these retinal diseases, minimal changes in the pigment epithelium or other layers of the retina may not be readily detected by ophthalmoscopy. A test to expose such subtle retinal changes is to estimate the time required for recovery of visual acuity following light stimulation (macular photostress test). The test is conducted by shining a strong light through the pupil of an affected eye for 10 s and measuring the time necessary for the acuity to return to the pretest level (normally 50 s or less). With macular lesions, recovery time is prolonged, but with lesions of the optic nerve, it is not affected. This phenomenon may also be observed in the eye on the side of a carotid occlusion, in essence, an ischemic retinopathy. Retinal diseases reduce or abolish the electrical activity generated by the outer layers of the retina, and this can be measured by the electroretinogram (ERG). Fluorescein retinography and various new imaging tests are now essential for proper diagnosis of retinal disease. OCT uses reflected light to construct a high-resolution two-dimensional image of the retinal layers; it is able to demonstrate with remarkable resolution retinal edema, tears, macular holes, and the thinning of the retinal nerve-fiber layer that follows optic neuropathy.

Age-Related Macular Degeneration

This is the most important cause of visual loss in the elderly. As ARMD begins to disturb vision, the straight lines on the Amsler grid are observed by the patient to be distorted. Examination discloses a central scotoma, and an alteration of the retina around the macula. Central vision is at first distorted, then gradually diminishes, impairing reading, but these patients can still get about because of retained peripheral vision. The two most common types of macular degeneration are an atrophic "dry" type, which is a true pigmentary degeneration associated with retinal drusen, of unknown cause but with a genetic component, and an exudative "wet" type, which is the result of choroidal neovascularization that results in secondary macular damage. The wet form is amenable to laser treatment and to the injection into the orbit of ranibizumab or similar antiangiogenic monoclonal antibodies against vascular endothelial growth factor. Progression of the dry form may be slightly reduced by the use of antioxidants and zinc. The pathophysiology and treatment of ARMD have been reviewed by DeJong.

Diabetic Retinopathy

Although not strictly speaking a problem taken up by neurologists, this is such an important cause of reduced vision and blindness that the basic facts should be known to all physicians. The earliest changes are of microaneurysms, and tiny intraretinal hemorrhages; these are present in almost all diabetics who have had type 1 disease for more than 20 years. Cotton-wool spots and small hemorrhages appear as the retina becomes ischemic. Subsequently, there is a more threatening proliferative retinopathy that consists of the formation of new blood vessels, and consequent leakage of proteins and blood. The proliferative feature occurs in half of type 1 diabetics, and 10 percent of those who have had type 2 disease for 15 to 20 years. The new vessels can grow into the vitreous, and hemorrhages from them may cause traction on the retina, which results in detachment. Visual loss may also be the result of macular edema. Reabsorption of the edema leads to the deposition of lipid "hard exudates." The maintenance of glucose control reduces the frequency and severity of retinopathy but does not prevent it. Locally elevated levels of vascular endothelial growth factor have been shown to be the involved in the pathophysiology of diabetic retinal neovascularization, and recent studies show that improvement in neovascular leakage can be obtained, at least in the short term, with intravitreal injections of the antivascular endothelial growth factor (anti-VEGF) antibody, bevacizumab. The review of the subject by David and colleagues is recommended.

Papilledema and Raised Intracranial Pressure

Of the various abnormalities of the optic disc, papilledema or optic disc swelling has the greatest neurologic implication, for it signifies the presence of increased intracranial pressure. The term papilledema has come to mean disc swelling due to raised intracranial pressure although there are other causes of a similar funduscopic appearance. It must be made clear, however, that an ophthalmoscopic appearance identical to that of papilledema can be produced by infarction of the optic nerve head (the "papillopathy" of anterior ischemic optic neuropathy) and by inflammatory changes in the intraorbital portion of the optic nerve ("papillitis", a form of optic neuritis). Certain clinical and funduscopic findings, listed in Table 13-2 and described below, assist in distinguishing between these processes, although all share the basic feature of conspicuous optic disc swelling.

In its mildest form, papilledema appears as slight elevation of the disc and blurring of the disc margins, especially of the superior and inferior aspects, and a mild fullness of the veins in the disc. Subtle disc elevation is also indicated by a loss of definition of the vessels overlying the disc as they approach the disc margin from the periphery; this appearance is produced by edema in the adjacent retina. Because many normal individuals, especially those with hypermetropia, have ill-defined disc margins, the early stage of papilledema may be difficult to detect (Fig. 13-9). Pulsations of the retinal veins, best seen where the veins turn to enter the disc, will have disappeared by the time intracranial pressure is raised, but this finding is not specific, as venous pulsations are not present in a proportion of normal individuals in the seated position. On the other hand, the presence of spontaneous venous pulsations is a reliable indicator of an intracranial pressure below 200 mm H2O, and thus usually excludes papilledema (Levin). Fluorescein angiography, red-free fundus photos (which highlight the retinal nerve fibers), and newer imaging techniques alluded to above (ocular coherence tomography) are helpful in detecting early edema of the optic discs.

More severe degrees of papilledema appear as further elevation, or "mushrooming" of the entire disc and surrounding retina. There is subtle or overt edema and obscuration of vessels at the disc margins and, in some instances, peripapillary hemorrhages (Fig. 13-10). When advanced as a result of raised intracranial pressure, papilledema is almost always bilateral although it may asymmetric. Purely unilateral edema of the optic disc is indicative of a perioptic meningioma or other tumor involving the optic nerve, but it can sometimes occur at an early stage of increased intracranial pressure. As the papilledema becomes chronic, elevation of the disc margin becomes less prominent and pallor of the optic nerve head, representing a dropout of nerve fibers (atrophy), becomes more evident (Fig. 13-11). Varying degrees of secondary optic atrophy remain in the wake of papilledema that has persisted for more than several days or weeks, leaving the disc pale, gliotic, and shrunken. Constriction in one quadrant of the nasal portion of the visual field is an early sign of the loss of nerve fibers from optic atrophy.

Acute papilledema, while it may enlarge the blind spot slightly, does not greatly affect visual acuity (except transiently during spontaneous waves of increased intracranial pressure). Therefore, acute optic disc swelling in a patient with severely reduced vision cannot be attributed to papilledema; instead, intraorbital optic neuritis (papillitis) or infarction of the nerve head (ischemic optic neuropathy) must be present. Chronic or recurrent papilledema may result in optic atrophy and cause a reduction in visual acuity by that mechanism.

The examiner is also aided by the fact that papilledema due to raised intracranial pressure is generally bilateral, although, as mentioned earlier, the degree of disc swelling may not be symmetrical. In contrast, papillitis and infarction of the nerve head affect one eye, but there are exceptions to both of these statements. The pupillary reaction to light is muted only with infarction and optic neuritis, not with acute papilledema (once secondary optic atrophy supervenes, the loss of afferent light reaction is indeed observed). The occurrence of papilledema on one side and optic atrophy on the other is referred to as the Foster Kennedy syndrome; it is typically caused by a frontal lobe tumor or an olfactory meningioma on the side of the atrophic disc. In its complete form, which is seen only rarely, there is also anosmia on the side of the optic atrophy. Another cause of the same funduscopic appearance has been called the "pseudo-Foster Kennedy syndrome," which occurs when papillitis in one eye occurs years after an optic neuropathy of the opposite one.

Although, as mentioned, the term papilledema is generally reserved for disc swelling from raised intracranial pressure, an identical appearance caused by infarction of the nerve head is characterized by extension of the swelling beyond the nerve head, as described below. The papilledema of increased pressure is associated with peripapillary hemorrhages whereas these are uncommon with infarction of the nerve. Often these distinctions cannot be made on the basis of the funduscopic appearance alone, in which case the most reliable distinguishing feature is again the presence or absence of visual loss (Table 13-2). Papilledema caused by increased intracranial pressure cannot be distinguished from combined edema of the optic nerve and retina, which typifies malignant hypertension.

Chronic papilledema, as occurs in pseudotumor cerebri (see Chap. 31), presents a special problem in diagnosis, and represents a risk for permanent reduction in visual acuity from secondary optic atrophy. In addition to testing visual acuity at regular intervals, our colleagues advise serial evaluation of the visual fields as constriction of the nasal field, detectable by automated perimetry and tangent screen testing, is an early and ominous optic atrophy.

The essential element in the pathogenesis of papilledema is an increase in pressure in the sheaths surrounding the optic nerves, which communicate directly with the subarachnoid space of the brain. This was demonstrated convincingly by Hayreh (1964), who produced bilateral chronic papilledema in monkeys by inflating balloons in the subarachnoid space and then opening the sheath of one optic nerve; the papilledema promptly subsided on the operated side but not on the opposite side. The appearance of the swollen disc, however, has also been ascribed to a blockage of axoplasmic flow in the optic nerve fibers (Minckler et al; Tso and Hayreh). It was found that compression of the optic nerve by elevated cerebrospinal fluid (CSF) pressure resulted in swelling of axons behind the optic nerve head and leakage of their contents into the extracellular spaces of the disc. In our opinion, the block in axoplasmic flow alone could not account for the marked congestion of vessels and hemorrhages that accompany papilledema and a component of vascular congestion is likely.

The mechanism of papilledema that on rare occasions accompanies spinal tumors, particularly oligodendrogliomas, and the Guillain-Barré syndrome is not entirely clear. Usually the CSF protein is more than 1,000 mg/100 mL, but this cannot be the entire or only explanation, as instances occur in which the protein concentration is only slightly elevated (also the concentration of protein in the ventricular and cerebral subarachnoid spaces is considerably lower than in the lumbar sac, where it is usually sampled; see Chap. 30). In other diseases that at times give rise to papilledema—e.g., chronic lung disease with hypercapnia, cancer with meningeal infiltration, or dural arteriovenous malformation—the mechanism is most often one of a generalized increase of intracranial pressure. Other causes of papilledema are cyanotic congenital heart disease, and other forms of polycythemia, hypocalcemia though an obscure mechanism, and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; see Chap. 46).

Diseases of the Optic Nerves

The optic nerves, which constitute the axonic projections of the retinal ganglion cells to the lateral geniculate bodies and superior colliculi can be inspected in the optic nerve head. Observable changes in the optic disc are therefore of particular importance. They may reflect the presence of raised intracranial pressure as already described; optic neuritis ("papillitis"); infarction of the optic nerve head; congenital defects of the optic nerves (optic pits and colobomas); hypoplasia and atrophy of the optic nerves; and glaucoma. Illustrations of these and other abnormalities of the disc and ocular fundus can be found in the atlas by E.M. Chester and in the text by Biousse and Newman. In general, optic neuropathies are distinguished from other causes of visual loss by a predominance of loss of color vision and by the presence of an afferent pupillary defect.

Table 13-3 lists the main causes of optic neuropathy, which are discussed in the following portions of this chapter.

Optic Neuritis (Papillitis; Retrobulbar Neuritis) (see Chap. 36)

This inflammatory process causes unilateral acute impairment of vision that may appear in one or both eyes, either simultaneously or successively. It develops in a number of clinical settings, but has a special relationship to multiple sclerosis. The most common situation is one in which an adolescent or young adult woman has a rapid diminution of vision in one eye as though a veil had covered the eye, sometimes progressing within hours or days to complete blindness.

The optic disc and retina may appear normal, in which case the condition is of the more common retrobulbar variety, but if the inflammation is near the nerve head, there is swelling of the disc, i.e., papillitis (Fig. 13-12). The disc margins are then seen to be elevated, blurred, and, rarely, surrounded by hemorrhages. As indicated above, papillitis is associated with marked impairment of vision and a central scotoma that encompasses the blind spot (cecocentral), thus distinguishing it from the acute papilledema of increased intracranial pressure. Pain on movement and tenderness on pressure of the globe, and a difference between the two eyes in the perception of brightness of light are other common, but not invariable findings (Table 13-2). The pupil on the affected side has a muted constriction response to direct light. In the following days and weeks, the patient may report an increase in blurring of vision with exertion or with exposure to heat (Uhthoff phenomenon). In papillitis, but not retrobulbar neuritis, examination may disclose haziness of the vitreous that causes difficulty in visualizing the retina. Inflammatory sheathing of the retinal veins, as described by Rucker, is known to occur but has been uncommon in our patients. In extreme cases, edema may suffuse from the disc to cause a rippling in the adjacent retina. However, as just noted, most cases of optic neuritis are retrobulbar, and little is seen when examining the optic nerve head. In approximately 10 percent of cases, both eyes are involved, either simultaneously or in rapid succession.

Sometimes, no cause can be found for optic neuropathy, but a first bout of multiple sclerosis is always suspected, as discussed in Chap. 36. After several weeks to months, there is spontaneous recovery; vision returns to normal in more than two-thirds of cases. Recovery of vision occurs spontaneously, or may be hastened by the intravenous administration of high doses of corticosteroids. In one frequently cited study, the oral administration of these drugs increased the frequency of a relapse of optic neuritis so that intravenous agents are used instead (see "Treatment of Optic Neuritis" in Chap. 36). Diminution of brightness, dyschromatopsia, or a scotoma may remain; rarely, the patient is left blind.

As time progresses, more than half of adults with optic neuritis will develop other symptoms and signs of multiple sclerosis, usually within 5 years, and probably even more do so when they are observed for longer periods. Conversely, in approximately 15 percent of patients with multiple sclerosis, the history discloses that retrobulbar neuritis was the first symptom. A proportion of patients with acute optic neuritis are found at the time of an acute attack to have characteristic features of multiple sclerosis on MRI of the cerebrum and spine.

Postinfectious demyelinating disease is a possible cause in some cases that do not later show signs of multiple sclerosis. Less is known about children with retrobulbar neuropathy, in whom the disorder is more often bilateral and frequently related to a preceding viral infection ("neuroretinitis," see below). Their prognosis is better than that of adults. Formerly, optic neuritis was often attributed to paranasal sinus disease, but this condition rarely affects vision and with a few exceptions, the association is tenuous, as discussed further on. Optic neuritis is a main component of neuromyelitis optica (Devic disease; see Chap. 36); the prognosis for recovery is generally poorer than for optic neuritis in multiple sclerosis, but there are many exceptions.

Despite the return of visual acuity in the majority of patients with optic neuritis, a degree of optic atrophy almost always results. The disc then appears shrunken and pale, particularly in its temporal half (temporal pallor), and the pallor extends beyond the margins of the disc into the peripapillary retinal nerve fibers. The pattern-shift visual evoked potential becomes delayed; as a result, this test is a highly sensitive indicator of previous, even asymptomatic, episodes of optic neuritis.

The treatment of optic neuritis is taken up with multiple sclerosis in Chap. 36.

Leber hereditary optic neuropathy, a maternally inherited mitochondrial disorder, is an infrequent but important cause of blindness in children and younger adults because it may simulate the more common inflammatory optic neuropathies, even at times causing a relatively abrupt onset of visual loss followed by some degree of recovery (see "Hereditary Optic Atrophy of Leber" in Chap. 37). The visual field defect typically takes the form of a cecocentral scotoma. Certain nutritional and toxic states may do the same, as well as sarcoidosis and the numerous other causes of optic neuropathy discussed further on.

Neuroretinitis is a rare post- or parainfectious process seen mostly in children and young adults, sometimes in association with exposure to the Bartonella henselae bacteria the cause of cat scratch fever. Papillitis is accompanied by macular edema and exudates situated radially in the Henle layer, producing a "macular star" appearance.

Ischemic Optic Neuropathy (Anterior, AION and Posterior, PION)

In persons older than 50 years of age, ischemic infarction of the optic nerve head is the most common cause of a persistent monocular loss of vision (Fig. 13-13). The onset is abrupt and painless, but on occasion the visual loss is progressive for several days. The field defect is often altitudinal and involves the area of central fixation, accounting for a severe loss of acuity. Swelling of the optic disc, extending for a short distance beyond the disc margin, and associated small, flame-shaped hemorrhages, is typical; less often, if the infarction is situated behind the optic nerve head, the disc appears entirely normal. The retina and retinal vessels are not affected, as they are in cases of embolic occlusion of the central retinal artery. AION may also complicate intraocular surgery. As the disc edema subsides, optic atrophy becomes evident. The second eye may be similarly affected at a later date, particularly in those patients with hypertension and diabetes mellitus. Usually, there are no premonitory symptoms or episodes of transient visual loss.

Despite these distinctive features, ischemic optic neuropathy can sometimes be difficult to differentiate from optic neuritis, as pointed out by Rizzo and Lessell. This proves particularly problematic when visual loss evolves over days, the disc is swollen, and pain accompanies the ischemic condition. However, the age of the patient and nature of the field defect (central in optic neuritis in contrast to sometimes altitudinal in ischemic neuropathy) further serve to clarify the situation. Furthermore, arteritic and non-arteritic forms of ischemic optic neuropathy are distinguished, the former being the result of temporal (giant cell) arteritis.

As to the pathogenesis of non-arteritic ischemic optic neuropathy, the usual (anterior) form has been attributed by Hayreh to ischemia in the posterior ciliary artery circulation and more specifically to occlusion of the branches of the peripapillary choroidal arterial system. A small cup-to-disc ratio is reportedly a risk factor. Infarction of the posterior portions of the optic nerve(s) is uncommon (posterior ischemic optic neuropathy, PION). Most cases of either type occur on a background of hypertensive vascular disease and diabetes, but not necessarily in relation to carotid artery atherosclerotic stenosis, which in our experience has accounted for only a few cases (see below).

A relationship has been observed between ischemic optic neuropathy and the use of nitric oxide inhibitors, such as sildenafil, for erectile dysfunction. The visual loss has occurred within 24 h of taking the drug and is usually unilateral. According to Pomeranz and colleagues, all affected patients have had risk factors for vascular disease such as hypertension, diabetes, or hyperlipidemia, but there have been exceptions, and these risk factors are likely to be present in older men who are also likely to use the drug. There may be complete recovery or persistent blindness. Massive blood loss or intraoperative hypotension, particularly in association with the use of cardiac surgery with a bypass pump, may also produce visual loss, and ischemic infarction of the retina and optic nerve.

A remarkable unilateral or bilateral optic neuropathy, which we have observed and which is also presumably ischemic in nature, occurs after prolonged laminectomy operations that are performed with the patient in the prone position. Obese individuals and those with small optic cups are seemingly at risk for this complication. Some recovery is possible after many weeks but most patients remain blind from infarction of the optic nerve heads. Blood loss of greater than 1 L, and surgery longer than 6 hours seem to be common to most cases. The reported cases have been summarized from a registry by Lee and coworkers.

Temporal, or giant cell, arteritis is another important cause of AION or PION (see also Chap. 10 on the related headache and Chap. 34 for a discussion of cerebrovascular disease in association with giant cell arteritis). Fleeting premonitory symptoms of visual loss (amaurosis fugax) may precede infarction of the nerve. Infarction caused by cranial arteritis may affect both optic nerves in close succession and, less often, ocular motor function. Temporal arteritis less often presents with the picture of central retinal artery occlusion or posterior ischemic optic neuropathy (in which ischemic injury to the optic nerve is not accompanied by acute changes in the appearance of the disc).

The condition called "orbital pseudotumor", essentially an inflammatory condition of all the orbital contents, is discussed in Chap. 14 on oculomotor disorders but is mentioned here because optic neuropathy and visual loss can be a component of the syndrome.

Systemic lupus erythematosus, diabetes, sarcoidosis, neurosyphilis, and AIDS rarely give rise to optic neuropathies.

Optic Neuropathy Caused by Acute Cavernous and Paranasal Sinus Disease

A number of disease processes adjacent to the orbit and optic nerve can cause blindness, usually with signs of compression or infarction of the optic and oculomotor nerves. They are seen far less frequently than are ischemic optic neuropathy and optic neuritis. Septic cavernous sinus thrombosis (see "Cavernous Sinus Thrombosis" in Chap. 34), for example, may be accompanied by blindness of one eye or both eyes asymmetrically. In our experience with 4 such patients, the visual loss appeared days after the characteristic chemosis and oculomotor palsies of the venous sinus occlusion. The mechanism of visual loss, sometimes without swelling of the optic nerve head, is unclear but most likely relates to retrobulbar ischemia of the nerve.

Similarly, optic and oculomotor disorders may rarely complicate ethmoid or sphenoid sinus infections. Severe diabetes with mucormycosis or other invasive fungal or bacterial infection is the usual setting for these complications. Although the formerly held notion that uncomplicated sinus disease is a cause of optic neuropathy is no longer tenable, there are still a few instances in which such an association occurs but the nature of the visual loss remains unclear. Slavin and Glaser described a case of loss of vision from a sphenoethmoidal sinusitis with cellulitis at the orbital apex. Visual symptoms in these exceptional circumstances can occur prior to overt signs of local inflammation. An otherwise benign sphenoidal mucocele may cause a compressive optic neuropathy, usually with accompanying ophthalmoparesis and slight proptosis.

Toxic and Nutritional Optic Neuropathies (Table 13-3)

Simultaneous impairment of vision in the two eyes, with central or centrocecal scotomas, is often caused not by a demyelinative process but also by toxic or nutritional processes. The latter condition is observed most often in the chronically alcoholic or malnourished patient. Impairment of visual acuity evolves over several days or a week or two, and examination discloses bilateral, roughly symmetrical central or centrocecal scotomas, the peripheral fields being intact. With appropriate treatment (nutritious diet and vitamins B) instituted soon after the onset of amblyopia, complete recovery is possible. If treatment is delayed, patients are left with varying degrees of permanent defect in central vision and pallor of the temporal portions of the optic discs. This disorder has been referred to as "tobacco-alcohol amblyopia," the implication being that it is caused by the toxic effects of tobacco or alcohol or both. In fact, the problem is one of nutritional deficiency and is more properly designated as deficiency amblyopia or nutritional optic neuropathy (see Chap. 41). The same disorder may be seen under conditions of severe dietary deprivation (see Chap. 41) and in patients with vitamin B12 deficiency.

A subacute optic neuropathy of possible toxic origin was described in Jamaican natives. It was characterized by bilaterally symmetrical central visual loss and had additional features of nerve deafness, ataxia, and spasticity in some cases. A similar condition is described periodically in other Caribbean countries, two decades ago in Cuba, where an optic neuropathy of epidemic proportions was associated with a sensory polyneuropathy. A nutritional etiology, possibly contributed to by tobacco use (putatively cigars in the Cuban epidemic), was the likely cause of these outbreaks (see Sadun et al and The Cuba Neuropathy Field Investigation Team report). A putative role of exposure to cyanide, either from smoking or consumption of cassava, has been a feature of some of these epidemics.

Impairment of vision because of methyl alcohol intoxication (methanol) is abrupt in onset and characterized by large symmetrical central scotomas as well as symptoms of acidosis. Treatment is directed mainly to correction of the acidosis and possibly, the administration of fomepizole. The same may occur with ethylene glycol ingestion. The subacute development of central field defects is attributable to other toxins and to the chronic administration of certain therapeutic agents, notably halogenated hydroxyquinolines (clioquinol), chloramphenicol, ethambutol, linezolid, isoniazid, streptomycin, chlorpropamide (Diabinese), infliximab, and various ergot preparations. The main drugs reported to have a toxic effect on the optic nerves are listed in Table 13-3 and have been catalogued more extensively by Grant.

Developmental Abnormalities of the Optic Nerve

Congenital cavitary defects because of defective closure of the optic fissure may be a cause of impaired vision because of failure of development of the papillomacular bundle. Usually the optic pit or a larger coloboma is unilateral and unassociated with developmental abnormalities of the brain (optic disc dysplasia and dysplastic coloboma). A hereditary form is known (Brown and Tasman). Vision may also be impaired as a result of a developmental anomaly in which the discs are of small diameter (hypoplasia of the optic disc, or micropapilla).

Other Optic Neuropathies

Optic nerve and chiasmal compression and infiltration by gliomas, meningiomas, craniopharyngiomas, and metastatic tumors may cause scotomas and optic atrophy (see Chap. 31). Pituitary tumors characteristically cause bitemporal hemianopia, but very large adenomas, in particular if there is pituitary apoplexy (involutional bleeding into the pituitary), can cause blindness in one or both eyes (see "Pituitary Apoplexy" in Chap. 31). Infiltration of an optic nerve may occur in sarcoidosis (see Fig. 32-4, bottom panel), granulomatosis with polyangiitis (formerly Wegener granulomatosis), and with certain neoplasms, notably leukemia and lymphoma.

Of particular importance is the optic nerve glioma that occurs in 15 percent of patients with type I von Recklinghausen neurofibromatosis. Usually, it develops in children, often before the fourth year, causing a mass within the orbit and progressive loss of vision. If the eye is blind, the recommended therapy is surgical removal to prevent extension into the optic chiasm and hypothalamus. If vision is retained, radiation and chemotherapy are the recommended forms of treatment. Although most such gliomas are of low grade, a rare malignant form (glioblastoma) has been described in adults.

Thyroid ophthalmopathy with orbital edema, exophthalmos, and usually, swelling of extraocular muscles is an occasional cause of optic nerve compression.

Radiation-induced damage of the optic nerves and chiasm has been well documented. In a series of 219 patients at the M.D. Anderson Cancer Center who received radiotherapy for carcinomas of the nasal or paranasal region, retinopathy occurred in 7, optic neuropathy with blindness in 8, and chiasmatic damage with bilateral visual impairment in 1. These complications followed the use of more than 50 Gy (5,000 rad) of radiation (see Jiang et al). Radiation-induced optic neuropathy is typically delayed, occurring at an average of 18 months after radiation exposure, and is often accompanied by enhancement of the nerve on MRI. This is also addressed in Chap. 31.

In the case of pseudotumor cerebri, the visual loss may be unexpectedly abrupt, appearing in a day or less, and even sequentially in both eyes. This seems to happen most often in patients with constitutionally small optic nerves, no optic cup of the nerve head and, presumably, a small aperture of the lamina cribrosa. Such explosive visual loss in pseudotumor cerebri may respond to urgent optic nerve fenestration, but this approach is controversial, as discussed in "Pseudotumor Cerebri" in Chap. 30.

From the retina there is a point-to-point projection to the lateral geniculate nucleus and from there, to the calcarine cortex of the occipital lobe. Thus the visual cortex receives a spatial pattern of stimulation that corresponds with the retinal image of the visual field. Visual impairments caused by lesions of the central pathways usually involve only a part of the fields, and a plotting of the fields provides fairly specific information as to the site of the lesion.

For purposes of description of the visual fields, each retina and macula are divided into a temporal and nasal half by a vertical line passing through the fovea. A horizontal line represented roughly by the junction of the superior and inferior retinal vascular arcades also passes through the fovea and divides each half of the retina and macula into upper and lower quadrants. Visual field defects are always described from the patient's view (nasal, temporal, superior, inferior) rather than of the retinal defect or the examiner's perspective. The retinal image of an object in the visual field is inverted and reversed from right to left, like the image on the film of a camera. Thus the left visual field of each eye is represented in the opposite half of each retina, with the upper part of the field represented in the lower part of the retina (Fig. 13-3). Figure 13-5 illustrates the retinal projections to the geniculate nuclei and occipital cortex.

Testing for Abnormalities of the Visual Fields

Figure 13-3 illustrates the visual field defects caused by lesions of the retina, optic nerve and tract, lateral geniculate body, geniculocalcarine pathway, and striate cortex of the occipital lobe. In the alert, cooperative patient, the visual fields can be plotted fairly accurately at the bedside. With one of the patient's eyes covered and the other fixed on the corresponding eye of the examiner (patient's right with examiner's left), a target—such as a moving finger, a cotton pledget, or a white disc mounted on a stick—is brought from the periphery toward the center of the visual field (confrontational testing). With the target at an equal distance between the eye of the examiner and that of the patient, the fields of the patient and examiner are then compared. Similarly, the patient's blind spot can be aligned with the examiner's, and its size determined by moving a small target outward from the blind spot until it is seen. Central and paracentral defects in the field can be outlined the same way. For reasons not known, red-green test objects are more sensitive than white ones in detecting defects of the visual pathways.

It should be emphasized that movement of the visual target provides the coarsest stimulus to the retina, so that a perception of its motion may be preserved while a stationary target of the same size may not be seen. In other words, moving targets are less useful than static ones in confrontational testing of visual fields. Finger counting and comparison of color intensity of a red object or the clarity of the examiner's hand from quadrant to quadrant are simple confrontation tests that will disclose most field defects. Glaser recommends presenting the examiner's hands simultaneously, one on each side of the vertical meridian; the hand in the hemianopic field appears blurred or darker than the other. Similarly, a scotoma may be defined by asking the patient to report changes in color or brightness of a red test object as it is moved toward or away from the point of fixation. Similarly, a central scotoma may be identified by having the patient fix with one eye on the examiner's nose, on which the examiner places the index finger of one hand or a white-headed pin and has the patient compare it for brightness, clarity, and color with a finger or pin held in the periphery.

We continue to teach that these confrontation techniques are reasonably sensitive for routine clinical work if performed carefully, but we are chastened by the article from Pandit and colleagues, who found false-negative findings in 42 percent of patients tested with quadrant finger counting, using static automated perimetry as a standard. If any defect is found or suspected by confrontational testing, the fields should be charted and scotomas outlined on a tangent screen or perimeter. Accurate computer-assisted perimetry is now available in most ophthalmology clinics. Although the commonly used automated techniques encompass only the central visual field, this is adequate to detect most clinically important changes.

The method of testing by double simultaneous stimulation may elicit defects in the central processing of vision that are undetected by conventional perimetry. Movement of one finger in all parts of each temporal field may disclose no abnormality, but if movement is simultaneous in analogous parts of both temporal fields, the patient with a parietal lobe lesion, especially on the right, may perceive only the one in the normal right hemifield. In young children or uncooperative patients, the integrity of the fields may be roughly estimated by observing whether the patient is attracted to objects in the peripheral field or blinks in response to sudden threatening gestures in half of the visual field.

A type of abnormality disclosed by visual field examination is concentric constriction. This may be a result of severe papilledema, in which case it is usually accompanied by an enlargement of the blind spot. A progressive constriction of the visual fields, at first unilateral and later bilateral, associated with pallor of the optic discs (optic atrophy), should suggest a chronic meningeal process involving the optic nerves (syphilis, cryptococcosis, sarcoidosis, lymphoma). Long-standing, untreated glaucoma and retinitis pigmentosa are other causes of concentric constriction. Marked constriction of the visual fields of unvarying degree, regardless of the distance of the visual stimulus from the eye ("gun-barrel" or "tunnel" vision), however, is a sign of hysteria. With organic disease, the constricted visual field naturally enlarges as the distance between the patient and the test object increases.

A regional constriction of the field, especially in a nasal quadrant, usually signifies early optic atrophy, as mentioned earlier; it is the first sign that chronic papilledema is threatening the patient's vision.

Prechiasmal Lesions

Lesions of the macula, retina, or optic nerve cause a scotoma (an island of impaired vision surrounded by normal vision) rather than a defect that extends to the periphery of one visual field ("field cut"). Scotomas are named according to their position (central, cecocentral) or their shape (ring, arcuate). A small scotoma that is situated in the macular part of the visual field may seriously impair visual acuity.

Scotomas are the main features of optic neuropathy, the main causes of which were discussed earlier and are listed in Table 13-3. Demyelinatng disease (optic neuritis), Leber hereditary optic atrophy, toxins and nutritional deficiencies, and vascular disease (ischemic optic neuropathy or occlusion of a branch of the retinal artery) are the main ones. Orbital or retroorbital tumors and infectious or granulomatous processes (e.g., sarcoidosis, retinal toxoplasmosis in AIDS) are other common causes. In the elderly, there may be compression of the optic nerve by a dolichoectatic aneurysm of the carotid, ophthalmic, or basilar arteries.

As discussed earlier, certain toxic and malnutritional states are characterized by more or less symmetrical bilateral central scotomas (involving the fixation point), or cecocentral ones (involving both the fixation point and the blind spot). The cecocentral scotoma, which tends to have an arcuate border, represents a lesion that is predominantly in the distribution of the papillomacular bundle. However, the presence of this visual field abnormality does not establish whether the primary defect is in the cells of the origin of the bundle, i.e., the retinal ganglion cells, or in their fibers. Demyelinating disease is characterized by unilateral or asymmetrical bilateral scotomas. Vascular lesions that take the form of retinal hemorrhages or infarctions of the nerve-fiber layer (cotton-wool patches) give rise to unilateral scotomas; occlusion of the central retinal artery or its branches causes infarction of the retina and, as a rule, a loss of central vision, while occlusion of a branch of the retinal artery may cause an altitudinal defect. As pointed out earlier, AION causes sudden monocular blindness, or an altitudinal field defect. Since the optic nerve also contains the afferent fibers for the pupillary light reflex, extensive lesions of the nerve will cause an afferent pupillary defect, which was mentioned earlier and is considered further in Chap. 14.

Lesions of the Chiasm, Optic Tract, and Geniculocalcarine Pathway

Hemianopia (hemianopsia) means blindness in half of the visual field. Bitemporal hemianopia indicates a lesion of the decussating fibers of the optic chiasm and is caused most often by the suprasellar extension of a tumor of the pituitary gland (Fig. 13-3C). It may also be the result, at this same site, of a craniopharyngioma, a saccular aneurysm or dolichoectatic artery of the anterior circle of Willis, and a meningioma of the tuberculum sellae; less often, it may be a result of sarcoidosis, metastatic carcinoma, ectopic pinealoma or dysgerminoma, Hand-Schüller-Christian disease, or hydrocephalus with dilatation and downward herniation of the anterior part of the third ventricle (Corbett). In some instances a tumor pushing upward presses the medial parts of the optic nerves, just anterior to the chiasm, against the anterior cerebral arteries. Chiasmal syndromes from causes other than pituitary adenoma are usually associated with unilateral optic disc atrophy, a relative afferent pupillary defect and a greater defect in the inferior field.

Heteronymous field defects, i.e., scotomas or field defects that differ in the two eyes, are a sign of involvement of the optic chiasm or the adjoining optic nerves or tracts; they are caused by craniopharyngiomas, or other suprasellar tumors and, rarely, by mucoceles, angiomas, giant carotid aneurysms, and opticochiasmic arachnoiditis.

The visual field pattern created by a lesion in the optic nerve as it joins the chiasm typically includes a scotomatous defect on the affected side coupled with a contralateral superior quadrantanopia ("junctional field defect"). As noted previously, the latter is caused by interruption of nasal retinal fibers from the contralateral optic nerve. This was originally attributed to fibers projecting into the base of the affected optic nerve but there is now evidence against the existence of this structure as mentioned earlier, and discussed in the reference by Horton. Variations in the pattern of visual loss from chiasmal lesions are frequent, in part accounted for by the location of the chiasm in an individual patient—a postfixed chiasm making unilateral eye findings more common.

Homonymous hemianopia (a loss of vision in corresponding halves of the visual fields) signifies a lesion of the visual pathway behind the chiasm and, if complete, gives no more information than that. Incomplete homonymous hemianopia has more localizing value. As a rule, if the field defects in the two eyes are identical (congruous), the lesion is likely to be in the calcarine cortex and subcortical white matter of the occipital lobe; if they are incongruous, the visual fibers in the optic tract or in the parietal or temporal lobe are more likely to be implicated. Absolute congruity of field defects is actually infrequent, even with occipital lesions.

The lower fibers of the geniculocalcarine pathway (from the inferior retinas) swing in a wide arc over the temporal horn of the lateral ventricle and then proceed posteriorly to join the upper fibers of the pathway on their way to the calcarine cortex (Fig. 13-3). This arc of fibers is known variously as the Flechsig, Meyer, or Archambault loop, and a lesion that interrupts these fibers will produce a superior homonymous quadrantanopia (contralateral upper temporal and ipsilateral upper nasal quadrants; Fig. 13-3E), or in incomplete cases, a homonymous superior wedge defect respecting the vertical meridian. This clinical effect was first described by Harvey Cushing, so that his name also was in the past applied to the loop of temporal visual fibers. Parietal lobe lesions are said to affect the inferior quadrants of the visual fields more than the superior ones, but this is difficult to document; with a lesion of the right parietal lobe, the patient ignores the left half of space; with a left parietal lesion, the patient is often aphasic. As to the localizing value of quadrantic defects, the report of Jacobson is of interest; he found, in reviewing the imaging studies of 41 patients with inferior quadrantanopia and 30 with superior quadrantanopia, that in 76 percent of the former and 83 percent of the latter the lesions were confined to the occipital lobe.

If the entire optic tract or calcarine cortex on one side is destroyed, the homonymous hemianopia is complete. But often that part of the field subserved by the macula is spared, i.e., there is a 5- to 10-degree island of vision around the fixation point on the side of the hemianopia (sparing of fixation, or macular sparing). With infarction of the occipital lobe as a result of occlusion of the posterior cerebral artery, the macular region, represented in the most posterior part of the striate cortex, may be spared by virtue of collateral circulation from branches of the middle cerebral artery. With other types of destructive lesions, this effect is not seen. Incomplete lesions of the optic tract and radiation also usually spare central (macular) vision. Nonvascular lesions of both occipital poles result in bilateral central scotomas; if all the calcarine cortex or all the subcortical geniculocalcarine fibers on both sides are completely destroyed, the bilateral hemianopias cause cerebral, or "cortical," blindness (see below and Chap. 22).

An altitudinal defect is one that is confined by a horizontal border and crosses the vertical meridian. Homonymous altitudinal hemianopia is usually caused by lesions of both occipital lobes below or above the calcarine sulcus, and rarely to a lesion of the optic chiasm or nerves. Just as with the contralateral representation of the visual fields in respect to the vertical meridian, the representation of the upper visual field is in the bank of neurons below the calcarine fissure and vice versa. The most common cause of this rare phenomenon is still occlusion of both posterior cerebral arteries. Herniation of the occipital lobe over the tentorial margin can produce a homonymous superior altitudinal defect by selectively compressing the inferior branches of the posterior cerebral arteries. A monocular altitudinal hemianopia, by contrast, is almost invariably an ischemic optic neuropathy that arises from occlusion of the posterior ciliary vessels.

In certain instances of homonymous hemianopia, the patient is capable of some visual perception in the hemianopic fields, a circumstance that permits the study of the vulnerability of different visual functions. Colored targets may be detected in the hemianopic fields, whereas achromatic ones cannot. But even in seemingly complete hemianopic defects, in which the patient admits to being blind, it has been shown that he may still react to visual stimuli when forced-choice techniques are used. Blythe and coworkers found that 20 percent of their patients with no ability to discriminate patterns in the hemianopic field nonetheless could still reach accurately and look at a moving light in the "blind" field. This type of residual visual function has been called "blindsight" by Weiskrantz and colleagues. These residual visual functions are generally attributed to the preserved function of retinocollicular or geniculoprestriate cortical connections, but in some cases, they may be a result of sparing of small islands of calcarine neurons. In yet other instances of complete homonymous hemianopia, the patient may be little disabled by visual field loss (Benton et al; Meienberg). This is because of preservation of vision in a small monocular part of the visual field known as the temporal crescent. The latter is a peripheral unpaired portion of the visual field, between 60 and 100 degrees from the fixation point, and is represented in the most anterior part of the visual striate cortex. In particular, the temporal crescent is sensitive to moving stimuli, allowing the patient to avoid collisions with people and objects. The tendency for patients with occipital lesions to have greater sensitivity for kinetic stimuli than for static ones was described by Riddoch in 1917.

Blindness in the Hysterical or Malingering Patient

Hysterical, or psychogenic blindness, is described in Chap. 51, along with other features of hysteria, but a few comments are in order here. Feigned or hysterical visual loss is usually detected by attending to the patient's activities when he thinks he is unobserved, and it can be confirmed by a number of simple tests. Complete feigned blindness is disproved by observing the normal ocular jerk movements in response to a rotating optokinetic drum or strip, or by noting that the patient's eyes follow their own image in a mirror that is moved in front of them. The hysterical nature of total monocular blindness is apparent from the presence of a normal direct pupillary response to light. An optokinetic response in the nonseeing eye (with the good eye covered) is an even more convincing test. The visual evoked potential from the allegedly blind eye is also normal. Hysterical monocular loss may also be revealed by the use of red-green glasses and an acuity chart with red and green letters, where each eye can only see letters with the color of its lens. The patient cannot tell which letters should be visible to them, and the intact acuity in the involved eye is soon exposed. Hysterical homonymous hemianopia is rare and is displayed mostly by practiced malingerers; all manner of field defects are common in this population (Keane). The uniformly constricted tubular field defect of hysteria has already been mentioned. Star- and spiral-shaped visual fields are also indicative of psychogenic visual loss.

Cerebral Forms of Blindness and Visual Agnosia (See Also Chap. 22)

The ability to recognize visually presented objects and words depends on the integrity not only of the visual pathways and primary visual area of the cerebral cortex (area 17 of Brodmann) but also of those cortical areas that lie just anterior to area 17 (areas 18 and 19 of the occipital lobe and area 39—the angular gyrus of the dominant hemisphere). Blindness that is the result of destruction of both visual and adjacent regions of the occipital lobes is termed cortical or cerebral blindness. Another remarkable condition exists in which the patient denies or is oblivious to blindness despite overt manifestations of the defect (Anton syndrome).

In distinction to these forms of blindness, there is a less-common category of visual impairment in which the patient cannot understand the meaning of what he sees, i.e., visual agnosia. Primary visual perception is more or less intact, and the patient may accurately describe the shape, color, and size of objects and draw copies of them. Despite this, he cannot identify the objects unless he hears, smells, tastes, or palpates them. The failure of visual recognition of words alone is called visual verbal agnosia, or alexia. Visual-object agnosia rarely occurs as an isolated finding: as a rule, it is combined with visual verbal agnosia, homonymous hemianopia, or both. These abnormalities arise from lesions of the dominant occipital cortex and adjacent temporal and parietal cortex (angular gyrus) or from a lesion of the left calcarine cortex combined with one that interrupts the fibers crossing from the right occipital lobe (see Fig. 22-6). In the latter case, fibers responsible for writing are spared, and the patient remains with a syndrome of alexia without agraphia.

Failure to understand the meaning of an entire picture even though some of its parts are recognized is referred to as simultanagnosia, and is found in bilateral lesions of the occipital–parietal junction. When combined with deficits in visual control of eye and hand movements (optic ataxia and ocular apraxia), the resulting condition is referred to as Balint syndrome. A failure to recognize familiar faces is called prosopagnosia and typically results from occipital–temporal lesions. These and other variants of visual agnosia (including visual neglect) and their pathologic bases are dealt with more fully in Chap. 22.

Other cerebral disturbances of vision include various types of distortion in which images seem to recede into the distance (teleopsia), appear too small (micropsia), or, less frequently, seem too large (macropsia). If such distortions are perceived with only one eye, a local retinal lesion should be suspected. If perceived with both eyes, they usually signify disease of the temporal lobes, in which case the visual disturbances tend to occur in attacks and are accompanied by other manifestations of temporal lobe seizures (see Chap. 16). Palinopsia, a persistence of repetitive afterimages, similar to the appearance of a celluloid movie strip, occurs with right parietooccipital lesions; it has been a consequence of seizures in the cases we have encountered, but instances associated with static disorders (tumor, infarction) have been described as well. Patients describe the images as "trailing" or "echoing." With parietal lobe lesions, objects may appear to be askew or even turned upside down. More often, lesions of the vestibular nucleus or its immediate connections produce the illusion that objects are tilted or turned upside down (tortopsia), or that straight lines are curved. Presumably this is the result of a mismatch between the visual image and the otolithic, or vestibular input to the visual system.

Abnormalities of Color Vision

Normal color vision depends on the integrity of cone cells, which are most numerous in the macular region. When activated, they convey information to special columns of cells in the striate cortex. Three different cone pigments with optimal sensitivities to blue, green, and orange-yellow wavelengths are said to characterize these cells; presumably each cone possesses only one of these pigments. Transmission to higher centers for the perception of color is effected by neurons and axons that encode at least two pairs of complementary colors: red-green in one system and yellow-blue in the other. In the optic nerves and tracts, the fibers for color are of small caliber and seem to be preferentially sensitive to certain noxious agents and to pressure. The geniculostriate fibers for color are separate from fibers that convey information about form and brightness, but course alongside them; hence, there may be a homonymous color hemianopia (hemiachromatopsia). The visual fields for blue-yellow are smaller than those for white light, and the red and green fields are smaller than those for blue-yellow.

Diseases may affect color vision by abolishing it completely (achromatopsia) or partially by quantitatively reducing one or more of the three attributes of color—brightness, hue, and saturation. Or, only one of the complementary pairs of colors may be lost, usually red-green. The disorder may be congenital and hereditary or acquired. The most common form, and the one to which the term color blindness is usually applied, is a male sex-linked inability to see red and green while normal visual acuity is retained. The main problem arises in relation to traffic lights, but patients learn to use the position of the light as a guide. Several other genetic abnormalities of cone pigments and their phototransduction have been identified as causes of achromatopsia. The defect cannot be seen by inspecting the retina. A failure of the cones to develop or a degeneration of cones may cause a loss of color vision, but in these conditions visual acuity is often diminished, a central scotoma may be present, and, although the macula also appears to be normal ophthalmoscopically, fluorescein angiography shows the pigment epithelium to be defective. Whereas congenital color vision defects are usually protan (red) or detan (green), leaving yellow-blue color vision intact, most acquired lesions affect all colors, at times disparately. Lesions of the optic nerves usually affect red-green more than blue-yellow; the opposite is true of retinal lesions. An exception is a rare, dominantly inherited, optic atrophy, in which the scotoma mapped by a large blue target is larger than that for red.

Damasio has drawn attention to a group of acquired deficits of color perception with preservation of form vision, the result of focal damage (usually infarction) of the visual association cortex, and subjacent white matter. Color vision may be lost in a quadrant, half of the visual field, or the entire field. The latter, or full-field achromatopsia, is the result of bilateral occipitotemporal lesions involving the fusiform and lingual gyri, a localization that accounts for its frequent association with visual agnosia (especially prosopagnosia), and some degree of visual field defect. A lesion restricted to the inferior part of the right occipitotemporal region, sparing both the optic radiations and striate cortex, causes the purest form of achromatopsia (left hemiachromatopsia). With a similar left-sided lesion, alexia may be associated with the right hemiachromatopsia.

Other Visual Disorders

In addition to the losses of perception of form, movement, and color, lesions of the visual system may also give rise to a variety of positive sensory visual experiences. The simplest of these are called phosphenes, i.e., flashes of light and colored spots in the absence of luminous stimuli. Mechanical pressure on the normal eyeball may induce them at the retinal level, as every child discovers. Or they may occur with disease of the visual system at many different sites. As mentioned earlier, elderly patients commonly complain of flashes of light in the peripheral field of one eye, most evident in the dark (Moore lightning streaks); these are related to vitreous tags that rest on the retinal equator, and may be quite benign, or may be residual evidence of retinal detachment. Cancer associated retinopathy is frequently associated with photopsias prior to visual loss. Retinal toxicity from digitalis causes chromatopsia with a characteristic "yellowish vision" and may also cause photopsias. In patients with migraine, activation of nerve cells in the occipital lobe, gives rise to the bright zigzag lines of a fortification spectrum. Stimulation of the cortical terminations of the visual pathways accounts for the simple or unformed visual hallucinations in epilepsy. Formed or complex visual hallucinations (of people, animals, landscapes) are observed in a variety of conditions, notably in old age when vision fails (Charles Bonnet syndrome, discussed in "Visual Hallucinations" in Chap. 22), in the withdrawal state following chronic intoxication with alcohol and other sedative-hypnotic drugs (see Chaps. 42 and 43), in Alzheimer disease, and in infarcts of the occipitoparietal or occipitotemporal regions (release hallucinations) or the diencephalon ("peduncular hallucinosis"). These disorders are also discussed in Chap. 22.

Occasionally, patients in whom a hemianopia is evident only when tested by double simultaneous stimulation (a component of visual neglect) may displace an image to the non-affected half field (visual allesthesia), or a visual image may persist for minutes to hours or reappear episodically, after the exciting stimulus has been removed (palinopsia or paliopsia mentioned earlier); the latter disorder also occurs in defective but not blind homonymous fields of vision. Polyopia, the perception of multiple images when a single stimulus is presented, is said to be associated predominantly with right occipital lesions and can occur with either eye. Usually there is one primary and a number of secondary images, and their relationships may be constant or changing. Bender and Krieger, who described several such patients, attributed the polyopia to unstable fixation. When this is monocular, there is either a defect in the lens or, more often, hysteria. Oscillopsia, or illusory movement of the environment, is a perception caused by nystagmus and occurs mainly with lesions of the labyrinthine-vestibular apparatus; it is described with disorders of ocular movement. A rare idiopathic myokymia of one superior oblique muscle may produce a monocular oscillopsia (see "Fourth Nerve Palsy" in Chap. 14).

Chapter 22 further discusses the clinical effects and syndromes that result from occipital lobe lesions.

Amblyopia Because of Early Life Strabismus (Amblyopia Ex Anopsia)

As noted in the introductory part of this chapter, the generic term "amblyopia" has been adopted for a special circumstance in which a normal eye fails to acquire its potential visual acuity because images are not properly projected onto the fovea during a formative period of cerebral development. It is a disorder, as in the quip by van Noorden and Campos, "in which the patient sees nothing and the doctor sees nothing." The period of risk is during the first 7 years but is greatest in the earlier part of this epoch, and the visual loss may still be rectifiable beyond the time.

The degradation of vision and disuse of the fovea may be the result of a number of processes, most often misaligned ocular axes (strabismus) and also including unequal refractive errors (anisometropia; discussed in Chap. 14). These conditions are the most common sources of visual disturbance in children. The uncorrected condition also accounts for an estimated 3 percent of monocular visual loss in adults. By convention, the diagnosis of amblyopia requires that a loss of 2 lines or more between eyes be observed on the Snellen chart.

The developmental deficiency in the occipital cortex that gives rise to amblyopia has been extensively studied in animals and humans; a discussion of the subject can be found in numerous texts including the one by van Noorden and Campos. Neurologists should be aware that screening children for the disorder is highly valuable even if treatment is not always successful. The correction of refractive errors, cataract, and other correctible ocular problems are attended to first. Attempts are then made to force the utilization of the disadvantaged eye in preference to the normal one; patching and atropine drops are the typical methods to accomplish this. Other techniques of management and a summary of clinical trials of each can be found in the review by Holmes and Clarke. Chapter 14 discusses the problem of strabismus and the latent phorias that create confusion in the neurologic examination.