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.
Appearance of the fundus in central retinal artery occlusion. In addition to the paucity of blood flow in retinal vessels, the retina has a creamy gray appearance, and there is a "cherry-red spot" at the fovea. (Courtesy of Dr. Shirley Wray.)
Glistening "Hollenhorst plaque" occlusion of a superior retinal artery branch (arrow). These occlusions represent atheromatous particles or, less often, platelet-fibrin emboli. Some are asymptomatic and others are associated with segmental visual loss or are seen after central retinal artery occlusion. (Courtesy of Dr. Shirley Wray.)
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.
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.
Occlusion of the central retinal vein with suffusion of the veins, swelling of the disc, and florid retinal hemorrhages. (Courtesy of Dr. Shirley Wray.)
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.
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.
Table 13-2 Causes of Optic Disc Swelling ||Download (.pdf)
Table 13-2 Causes of Optic Disc Swelling
Increased intracranial pressure
None or transient blurring; constriction of visual fields and enlargement of blind spot; findings almost always binocular
Headache; signs of intracranial mass
Normal unless succeeded by optic atrophy
Anterior ischemic optic neuropathy
Infarction of disc and intraorbital optic nerve due to atherosclerosis or temporal arteritis
Acute visual loss, monocular (usually); may be an altitudinal defect
Headache with temporal arteritis
Afferent pupillary defect
Optic neuritisa ("papillitis")
Inflammatory changes in disc and intraorbital part of optic nerve—usually due to MS, sometimes to ADEM
Rapidly progressive visual loss; usually monocular
Tender globe, pain on ocular movement
Afferent pupillary defect
Hyaline bodiesb (drusen)
Usually none but may be slowly progressive
Enlargement of blind spot or arcuate inferior nasal defect
Usually none; rarely transient visual obscurations
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.
Mild papilledema with hyperemia of the disc and slight blurring of the disc margins. (Courtesy of Dr. Shirley Wray.)
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.
Fully developed papilledema. The main characteristics are marked swelling and enlargement of the disc, vascular engorgement, obscuration of small vessels at the disc margin as a result of nerve-fiber edema, and white "cotton-wool spots" that represent superficial infarcts of the nerve-fiber layer. (Courtesy of Dr. Shirley Wray.)
Chronic papilledema with beginning optic atrophy, in which the disc stands out like a champagne cork. The hemorrhages and exudates have been absorbed, leaving a glistening residue around the disc. (Courtesy of Dr. Shirley Wray.)
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.
Table 13-3 Causes of Unilateral and Bilateral Optic Neuropathy ||Download (.pdf)
Table 13-3 Causes of Unilateral and Bilateral Optic Neuropathy
I. Demyelinative (optic neuritis)
Postinfectious and viral neuroretinitis
Arteriosclerotic (usually in-situ occlusion; occasionally carotid artery disease)
Granulomatous (giant cell) arteritis
Cavernous sinus thrombosis
Paranasal sinus infection
IV. Toxins and drugs
V. Deficiency states
Thiamine or possibly several B vitamins ("tobacco-alcohol" amblyopia)
Epidemic nutritional types (Cuban, Jamaican)
VI. Heredofamilial and developmental
Dominant juvenile optic atrophy
Leber optic atrophy
Developmental failure of disc or papillomacular bundle
Progressive hyaline body encroachment
VII. Compressive and infiltrative
Meningioma of sphenoid wing or olfactory groove
Metastasis to optic nerve or chiasm
Glioma of optic nerve (neurofibromatosis type I)
Optic atrophy following long-standing papilledema
Pituitary tumor and apoplexy
VIII. Radiation-induced optic neuropathy
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.
Acute optic neuritis in a patient with multiple sclerosis. The disc is swollen from an inflammatory process near the nerve head (papillitis), and the patient is virtually blind in the affected eye.
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.
Anterior ischemic optic neuropathy (AION) related to hypertension and diabetes. There is diffuse disc swelling from infarction that extends into the retina as a milky edema. The veins are engorged. "Cotton-wool" infarcts can be seen to the left of the disc and a "flame" hemorrhage extends from the right disc margin.
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).
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.