Cellular Elements of the Retina

The retina is a transparent structure that arises from the inner and outer layers of the embryologic optic cup. The outer layer consists of the retinal pigment epithelium (RPE), and the inner layer is a multicellular layer that makes up the neurosensory retina. The RPE consists of hexagonal cells extending from the optic nerve to the ora serrata. The major functions of the RPE are to maintain the photoreceptors through vitamin A metabolism and phagocytosis of photoreceptor outer segments. Other functions include maintenance of the outer blood–retina barrier, heat and light absorption, and production of extracellular matrix. The basal aspect of the RPE cells forms the inner layer of Bruch’s membrane, separating the retina from the choroid. Separation of the RPE from the neurosensory retina is called a retinal detachment.

The neurosensory retina consists of neural, glial, and vascular elements. The outermost layer of the retina (furthest from the cornea and closest to the RPE) is the photoreceptor layer, consisting of rods and cones. The outer segments of the photoreceptors make contact with the RPE cells. The cell bodies of the photoreceptors make up the outer nuclear layer and are in contact with horizontal and bipolar cells through their process in the outer plexiform layer. The bipolar cells are oriented more vertically and bridge the connection to the inner plexiform layer, where they synapse with ganglion cells and amacrine cells. The cell bodies of the bipolar cells, horizontal cells, and amacrine cells make up the inner nuclear layer, located between the inner and outer plexiform layer. The ganglion cell axons run parallel to the surface of the retina and form the nerve fiber layer. The major glial cell of the retina is the Mueller cell, whose nucleus is in the inner nuclear layer and whose processes extend from the surface of the retina (inner limiting membrane) to the end of the outer nuclear layer (external limiting membrane). Together with some astrocytes and microglia these cells provide the nutritional and structural support to the retina.

Blood Supply

The first major branch of the internal carotid artery, the ophthalmic artery, provides the blood supply of the retina. It gives rise to the central retinal artery, which supplies the inner two-thirds of the retina, and the posterior ciliary arteries, which supply the outer portions of the retina ( Fig. 4.1 ). The temporal blood vessels arc above and below the macula along with the arcuate nerve fiber bundles (ganglion cell axons). The vessels are found in the inner retinal layers and usually do not extend deeper than the inner plexiform layer. The outer retinal layers (photoreceptors and RPE) receive their oxygen and nutrients through diffusion from the vascular supply in the choroid. There is a capillary-free zone of approximately 400 µm in the fovea called the foveal avascular zone where an absence of vascular elements is best for optimal visual acuity. At arteriovenous crossings, the arteries lie over the veins and share a basement membrane. This crossing, along with pathologic changes in the arteriole walls, may be the basis for retinal vein occlusion. The central retinal vein lies temporal to the central retinal artery in the optic nerve head and eventually drains into the superior orbital vein and cavernous sinus. The retinal blood vessels, like the cerebral blood vessels, are responsible for maintenance of the blood–retina barrier. This is accomplished through tight junctions between endothelial cells. The retinal blood vessels do not have smooth muscles or an internal elastic lamina.

A lateral view of the orbit, showing the arterial circulation, globe, and lacrimal gland. The blood supply of the retina and optic nerve derives from the ophthalmic artery, which gives rise to the central retinal artery (which enters the optic nerve about 1 cm from the nerve–globe junction and travels within it to the optic nerve head and the retina) and the medial and lateral posterior ciliary arteries, which in turn supply the choriocapillaris and optic nerve head.

A cilioretinal artery arises from the choroidal circulation and is present in about 20% of individuals (see Fig. 4.11 for an example of a cilioretinal artery). The blood supply of the choroid is from the ophthalmic artery via the branches of the anterior and posterior ciliary arteries. Branches of these arteries form discrete capillary lobules of circulation. The choroid drains through the vortex veins and then into the superior and inferior orbital veins into the cavernous sinus. The separate drainage pathway for the retina (central vein) and choroid (vortex veins) provides the anatomic basis for the development of collateral vessels in certain conditions. Pathologic processes that cause central vein obstruction (e.g., central retinal vein occlusion (CRVO), papilledema, optic nerve sheath meningioma) can cause collateral or “shunt” vessels to develop between the retinal veins at the optic nerve head and the choroidal circulation.

Other details of the internal carotid and ophthalmic artery blood supply are discussed in Chapters 5 and 10 .

Symptoms

The presence of metamorphopsia or photopsia is indicative of retinal disease. Patients with metamorphopsia describe distortion of images, while those with photopsia complain of seeing sparkles of light. Both of these symptoms are very unusual in optic neuropathies unless accompanied by macular edema or subretinal fluid. The complaint of light blindness or abnormal glare sensitivity (hemeralopia) also suggests the presence of retinal dysfunction and may be a prominent symptom in patients with cone dysfunction. In contrast, patients who detect a darkening of their vision or loss of color perception usually have optic nerve disease. Night vision loss, or nyctalopia, can commonly accompany widespread retinal photoreceptor disease. Pain in association with vision loss is exceedingly uncommon in patients with retinal problems and is more characteristic of inflammatory optic neuropathies.

Signs

Although loss of visual acuity is common in optic nerve and retinal conditions, color vision impairment is more prominent in optic neuropathies. Similarly, when visual acuity is poor yet color vision is preserved, macular disease is much more likely. Two exceptions to this important clinical observation include patients with cone degenerations, who typically have very poor color vision, and patients with ischemic optic neuropathy, who may maintain excellent color vision in their intact visual field.

Photostress testing can be helpful in identifying patients with maculopathies. In macular disease there can be a prolonged recovery time of the photoreceptor visual pigments after bright light exposure. The test, which is described in more detail in Chapter 2 , is performed by shining a bright light in the eye; a prolonged recovery time for visual acuity in the affected eye compared with the unaffected eye is considered a positive result. Patients with optic neuropathy will not have a prolonged recovery time after photostress.

The presence of an afferent pupillary defect (APD) also strongly suggests the presence of optic nerve disease, although widespread and asymmetric retinal dysfunction can give rise to an APD as well. In addition, visual field testing may be useful in distinguishing optic neuropathies and maculopathies. Both entities may be associated with central or centrocecal scotomas, although the presence of the latter field deficit favors optic nerve disease. Midperipheral, ring-type scotomas are typical of retinal dysfunction, but blind spot enlargement can be seen in either. Optic nerve–type field defects are reviewed in Chapter 5 , and they usually assume characteristic patterns that respect the organization of the nerve fiber bundles. However, on automated visual field testing, both optic nerve and retinal disease may produce generalized depression of the visual field, which does not distinguish between the two conditions.

Ophthalmoscopic examination of the optic nerve and macula is key to distinguishing optic neuropathies from maculopathies. In general, abnormalities will be identified in almost all patients with significant macular or optic nerve disease. Macular lesions that produce subretinal fluid, exudates, pigmentary changes, atrophy, or hemorrhage are usually visible on fundus examination. Optic nerve atrophy with or without nerve fiber layer dropout can also be observed on ophthalmoscopy, particularly when using the green filter light and by OCT. Significant overlap may exist in the early phases of an optic neuropathy when pallor has not yet developed or in the later phases of retinal disease when mild optic disc pallor may be associated with widespread retinal disease.

Ancillary Testing

In some patients in whom it is difficult to distinguish between optic nerve and retinal disease due to ocular media disturbance or various other comorbidities, spectral domain (SD)–OCT is a useful noninvasive imaging technique that provides high resolution cross-sectional images of the retina, the retinal nerve fiber layer and the optic nerve head by using low coherence interferometry. With axial resolution in the 5–7 µm range, the various layers of the retina can be resolved ( Fig. 4.2 ), and pathologies such as retinal edema, macular hole, choroidal neovascularization, vitreoretinal interface abnormalities, and abnormal retinal thinning or thickening can be easily identified.

Spectral domain ocular coherence tomography section of a normal human retina. See Fig. 5.10 for a diagram with labeling of the layers of the retina.

Fundus autofluorescence (FAF) is a noninvasive method for identifying pathologic changes and disease states of the retina and RPE. The degradation products of the RPE and photoreceptors, such as lipofuscin deposits and melanin, may alter the normal FAF. This technique is useful in identifying outer retinopathies (idiopathic blind spot enlargement syndrome or multiple evanescent white dot syndrome (MEWDS), for example) that may be more difficult to detect on ophthalmoscopy.

Traditional fluorescein angiography (FA) is helpful in identifying ocular perfusion abnormalities such as capillary nonperfusion in those with diabetic retinopathy, cystoid macular edema (CME), or leakage from choroidal neovascularization. FA can also be used to demonstrate blood flow abnormalities, including delayed arterial venous transit time in conditions affecting ocular perfusion, impaired choroidal circulation in giant cell arteritis, and occult arterial occlusions in Susac syndrome. FA may also show blood vessel wall staining and leakage in patients with retinal vasculitis.

Electroretinography (ERG) is another useful diagnostic tool, particularly for patients who present with unexplained vision loss in the presence of a normal-appearing fundus and in whom rod and cone photoreceptor dysfunction is suspected. The ERG is usually recorded using a corneal contact lens, and the signal is evoked from the retina using a flash of light. The recording is characterized by a negative waveform (a-wave) that represents the response of the photoreceptors and a positive waveform (b-wave) that is generated by a combination of cells including the Mueller and bipolar cells. The ERG is recorded under scotopic and photopic conditions to isolate the rod and cone responses. The cone-mediated response (photopic) is obtained by keeping the patient light-adapted and using a bright flash to evoke the response. In this setting the rods are bleached and do not contribute to the waveform. The rod-mediated response (scotopic) is recorded after a prolonged period of dark adaptation and evoked with a dim light that is below the threshold of the cones. The a-wave is greatly reduced in scotopic conditions. Cone responses can also be isolated using a flickering light (30 cycles/second) since the rods cannot respond at that rate. While full-field ERG is helpful for detection of diffuse retinal disease, multifocal ERG can be used to detect subtle or more localized macular or perimacular retinal dysfunction.

Despite extensive evaluation, it may be impossible to localize the cause of the patient’s vision loss. In this setting it is important to consider the possibility of nonorganic or functional vision loss. When doubt exists about the cause of the visual loss, one should consider screening the patient for the treatable causes of optic nerve dysfunction, including mass lesions, infections, and nutritional processes.

Central Serous Chorioretinopathy

Central serous chorioretinopathy (CSCR) results from abnormal leakage of fluid from the RPE into the subretinal spaces. It is a disorder that often affects young men, classically those with “type A” personalities, and women during pregnancy. Other etiologies associated with CSCR include use of systemic steroids, psychopharmacologic medications, systemic hypertension, and immune suppression in organ transplantation. The patient may complain of sudden central visual loss, distortion, and metamorphopsia. On examination, there is reduced visual acuity and a central scotoma on visual field testing. An afferent pupil defect is usually not seen. The diagnosis is established ophthalmoscopically, and OCT and FA may demonstrate a serous detachment of the neurosensory retina, sometimes associated with serous RPE detachment (see Fig. 4.4 ). On the FA there is a single pinpoint leak that is identified at the level of the RPE. Retrobulbar optic neuritis may be confused with CSCR when the ophthalmoscopic findings are subtle.

Cystoid Macular Edema

CME most commonly occurs after cataract surgery but may present in ocular inflammatory disease, macular degeneration, and diabetic retinopathy. Metamorphopsia is a common complaint. Small, shallow central visual field defects are common, and some patients will struggle with the color plates, although they do not have true dyschromatopsia. CME may be “ophthalmoscopically occult.” In these cases, the thickening or elevation of the macula may be very subtle, and the typical cysts may either be absent or difficult to see.

FA and OCT are usually very helpful in identifying patients with CME not recognized by ophthalmoscopy (see Fig. 4.5 ). However, patients with resolved CME but persisting reduced vision may be difficult to diagnose, because only mild pigmentary changes may be evident.

Diabetic Ischemic Maculopathy

Macular edema is responsible for central vision loss in most patients with diabetic retinopathy. However, diabetic maculopathy, which may be associated with either nonproliferative or proliferative retinopathy, can be of exudative or ischemic types. Closure of retinal capillaries is an early microvascular manifestation of diabetic retinopathy. Fortunately, this is usually not associated with significant vision loss. However, if the closure involves the arterioles, and the foveal avascular zone increases to 1000 µm, then acuity loss is common. Although this type of vessel closure is easily identified on FA in the form of capillary dropout, other ophthalmoscopic clues include large dark retinal hemorrhages, multiple cotton-wool spots, and narrowed vessels.

The degree to which vision loss can be ascribed to this disorder may not correspond to the extent of ophthalmoscopic findings, and commonly there are confounding factors. Patients with advanced diabetic retinopathy and vision loss may exhibit mild optic atrophy and pigmentary changes. The visual field loss that may occur after panretinal photocoagulation also complicates the clinical picture. The full-field and multifocal ERG may be useful in identifying retinal dysfunction in patients with diabetic retinopathy. When unusual types of visual field defects are encountered, such as altitudinal defects or those respecting the vertical midline, it is mandatory that alternative causes be considered, especially compressive optic nerve or chiasmal lesions.

Acute Macular Neuroretinopathy

Acute macular neuroretinopathy (AMN) is a rare condition characterized by dark wedge-shaped intraretinal lesions pointing to the fovea; it is most common in young women taking oral contraceptives. The majority of affected patients are females who present with an acute onset of photopsias, black spots, and blurred vision, often preceded by a viral illness. These patients have tiny, often multifocal, discrete central transient or permanent visual field defects that are apparent only on Amsler grid testing. These subtle lesions can often be missed, and if there is a central scotoma these patients can often be misdiagnosed as having retrobulbar optic neuritis. Scotomas correlate with an orange-brown, wedge-shaped, petaloid, retinal lesion seen on ophthalmoscopy (see Fig. 4.6 ). SD-OCT findings in AMN reveal a transient hyperreflective band in the outer nuclear and outer plexiform layers followed by thinning of the outer nuclear layer and disruption of outer segments and RPE. En face SD-OCT also shows hyporeflective well-defined petaloid lesions at the level of the inner segment–outer segment junction. Multifocal ERG in such patients may be focally depressed. The pathologic process occurs in the outer retinal layers.

The exact cause for this condition is unknown, although infectious immunologic and vascular etiologies have been proposed. About half of the patients show a variable degree of improvement over time.

Two other maculopathies commonly encountered in neuro-ophthalmic differential diagnosis, cone dystrophies and toxic maculopathies, are also discussed in this chapter.

Retinal Emboli

Types. There are three main types of retinal emboli: cholesterol, calcific, and platelet–fibrin. Other more rare types of emboli include those composed of amniotic fluid, bacteria, parasites, metastatic tumors, fat, air, and talc. These types of emboli are recognized within their specific settings (i.e., talc with intravenous drug abuse and bacterial with endocarditis).

Cholesterol emboli (Hollenhorst plaques ), seen as gold-colored refractile bodies ( Fig. 4.7 ), are the most common and lodge at bifurcations of the retinal vessels in the temporal retinal circulation. Platelet–fibrin emboli are gray and form castlike elongated opacifications in retinal vessels ( Fig. 4.8 ). These emboli may follow acute carotid thrombosis or more rarely myocardial infarction. Calcific emboli are large, globoid, and white ( Fig. 4.9 ) and occur in the setting of cardiac valvular disease but may also originate from a carotid source.

Cholesterol emboli. A . Hollenhorst plaque ( arrow ) at a bifurcation of a temporal retinal artery. These emboli typically have a shiny, yellow, refractile appearance. There is no corresponding retinal infarction in this case. B . In another patient, multiple retinal emboli (shiny yellow lesions in the retinal vasculature) caused areas of retinal infarction characterized by retinal edema and whitening.

Platelet–fibrin emboli in retinal arteries. A . Note the yellow-gray, elongated, castlike nature of the emboli ( straight arrows ) within the retinal arteries. A twig branch retinal artery occlusion ( curved arrow ) is seen distal to the involved artery. B . A platelet–fibrin embolus ( arrow ) without associated retinal infarction.

Calcific embolus of the inferotemporal retinal artery in a patient with a bicuspid aortic valve. The embolus ( white arrow ), which has a large, globoid, gray appearance, caused a branch retinal artery occlusion with retinal whitening ( black arrows ).

Prevalence and Associations. The prevalence of retinal emboli in various populations has been reported to be approximately 0.9–3%. They are more common in men, and their prevalence increases with age. Retinal emboli are associated with hypertension, smoking, vascular disease, and previous surgery.

Carotid Disease. The presence of significant carotid stenosis (>75%) in patients with retinal emboli is approximately 20% in either asymptomatic or symptomatic patients. In patients with retinal arterial occlusion, the presence of a retinal embolus does not predict a higher degree of stenosis. Asymptomatic patients with retinal emboli and carotid stenosis may in some cases benefit from carotid endarterectomy. However, the decision for surgery should be made on an individual basis, because surgery for asymptomatic carotid stenosis is controversial (see Chapter 10 ).

Cardiac Disease. In patients with retinal emboli or vessel occlusions, echocardiography may identify a cardiac source. Transesophageal echocardiography is superior to transthoracic echocardiography and should be obtained when there is a high index of suspicion for an embolic process.

Associated Morbidity and Mortality. Cholesterol and platelet–fibrin emboli are associated with an increased risk for stroke, myocardial infarction, and, as a result, reduced life expectancy.

Clinical Presentations of Retinal Vascular Insufficiency

Amaurosis Fugax. Amaurosis fugax (AF), or “fleeting” or transient monocular blindness, is usually sudden and is often described as a shade or curtain that obscures vision in one eye (see further discussion in Chapter 10 ). Visual loss may be altitudinal, peripheral, central, or even vertical. As opposed to migrainous episodes of transient vision loss, there usually are no photopsias or positive visual phenomena. Most episodes last 10 minutes or less and are painless.

Carotid or cardiac sources of emboli should be considered with typical AF. A nasal visual field defect may suggest an embolic mechanism because of the tendency of these particles to lodge in the temporal retinal circulation. Some emboli lodge behind the lamina cribrosa and are not visible. Others that enter the retinal circulation break up and pass distally.

AF is associated with an increased risk of a large vessel stroke on the ipsilateral side. Other rare causes of AF and retinal vascular occlusions include antiphospholipid antibody syndrome (APS; see later discussion). APS is most common in patients with lupus and can lead to AF even in children. Heritable thrombophilia (factor V Leiden mutation), low protein S, high factor VIII, resistance to activated protein C, and the methylenetetrahydrofolate reductase (MTHFR) mutation may be identified in patients with AF and no other identifiable etiology (carotid or cardiac source).

Retinal artery occlusion. Permanent vascular disruption may cause a central retinal artery occlusion (CRAO) or branch retinal artery occlusion (BRAO). Affected patients have a higher prevalence of diabetes mellitus, hypertension, ischemic heart disease, and cerebrovascular accidents. Carotid artery disease causing a retinal embolism is the most common cause for retinal artery occlusion, followed by aortic arch atheroma and cardiac emboli. CRAO can be associated with visible emboli in up to 20% of patients, but BRAO has a higher rate, approaching 60– 70%. However, the absence of visible retinal embolus does not rule out an embolic cause for retinal artery occlusion since the embolus can migrate and disintegrate by the time the eye is examined. More recent evidence points to the presence of internal carotid artery plaques proximal to the origin of the ophthalmic artery as the source of retinal emboli in 40% of patients with CRAO. Other mechanisms of retinal vascular occlusion besides emboli include local thrombosis, hypercoagulability, vasculitis (especially temporal arteritis), vasospasm and hypoperfusion due to stenosis or occlusion of the internal carotid artery, severe shock, hemodialysis, “spasm” of the central retinal artery, and orthostatic hypotension. Rarely CRAO can result from a rise in intraocular pressure from orbital swelling, neovascular glaucoma, or angle-closure glaucoma. Although the frequency of operable carotid stenosis ipsilateral to a CRAO or BRAO varies from series to series, approximately 30–40% of patients will have >60% ipsilateral carotid stenosis. Workup involves evaluation of carotid vasculature and echocardiogram to exclude an embolic source.

Central retinal artery occlusion. An acute CRAO is a true emergency because the potential to restore vision may exist for a few hours. Since there are no ganglion cell axons overlying the fovea, ophthalmoscopy reveals a foveal cherry-red spot that results from the deep reddish color of the choroid showing through the surrounding whitened and opacified retina ( Fig. 4.10 ). Ophthalmoscopic findings in CRAO include retinal opacity in the posterior pole (58%), cherry-red spot (90%), box-caring in retinal vessels (19%), retinal arterial attenuation (32%), visible emboli (20%), optic disc edema (22%), and pallor (39%). With the advent of SD-OCT imaging, the extent of retinal ischemia can be precisely localized to the superficial and/or deep retinal capillary plexuses. The superficial capillary plexus resides in the ganglion cell layer, and ischemia involving this layer usually presents clinically as a fluffy “cotton-wool spot” in the acute phase. The intermediate and deep capillary plexuses reside in the inner and outer border zone of the inner nuclear layer and are seen as a deeper gray-white lesion in the acute phase of retinal ischemia. During the chronic phase of a CRAO, a decrease in reflectivity and thinning of the inner retina has been observed.

Central and branch retinal artery occlusions. Cherry-red spots from a central retinal artery occlusion can have a varied appearance depending on the time elapsed from the occlusion and the patient’s pigmentation. A . A cherry-red spot ( arrow ) with extensive area of whitening around an area of cilioretinal sparing ( asterisk ). B . Cherry-red spot ( asterisk ) surrounded by diffuse retinal whitening ( arrows ). The deep pigmentation superior to the macula is incidental. C . Superior branch retinal artery occlusion in a 14-year-old boy. There is a partial cherry-red spot. Extensive retinal whitening and swelling is seen, and the optic nerve also appears slightly swollen. D . Superior branch retinal artery occlusion with retinal whitening along the affected artery. This patient had temporal arteritis, and there is simultaneous swelling of the disc from ischemic optic neuropathy. E . In another patient, spectral domain optical coherence tomography showing obliteration of inner and outer retinal layers and inner retinal swelling ( arrow ) because of a branch retinal artery occlusion.

The prognosis for visual improvement after CRAO is poor even with interventions such as paracentesis, inhalation of carbogen (95% oxygen, 5% carbon dioxide) for vasodilation and increased blood flow, lowering intraocular pressure with various drugs, and ocular massage. Hayreh and colleagues have shown, in an experimental monkey model, that the retina may survive as long as 97 minutes with CRAO but after that damage increases with time; after 4 hours there is profound irreversible damage. This suggests a narrow but realistic time frame for intervention with clot lysis.

Surgical embolectomy has been shown to improve vision in some published case reports, although other studies have not shown effectiveness. Hayreh and Zimmerman emphasized that the prognosis varies significantly depending on whether there was cilioretinal artery sparing and whether reperfusion occurs, noting that, in Hayreh’s personal series of 244 patients, 50% had a residual peripheral island of vision while two-thirds of patients (particularly those with cilioretinal arteries and transient CRAO) had significant improvement. Approximately 2.5–20% of patients develop iris neovascularization.

Intraarterial fibrinolysis by administering urokinase or recombinant tissue plasminogen activator in the ophthalmic artery has been used with some success in patients with CRAO, but multicenter, prospective data demonstrating their efficacy are lacking.

Branch retinal artery occlusion. Patients with BRAO similarly represent a heterogeneous group. Ophthalmoscopy reveals retinal whitening involving a section of retina with a partial cherry-red spot (see Fig. 4.10 ). Nearly all BRAOs involve the temporal retinal arteries. Workup for carotid and cardiac sources of emboli should be pursued in patients with BRAO as well. BRAO has also been described in a variety of other conditions, including infectious retinopathies (toxoplasmosis, cat scratch disease), carotid dissection, APS, protein S deficiency, Susac syndrome, temporal arteritis, and the presence of anticardiolipin antibody and lupus anticoagulants. One study suggested that the presence of a visible embolus and BRAO were factors correlated with a significantly worse survival than age-matched controls. As in the management of CRAO, aggressive maneuvers to move the embolus by lowering intraocular pressure and using vasodilators have no proven benefit. OCT in BRAO reveals inner retinal thickening, often extending from the internal limiting membrane to the inner nuclear layer ( Fig. 4.10e ).

Cilioretinal artery occlusions. Similar embolic events can lead to the obstruction of the cilioretinal artery. If present, a cilioretinal artery can protect central vision when CRAO occurs. Isolated cilioretinal artery occlusions can occur as well with loss of central vision and preservation of peripheral vision. Cilioretinal artery occlusions have also been described in systemic lupus erythematosus, temporal arteritis, carotid artery dissection, antiphospholipid syndromes, as a complication of embolization of central nervous system (CNS) lesions and laser refractive surgery, sickle cell disease, and in association with CRVO in young patients ( Fig. 4.11 ).

Nonischemic central retinal vein occlusion in a young man complicated by cilioretinal artery ( arrow ) occlusion. Retinal whitening is seen extending around the affected cilioretinal artery. Visual acuity was normal, but there was a dense superior paracentral scotoma.

Ocular ischemic syndrome. Hypoperfusion and subsequent ischemia of the globe associated with severe carotid disease may produce a variety of signs involving the posterior and anterior segments of the eye. Patients may present with AF or gradual or sudden loss of vision. A venous stasis retinopathy characterized by midperipheral dot and blot hemorrhages may occur (see Fig. 10.3 ). Optic nerve disc swelling is typically not seen until the very late stages of posterior segment ischemia. FA may reveal delayed retinal and choroidal perfusion. The vascular occlusion is typically either in the ipsilateral internal carotid or a more distal occlusion occurs in the ophthalmic artery. Severe ocular ischemia may also be caused by a carotid dissection or temporal or Takayasu arteritis, by fibromuscular dysplasia, by Behçet disease, as a complication after intravitreal anti–vascular endothelial growth factor (VEGF) injections, and by radiotherapy for nasopharyngeal carcinoma. Other manifestations of this condition are discussed in more detail in Chapter 10 .

Cotton-wool spots. Cotton-wool spots ( Fig. 4.12 ) are well-recognized markers of retinal ischemia and can be seen in isolation or in association with several disease states such as diabetic and hypertensive retinopathy, in association with retinal arteriolar or venous occlusions and Purtscher retinopathy. OCT of cotton-wool spots can reveal thickening and hyperreflectivity of the inner retinal layers.

Fundus photograph showing a cotton-wool spot ( arrow ) in the superotemporal arcade.

Retinal Microvascular Disease and Associations

The presence of other retinal vascular abnormalities such as microaneurysms, arteriolar narrowing, and hemorrhages may be predictive of or associated with neurologic disease such as lacunar infarcts and small vessel ischemic disease. In addition, migraine and other headache patients are more likely to have retinal microvascular abnormalities such as narrowing and arteriovenous nicking and cotton-wool spots.

Recent evidence indicates that acute retinal arterial ischemia (both transient and permanent) is often associated with cerebral ischemia. In 129 patients who presented with symptoms of retinal ischemia, one-fourth had acute brain infarctions on diffusion-weighted MRI. The occurrence of brain lesions was higher in embolic versus nonembolic retinal ischemia (28% vs 8%) and higher in those with permanent visual loss versus retinal transient ischemic attack (33% vs 18%). The brain infarctions were small and multiple and often asymptomatic. This has led to the recommendation that patients with visual loss resulting from a retinal ischemic event should be managed with the same urgency as those presenting with cerebral ischemia.

Retinal Venous Occlusion

Occlusive disease of the retinal venous system (branch and CRVO) does not result from carotid disease and is not usually associated with optic neuropathy or other neurologic disease. However, retinal vein occlusion is the second most common retinal vascular disorder, after diabetic retinopathy. It causes acute vision loss, photopsia, optic nerve swelling, cotton-wool spots, and retinal hemorrhages and therefore is an important condition to consider in neuro-ophthalmic differential diagnosis of monocular visual acuity and field loss. Retinal vein occlusion may also be associated with systemic disorders such as hypertension, connective tissue abnormalities, and hypercoagulability.

Central retinal vein occlusion. Acute CRVO has a characteristic and dramatic appearance of tortuosity and dilation of retinal veins, retinal edema, and intraretinal hemorrhages extending away from the disc into all four quadrants. CRVO can present with or without disc edema, depending on the position of the occlusion ( Fig. 4.13 ). The presence of disc edema is associated with younger age, better visual function, and less likelihood of vascular nonperfusion, suggesting occlusion behind the lamina cribrosa.

Examples of central retinal vein occlusion (CRVO). A . Optic disc edema ( arrow ) and four-quadrant extensive intraretinal hemorrhages from CRVO. B . CRVO with intraretinal hemorrhages in the nerve fiber layer but without disc edema.

CRVOs are divided into two categories, ischemic and nonischemic, based on the degree of vision loss and the amount of capillary nonperfusion on FA. Nonischemic vein occlusions reveal a well-perfused retina on FA. Patients with ischemic CRVO are more likely to have poor vision at presentation (including an APD), develop rubeosis, and require treatment with panretinal photocoagulation. FA will reveal severe capillary nonperfusion.

The mechanism of CRVO is believed to be thrombosis of the central retinal vein that causes a marked increase in retinal venous pressure leading to rupture of capillaries, retinal hemorrhages, and ischemia resulting from a decrease in retinal arterial perfusion pressure. Both ocular and systemic conditions have been associated with CRVO, including glaucoma, retrobulbar compressive and infiltrative lesions such as neoplasm, systemic hypertension, hyperlipidemia, diabetes, cardiovascular disease, and smoking.

The main cause of vision loss in retinal vein occlusions is macular edema. In those with nonischemic CRVO, 34% convert to an ischemic form with further visual acuity decline. Moreover, retinal neovascularization and neovascular glaucoma are common vision-threatening sequelae of CRVO. Panretinal photocoagulation of an ischemic retina is indicated in CRVO when there is retinal neovascularization. VEGF inhibitors and steroids are now commonly used to treat macular edema secondary to retinal vein occlusion.

Branch retinal vein occlusion. In branch retinal vein occlusion (BRVO) the findings of venous insufficiency develop in just a portion of the retina. Such occlusions tend to occur at the point where a retinal artery and vein cross and share a common adventitia. The retinal findings typically occur in the superotemporal quadrant in an arcuate pattern of hemorrhages, cotton-wool spots, hard exudates, dilated tortuous veins, and retinal edema. Hypertension, hyperlipidemia, diabetes mellitus, thrombophilia, hypercoagulation, systemic and inflammatory diseases, male gender, medications, and ocular conditions such as glaucoma and hyperopia are all risk factors for BRVO. BRVOs may be complicated by macular edema and/or ischemia, which may result in central vision loss. Treatment modalities for macular edema in BRVO include grid laser photocoagulation, intravitreal injections of steroids, and VEGF inhibitors.

Paraneoplastic Retinopathy

Primary malignancies and secondary tumors (metastatic and direct extension from adjacent structures) may produce vision loss by displacement, invasion, or compression of ocular tissues. Paraneoplastic syndromes are combinations of signs and symptoms in patients with cancer, resulting from tissue dysfunction that occurs remotely from the site of primary malignancy or its metastases. Most paraneoplastic syndromes result from hormone production by the tumor such as Cushing syndrome, syndrome of inappropriate antidiuretic hormone secretion, and hypercalcemia related to parathyroid hormone–related protein. Others are believed to involve immune-mediated cross-reactivity between tumor antigens and normal host tissues (e.g., Lambert–Eaton myasthenic syndrome, opsoclonus–myoclonus syndrome, and cerebellar degeneration). Paraneoplastic syndromes involving the eye and CNS are rare and occur in 0.01% of individuals.

Sawyer et al. were the first to recognize the unusual features of a retinopathy occurring as a remote effect of cancer. The clinical features of the paraneoplastic retinopathies are summarized in Table 4.2 . This broader term encompasses several distinct entities, including cancer-associated retinopathy (CAR), which is the most common; cancer-associated cone dysfunction (CACD); melanoma-associated retinopathy (MAR); diffuse uveal melanocytic proliferation (DUMP); and paraneoplastic ganglion cell neuronopathy (PGCN).

Despite some fairly characteristic complaints and examination findings, the diagnosis of PR is rarely made at presentation, and a high index of suspicion is needed, especially when symptoms develop before the diagnosis of primary malignancy.

Symptoms, signs, and electroretinography. Patients usually report a subacute onset of decreased vision or a halo of missing peripheral vision along with photopsias (flashing lights) or other positive visual phenomena. Differences in symptoms among the various entities correlate with the degree to which the rods versus cones are affected.

Visual acuity ranges from normal to markedly reduced with dyschromatopsia and prolonged photostress recovery time. An afferent pupil defect may be evident in cases with asymmetric retinal involvement. Midperipheral scotomas may develop ( Fig. 4.14 ). As the retinal degeneration evolves, the paracentral defects eventually connect to form a classic ring scotoma. Since the visual field defects result from retinal dysfunction, the “arcuate-type” defects typically do not respect the horizontal meridian. The outer retina does not have an anatomic demarcation along the horizontal meridian like the nerve fiber layer.

Paraneoplastic and autoimmune retinopathy. A . Goldmann visual field of the left eye of a patient with cancer-associated retinopathy. Photoreceptor dysfunction is manifested by midperipheral scotomas that do not respect the vertical or horizontal meridians. The scotomas are beyond 15 degrees of eccentricity. B. In another patient with autoimmune retinopathy but without a known cancer, computerized perimetry (Humphrey 30–2) with the right eye demonstrates similar midperipheral scotomas (ring scotoma). Perimetry with the left eye was similar. C . In the same patient as in B , fundus autofluorescence of the right eye shows a ring of hyperfluorescence ( arrows ) representing breakdown products of retinal pigment epithelium surrounding the fovea. Findings in the left eye were similar.

In general, there is usually a paucity of ocular findings compared with the symptoms and level of visual dysfunction. However, ocular examination may reveal a mild vitritis, vascular attenuation, and CME. Other findings described in these patients include optic disc pallor, granularity of the RPE, and peripheral retinal pigmentation, although these changes can be subtle.

The diagnosis of PR is strongly suggested when the ERG shows evidence of diffuse retinal dysfunction in a patient with relatively subacute visual loss. The ERG varies in PR depending on the particular syndrome. It is important to differentiate these syndromes from non–cancer-related autoimmune entities such as autoimmune-related retinopathy and optic neuropathy (ARRON) and acute zonal occult outer retinopathy (AZOOR), which are likely more common and are discussed later.

Each subtype has several distinguishing signs and symptoms, ERG features, and systemic associations (see Table 4.2 ).

Cancer-associated retinopathy. CAR is the most common of ocular paraneoplastic syndromes, with an average age of onset of 65 years and females being twice as likely to be affected as males. Affected individuals typically present with painless vision loss that progresses over weeks to months and precedes the diagnosis of underlying malignancy in nearly half of patients. The tumors most commonly associated with CAR are breast cancer and small cell lung cancer; gynecologic (ovarian, endometrial, and cervical), hematologic, prostate, and colon cancer are less common. Visual symptoms reflect both rod and cone dysfunction and include photosensitivity, photopsias, decreased central vision, and dyschromatopsia. The presence of night blindness, impaired dark adaptation, and ring scotomas indicates rod dysfunction. Visual field defects in CAR can manifest as generalized depression or central, paracentral, arcuate, or ring scotomas.

The fundus examination may be normal initially, although optic nerve pallor, retinal arteriolar attenuation, and retinal pigment epithelial mottling are observed later in the disease course. A subtle vitritis may be present in some cases. SD-OCT shows findings of retinal degenerative changes, especially in the outer retina, including macular atrophy, thinning of the photoreceptor layer, and loss of the inner segment–outer segment junction. On FAF a parafoveal ring of hyperfluorescence may be seen corresponding to loss of RPE function and accumulation of metabolic byproducts.

The ERG in CAR shows diffuse retinal dysfunction with severely reduced scotopic and photopic a- and b-waves early in the disease course even when the fundus examination is entirely normal.

Several reports have described the histopathologic findings in CAR. As expected, loss of photoreceptor inner and outer segments occurred in each case. The degree of macular involvement is variable, and in general there is more rod than cone involvement. Outer nuclear cell loss and the presence of inflammatory infiltrates are other notable features. The inner nuclear layer (ganglion cells) is spared. In areas of photoreceptor loss, scattered melanophages and disruption of the RPE have been observed.

Keltner and associates were the first to propose an autoimmune pathogenesis in CAR by demonstrating an antiretinal antibody in a patient with cervical carcinoma in 1983. This antibody, called recoverin, reacted with photoreceptors from a normal human retina and was later identified as binding 23-kDa CAR antigen by enzyme-linked immunosorbent assay and Western blot testing. Over 20 other antigens have since been identified, including α-enolase (46-kDA) ; transducin-α, a 70-kDa, heat shock cognate (hsc) protein ; the photoreceptor nuclear receptor ; neurofilaments ; and transient receptor–potential cation channel, subfamily M, member 1 (TRMP1), suggesting that CAR is a heterogeneous group of autoimmune conditions rather than a single entity. Autoantibodies against TRMP1 have been identified in small cell lung cancer, ovarian cancer, and melanoma.

Although antiretinal antibodies also can be found in normal patients, higher titers are seen in those with retinopathy and in many systemic and ocular conditions such as retinitis pigmentosa (RP), Vogt–Koyanagi–Harada (VKH) disease, Behçet disease, sympathetic ophthalmia, diabetic retinopathy, and age-related macular degeneration. Molecular mimicry underlies development of CAR. Presumably, antibodies are formed as part of an autoimmune reaction to tumor antigens. These antigens cross-react with retinal antigens because of shared epitopes (antigenic mimicry). Tumor necrosis can expose antigens to immunologic surveillance and result in antibody production.

The exact mechanism by which the antibody-recoverin molecule complex causes cell death is unknown. An effect on energy production seems likely since the classic immune-mediated form of destruction that includes lymphocytic cellular infiltration is not observed in most cases. Outer retinal involvement on both histopathology and immunohistochemistry supports the theory that these antibodies have a role in the pathogenesis of the disease.

Although there is no effective therapy for CAR, long-term immunosuppression remains the mainstay of therapy. Treatment of underlying malignancy alone does not improve vision in most cases. Benefit has been reported with a combination of systemic corticosteroids, plasmapheresis, and intravenous immunoglobulin. Monoclonal antibodies such as alemtuzumab and rituximab, targeting B cells, have shown some efficacy. Recently improvement in visual function has also been reported with periocular steroid injections.

Cancer-associated cone dysfunction. In contrast, patients with CACD may complain of decreased acuity, dyschromatopsia, glare, photosensitivity, or reduced vision in bright light (hemeralopia), more suggestive of cone dysfunction. CACD is characterized by an abnormal cone ERG. Patients typically have color vision loss and central scotomas. Signs and symptoms are caused by loss of cones in the macula. Antibodies to 23-kDA, 40-kDa and 50-kDa retinal proteins have been identified as pathologic.

Melanoma-associated retinopathy. Most patients with MAR have an established diagnosis of cutaneous melanoma and present uniformly with rod-mediated dysfunction with shimmering photopsias, night blindness, and floaters. The presence of MAR often heralds the onset of nonocular metastases. Noncutaneous melanoma causing MAR is rare.

The average age at presentation of MAR is in the 50s, with a latent period of more than 3.5 years from diagnosis of the melanoma to the onset of MAR common. The male-to-female ratio is 4.7 : 1. Visual acuity is better in MAR, with more than 80% of patients having visual acuity of 20/60 or better in Keltner’s series. There are associated dyschromatopsia and visual field defects (central scotomas, arcuate defects, and generalized constriction). The fundus appears normal in 50% of patients, but optic disc pallor, retinal vessel attenuation, and vitritis may be evident in other patients. Unlike patients with CAR, patients with MAR typically do not experience the relentless progression to blindness. OCT may be initially normal in MAR but may demonstrate inner retinal thinning in the paramacular region.

Patients with MAR have a highly specific ERG with absent b-waves under dark-adapted conditions and normal cone amplitudes, suggesting bipolar cell dysfunction. Antibipolar cell antibodies are the defining marker for MAR. More recently autoantibodies to transient receptor potential cation channel in patients with MAR have been identified. This protein resides on the optic nerve bipolar cells in the inner nuclear and outer plexiform layers. A distinct type of MAR like retinopathy with associated detachments of the RPE and neurosensory retina has been described and termed paraneoplastic vitelliform retinopathy. This is characterized by multifocal shallow exudative retinal detachments and can result from metastatic melanoma or carcinoma. Histopathology of autopsied eyes has revealed an inner nuclear layer and outer plexiform layer involvement with thinning further providing evidence of bipolar cell involvement. In most cases the a- and b-wave amplitudes are markedly reduced. Progressive visual loss has been correlated with progressive reduction of ERG amplitudes. Abnormal EOGs have also been reported. MAR antiretinal antibodies have been found in the serum of patients with melanoma but no clinical evidence of MAR. Other patients with MAR may be asymptomatic despite abnormal perimetry and ERGs.

The treatment for MAR is largely ineffective and is primarily directed to decrease the tumor burden by surgery followed by immunotherapy.

Bilateral diffuse uveal melanocytic proliferation. Bilateral DUMP manifests with subacute loss of vision that often develops before diagnosis of the primary neoplasm. The most common primary tumors associated with this syndrome are carcinoma of the reproductive tract in women and cancers of the retroperitoneal area and the lungs in men. Ophthalmoscopic examination reveals bilateral proliferation of subretinal pigment and yellow-orange lesions at the level of the RPE that appear hyperfluorescent on FA, diffuse choroidal thickening with focal elevated pigmented and nonpigmented uveal melanocytic tumors, serous retinal detachment, and rapidly progressing cataract formation. The fundus appearance is akin to a “giraffe pattern,” with patches of RPE atrophy surrounded by orange zones of hypertrophied RPE.

The underlying mechanism of bilateral DUMP appears to be proliferation of uveal tract melanocytes, likely related to secretion of melanocytic growth factors by tumor cells. The serous retinal detachments may respond to systemic corticosteroids or radiation. Treatment of the primary tumor may not alter the course of the progressive visual loss. Two reports have advocated plasmapheresis with promising results.

Paraneoplastic ganglion cell neuronopathy. PGCN is essentially a form of paraneoplastic optic neuropathy. These conditions are discussed in Chapter 5 . There have been scattered reports of patients with cancer presenting with demyelinating optic neuropathies without any evidence of cancer spread to the optic nerve or meninges. One report noted the presence of immune deposits in the retina and diffuse ganglion cell loss on histopathologic evaluation.

Paraneoplastic optic neuritis and retinitis. Because of antibodies to CV2/CRMP-5, paraneoplastic optic neuritis and retinitis is characterized more by an optic neuropathy than retinal disease and is therefore discussed in more detail in Chapter 5 .

Diagnostic and prognostic role of antiretinal antibodies. In many patients the visual symptoms of a paraneoplastic retinal disorder may precede the systemic appearance of cancer. In such cases other causes of retinal dysfunction such as autoimmune nonparaneoplastic outer retinopathies, hereditary retinal degeneration, and toxic retinopathy must be ruled out. Testing for antiretinal antibodies can be carried out to support the diagnosis, although this has its own challenges. The presence of antiretinal antibodies can be pathogenic or a normal unrelated finding. Concordance between different laboratories for the detection rate of antiretinal antibodies is about 36%, and it is recommended that confirmation of a positive result be obtained from two different laboratories. It is important to remember that diagnosis of these disorders is based on clinical grounds and testing for antiretinal antibodies should be used to support the diagnosis of CAR and MAR but should not be used in isolation as a diagnostic test. Autoantibodies against recoverin and α-enolase and rod transducin-α in CAR have been most widely studied and appear to be most specific and highly corroborative.

Systemic evaluation. In individuals with suspected PR, a careful review of the patient’s medical history and laboratory investigations should be undertaken to identify the underlying systemic malignancy. Approximately one-half of the cases of PR are diagnosed before the discovery of the malignancy. Like many of the other paraneoplastic syndromes, two-thirds of patients with PR will have small cell carcinoma of the lung, followed by gynecologic (ovarian, endometrial, and cervical), hematologic, prostate, and colon cancer. Other associated tumors include cutaneous melanoma in MAR, breast carcinoma, and thymoma. Hematologic malignancies (leukemia, lymphoma, and myeloma) have also been linked to CAR.

Differential diagnosis. PR must be distinguished from four broad categories of anterior visual pathway disease which may occur in this setting, including conditions that appear clinically similar but are not associated with systemic malignancy, conditions secondary to direct spread of tumor, toxic effects of chemotherapy, and other paraneoplastic conditions. Compressive or inflammatory lesions of the anterior visual pathway must be considered in all instances of subacute visual loss. Optic neuritis is a common misdiagnosis in patients ultimately shown to have PR. However, optic neuritis and ischemic optic neuropathy can usually be excluded on clinical grounds. Less common causes of subacute visual loss such as toxic, hereditary, and nutritional optic neuropathies should be considered and excluded based on historical and laboratory information. Ultimately, an abnormal ERG will distinguish PR from optic neuropathy.

The rapid rate of visual deterioration distinguishes PR from other retinal degenerations such as RP. The two conditions otherwise may mimic each other since both conditions result from photoreceptor dysfunction. In contrast to PR patients, most individuals with RP have abnormal fundi with pigmentary deposition.

The Big Blind Spot Syndromes and Acute Zonal Occult Outer Retinopathy

The term big blind spot syndrome has been used to describe several different entities, all of which present with enlargement of the physiologic blind spot. These disorders include acute idiopathic blind spot enlargement (AIBSE) and MEWDS. Enlargement of the blind spot is related either to optic nerve head swelling with displacement of the peripapillary retina or to dysfunction of the peripapillary retina when the optic nerve is ophthalmoscopically normal. Patients with AIBSE and MEWDS have a fairly uniform presentation, with an acute onset of a visual field defect around the physiologic blind spot accompanied by photopsia. Visual acuity is usually normal, and the visual field defects typically have steep borders. These disorders all likely affect the outer retina and therefore may lie within the spectrum of a single disease. These diseases are more common in women.

Acute idiopathic blind spot enlargement. In 1988 Fletcher et al. described seven patients, aged 25–39 years, with an acute onset of photopsia and enlargement of the blind spot without optic disc swelling. Two patients had abnormal multifocal ERGs, and the authors concluded that the syndrome resulted from peripapillary retinal dysfunction. Their patients had no abnormalities on FA, although two patients had peripapillary retinal pigment abnormalities. Two patients had recurrences, and three had recovery of their visual fields.

The term AIBSE syndrome is now used to describe patients with an acute onset of positive visual phenomena and an enlarged blind spot, occasionally associated with mild disc swelling ( Fig. 4.15 ). Peripapillary pigmentary changes are common (see Fig. 4.15 ). The field defects, which may be more easily detected with blue-on-white perimetry, generally have steep borders and can mimic the temporal visual field defects of chiasmal disease ( Fig. 4.16 ). Retinal pigment epithelial or choroidal abnormalities and disc staining on FA may be seen. Full-field ERGs are often normal, but focal and multifocal ERGs directed at the peripapillary retina are abnormal ( Fig. 4.17 ). Photopsias tend to resolve over time, although in most patients the visual field defect persists.

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