Diseases affecting primarily the retinal arteries, capillaries, and veins or any combination of the three may be the underlying cause of central vision loss. Angiography provides information concerning alterations in retinal blood flow, the normal retinal vascular pattern, and retinal vascular permeability. In addition, in the sensory retina, which normally has very little extracellular space, stereo angiography provides a means of pictorially defining expansions of the extracellular space produced by extracellular fluid accompanying alterations in vascular permeability and cellular destruction. Optical coherence tomography (OCT) has enhanced the ability to define these lesions in a vertical cross-section and three-dimensional layout. For a more detailed discussion of the basic pathophysiologic and histopathologic changes occurring in retinal vascular disorders and their correlation with fluorescein angiographic and biomicroscopic changes, the reader should see Chapter 2.
Retinal Vascular Anomalies
A variety of minor anomalies of the retinal vascular tree occur commonly and are unassociated with visual morbidity. Some of the vascular anomalies, however, may cause visual loss.
Hereditary Retinal Artery Tortuosity
Recurrent macular hemorrhages occurring in family members with congenital arteriolar tortuosity constitute a recognized syndrome ( Figure 6.01A–C ). Visual loss in these patients may occur spontaneously or following relatively minor trauma (see the discussion on Valsalva maculopathy, p. p0315 in Chapter 8). Retinal arteriolar tortuosity may increase with age, particularly during adolescence. The tortuosity affects primarily the second- and third-order retinal arterioles in the macular area and the veins are spared. Fluorescein angiography has failed to disclose any primary alterations in the retinal vascular tree that would account for the predilection for hemorrhages. The pathogenesis is unknown. Despite recurrent bleeding, vision usually returns to normal. Retinal bleeding during scleral buckling procedure has been reported. There is no evidence that a systemic hemorrhagic diathesis is present in patients with this disease, which is inherited as an autosomal-dominant trait. Families with increased nail bed capillary tortuosities, carotid aneurysm, and microscopic hematuria have been described. Congenital retinal arteriolar tortuosity must be differentiated from other diseases associated with acquired retinal vascular tortuosity, including polycythemia, leukemia, dysproteinemia, sickle-cell disease, familial dysautonomia, mucopolysaccharidosis VI, and Fabry’s disease. Pulsatile three-dimensional arteriolar tortuosity, previously reported in patients with coarctation of the aorta, rarely occurs now because of early surgical intervention.
Spontaneous retinal hemorrhages may occur in multiple family members in the absence of related systemic disease or retinal arterial tortuosity.
Inherited Retinal Venous Beading
Meredith described five affected members in two generations with sausagelike beading of the major retinal veins and conjunctival venules, focal retinal infarctions, altered retinal vascular permeability, and in some cases abnormalities of arteriolar and venular distribution. Large venules crossed the horizontal raphe in some cases. Three members had retinal and/or optic disc neovascularization and vitreous hemorrhage. Some members had renal disease (Alport’s disease) and decreased leukocyte counts. Stewart and Gitter reported four affected members of two generations with retinal venous beading but no conjunctival vessel tortuosity. The affected members had low to normal neutrophil leukocyte counts that differed significantly from unaffected members.
Retinal Venous Tortuosity in Infants
Neonates born to mothers who smoke during pregnancy have a higher incidence of venous dilation and tortuosity, arteriolar straightening and narrowing, and intraretinal hemorrhages. This is likely the result of a combination of higher hematocrit and higher peripheral vascular resistance in these babies. All vascular changes correct by age 6 months. Infants with congenital heart diseases show a higher incidence of retinal vascular tortuosity (46%), more so those with cyanotic heart disease, low hematocrit, and low oxygen saturation.
Congenital Prepapillary Vascular Loops
Dilated loops involving either the veins or the arteries may occur in and around the optic nerve head ( Figure 6.01D–L ). Loops involving the retinal arteries are more common than those involving veins (4:1). Retinal arterial loops may arise on or near the optic disc from a major branch retinal artery, the central retinal artery, or a cilioretinal artery ( Figure 6.01D–F ). They extend anteriorly into the vitreous, are composed of one or more twists, and usually supply one of the retinal quadrants. The loops often exhibit movement within the vitreous and cast a shadow on the surrounding fundus. They may pulsate. They occasionally occur bilaterally, may be familial, and may be partly surrounded by glial or fibrous sheaths. Retinal circulation time in the affected quadrant may be slightly increased. There is a high incidence of cilioretinal arteries in these eyes, and they often supply much of the retinal circulation. A small percentage of these patients may lose vision secondary to occlusion of the arterial loop ( Figure 6.02A–G ), vitreous hemorrhage, amaurosis fugax, and hyphema. Thrombosis or twisting of the loop probably causes the obstruction ( Figure 6.02A–G ). Histologically the artery comprising the loop is of normal structure. The pathogenesis of the vitreous hemorrhage occurring in and around these loops is uncertain but probably is caused by rupture of small vessels near the base of the loop caused by its movement.
Congenital prepapillary venous loops ( Figure 6.01J–L ) and macroretinal vessels should be differentiated from acquired dilated venous collateral channels caused by retinal venous obstruction (see Figure 6.81J and K ) and meningioma of the optic nerve (see Figure 15.16 ).
Congenital Retinal Macrovessels and Arteriovenous Communications
A large aberrant retinal vessel, more often a vein than artery, may extend from the optic disc into the central macular area, where it typically sends tributaries across the horizontal raphe ( Figures 6.02H–J and 6.03A–I ). In some patients, both an artery and a vein are affected. Visual function is usually normal. Fluorescein angiography typically shows no permeability alterations but may show small areas of capillary nonperfusion and focal capillary dilations ( Figure 6.03C and D ). In some cases the capillary bed separating the dilated artery and vein may be normal ( Figure 6.02H–J ). In others there is a direct arteriovenous anastomosis ( Figure 6.03E–G ). Changes in blood flow or permeability within these communications may precipitate loss of visual function ( Figure 6.03A and B, and E–G ) and are reported following bungee jumping. These malformations typically occur unilaterally in single or multiple sites. There is a predilection for involvement of the papillomacular bundle area and the superotemporal quadrant. Both sexes are affected. Detection of the anomaly usually occurs on routine examination. Retinal macrovessels may occasionally be associated with similar vascular anomalies affecting the conjunctiva and mouth ( Figure 6.03J–L ). Macrovessels are isolated findings and should be differentiated from large-caliber retinal vessels (artery or vein) associated with anomalies such as Coats’ disease, retinal capillary hemangioma, familial exudative vitreoretinopathy (FEVR), incontinentia pigmenti, and other peripheral vascular occlusive diseases.
Retinal arteriovenous anomalies have been subdivided into groups, depending on the severity of the anomaly. Archer’s group 1 comprises patients with retinal macrovessels with interposition of an arteriolar or abnormal capillary plexus between the major communicating artery and vein. These well-compensated arteriovenous communications rarely extend to involve the papillary vasculature and are rarely associated with cerebrovascular malformations.
Patients in group 2 demonstrate direct arteriovenous communications without the interposition of capillary or arteriolar elements ( Figure 6.04 ). These dilated arteriovenous communications, sometimes referred to as arteriovenous aneurysms or racemose aneurysms, may be single or multiple. Leaking macroaneurysms occasionally develop on these enlarged vessels ( Figure 6.04B ). Angiography demonstrates a short dye transit time but usually no evidence of extravascular leakage. The neighboring microvasculature may be altered, and there may be beading and multiple fusiform dilations of the large-vessel walls. Capillary nonperfusion or an absence of capillaries may be evident in the neighborhood of major vessels. These arteriovenous communications typically remain stationary. In some cases decompensation may occur and cause hemorrhages ( Figure 6.04F and G ), focal areas of extravascular exudation and perivascular scarring ( Figure 6.04B ), and neovascular glaucoma. Occlusion of a portion of or the entire malformation may occur ( Figure 6.04D and E, and H and I ).
In group 3 patients ( Figure 6.05 ) there are many anastomosing channels of large caliber that are so intertwined and convoluted that separation into their arterial and venous components may be difficult. Visual acuity is usually poor. Ophthalmoscopically and angiographically, the retina may show perivascular sheathing, exudation, and pigmentary degeneration. Some eyes may be blind from birth. Patients with severe retinal involvement are the most likely to have periorbital or cerebral involvement (Wyburn–Mason syndrome).
Complications of these vascular anomalies include intraretinal hemorrhage, aneurysm formation with intraretinal exudation, retinal artery occlusion, Valsalva retinopathy, central and peripheral retinal vein occlusions, neovascular glaucoma, vitreous hemorrhage, arterial macroaneurysm, and macular hole ( Figure 6.04B, E, G, and I ). Severe visual loss caused by occlusion of the malformation occurs infrequently ( Figure 6.04D and E ). Slow visual loss may occur because of mechanical compression of the optic nerve. Spontaneous regression of the lesions may occur occasionally. The histopathology of arteriovenous communications identical to those seen in humans has been described in rhesus monkeys ( Figure 6.04J–L ). Anomalous arteriovenous communications should be distinguished from those acquired secondary to peripheral vascular occlusive disease (see Figure 6.81J and K ).
Photocoagulation treatment may occasionally be warranted in those patients who develop exudative maculopathy.
Anomalous Foveal Avascular Zone
Controversy exists about the development of the foveal avascular zone (FAZ); one school believes the future FAZ is initially vascularized, and by a process similar to apoptosis the capillaries are lost to form a capillary-free zone. Absence of the FAZ and multilayered foveola seen in retinopathy of prematurity (ROP) is explained by this theory. The other school studied seven retinal whole mounts aged between 26 and 41 weeks’ gestation and found a blood vessel-free zone in all retinas, including at the 26-week gestational age. This ring was open temporally at age 26 weeks and closed by 37 weeks’ gestation to form a complete circle. It is believed that the superior and inferior blood vessels grow faster than the horizontal raphe and the nasal vessels grow faster than the temporal ones, resulting in the open temporal ring till about the 37-week gestational age. The diameter of the FAZ gradually decreased in size from 500 μm at 35 weeks to 300–350 μm at 40 weeks. After birth, the accelerated retinal growth stretches the foveal pit, making it wider and shallower; this remodeling of the FAZ continues to occur even up to 15 months to eventually yield an FAZ that is 500–750 μm in size.
It is likely various factors influence formation of the foveal vascular zone during development: astrocytes, macular pigment, ganglion cells, vasoendothelial growth factor (VEGF) levels and their alteration in hypoxia, to consider a few. Whatever the insult that allows blood vessels to invade the future foveal pit during development ( Figure 6.06 ), this in turn likely prevents normal foveal pit formation, resulting in a multilayered foveal center ( Figure 6.06E, F, K, and L ). Hypoplastic fovea with small or absent FAZ associated with multilayered foveal pit on OCT is a feature of albinism, chiasmal misrouting, ROP, and aniridia. It is likely we will discover more developmental vasculopathies and other disorders that harbor a multilayered foveal center.
Obstructive Retinal Arterial Diseases
Pathophysiologically, diseases may cause obstruction of the retinal arterial blood flow, primarily through one or a combination of the following processes: (1) embolism; (2) vascular narrowing; (3) thrombosis; (4) arterial spasm; (5) vascular narrowing caused by extravascular disease; and (6) reduction in blood flow caused by carotid or ophthalmic artery obstruction, lowered systemic blood pressure, or elevated intraocular pressure.
Obstruction of the retinal circulation may be caused by emboli derived from within the human body (endogenous emboli) or from without (exogenous emboli).
Endogenous Embolization From the Major Arteries and Heart
Emboli derived from ulcerated atheromatous plaques in the carotid artery, occurring either spontaneously or during manipulation of the carotid artery during arteriography or surgery, are probably the most common cause of major retinal arterial occlusions ( Figures 6.07–6.10 ). Other important sources of emboli are diseased or anomalous heart valves. Embolization from the heart may occur spontaneously or during open-heart surgery or coronary artery angioplasty. Patients with embolic occlusion usually experience sudden monocular loss of vision. This loss may be antedated by episodes of transient loss of monocular vision lasting 1–2 minutes (amaurosis fugax) in 20–25% of cases, and transient ischemic attacks in approximately 5–10% of cases. The average age of onset of symptoms is approximately 60 years. Fewer than 10% of occlusions occur in persons under 30 years of age. Occlusion is more common in men than in women. In all, 50–75% of patients over 40 years of age with retinal artery occlusion will have clinical evidence of carotid artery disease. In younger patients the emboli are usually derived from heart valves damaged by rheumatic fever, congenital anomalies of the heart valves and great vessels, or prolapse of the mitral valve (Barlow’s syndrome) ( Figure 6.07E–I ). Most patients with central retinal artery occlusion (CRAO) will have a small area of preservation of light perception caused by the presence of small cilioretinal arteries ( Figure 6.08D and K , arrow). In patients with no light perception, the physician should look for evidence of abnormalities of choroidal and optic nerve head circulation.
If retinal artery obstruction is incomplete and of short duration, only a slight gray haze may result, and little or no permanent damage to the retina may occur ( Figure 6.09G and H ). If the block is more complete, progressive whitening and swelling of the inner half of the retina develop ( Figure 6.07A and E ). These physical changes are caused by denaturation and breakdown of the normally transparent intracellular protein, an increase in the intracellular water, and, finally, complete cellular necrosis ( Figure 6.10I ). Acute ischemic whitening of the retina is a more accurate descriptive term for this change than retinal edema, which is best reserved for retinal thickening secondary to the accumulation of serous fluid escaping from retinal capillaries into the extracellular space, producing multiple cystoid changes in the outer retinal layers. Acute ischemic retinopathy may be localized (cotton-wool patch), as in small arteriolar obstruction, or more diffuse, as in obstruction of the central retinal artery or one of its major branches. Intensified retinal whitening along the peripheral edge of ischemic areas that cut across nerve fiber layers is related to the damming effect of the orthograde and retrograde axoplasmic flow.
Patients with visual loss caused by acute retinal artery obstruction usually seek treatment in the first week after obstruction and show a variety of clinical pictures, depending on the portion of the retinal arterial tree involved. In central retinal artery obstruction, widespread ischemic whitening of the retina occurs, except in the foveolar area (cherry-red spot), whose blood supply is derived from the choriocapillaris ( Figures 6.07A and 6.08G ), and except in some patients in whom focal peripapillary areas are supplied by a cilioretinal artery. Absence of the cherry-red spot in patients with CRAO should suggest the presence of choroidal vascular ischemia as well. In some patients, particularly those with chronic systemic hypertension, transient obstruction of the central retinal artery may produce a peculiar picture of multiple gray patches of retinal whitening simulating that seen in Purtscher’s retinopathy ( Figures 6.07J–L ; see Figures 6.23H, and 6.25J ). This pattern is probably the result of regional variations in arterial perfusion that occur normally or that are the result of formation of collateral pathways of retinal capillary flow caused by focal narrowing of the origin of the first-order arterioles in hypertensive patients. The visual prognosis in patients showing this pattern of retinal whitening is relatively good.
Branch artery obstruction may be overlooked or mistaken for other disease processes, particularly if the patient has a central scotoma caused by obstruction of a cilioretinal artery or other small arterioles supplying most of the macular area. Varying degrees of arterial narrowing occur. Segmentation of the blood column indicates marked slowing of arterial flow ( Figure 6.07A, H, and I ). Often one or more emboli are visible in the arterial tree, either as a large embolus at a bifurcation of the central retinal artery on the optic nerve head ( Figures 6.09 G and H and 6.10K and L ) or as one or more emboli lodged at distal bifurcations ( Figure 6.09D ).
Three major types of emboli occur. Platelet fibrin emboli are dull, gray-white, often elongated plugs that are subject to fragmentation and movement into more distal arterioles ( Figure 6.09J and K ). They may be either single or multiple and are most often lodged at a bifurcation. Cholesterol emboli are often multiple, yellow or copper-colored iridescent globules that are most often seen in the peripheral radicles on the temporal side of the fundus ( Figures 6.09D and 6.10C ). They are often unassociated with obstruction of blood flow. When causing obstruction, cholesterol emboli are usually located near the optic nerve head. Calcific emboli are usually single, solid, white, nonrefractile, ovoid or angulated emboli derived from the aortic or mitral valve ( Figure 6.10A, B, K, and L ). They are usually near the optic nerve head and, unlike cholesterol emboli, which often disappear in a few days, they may remain visible permanently. Occult calcified emboli may be detected ultrasonographically at the level of the lamina cribrosa in patients with CRAO and in some patients who present with ischemic optic neuropathy. The narrowest site of central retinal artery is where the artery perforates the dural sheath and enters the optic nerve; any of the three types of emboli can lodge here and not be visible. Occasionally a stream of emboli may be present, many behind the lamina cribrosa, hence not visible. Cholesterol emboli arise primarily from atheromatous disease affecting the proximal carotid artery. Calcific emboli arise primarily from the aortic valve and less often the aorta and carotid artery.
Focal areas of periarterial sheathing and focal accumulation of serum lipids within the artery wall at the site of embolic damage to the endothelium may be evident rather than the emboli themselves ( Figure 6.09J ).
Because both platelet fibrin and cholesterol emboli are soft and consequently become rapidly fragmented and cast into the distal radicles of the retinal circulation, fluorescein angiography often fails to demonstrate complete obstruction of either a branch or the central retinal artery by the time the patient reports for examination ( Figure 6.09J and K ). Likewise, the rapid development of collateral flow around an embolus obstructing the central retinal artery behind the level of the lamina cribrosa may restore intraocular blood flow to nearly normal levels soon after the occlusion. The best scenario for improvement in vision is with occlusion at the entry of the central retinal artery into the optic nerve, since several pial and intraneural collaterals vessels can contribute to filling the central retinal artery distal to its occlusion. In most cases, however, fluorescein angiography reveals a delayed appearance time and an increased retinal circulation time in the area of the occluded segment ( Figure 6.09B ). In complete occlusion of the central retinal artery, no dye enters the eye by the artery, but dye filling the optic nerve capillaries by way of the ciliary artery circulation may pass through collateral channels and fill the proximal branches of both the central retinal vein and artery ( Figure 6.07A–D ). In complete branch artery obstruction the arterial tree may be perfused in a retrograde fashion by neighboring collateral vessels. In most instances an embolus lodged in an arterial bifurcation either on the optic nerve head or in the periphery is only partly successful in impeding the flow of fluorescein into the artery distal to the site of obstruction. In some instances the dye seeps by the embolus, and in others it bypasses the embolus by way of collateral flow. A significant reduction in flow is usually demonstrated angiographically in either case ( Figure 6.07A–D ). Retinal flow remains depressed even after dissolution of the embolus because of the collapse of the capillary bed by the ischemic and swollen retinal tissue. Fragmented emboli may completely plug the paramacular arterioles. The dye column entering the partly blocked area may show a pattern of laminar flow. In other cases there may be alternating nonfluorescent zones caused by packets of erythrocytes and hyperfluorescent zones caused by stagnant plasma ( Figure 6.07D and H ). Focal fluorescein leakage may occur at the site of the obstructing emboli and less often at sites where emboli have previously impacted on the arterial wall ( Figures 6.07F and 6.09 ). Failure of fluorescein to leak from the blood vessels distal to the site of arterial obstruction, even when circulation has been partly restored, testifies to the resistance of the retinal vessel endothelium to the effects of ischemia. In rare instances massive embolization of the retinal circulation may cause marked damage to the endothelium of the major retinal artery segments and produce striking periarterial dye leakage. Small emboli frequently observed in the arterial tree beyond the site of obstruction and elsewhere in the fundus usually show little or no tendency to alter the flow of fluorescein. No staining occurs at the site of these nonobstructing emboli. Very few patients with endogenous retinal arterial embolization show angiographic evidence of embolic occlusion of the choroidal circulation.
Some patients with branch artery occlusion may subsequently develop another branch artery occlusion or central retinal artery obstruction ( Figure 6.09G–I ). Patients with recurrent episodes of multiple branch retinal artery occlusions are more likely to have a nonembolic cause for the obstruction. (See discussion of recurrent branch retinal artery occlusion (Susac syndrome), p. p0380 in Chapter 6.)
Electroretinography in eyes with central retinal artery obstruction reveals loss of the oscillatory potential and transient depression of the b-wave with either a normal or supernormal a-wave. The electro-oculogram is diminished or absent.
The intraocular pressure may be subnormal in both the affected and the opposite eye in some patients with both branch artery and CRAO. Relative hypotony in the affected eye suggests the presence of ciliary as well as retinal arterial obstruction. The reported incidence of neovascular glaucoma after CRAO varies from under 2.5% to 15% or more. Some authors suggest that it occurs most often in patients with chronic ocular ischemia associated with severe carotid or ophthalmic artery disease, whereas others have not found this association. Glaucoma usually develops within 2–3 months, often earlier than occurs with central retinal vein occlusion likely due to the rapid onset of retinal ischemia. Even rarer is the development of neovascularization of the disc and subsequent vitreous hemorrhage ( Figure 6.08D ).
During the first few days after retinal artery occlusion, light microscopy reveals swelling of the inner half of the retina. The swelling is caused by intracellular edema and cellular dissolution ( Figure 6.10I ). Histologic examination 3 or 4 weeks later reveals marked loss of the inner retinal layers and preservation of the outer retinal layers ( Figure 6.10J ).
The white inner retinal lesions caused by arterial obstruction should be differentiated from white lesions caused by: (1) retinitis (e.g., toxoplasmosis, acute multifocal inner retinitis ; see Behçet’s disease, Fig. 11.40 , Fig. 11.41 ); (2) inflammatory disease of the choroid and retinal pigment epithelium (RPE) (e.g., acute posterior multifocal placoid pigment epitheliopathy); (3) outer retinal whitening from choroidal ischemia caused by prolonged elevation of the intraocular pressure (see Figure 3.63 ); (4) retinal contusion (commotio retinae, Berlin’s edema); (5) neoplasia (e.g., reticulum cell sarcoma); and (6) opaque subretinal fibrin (e.g., idiopathic central serous chorioretinopathy; Figure 3.03J , Figure 3.04J and L ). Emboli may be simulated by atheromatous plaques developing within the arterial wall at a focal site of retinal artery endothelial defect, e.g., patients who are prone to develop arterial macroaneurysms (see p. p0515 in Chapter 6) or focal arterial wall damage caused by previous impact of an embolus, an immune complex, or inflammatory reaction, e.g., in patients with bilateral idiopathic recurrent branch retinal artery occlusion (see Figures 6.19–6.21 ); acute retinal necrosis caused by herpes zoster virus (see Chapter 10); toxoplasmosis (see Kyrieleis plaques, and Figure 10.22F–H ); chronic uveitis ; or neoplasia (see Figure 13.31H ).
Inner retinal infarction occurs experimentally after complete occlusion of the central retinal artery lasting beyond approximately 1 1 / 2 hours. Only occasionally does the patient who develops an acute retinal arterial obstruction report for therapy within the first few hours. Treatment, therefore, is infrequently beneficial. Nevertheless, in some patients with incomplete arterial obstruction, obstruction due to spasm, or obstruction of short duration, the ischemic damage associated with the retinal whitening may be reversible ( Figure 6.09G and H ). Even the presence of biomicroscopic evidence of slow blood flow (rouleaux formation) does not exclude the possibility of visual recovery. Therefore, in any patient with a history of occlusion of 24 hours or less, therapy consisting of paracentesis, intermittent massage, breathing of 95% oxygen and 5% carbon dioxide, and administration of acetazolamide may be helpful. Other modes of therapy that have been employed include the intravenous administration of vasodilators such as papaverine, perfusion of the ocular circulation by cannulation of the supraorbital artery, hyperbaric oxygen, surgical removal of the embolus, and Nd-YAG laser disruption of the embolus. Experimental use of recombinant tissue plasminogen activator to lyse retinal arterial thrombi was first reported with retinal artery occlusion. Most recent, has been the interest in intra-arterial thrombolysis by cannulating the ophthalmic artery via the femoral artery and injecting tissue plasminogen activator. This treatment has a role if it can be performed within 4 hours of occlusion. When arrangements for intra-arterial cannulation are not possible, intravenous use of tissue plasminogen activator in the correct settings to manage any complications can be tried if the patient arrives within 4 hours of visual loss. Even without therapy some patients will experience a remarkable visual recovery.
In the absence of ophthalmoscopic evidence of emboli in patients over 65 years of age, a sedimentation rate should be obtained along with an exhaustive review of systems to exclude the possibility of cranial arteritis as the cause of the occlusion. Auscultation of the heart and carotid arteries and comparison of the pulsation of the carotid arteries with the ophthalmic artery pressures, either by ophthalmodynamometry or by finger pressure, are useful measures for determining the source of the emboli. Transesophageal echocardiography in addition to transthoracic echocardiography is necessary for detecting mitral valve prolapse or other cardiac abnormalities such as patent foramen ovale, endocardial vegetations, and noninfectious masses. All patients should have a medical evaluation. In patients who are reasonable surgical candidates and who have no other explanation for the emboli, the evaluation should include at least digital subtraction carotid arteriography, which may demonstrate evidence of carotid stenosis and/or atheromatous plaques ipsilaterally in approximately 50% of cases.
Normal retinal transparency usually returns 2–3 weeks after acute retinal artery obstruction, but the retinal flow through the involved area is only partly restored. This probably is primarily caused by collapse of the capillary bed accompanying the postnecrotic atrophy of the retina. In most cases following central artery obstruction and in many cases following branch artery obstruction, optic atrophy and some narrowing of the retinal arterial tree occur. In others with less ischemic retinal damage the retina may return to a relatively normal appearance. Some with persistent low-grade chronic retinal ischemia may show multiple peripheral retinal hemorrhages (venous stasis retinopathy) identical to that seen in patients with carotid artery obstruction. Although visual recovery is generally poor, as many as 35% of patients after central retinal artery obstruction regain 20/100 or better visual acuity. Only 1–5% of patients with CRAO will develop rubeosis and glaucoma, usually within 1–3 months. These latter patients are likely to have significant obstruction of the carotid artery on the ipsilateral side. Relatively few patients with embolic retinal artery obstruction in one eye develop a similar process in the second eye. Some authors have found that the life expectancy for patients with retinal artery obstruction is reduced, whereas others have not. Although there is an increased incidence of stroke, most patients die of atherosclerotic heart disease.
It is clinically relevant to classify CRAO into:
nonarteretic CRAO: most often due to embolism
arteretic CRAO: secondary to giant cell arteritis, almost all associated with ischemic optic neuropathy
transient CRAO: recovers almost complete vision within a few hours of occlusion.
Systemic risk factors and retinal artery occlusion
In 33 patients with CRAO seen over 11 years, 64% (21 patients) showed additional vascular risk factors after the event; hyperlipidemia was seen in 36%, new diagnosis or poor control of hypertension in 21%, 27% had >50% carotid stenosis, 18% (6 patients) needed carotid endarterectomy, and two developed a vascular event, with coronary artery syndrome in one and a stroke in the other. Hayreh et al. have reported in 439 patients (499 eyes) with CRAO and branch retinal artery occlusion a significantly higher prevalence of hypertension, smoking, diabetes mellitus, ischemic heart disease, and cerebrovascular disease compared to a comparable US population. They also report a 71% incidence of carotid plaques in patients with CRAO and 66% in branch retinal artery occlusion, abnormal echocardiogram in 52% of CRAO and 42% of branch retinal artery occlusion. Hence patients who present with a central or branch retinal artery occlusion should be (re)assessed for the associated risk factors and necessary corrections undertaken.
Atheromatous Retinal Arterial Embolization Following Use of Onyx to Embolize Internal Carotid Aneurysm
Onyx is a liquid embolic agent used for occluding intracranial, renal, and peripheral aneurysms and arteriovenous malformations (AVMs). It comes in ready-to-use vials containing ethylene-vinylalcohol copolymer, dimethylsulfoxide, and tantalum. The polymer is dissolved in dimethylsulfoxide, and micronized tantalum powder, which is radiopaque, is added. Concentrations of 6, 6.5, and 8% are variably used. The higher the concentration, the more viscous is the agent. After injecting heparin, a microcatheter is threaded to the nidus of the aneurysm and dimethylsulfoxide is first injected to fill the dead space in the catheter, followed by the selected onyx concentration. The aneurysm is filled to its neck under fluoroscopic guidance. This material forms an acrylic cast occluding the aneurysm completely.
During the procedure, manipulation of the guidewire/catheter and other hardware near the carotid bulb can dislodge a stream of cholesterol plaques that can embolize the retinal and choroidal vessels. Two such cases are illustrated in Figures 6.11 and 6.12G–J . The overwhelming feature seems to be the multiple emboli affecting the retinal and/or the choroidal circulation. Since these two cases, attention is being paid by the interventional neuroradiologists to minimize manipulation of the guidewire and other hardware at the carotid root. Other complications include bleeding at the site of the AVM, bleeding at the percutaneous entry site, and anesthetic complications resulting in oxygen desaturation from dimethylsulfoxide, though small and transient most of the time.
Other Causes of Endogenous Embolization
Emboli from atrial myxomas, benign polypoid tumors of endocardial origin arising in the left atrium, should be suspected in patients who have symptoms of retinal artery occlusion, usually involving the left eye, and repetitive neurologic symptoms suggestive of ipsilateral ischemia affecting the distribution of the middle cerebral artery. Signs and symptoms suggesting pulmonary hypertension and bacterial endocarditis also may be present. The tumor is more common in middle-aged women and 75% originate in the left atrium. Tumor embolization of the ciliary arteries (swelling of the optic discs and choroidal lesions) has been shown clinically and histopathologically. The relatively large size and friable nature of the embolus or emboli as compared to a cholesterol or fibrin platelet embolus is likely the reason for multiple, large-caliber vessels such as the ophthalmic, choroidal, and cerebral involvement. Embolization of the ciliary and retinal vessels with tumor emboli from extracardiac sources has been observed ( Figure 6.10D–F ).
Following liberation of neutral fat into the circulation at the time of long-bone fracture or, less often, after injury to fatty tissues, patients may experience sudden cardiopulmonary and neurologic deterioration. This usually occurs after a latent period of 12–36 hours. The pathogenesis is poorly understood but apparently is the result of release of free fatty acids, a toxic vasculitis, platelet fibrin thrombosis, and obstruction of small vascular radicles by macroaggregates of fat. Approximately 50% of patients with fat embolism syndrome may show retinal abnormalities, including cotton-wool patches, small blot hemorrhages, and, rarely, obstruction of major branches of the central retinal artery ( Figure 6.12A and B ) or a fundus picture of Purtscher’s retinopathy (see discussion to follow). Young people presenting with retinal artery occlusion following a fracture should alert the physician for presence of a patent foramen ovale, the incidence of which is approximately 29% in the general population ( Figure 6.12A and B ).
Embolization Caused by Intravascular Aggregation of Blood Elements
The spontaneous aggregation of thrombocytes, leukocytes (Purtscher’s), or erythrocytes (sickle-cell; see later) may be the cause of embolic occlusion of the retinal vasculature in certain disease states.
Disseminated Intravascular Coagulopathy
Disseminated intravascular coagulopathy, or pathologic aggregation of thrombocytes, may cause vascular occlusion in many of the body organs. This occlusion is much more likely to affect the choroidal arterioles and choriocapillaris than the retinal circulation (see Chapter 3). Thromboembolization of the retinal circulation is probably responsible for arterial occlusions that may affect the brain, heart, lungs, and kidneys of patients with idiopathic persistently elevated blood eosinophilic count (Churg–Strauss syndrome; see Chapter 11).
Protein S Deficiency
Protein C and protein S are vitamin K-dependent proteins. Protein S is a cofactor for protein C. Protein C is activated to protein Ca, which inactivates factor Va and VIIIa, thus acting as an anticoagulant, and proteolytically inactivates the inhibitor to tissue plasminogen activator, thus increasing fibrinolytic activity. Deficiency of protein C and S can increase thrombus formation in both venous and arterial circulation. The deficiencies can be congenital (autosomal-dominant) or acquired. Homozygous deficiency results in life-threatening thrombotic disease in the neonatal period, whereas heterozygous deficiency may result in symptoms in early adulthood or later. Acquired deficiency occurs due to poor hepatic synthesis of proteins. The thrombus occurs at the site of the occlusion and has been reported in the central and branch retinal artery ( Figure 6.12C and D ), cerebral, common carotid, brachiocephalic, and as a cause of anterior ischemic optic neuropathy. Recurrent branch arterial occlusions may occur in some patients, simulating Susac syndrome. The absence of arterial wall staining on fluorescein angiography (see Figure 6.21C and E ) helps differentiate Susac sydrome from this. Any artery or vein can be affected. Other factors such as pregnancy, trauma, childbirth, or surgery can sometimes precipitate thrombosis in these patients. Treatment involves anticoagulation with heparin and warfarin.
Leukoembolization (Purtscher’s and Purtscher’s-Like Retinopathy)
Intravascular aggregation of leukocytes in response to unusual activation of complement C5a has been incriminated as the possible cause of retinal arterial embolization that produces the ophthalmoscopic picture of Purtscher’s retinopathy. This response occurs after trauma (see Figure 8.06 ) and in patients with acute pancreatitis ( Figure 6.13A–F ). Similar findings have been reported in patients with collagen vascular diseases ( Figure 6.14 ) ; in patients receiving hemodialysis ; in patients with chronic renal failure or hemolytic–uremic syndrome ; during plasmapheresis for thrombotic thrombocytopenic purpura and thrombotic thrombocytopenic purpura per se, Still’s disease and ( Figure 6.15A–E ), in normotensive obstetric patients after a precipitous delivery induced with intravenous oxytocin (Pitocin), following delivery by cesarean section ( Figure 6.13G–K ); and in patients with amniotic fluid embolism, HELLP syndrome (see Figure 3.58 ), fat embolism, cardiac aneurysm, ophthalmic artery obstruction, hypereosinophilia syndrome ( Figure 6.15F–H ), post bone marrow transplant, cytotoxic drug therapy and retrobulbar anesthesia (see Figure 8.12J ). The frequent association of central nervous system symptoms in patients whose ophthalmoscopic picture resembles Purtscher’s retinopathy suggests that leukoembolization may affect the cerebral vessels as well.
Purtscher described multiple, superficial, white retinal patches, superficial retinal hemorrhages, and papillitis occurring in five patients with severe head trauma (see Figure 8.06 ). The pathogenesis of the fundus changes is not completely understood. The white lesions were attributed to lymphatic extravasations secondary to a sudden increase in intrathoracic pressure, fat embolism, reflux shock waves through the venous system, air embolism, and, later, granulocytic aggregation.
Chronic alcoholics hospitalized for treatment of acute pancreatitis, with or without signs of central nervous system involvement, may suddenly lose vision in both eyes secondary to a fundoscopic picture identical to that of Purtscher’s retinopathy ( Figure 6.13A–F ). Shapiro and Jacob studied blood samples of 12 consecutive alcoholic patients admitted for acute pancreatitis and were able to demonstrate marked granulocyte aggregation, reflecting the presence of activated complement C5a in eight patients. This lends some support to the concept that leukoembolization may be responsible for the fundus picture.
Complement, platelet, and neutrophil activation and endothelial dysfunction and inflammation characterize pre-eclampsia. These likely exert an effect similar to the mechanism of pancreatitis causing leukocyte and platelet aggregation and vascular thrombosis in Purtscher’s-like retinopathy occurring around childbirth.
Most patients with collagen vascular disease have normal fundi. Some patients, usually those who have hypertension, may develop retinal or choroidal changes (see pp. p0495-p0510 in Chapter 6, and s0390 in Chapter 3). A few patients, particularly those with an exacerbation of disseminated lupus erythematosus, lupuslike syndrome associated with autoantibodies to Sjögren’s syndrome A antigen, dermatomyositis, Still’s disease and scleroderma, may develop acute loss of vision in one or both eyes with a fundoscopic picture suggesting multifocal embolic retinal arterial occlusions simulating those seen in Purtscher’s retinopathy ( Figures 6.16 and 6.14 ). These patients often have central nervous system symptoms as well. The occlusive process may be confined to the posterior pole or may involve extensively the peripheral fundus ( Figures 6.16 and 6.14A–F ). The retinal arterioles and arteries may be partly filled with a milky white material. Those with involvement of the periphery may develop severe retinal neovascular proliferation and vitreous hemorrhage. The presence of antiphospholipid antibodies in patients with systemic lupus erythematosus also plays an important role in retinal vascular thrombosis. (See unusual causes for retinal artery and arteriolar thrombosis in subsequent sections.)
The retinal whitening is referred to as a Purtscher “flecken” and it typically has a clear zone between its edge and an adjacent retinal arteriole ( Figure 6.13A, L ). Fluorescein angiography in all of these patients who have an ophthalmoscopic picture simulating Purtscher’s retinopathy is similar. It reveals multiple focal areas of retinal arteriolar and arterial obstruction, adjacent areas of capillary nonperfusion, and extensive leakage from the vessels in the areas of infarction ( Figures 6.13 and 6.14 ). This latter feature is uncommonly seen in branch arterial occlusion caused by emboli from the heart and great vessels. Resolution of the white peripapillary and macular ischemic areas may require several months. Varying degrees of narrowing and sheathing of the retinal arteries, optic atrophy, and retinal neovascularization may occur ( Figure 6.14D–F ). In some patients with collagen vascular disease, evidence of occlusive arterial disease may be confined to the peripheral fundus and be associated with evidence of vasculitis and venous stasis.
Histopathology of an eye studied 23 days after onset of Purtscher’s retinopathy in a patient secondary to pancreatitis, showed material occluding retinal and choroidal arterioles to be positive for fibrin. Focal areas of retinal edema, cystoid degeneration, and loss of inner retinal architecture with a sharp demarcation from an area of normal retina was noted.
Further research is required to determine the role of complement activation and leukocytic aggregation and embolization in all of these disorders resembling Purtscher’s retinopathy. By the time many of these patients consult the physician, the level of complement C5a may have returned to nearly normal. If elevation of complement proves to be important, then the use of systemic corticosteroids has some rationale.
Although the role of erythrocytic aggregation in the pathogenesis of retinal vascular occlusion is uncertain in diseases such as diabetes mellitus and Eales’ disease, there is good evidence that it is important in the case of sickle-cell disease. Increased deformity of the erythrocytes caused by hypoxia in the peripheral fundus is probably responsible for occluding the small retinal arterioles, capillary nonperfusion, and reactive proliferation of new vessels into the vitreous (for further discussion, see 118 in Chapter 6).
Drug users may prepare a suspension for injection by dissolving crushed tablets, most often methylphenidate (Ritalin), in boiling water. The suspension may be inadequately filtered and injected intravenously, causing showers of insoluble fillers, principally talc and cornstarch, to embolize the pulmonary vasculature. Large-caliber collateral vessels are created around areas of occluded pulmonary vasculature after repeated embolization. The trapped particles also produce pulmonary granulomatosis and pulmonary hypertension; particles that are 7 μm or smaller can traverse the intact pulmonary bed. Together with larger particles that pass through the pulmonary collateral vessels, they may be deposited as multiple, tiny, glistening, irregularly shaped particles in the retinal vasculature, particularly in the macular area ( Figure 6.17A, B, and D ). In most patients they produce no symptoms. In some patients deposits of this material in the peripheral retina may cause areas of retinal capillary nonperfusion and retinal neovascularization at the junction of perfused and nonperfused retina similar to that in sickle-cell disease. Angiography may show no evidence of obstruction or may show small areas of capillary nonperfusion, microaneurysmal changes, and widening and irregularities of the FAZ. Some such patients may have subnormal acuity. Optic disc neovascularization, vitreous hemorrhage, and traction retinal detachment have occurred. Only those patients with long-term drug use develop fundoscopic changes. The retinopathy has been produced experimentally in primates. In patients with a patent foramen ovale, that is prevalent in 29% of population, larger particles can occlude branch retinal arteries ( Figure 6.17C ). Biopsy of the pulmonary nodules showed material consistent with talc that was birefringent under polarizing microscope ( Figure 6.17F and G ). Other foreign materials may occasionally lodge in the retinal vessels of drug addicts. In those with retinal artery occlusion after use of cocaine, heroin, and methamphetamine, the mechanism of the retinal artery occlusion may be pharmacologic rather than embolic. (See Chapter 9). Very tiny talc particles in a chronic methamphetamine snorter using for more than 15 years has been reported. The mechanism may be from absorption of the particles into the nasal mucosal vessels eventually reaching the lungs and the retina.
Retinal Emboli From Artificial Cardiac Valves
Cloth particles derived from cloth-covered artificial cardiac valves may cause loss of central vision secondary to retinal arterial embolization.
Retinal Arterial Embolization Following Corticosteroid Suspension Injection
Injection of corticosteroid suspensions such as methylprednisolone acetate (Depo-Medrol) into the nasal mucosa, lips, face, scalp, tonsillar fossa, and orbit, as well as directly into periocular lesions (chalazion, hemangioma), may pass in a retrograde fashion into the ophthalmic, central retinal, and short ciliary arteries and produce visual loss caused by infarction of either the retina or the optic nerve. Both eyes may occasionally be affected. The presence of the drug in both the retinal and choroidal circulation may be evident over widespread areas in the fundus ( Figures 6.17I and J and 6.18A–C ). In some cases the patient may regain normal visual acuity. A similar picture has been produced experimentally in dogs.
Other causes of exogenous embolization include retrobulbar injection of silicone and fat ( Figure 6.18F–I ), 2205 surgical embolization of intracranial arteries with polyvinyl alcohol, platelet transfusion, fragments of artificial heart valves and arterial implants, and air. A picture suggesting multifocal retinal artery occlusions after local anesthesia for blepharoplasty was attributed to tissue substance released into the lacrimal artery.
Obliterative Retinal Arterial Diseases
Arteriosclerosis and Atherosclerosis
Focal narrowing of the major arteries supplying the retina caused by arteriosclerosis and atherosclerosis with thrombosis may cause the typical picture of CRAO or, less often, branch retinal artery occlusion. It is probable that this mechanism for occlusion occurs less commonly than embolization, particularly in cases of branch artery occlusion. Systemic atherosclerosis may affect the ophthalmic artery and the central retinal artery up to the level of the lamina cribrosa, but rarely does it affect the more anterior portions of the central retinal artery. The reason for this is uncertain but may be related to the absence of the internal elastic lamina in the retinal arteries, which have a complete muscular coat out as far as the equator. Although primary atherosclerosis of the retinal arterial tree is rare, the formation of secondary, often nonobstructive atheromatous plaques at focal sites of retinal arterial wall damage may develop in association with a variety of disorders, including arterial macroaneurysms, usually in patients with hypertension (see p. s0210 in Chapter 6), toxoplasmosis retinitis (see Kyrieleis plaques, figure 10.22F-H ), bilateral idiopathic recurrent branch retinal artery occlusion (see p. s0150 in Chapter 6), acute retinal necrosis caused by herpes zoster (see Chapter 10) large-cell lymphoma (see figure 13.31H ), and chronic uveitis.
Unusual Causes of Retinal Artery and Arteriolar Thrombosis
Occlusion of the central retinal artery, presumably caused by thrombosis, may occur occasionally in association with systemic diseases including essential thrombocythemia, thrombotic thrombocytopenic purpura, homocystinuria, mild hyperhomocysteinemia in heterozygotes, antiphospholipid antibody syndrome (Snedden’s syndrome), protein S deficiency, ( Figure 6.16C–F ) protein C deficiency, and Lyme disease. Multifocal arteriolar occlusions associated with bone marrow transplantation may simulate Purtscher’s retinopathy. It is uncertain whether these arteriolar occlusions occur primarily as a complication of irradiation or some other mechanism such as leukoembolization. The administration of fibrinolytic agents, such as tranexamic acid, to reduce the chances of bleeding may occasionally promote spontaneous thrombosis and branch retinal artery occlusion.
Arteritis and Arteriolitis
A variety of inflammatory disorders, some infectious and some of unknown etiology, may cause acute obstruction of either or both the ophthalmic and retinal arterial circulation, e.g., cat-scratch disease, (see p. s0030 in Chapter 10), herpes zoster (see p. s0345), mucormycosis (see p. p0310 in Chapter 10), toxoplasmosis (see pp. p0325-p0395 in Chapter 10), giant cell arteritis (see figure 6.23 G-I ), hypereosinophilic syndrome, eosinophilic fasciitis ( Figure 6.13L and 6.15F–H ), Churg–Strauss syndrome (allergic angiitis and granulomatosis, Figure 11.51 ), Kawasaki disease, idiopathic multifocal retinitis (see p. 82 in Chapter 11), and acute multiple sclerosis (MS). Although the retinal occlusive disease seen in these patients, as well as in patients with collagen vascular disease, has been attributed by some authors to arteritis, the arterial obstruction may be caused by other mechanisms, including hypertensive arteriolar narrowing, immune complex vascular damage, thromboembolization or leukocytic aggregation, and embolization (see discussion under leukoembolization, pp. 28 in Chapter 6).
Idiopathic Recurrent Branch Retinal Arterial Occlusion (Susac Syndrome)
Apparently healthy individuals may develop, in one or both eyes, visual loss caused by recurrent episodes of multiple branch retinal arterial and arteriolar occlusions that often spare central vision ( Figures 6.19–6.21 ). The scotomata may be accompanied by photopsia, typically characterized as irregular shimmering, geometric lines or shapes of light just preceding a new scotoma and confined to the area destined to become scotomatous (45%); vestibuloauditory symptoms (50%); other transient focal neurologic symptoms, often affecting the face and upper extremities (30%) ( Figure 6.19A–F ); and a history of migraine (40%), defined as recurrent episodes of scintillating scotoma (with or without headache) or severe one-sided headache with nausea. Memory and cognition disturbances with confusion and bizarre behavior with mood and personality changes may accompany, precede, or antecede the other symptoms. The disease affects 20–40-year-olds of both sexes with a slight preponderance in females.
It is considered to be an autoimmune endotheliopathy involving the arterioles of the brain, eye, and cochlea and is also referred to as retinocochleocerebral vasculopathy. The focal retinal arterial obstruction is unassociated with visible emboli, may occur in the midportion of an artery and at arterial bifurcations, and is frequently associated with focal periarterial whitening and fluorescein angiographic evidence of segmental arterial staining near the site of the obstruction and elsewhere in the fundus ( Figure 6.19A–F ). Sheathing and multiple periarterial yellow-white plaques often develop along the obstructed arterial segment and may remain permanently ( Figure 6.19G, H, K, and L ). Egan et al. named these Gass plaques ( Figure 6.19 K ). In some cases only a ghost remnant of the completely occluded arterial segment remains ( Figure 6.21A and G ). These patients are subject to recurrent retinal artery occlusive events that, in some cases, may extend over a period of 10 years or more. Retinal, optic disc, and iris neovascularization may develop in 25% of eyes and requires photocoagulation or in some cases vitrectomy ( Figure 6.19I and J ). These patients are frequently subjected to multiple extensive unrewarding medical evaluations. Standard screening tests for blood dyscrasia, dysproteinemias, and coagulopathies, including those for antiphospholipid antibodies and natural anticoagulant deficient states; imaging tests of the carotid arteries, heart, and brain; and screening tests (excluding magnetic resonance imaging: MRI) for systemic vasculitis are typically negative. Johnson et al. found multiple lesions compatible with focal brain infarcts in one of three patients studied with MRI. The angiographic and ophthalmoscopic findings suggest that focal retinal arteritis and arteriolitis, perhaps caused by precipitation of immune complexes along the arterial wall, are responsible for the occlusions. The occasional association with serologic evidence of cytomegalic infection and protein S and protein C deficiency disease in these patients may be coincidental.
Most patients with idiopathic recurrent branch retinal artery occlusion are part of the triad of the syndrome of multiple branch retinal arterial occlusions, hearing loss, and encephalopathy (Susac sydrome). The triad sometimes is not apparent for a few years and the diagnosis may be delayed. The encephalopathy usually develops subacutely and often includes psychiatric features, personality change, and bizarre and paranoid behavior. The hearing loss is usually bilateral, asymmetric, and is often associated with tinnitus, vertigo, and ataxia. Low and medium frequencies are affected, localizing the lesion to the apical portion of the cochlea. MRI of the inner ear fails to show microinfarcts in the inner ear. MRI typically shows numerous infarcts in white and gray matter, more often in the periventricular region and the central part of the corpus callosum, and may show leptomeningeal involvement. The lesions in the corpus callosum are small, multifocal, and enhance in the early stages of the diseases ( Figure 6.21J ). They are responsible for the behavioral manifestations. The lesions are hyperintense on T2 fluid-attenuated inversion recovery (FLAIR). Diffuse tensor imaging may be able to detect white-matter abnormalities in the early phase of the disease. The clinical findings and MRI changes are often attributed to MS or acute disseminated encephalomyelitis. The key differentiating features on MRI are central corpus callosum involvement in Susac’s but peripheral in MS and acute disseminated encephalomyelitis, leptomeningeal involvement is limited to Susac, and basal ganglial lesions are seen more often in Susac and are rare in MS. The cerebrospinal fluid examination usually reveals minimal pleocytosis. The clinical course in these patients with encephalopathy, hearing loss, and multiple branch retinal artery occlusion can be self-limited, ranging from 1 to 2 years, with a good prognosis. However, in some patients, the disorder may be progressive and result in severe visual loss and death ( Figure 6.11G–L ).
Pathogenesis of the disease is poorly understood. Endothelial deposition of C4d demonstration histologically (Magro CM, unpublished data), serum anti endothelial antibodies at a titre of 1:960, and indirect immunofluorescence demonstration of IgG 1 subclass antibodies suggest the disorder to be autoimmune in nature. Elevated levels of factor VIII and von Willebrand factor antigen may be the result of endothelial damage. Response to steroids and immunosuppressives also lends strength to the autoimmune hypothesis.
A specific treatment is yet to be confirmed since the disease etiopathogenesis is not completely understood. Treatment has evolved over the years and currently is a combination of systemic corticosteroids, immunosuppressives, and immunomodulating drugs. For an acute severe presentation, intravenous immunoglobulin (IVIG, 2 g/kg divided over five doses) every other day along with a high dose of systemic steroids is begun. IVIG is given every month for the first year or so and then maintained at 2-monthly intervals indefinitely till the disease shows no flareups over a few years. Systemic steroid is maintained at a moderate dose for the first few months then at a low dose for a few years. Mycophenolate mofetil has been substituted as a steroid-sparing agent in some patients. Cyclophosphamide has also been used as a long-term immunosuppressant in place of IVIG. Most recently rituximab, a monoclonal antibody, is being tried. Some patients have a self-limiting disease that quietens in 1–2 years and do not require long-term maintenance therapy.
Young patients with branch retinal artery occlusion associated with idiopathic multifocal retinitis and neuroretinitis (cat-scratch disease) may simulate idiopathic recurrent branch retinal artery occlusion (see Chapter 10, Figure 10.04 ).
Retinal Arterial Obstruction Caused by Spasm
Some degree of reflex spasm probably plays a role in retinal arterial obstruction from many causes. The ocular fundi of patients with amaurosis fugax have been observed numerous times during an attack. The characteristic picture described is pallor of the optic disc and marked narrowing of the retinal arteries. With restoration of circulation, vision promptly returns. In some cases this spasm may be associated with recognizable causes, such as ocular migraine, collagen vascular disease, sickle-cell disease (see Figure 6.60A–H ), inhalation of cocaine ( Figure 9.13 ) and amphetamines, and administration of propranolol. It is probable that some cases of ischemic infarction resulting from retinal artery occlusion are caused by prolonged spasm of the central retinal artery. In the review by Brown and associates of a series of 27 patients under the age of 30 years who had retinal artery occlusion, the only associated finding was migraine headaches. Wolter and Burchfield reported a 12-year history of recurrent episodes of total vision loss in one eye associated with a cherry-red spot and complete recovery of vision in a 20-year-old man with ocular migraine. It is of interest that the photographs in their case show narrowing of the retinal veins rather than the arteries. This same phenomenon was noted in another patient by Dr. Mark Daily ( Figure 6.22H and I ).
Retinal migraine is a rare cause of transient monocular visual loss, first described by Galezowski in 1882. It is usually characterized by episodes of partial or complete reversible monocular visual loss ipsilateral to the headache and lasting less than an hour. Sometimes it can result in irreversible visual loss. The 2004 International Headache Society criteria for the diagnosis of retinal migraine are as follows :
At least two attacks fulfilling criteria B and C
Fully reversible monocular positive and/or negative visual phenomena confirmed by examination during an attack or by the patient’s drawing of a monocular field defect during an attack
Headache fulfilling criteria – migraine without aura begins during the visual symptoms or follows them within 60 minutes
Normal ophthalmological examinations between attacks
Not attributed to another disorder.
The condition is more common in young women in their second and third decades. The field defect may not always be from the retina; the optic nerve or the choroid may be the site of spasm, hence “monocular migraine” may be a better term. When examined during an episode these patients may have an afferent pupillary defect, constricted retinal arterioles, pallor of the optic disc, retinal whitening, and occasionally retinal venous constriction. The documentation of a visual field defect that completely reverses in association with headache on the side of the visual loss is necessary to make the diagnosis. Treatment with propranolol can prevent future episodes and should be begun in a confirmed case. These patients should be differentiated from patients with recurrent branch retinal artery occlusion of Susac syndrome, amaurosis fugax from carotid embolic disease, retinal artery occlusions from collagen vascular disease such as lupus and antiphospholipid syndrome, protein C and S deficiency, and in older patients from giant cell arteritis, polyarteritis nodosa, and eosinophilic vasculitis.
Retinal Arterial Obstruction Caused by Diseases of Surrounding Structures
Acute closure of the retinal arterial circulation may be caused by diseases primarily affecting the surrounding tissues, including inflammatory diseases such as retinal toxoplasmosis ( Figure 10.22A–C ), neuroretinitis, Bartonella associated multifocal retinitis and neuroretinitis (see Figure 10.04 ), and orbital cellulitis; external pressure on the ophthalmic, central retinal, and cilioretinal arteries such as in orbital hemorrhage, cavernous sinus thrombosis, intersheath perioptic hemorrhage, papilledema, ischemic optic neuropathy, optic disc drusen, central retinal vein occlusion, and neoplastic diseases of the orbit, optic nerve, and retina ; carcinomatosis of the meninges of the brain and optic nerve ; and surgical manipulation such as retrobulbar procedures.
Branch retinal or cilioretinal artery occlusion may accompany central retinal vein obstruction in the same eye. In some cases both may be the result of primary disease affecting the optic nerve head. In other patients, particularly those with cilioretinal artery obstruction, the central retinal vein obstruction may be the cause of decreased perfusion within the cilioretinal artery that normally has a lower perfusion pressure than the central retinal artery.
Retinal Arterial Hypoperfusion Caused by Systemic Hypotension and Ocular Hypertension
Reduction of retinal blood flow in patients during systemic hypotensive episodes rarely produces evidence of retinal ischemia unless it occurs in patients with pre-existing disease causing reduced retinal flow. Marked elevation of intraocular pressure may cause symptomatic optic nerve or retinal ischemia, particularly when it occurs in patients with other diseases, such as sickle-cell disease. Compression of the eye and orbital tissues during general anesthesia in the face-down position may occlude the ciliary and central retinal arterial blood supply to the eye. (See Figure 3.54K and L .) This can also cause posterior ischemic optic neuropathy.
Retinal Arterial Hypoperfusion Caused by Carotid and Ophthalmic Artery Obstruction
Reduction of retinal arterial blood flow may be caused by obstruction of either or both the ipsilateral carotid and ophthalmic arteries. Whereas this obstruction is usually caused by slow progressive narrowing associated with atheromatous disease, it may have a variety of other causes, including giant-cell arteritis, spontaneous dissection, fibromuscular dysplasia (FMD), surgical complication, Takayasu’s disease, and cavernous sinus thrombosis. Rapid obstruction such as may occur in cranial arteritis ( Figure 6.23G–L ), mucormycosis, or herpes zoster causes acute visual loss and ischemic retinal infarction. This is often accompanied by signs of ciliary artery obstruction, pallor of the optic disc, and hypotony ( Figure 6.23J and K ) In a few patients multifocal areas of ischemia simulating Purtscher’s retinopathy may occur ( Figure 6.16H ). If obstruction of the major arteries occurs more slowly from atheromatous disease or chronic inflammation of the large arteries (Takayasu’s disease), reduction in blood flow to the eye may or may not be sufficient to cause visual complaints ( Figure 6.23A–C ). A variety of fundus pictures may occur: (1) minimal or no ophthalmoscopic changes in patients complaining of transient loss of vision in one eye (amaurosis fugax) ; (2) few widely scattered blot and dot retinal hemorrhages and mild dilation of the retinal veins (venous stasis retinopathy), usually in patients with minimal visual complaints ( Figure 6.23A–C ) ; (3) dilation of the retinal arterial tree, dilation of the retina veins, and cotton-wool ischemic patches ( Figure 6.23H ); (4) retinal capillary changes, including microaneurysms, cystoid macular edema (CME), and angiographic evidence of areas of capillary nonperfusion that may be confined to the area along the horizontal raphe ( Figure 6.23A–C ) ; (5) larger areas of peripheral capillary nonperfusion, retinal neovascularization, and hemorrhage; (6) any degree of branch or central retinal vein or arterial obstruction ( Figure 6.23H ); (7) ischemic optic neuropathy ( Figure 6.23I ); and (8) any of the above associated with panuveitis, neovascular glaucoma, and a rapidly progressing cataract (ischemic ocular syndrome).
Dr. Gass has seen one aphakic patient with carotid artery obstruction develop loss of vision caused by acute exudative detachment of the choroid and ciliary body ( Figure 6.23D–F ). The detachment resolved rapidly after carotid endarterectomy. The ophthalmologist faced with any patient who has these ocular signs or symptoms should inquire about other signs or symptoms of transient ischemic attacks and should look for other evidence of ipsilateral carotid artery obstruction, such as reduction of carotid artery pulsation, a bruit over the carotid artery and orbit, and ease of collapse of the ipsilateral central retinal artery with finger pressure on the eye compared with that of the contralateral eye. Fluorescein angiography in all such cases should show a late appearance time of the dye in the central retinal artery and choroid and a prolonged retinal circulation time. In some cases a dramatic improvement in the fundus changes may occur after carotid endarterectomy.
Mikito Takayasu in 1908 described the ocular manifestations of this condition as “peculiar changes in the central retinal vessels and wreath of arertiovenous communication” around the optic disc. The retinal changes include dilatation of the retinal arteries and veins with beading ( Figure 6.24I and J ), microaneurysms at the capillary level and along the arterioles (very typical; Figure 6.24A–F, I–L ), vascular occlusion, large zones of nonperfusion, arteriovenous shunts, retinal and optic disc neovascularization ( Figure 6.24I and L ), and, occasionally, vitreous hemorrhages. The arm to retina time and the arteriovenous transit times are prolonged. Poor blood flow to the eye is the basis of the ocular findings and is seen in those patients with involvement of the common carotid arteries ( Figure 6.24G and H ). The left side is more commonly involved than the right. Since the intravascular hydrostatic pressure is low, these patients have very few retinal hemorrhages, and minimal leakage from the new vessels ( Figure 6.24L ) and microaneurysms. The poor endothelial oxygenation causes a break in the blood–retinal barrier and mild fluorescein leakage, but much less intensely than other conditions such as diabetic retinopathy. Intraocular pressure is low due to poor perfusion of the ciliary body; eventually rubeosis irides (but rarely neovascular glaucoma) and cataract develop. Traction retinal detachment and phthisis bulbi have been seen very occasionally. Those patients with renal artery stenosis without involvement of the carotids show features of hypertensive retinopathy in the form of arteriolar narrowing, retinal hemorrhages, and arteriovenous crossing changes.
Takayasu arteritis, also known as “aorta arteritis” and “pulseless disease,” is a form of chronic granulomatous panarteritis with possible autoimmune origin that affects the aorta and its branches. The coronary and pulmonary arteries can sometimes be involved. Why it is more common in Asia, Mexico, and other tropical countries is not fully understood. A link to poststreptococcus autoimmune change or to tuberculosis has been postulated. Intimal proliferation and fibrosis of the media with scarring, thrombus formation, and eventual stenosis of the affected artery occur.
A female preponderence of up to 9:1 is seen in Asia, and affects young adults who present with clinical features based on the vessels involved. Those with involvement of the branches of the aortic arch present with amaurosis fugax, dizziness, and syncope. Renal artery stenosis leads to hypertension and its manifestations.
Takayasu arteritis is classified based on vessel involvment using radiological imaging into six groups :
Type I: branches of aortic arch
Type IIa: ascending aorta, aortic arch, and its branches
Type III: descending thoracic aorta and abdominal aorta
Type IV: abdominal aorta only
Type V: aortic arch, descending thoracic aorta, and abdominal aorta.
Therapy depends on the stage of the disease. If the patient is seen early in the course of arteritis without significant occlusion, systemic steroids and immunosuppressives alone are indicated. Once occlusion or significant stenosis occurs, angioplasty and bypass grafts are needed in addition to the immunosuppressives. Medical management of hypertension, nephrectomy, and autotransplantation of the kidney may be necessary. Antituberculous drugs in those patients with highly positive Mantoux test is indicated.
FMD is a nonatheromatous, noninflammatory vascular disorder that commonly affects the renal and internal carotid arteries. It is known to cause choroidal hypoperfusion central retinal artery, and cilioretinal artery occlusion, though extremely rarely. Retinal hypoperfusion, and its various manifestations, leading to retinal neovascularization and traction retinal detachment, similar to Takayasu retinopathy, has been described in one patient. A fatal stroke and multiple retinal hemorrhages have been seen in an 11-month-old infant. When a young patient without cardiovascular risk factors presents with a CRAO, one should rule out FMD. These patients may have recurrent strokes, transient ischemic attacks, syncope, headache, tinnitus, and cranial nerve palsies. Unlike atherosclerosis that affects the proximal or origin of the caroid artery, FMD affects the middle or distal part and has a typical appearance on carotid Doppler/angiogram with the “pulled screw” configuration, focal tubular narrowing, or localized outpouching of the artery. These configurations occur specifically in the three types of FMD (1) pulled screw or multiple constrictions in the medial type; (2) focal tubular narrowing in the intimal type; and (3) outpouching in the adventitial type. Aneurysms and involvement of other medium-sized arteries can also occur. Genetic risk factors are being investigated, as the disease is known to occur in first-degree relatives.
Retinal Hypoperfusion Caused by Cardiac Anomalies
Young patients with congenital cyanotic heart disease commonly develop some dilation and tortuosity of the major retinal vessels often associated with polycythemia. Frank central retinal vein occlusion, atypical rubeosis iridis can be seen rarely. Patients with pulmonary hypertension and a reversed bidirectional shunt through an intracardiac defect (Eisenmenger’s syndrome) may develop retinal microvascular changes similar to that in patients with carotid artery obstruction. Paradoxical embolus due to a right-to-left shunt can cause retinal artery occlusion.
Retinal Arterial Hypoperfusion Caused by Occlusion of Retinal Venous Outflow
If severe and rapid obstruction of the central venous outflow occurs before collateral channels of venous outflow begin to function, severe ischemic whitening of the retina, in addition to widespread retinal hemorrhages, occurs, producing the ophthalmoscopic picture of combined central retinal arterial and venous occlusion. Obstruction of the central retinal vein may cause selective obstruction of a cilioretinal artery because of relatively low perfusion pressure of the cilioretinal arteries).
Retinal Arteriolar Obstruction Caused by Systemic Hypertension and Collagen Vascular Disease
Through autoregulation, retinal arteries respond to an elevation in systemic blood pressure by constriction. Most patients, however, with chronic mild to moderate degrees of systemic hypertension have no visual complaints and minimal or no fundoscopic changes (focal and diffuse narrowing of the retinal arteries, an increase in the arterial reflex, and arteriovenous crossing changes), which are caused by thickening of the small arterial and arteriolar walls (arteriolar sclerosis). Focal narrowing of the major retinal arterial branches is the single most reliable early sign of systemic hypertension. Fluorescein angiography usually shows no evidence of microvascular changes in patients with mild to moderate hypertension. Retinal and optic nerve arteriolar sclerosis is of pathogenetic importance in the following causes of central vision loss in hypertensive patients: (1) branch retinal vein occlusion (see p. 596); (2) arterial macroaneurysm formation (see p. 494); and (3) ischemic optic neuropathy (see pp. 1284–1288).
Patients with more severe chronic or with accelerated malignant hypertension may develop marked arterial and arteriolar constriction and evidence of focal vascular wall damage that is most severe at the origins of first- and second-order retinal arterioles in the posterior fundus ( Figures 6.25A–C and 6.26H and I ). Leakage of blood elements into the arteriolar wall causes narrowing or closure of arterioles and focal ischemic whitening of the retina (cotton-wool spots) in the vicinity of the optic disc and the major retinal vascular arcades posteriorly ( Figure 6.25A ). Part of the intense whitening in cotton-wool spots is caused by stasis of axoplasmic flow within the nerve fiber layer in the area of retinal ischemia. Microaneurysmal formation, irregular telangiectasis, occlusion, and increased permeability and remodeling of the retinal capillaries within and around these ischemic areas are best seen with fluorescein angiography ( Figure 6.25B, C, and E ). These changes may persist after disappearance of the cotton-wool patch. They are responsible for varying amounts of intraretinal serous exudation, yellowish exudation, and retinal hemorrhages that are usually confined to the peripheral macular area and are associated with varying degrees of loss of central acuity ( Figure 6.25A and 6.27 ). Focal depression of the inner retinal surface may be evident biomicroscopically after disappearance of a cotton-wool patch. In the presence of marked ischemic arteriolar and capillary permeability changes in the retina and optic nerve head, a macular star and swelling of the optic nerve head may develop ( Figures 6.25A and G, and 6.26D ). Some loss of central vision may accompany these changes and probably is primarily related to ischemic damage to the nerve fibers within the optic nerve rather than alterations in the macula, which is protected by the rich pattern of collateral circulation. Swelling of the disc caused by ischemic papillopathy may occasionally precipitate branch retinal arterial occlusion that, because of well-developed collateral arterial circulation, may show an unusual distribution of retinal whitening ( Figure 6.25G–I ). Some patients with severe hypertension may have mild blurring of vision, a macular star, and swelling of the optic nerve head (grade IV hypertensive retinopathy; Figure 6.27A–F ) and only minimal exudative and ischemic changes in the retina otherwise ( Figure 6.26A–C ). These patients, who often have headaches and undiagnosed malignant hypertension, may be mistakenly diagnosed as having neuroretinitis, Leber’s stellate maculopathy, or papilledema. Other patients, particularly children, may experience marked visual loss caused by severe ischemic papillopathy and massive extension of intraretinal and subretinal exudation into the macular area. Patients with moderate to severe chronic essential hypertension usually do not show ophthalmoscopic or fluorescein angiographic evidence of choroidal ischemia. (See Chapter 3, p. 182.) Patients with rapid acceleration of malignant hypertension are most likely to develop choroidal vascular complications ( Figures 6.27 and 6.28 ).
Angiographic changes in the microvasculature, even in the presence of grade IV hypertensive retinopathy, are primarily outside the central macular area. Following medical control of malignant hypertension, angiographic evidence of permanent remodeling of the retinal capillary bed (microaneurysms, capillary telangiectasis, small areas of capillary nonperfusion, and permeability alterations) is most prominent in the juxtapapillary area and along the course of the major retinal vessels posteriorly ( Figures 6.25D–F, and 6.26H and I ). Hemorrhagic detachments of the internal limiting membrane of the retina in the macula may arise from these permanent microvascular alterations ( Figures 6.25D–F, and 6.26G–J ). There is probably an increased incidence of epiretinal membrane formation in the macular region in patients who have severe hypertensive vascular changes ( Figure 6.26H and L ). These patients are susceptible to all of the complications of arteriolar sclerosis mentioned previously in patients with less severe hypertension.
During exacerbation of collagen vascular diseases patients may develop cotton-wool patches that may occur in the absence of significant elevation of systemic blood pressure. Although in some cases the cause of the arteriolar obstruction is identical to that produced by severe hypertension, in other cases it may occur by a different mechanism such as thrombosis from a hypercoagulable state associated with a lupus anticoagulant (see discussion of leukocytic aggregation and embolization, pp. 464, 565 and Figures 6.13 and 6.14 ). These patients also may show evidence of occlusive vascular disease affecting the choroidal vasculature (see pp. 40, 84, 464).
All of the retinal, choroidal, and optic nerve head changes seen in humans with accelerated hypertension have been reproduced in the rhesus monkey using a modified Goldblatt procedure. Hayreh and others described a peculiar focal intraretinal periarteriolar transudate that frequently develops during the first few weeks after the onset of experimentally induced malignant hypertension. Unlike cotton-wool spots, these pinhead-sized, dull-white, deep retinal lesions that are associated with punctate foci of fluorescein leaks are specific for malignant hypertension ( Figure 6.28 ). They probably represent focal ischemic damage to the RPE.
Acquired Retinal Arterial Macroaneurysms
Patients who develop acquired retinal arterial macroaneurysms are usually in their sixth to seventh decade of life when they seek treatment because of visual loss caused by exudation or bleeding from the aneurysm. Typically a solitary round or fusiform aneurysm arises on one of the four major branch retinal arteries, usually within the third-order branches ( Figures 6.29 and 6.30 ). The aneurysm occasionally develops on a cilioretinal artery or on the optic nerve head. It occurs more frequently in women. The superotemporal artery is most commonly affected. The aneurysm often occurs at the site of an arterial bifurcation or an arteriovenous crossing. In some cases it may pulsate. Pulsation is not a reliable indicator for high risk of hemorrhage. The author has seen one pulsating macroaneurysm spontaneously disappear. The right eye is affected more commonly than the left eye. Aneurysms may be present in both eyes in approximately 10% of cases. A total of 50–75% of patients with acquired arterial macroaneurysms have a history of systemic hypertension and/or ophthalmoscopic evidence of retinal arteriolar sclerosis. Some association with systemic sarcoidosis has been noted, though the relationship is not understood. Visual loss is most frequently caused by leakage of proteinaceous and lipid-rich exudates, often along with some blood from the aneurysm, into the surrounding retina. This leakage produces an area of circinate retinopathy that includes the macular area ( Figures 6.29A, F, and G, and 6.30D ). Serous detachments of the macula ( Figure 6.30D ) and bleeding beneath the retina, the internal limiting membrane, posterior hyaloid and into the vitreous are other causes of vision loss ( Figures 6.29J, 6.30H and K, and 6.31 ). Bleeding may occasionally be precipitated by a Valsalva maneuver. In cases associated with bleeding, the blood is often present in front of and posterior to the retina and may partly or totally obscure the aneurysm from view ( Figure 6.30H ). Full-thickness macular holes can occur as a complication. High pressure under the internal limiting membrane resulting in foveolar necrosis or secondary vitreofoveal traction as a sequela to the hematoma may play a role in the pathgenesis of the hole.
Subretinal neovascularization, though rare, has been reported. Occasionally multiple aneurysms occur along the same artery ( Figure 6.30G ) or elsewhere in the eye. Approximately 10% of patients have one or more focal yellow arterial wall plaques either proximal to or, less often, distal to the aneurysm ( Figure 6.29A and F ). These lesions, which often incompletely surround the blood column and do not interfere with blood flow, are probably localized deposits of serum fat (atheromata) occurring at the site of defects in the arterial wall. These represent potential sites for future development of an aneurysm. Previously these atheromata have been misinterpreted as emboli. Patients with these plaques show no clinical evidence to suggest embolic disease. Evidence of branch arterial occlusion distal to the aneurysm may be present ( Figure 6.30D and E ).
Branch retinal vein occlusions occasionally may occur within the same or opposite eye. The arterial macroaneurysm may be within the area of the branch vein obstruction or remote to it. This association of these two disorders is not unexpected since hypertension is a risk factor for the development of both. Fluorescein angiography may fail to demonstrate the aneurysm when it is partly obscured by blood or exudate ( Figure 6.30I ). Angiography may show evidence of complete ( Figure 6.30E ), partial ( Figure 6.29B ), or no obstruction of the artery at the site of the aneurysm. In some cases a few microvascular abnormalities may be present in the vicinity of the aneurysm. These include widening of the periarterial capillary-free zone around the aneurysm, capillary dilation, small areas of capillary nonperfusion, microaneurysms, and intra-arterial collateral vessels. Leakage of fluorescein occurs primarily from the site of the aneurysm and to a much lesser degree from the microvascular abnormalities immediately surrounding the aneurysm.
Histopathologically macroaneurysms show evidence of a linear break in the artery wall surrounded by a thick laminated layer of fibrin platelet clot and varying amounts of blood, exudate, lipid-laden macrophages, hemosiderin, and fibroglial reaction ( Figure 6.31C–E ). Similar miliary aneurysms may occur in the central nervous system on vessels that are 100–300 μm. These are more commonly found in hypertensive individuals than in normal individuals. Although the pathogenesis of these aneurysms in the eye and central nervous system is uncertain, they probably occur at sites of focal arterial wall developmental and aging defects, which particularly in a patient with hypertension are more likely to decompensate ( Figure 6.29A ). The presence of focal atheromata either adjacent to or in other parts of the retinal arterial tree is evidence of the presence of other focal defects in the arterial wall, which in some cases may lead to future development of additional aneurysms. Because of the association of hypertension, these patients probably are at higher than normal risk for stroke and cardiovascular disease.
Evidence suggests that, following a period of exudation and hemorrhage, the defect in the arterial wall may close spontaneously through a process of thrombosis and sclerosis ( Figures 6.29G–I and 6.30A and C ). In some cases the retinal artery may be almost completely restored to its normal caliber. Additional aneurysms may arise elsewhere ( Figures 6.29F and 6.30F and G ). The visual prognosis is excellent in most cases. Patients with chronic yellowish exudation in the macula and those with evidence of bleeding into the subfoveal area are the most likely to lose some vision permanently. Large hemorrhagic detachments of the retina in these patients are often mistaken for subretinal hematomas caused by age-related macular degeneration, and occasionally for a choroidal melanoma ( Figures 6.30H and I and 6.31A–C ). The eccentric location of the hematoma centered beneath a major retinal artery is an important clue to the correct diagnosis when the aneurysm is obscured by intraretinal or preretinal blood. When associated with circinate yellowish exudation, a macroaneurysm may be misdiagnosed as retinal telangiectasis, branch retinal vein occlusion, diabetes, and irradiation retinopathy. There is usually no difficulty in differentiating patients with acquired arterial macroaneurysms from older patients with congenital retinal telangiectasis. These latter patients, most of whom are males, usually have multiple arterial aneurysms, larger areas of capillary dropout, and more extensive telangiectatic changes involving both the capillaries and the veins (see p. 514). A peculiar disorder characterized by multiple Y-shaped macroaneurysms occurring at the bifurcation of the major retinal arteries of both eyes causing exudative neuroretinopathy is of uncertain etiology (idiopathic retinal vasculitis, aneurysms, and neuroretinopathy: IRVAN) (see Figures 6.52 and 6.53 ).
Since spontaneous healing of macroaneurysms is part of the natural course of this disorder, treatment is not always indicated. The primary indication for photocoagulation is the persistence or progressive accumulation of yellowish exudate in the central macular area ( Figure 6.29A–E ). Moderately heavy argon green or dye yellow laser photocoagulation using large-spot-size (500 μm), long-duration (0.5-second) applications directed to the aneurysm is successful in expediting the healing of the defect ( Figure 6.29A–E ). This treatment may cause a transient obstruction of the artery and occasionally may cause bleeding from the aneurysm. Since the site of the leakage is the aneurysm, the use of indirect treatment confined to the area surrounding the aneurysm has little rationale. Surgical drainage of the subretinal hematoma is technically possible but has not been demonstrated to produce visual results better than achieved by either laser treatment or by the natural course of the disease. It does expediate the visual recovery. The same can be said for the technique of using the Q-switched Nd:YAG laser to release subinternal limiting membrane hematomas into the vitreous or pneumatic displacement of the hematoma.
Retinal Capillary Diseases
The retina normally contains very little extracellular fluid. Some diseases primarily affect the structure and permeability of the retinal capillary bed. These alterations often result in leakage of exudate and, in some cases, escape of blood cells into the retinal tissue. The content of exudate depends on the severity of the capillary endothelial damage. Intravenous fluorescein is helpful in detecting the structural and permeability alterations in the retinal capillary bed and the degree to which the extracellular space of the retina is expanded (see Chapter 2).
Cystoid Macular Edema After Cataract Extraction
Approximately 50–70% of the patients who have an uneventful intracapsular cataract extraction will develop fluorescein angiographic evidence of leakage of fluorescein from the parafoveal retinal capillaries ( Figure 6.32 ). More than 90% of these patients will show no biomicroscopic evidence of CME, and they will not have any significant decrease in their visual acuity. The incidence of this subclinical CME is so high that it may be considered as a normal physiologic response to intracapsular cataract extraction. Approximately 5–15% of all patients will develop loss of visual acuity secondary to clinically significant CME after uneventful intracapsular cataract extraction. These patients will demonstrate the typical biomicroscopic and fluorescein angiographic changes caused by a polycystic pattern of expansion of the extracellular space by serous exudation ( Figures 6.32–6.34 ). These changes are described in detail in Chapter 2. The incidence is much lower after extracapsular cataract extraction and phacoemulsification surgery. Clinically significant CME usually occurs within 4–12 weeks postoperatively, but in some instances its onset may be delayed for months or many years after surgery. It infrequently occurs before the third postoperative week. Blurred vision is the usual complaint. Visual acuity is generally reduced to the range of 20/30–20/70. A few patients may complain of mild irritation of the eye and show some circumlimbal conjunctival injection. The anterior hyaloid face is ruptured in approximately 50% of patients after intracapsular cataract extraction or the posterior capsule is dehisced with or without anterior vitrectomy in eyes undergoing phacoemulsification. Some inflammatory cells may be present in the posterior vitreous, which typically shows evidence of extensive liquefaction. Vitreous attachment to the macula usually cannot be demonstrated. Mild and rarely severe degrees of papilledema may be present. Usually there is no ophthalmoscopically visible change in the structure of the capillary bed. An occasional small intraretinal hemorrhage or microaneurysm may be present. Approximately 10% of patients will show some evidence of epiretinal membrane formation, or so-called cellophane maculopathy (see Chapter 7). Over 50% of these patients will have either clinical evidence of systemic hypertension or fundoscopic evidence of focal retinal artery narrowing. The eyes are typically normotensive. CME after cataract extraction appears to be more common and more severe in patients with blue rather than brown irides. It occurs as a complication of cataract extraction less frequently in blacks than in whites and occurs infrequently after extracapsular cataract extraction in children. If lens extraction in infants is accompanied by an anterior vitrectomy, significant and persistent CME may occur.
Early phases of fluorescein angiography demonstrate dye leakage from the parafoveal retinal capillaries, and later phases show the characteristic picture of CME ( Figure 6.32 ). Angiography can be helpful in the diagnosis of CME in these patients, who often have hazy ocular media that prevent detailed biomicroscopic examination of the macula. Leakage of fluorescein often occurs from the capillaries of the optic nerve head and anterior uveal tract. The aqueous humor typically stains heavily with fluorescein. CME disappears spontaneously, and visual acuity returns to 20/30 or better within 3–12 months in two-thirds of these patients after intracapsular cataract extraction and no lens implant. Other patients will show clearing of the edema and return of good vision from 1 to 5 years following the onset of CME. The incidence of permanent visual loss caused by CME after extracapsular cataract extraction and posterior-chamber intraocular lens implantation is approximately 1–1.5%. The duration of CME is usually longer and recurrences are more frequent in patients with a history of vitreous loss at the time of extraction or in those who develop incarceration of vitreous in the wound postoperatively. Angiography of the opposite phakic eye shows no evidence of abnormal retinal or iris vessel permeability, except in the rare patient who has chronic bilateral vitritis of unknown cause before cataract extraction.
Vitreous fluorophotometry in patients with aphakic CME shows evidence of increased ocular vascular permeability that parallels the severity of the CME. Eyes with iris-supported implants that develop CME have a higher incidence of developing chronic CME and corneal edema.
Histopathologically, the extracellular space of the retina, particularly in the inner nuclear and outer plexiform layers, is expanded by serous fluid of low protein content ( Figures 6.34 and 6.35 ). Small numbers of chronic inflammatory cells have been found histologically in eyes with aphakic CME. Fine and Brucker’s electron microscopic findings suggested that the cystic spaces in CME might be caused by accumulation of intracellular fluid within expanded Müller cell processes. Gass et al., however, demonstrated that CME is caused by accumulation of serous exudate in the extracellular space, which is more in keeping with clinical, angiographic, and light microscopic findings in patients with CME.
The pathogenesis of aphakic and pseudophakic CME is unknown. Direct traction on the macula by the vitreous does not appear to be an important factor. The incidence of CME is higher in patients who have had vitreous loss during cataract extraction and patients who develop a peaked pupil with vitreous adherence to the wound following delayed rupture to the anterior hyaloid face. The typical findings of inflammatory cells in the posterior vitreous of most, but not all, patients suggest the possible importance of inflammation. It may however be that these cells are the result of, rather than the cause of, the retinal capillary abnormality. Comparable inflammatory reaction in the vitreous from other intraocular surgical procedures usually does not produce macular edema. Removal of the lens is undoubtedly a key factor in this disease, but the mechanism by which it leads to retinal edema is not clear. Diffusion of prostaglandins from the anterior segment to the retina, hyperosmolarity of the vitreous secondary to a ruptured anterior hyaloid face, smoldering low-grade cyclitis, and vitreous traction acting on the peripheral retina are suggested but unproved causes of CME. The frequent findings of narrowing of the retinal arterial tree and systemic hypertension suggest that underlying retinal vascular disease is also an important factor in the pathogenesis of CME. The incidence of CME occurring following cataract extraction in patients with background diabetic retinopathy is much higher than in healthy patients. In one study the incidence of clinically significant CME was 75% versus 6% of the control eyes, and the CME persisted for more than 1 year in 56% of diabetic eyes. The incidence of CME occurring in the second eye following an uneventful cataract extraction may be as high as 50%. It may occur soon after the subsequent opening of the posterior lens capsule. The incidence of CME after posterior-chamber lens implantation with simultaneous capsulotomy versus that after the same procedure without capsulotomy is probably slightly greater. The incidence of CME after delayed Nd:YAG laser capsulotomy is probably less than 1–2%.
The treatment of aphakic or pseudophakic CME with anti-inflammatory agents such as the antiprostaglandins and corticosteroids may result in some temporary improvement in visual acuity, yet there is no evidence that they significantly shorten the duration of clinically significant CME or reduce the incidence of the development of chronic CME. Topical nonsteroidal anti-inflammatory drops may be effective in reducing CME but probably are no more successful in this regard in most patients than topical corticosteroid drops. There is some evidence to suggest that in some patients the increase in the intraocular pressure induced by use of topical corticosteroids is partly responsible for its therapeutic effect. Excision of vitreous that is incarcerated in the wound is of value in some patients with persistent CME. Some patients with vitreous incarceration, particularly those with complaints of irritation and photophobia and those with many vitreous opacities, do obtain relief of symptoms and improvement in acuity following a vitrectomy. In the absence of chronic irritation, photophobia, or corneal edema, vitreous excision from the wound is not recommended for at least 1 year after the onset of edema because of the uncertainty of its value and the likelihood of spontaneous resolution. Carbonic anyhydrase inhibitors have been suggested for the treatment of aphakic and pseudophakic CME ( Figure 6.32G–L ).
In the aphakic or pseudophakic patient presenting with visual loss, contact lens examination usually is sufficient to determine the presence of CME as the cause. Fluorescein angiography and OCT are helpful in those cases where CME is not evident biomicroscopically, or in cases where an explanation of the visual loss is not evident. The physician should remember that CME identical to that complicating cataract extraction may be associated with many other disorders, some of which may have been unrecognized before, or have developed after, cataract extraction. Of particular importance is detection of the presence of a subtle rhegmatogenous retinal detachment, choroidal neovascularization in eyes with other evidence of age-related macular degeneration or vitreofoveal traction, that may play a role in causing the CME, or in producing a macular lesion that simulates CME biomicroscopically.
Cystoid Macular Edema Associated with Rhegmatogenous Retinal Detachment
A few patients may develop the biomicroscopic and fluorescein angiographic picture of CME secondary to a rhegmatogenous retinal detachment. CME may be present preoperatively or may appear initially during the postoperative course. Angiographic evidence of the edema has been described in 25% of phakic patients who have undergone a scleral buckling procedure and in 40–65% of aphakic eyes undergoing scleral buckling procedures. The incidence of CME appears to be higher in older patients, and in many instances it clears spontaneously. Late resolution of CME is responsible for the delayed improvement in visual acuity that sometimes occurs in patients 6 months or longer following successful repair of a retinal detachment. The general prognosis for spontaneous resolution of the CME is good. CME has been noted after cryotherapy of a retinal tear in the absence of rhegmatogenous detachment.
Cystoid Macular Edema Following Other Types of Intraocular Surgery
Transient CME also has been observed postoperatively in a few phakic patients who have had other intraocular procedures, such as glaucoma filtering operations and peripheral iridotomies. CME is a major complication after penetrating keratoplasty. Kramer found a 42% incidence of clinically significant CME in aphakic eyes in which penetrating keratoplasty and vitrectomy had been performed. He found an incidence of 19% of CME following combined cataract extraction and penetrating keratoplasty with a vitrectomy and only a 4% incidence following combined procedures without an anterior vitrectomy. In eyes with bullous keratopathy and CME with anterior-chamber and iris-supported lens, good visual recovery often occurs after penetrating keratoplasty and exchange of the intraocular lens for a posterior-chamber lens. CME has been noted following a laser iridotomy.
Complications Following Cystoid Macular Edema
Although visual acuity may return to 20/30 or better after 2 or more years of CME, some patients develop permanent retinal damage secondary to the prolonged edema. The spontaneous rupture of the inner wall of a large central cystoid space to form a lamellar hole is one of the complications of CME. When this occurs, it produces a characteristic biomicroscopic and a diagnostic angiographic change ( Figures 6.35 and 6.36 ). Biomicroscopically, a round or oval, one-third disc diameter, punched-out defect occurs in the center of the macula. The RPE in the base of the hole is undisturbed. A sheen or light reflex is usually evident on the surface of the remaining retina as a slit beam is moved across the hole. Yellow deposits within the hole and a halo of marginal retinal detachment typical of a full-thickness hole are not present. Small perifoveal cystoid spaces surrounding the inner lamellar hole may be difficult to visualize. Late-phase fluorescein angiography, however, demonstrates a polycystoid pattern of dye in the perifoveolar area surrounding a round or oval, nonfluorescent zone that corresponds with the inner lamellar hole ( Figure 6.36D ). Following rupture of the inner cyst wall, the fluorescein can no longer concentrate in the area of the lamellar hole ( Figures 6.35 and 6.36 ). Following resolution of the CME surrounding the lamellar hole, fluorescein angiography of the macula appears normal. Occasionally, multiple ruptures of the inner cyst walls produce a multifaceted lamellar macular hole, rather than a solitary oval or round hole.
In the aphakic patient with poor central vision and CME, failure to demonstrate the presence of central cysts during the late stages (10–60 minutes) of angiography suggests a poor prognosis caused by the presence of a lamellar hole, retinal atrophy, or a nonmacular cause for the visual loss.
Cellophane maculopathy and macular pucker caused by epiretinal membrane formation may be evident at the onset of CME, or they may occur as late complications of CME. When they occur, it is less likely that central acuity will return to normal following resolution of the CME. Occasionally, however, these membranes may peel spontaneously from the surface of the retina, and good acuity may be restored (see Figure 7.23 ).
Prolonged CME may occasionally produce atrophy of the outer retinal layers, and the macula may appear relatively normal except for the absence of a foveal reflex.
Infantile Cystoid Maculopathy
Infantile cystoid maculopathy that macroscopically resembled that seen in X-linked juvenile retinoschisis was observed on gross examination of the eyes of three premature infants of both sexes by Trese and Foos. Cystoid changes were noted at various retinal levels. Reduced numbers of ganglion cells were found in the retina and central nervous system of all patients.
Cystoid Macular Edema Associated with Choroidal Melanomas
Patients with peripherally located melanomas may develop the typical biomicroscopic and angiographic appearance of CME unassociated with serous detachment of the macula ( Figure 6.35 ). The cause of this edema may be the chronic inflammatory cell infiltration within the choroid adjacent to the melanoma and retinal vasculitis. It is important that patients with unilateral CME have a careful examination of the peripheral fundus to exclude the presence of a melanoma.
Cystoid Macular Edema and Topical Epinephrine and Prostaglandin Inhibitor Therapy
Either aphakic or phakic patients may develop the typical biomicroscopic and angiographic appearance of CME following the use of topical epinephrine-like and antiprostaglandin drops for glaucoma. If CME occurs and is caused by the drops, it can be reversed by discontinuing the medication.
Cystoid Macular Edema Associated with Ocular Inflammatory Diseases
Cystoid Macular Edema From Other Causes
Discussions of CME associated with tapetoretinal dystrophies, carotid artery occlusion, congenital juxtafoveolar capillary telangiectasia, overlying occult choroidal neovascularization, and occurring after occult central retinal vein occlusion are found on pp. 330, 522, 570, and 588, respectively.
Idiopathic Cystoid Macular Edema
CME of uncertain cause occasionally occurs in one or both eyes of patients ( Figures 6.37 and 6.38A–H ). The CME may be associated with a typical pattern of fluorescein leakage, or with no evidence of fluorescein staining. Some of these patients may eventually develop evidence of a tapetoretinal dystrophy.
Pseudocystoid Macular Edema
Superficial changes in the retina occurring in patients with sex-linked juvenile retinoschisis (see Figure 5.59A, C, and E , Figure 5.58 ), Goldmann–Favre syndrome (see Figure 5.57A, D, and H ), infantile cystoid maculopathy, and rhegmatogenous retinal detachment, lightning maculopathy (see Figure 8.16 ), and following spontaneous vitreoretinal separation (see Figure 7.14J–L ) may be mistaken for CME. Fluorescein angiography is helpful in this differential diagnosis. In patients with suspected CME and a negative angiogram, care must be taken to exclude the possibility of a tapetoretinal dystrophy (see Figure 5.42 ) and nicotinic acid maculopathy ( Figure 6.38I–L ).
Nicotinic Acid Maculopathy
A small percentage of patients (probably under 1%) receiving high oral doses of nicotinic acid (1.5–5 g/day) for the treatment of hypercholesterolemia will develop bilateral blurring of vision caused by CME ( Figure 6.38I–L ). Although the biomicroscopic appearance of CME is identical to that seen in patients after cataract extraction, it is unaccompanied by vitritis, other retinal vascular changes, and fluorescein angiographic evidence of retinal capillary permeability alterations ( Figure 6.38K ). Cystic spaces are seen in the outer plexiform and inner nuclear layer on OCT. The reason for the absence of fluorescein leakage is speculative. Whether the permeability change in the retinal capillaries is so mild that fluorescein particles do not leak out or Müller cell edema is the cause of the cystic spaces is still debated. Prompt recovery of normal vision and complete resolution of macular edema occur after nicotinic acid therapy is stopped ( Figure 6.38L ). Reinstitution of the therapy results in recurrence of the CME.
Dominantly Inherited Cystoid Macular Edema
Deutman et al. described an autosomally dominant macular dystrophy characterized by CME, fluorescein leakage from the retinal capillaries throughout the posterior pole, normal electroretinographic findings, subnormal electrooculographic findings, and hyperopia. Atrophic pigment epithelial changes with a “beaten bronze” appearance may eventually develop. Histopathologic examination reveals large retinal schisis spaces in the macula, marked disorganization of the inner retinal layers, and advanced degeneration of Müller cells. Treatment with oral acetazolamide has not been successful. However a somatostatin analog, octreotide acetate, stabilized visual acuity and decreased fluorescein leakage in seven out of eight eyes.
Primary or Congenital Retinal Telangiectasis (Leber’s Miliary Aneurysms, Coats’ Syndrome)
Retinal telangiectasis, a term originally proposed by Reese, is a nonfamilial, developmental, retinal vascular anomaly characterized by irregular dilation and incompetence of the retinal vessels that typically occurs in one eye of a male patient ( Figures 6.39–6.42 ). Although primarily the retinal capillaries are affected, multiple focal aneurysms of the major retinal vessels, particularly the arteries, may be present. Women are occasionally affected (fewer than 10% of cases), and a few patients may show bilateral involvement. The extent of the retinal involvement and the degree of permeability alterations are variable. At one end of the spectrum are patients, usually infants or children, in whom most or all of the retinal vessels, including the arteries and veins, are telangiectatic, with massive yellow exudative and occasionally hemorrhagic retinopathy and detachment of the retina. This clinical picture is referred to as “Coats’ disease,” or, more correctly, “Coats’ syndrome” ( Figure 6.40 ). Congenital retinal telangiectasis is only one of the three causes of yellow exudative retinal detachment described by Coats. At the other end of the spectrum are patients with the retinal telangiectasis confined to a small segment of the juxtafoveolar area. These patients constitute type I juxtafoveolar retinal telangiectasis ( Figures 6.42 and 6.43 ). Decompensation of these localized areas of telangiectasis and visual loss often do not occur until adulthood. Approximately one-third of patients are 30 years or older before the onset of symptoms.
Patients with loss of macular function may present a variety of ophthalmoscopic pictures: (1) telangiectasis of the capillary bed, which may or may not be confined to the macular area, with minimal evidence of intraretinal exudation ( Figure 6.43A, G, and H ); (2) telangiectasis of the macular capillaries with extensive evidence of intraretinal exudation, including CME and circinate maculopathy ( Figures 6.43E and I and 6.44A and E ); (3) telangiectasis of the macular capillaries with extension of the exudate into the subretinal space; (4) exudative detachment of the macula caused by gravitation of protein- and lipid-rich exudate derived from peripheral areas of retinal telangiectasis ( Figure 6.39A and J ); and (5) a focal, organized, subretinal disciform mass ( Figure 6.39L ) or atrophic scar ( Figure 6.39H ) caused by chronic pooling of exudate into the macular region, often seen after laser or cryo treatment of the telangiectasis. The latter two changes are most often seen in infants and children with extensive areas of peripheral retinal telangiectasis. These patients often have esotropia or an abnormal pupillary reflex caused by the massive accumulation of yellow exudate in the posterior pole ( Figures 6.39A and D and 6.42 ). The yellow exudate is always more prominent remote from the areas of the retinal telangiectasis, which in some cases may be confined to the equatorial region ( Figure 6.39A–C and J–L ). As the cloudy, often greenish, subretinal exudate gravitates more posteriorly, particularly during sleep, the serous component is reabsorbed into the retinal vessels, leaving the yellowish, lipid-rich residue beneath and within the outer retinal layers ( Figures 6.39A and J, 6.41G–I, and 6.42 ). The accumulation of this material in the macular region probably occurs during sleep. Over a period of many months the yellowish exudate in the macular area may incite the ingrowth of blood vessels and fibrous tissue into the submacular exudate ( Figure 6.39A ). Extension of exudation into the posterior fundus from telangiectasis confined to the periphery, particularly if it is located inferiorly, may not occur in some patients until late in life.
Fluorescein angiography is helpful in defining this structural and permeability alteration in the affected vessels and in demonstrating the extent of the extravascular leakage of serous exudate into and beneath the retina. Angiography demonstrates focal aneurysmal dilation of the capillaries ( Figures 6.39C, E, and I, 6.40D–F, 6.42D, E, and H, and 6.43B and C ), retinal arteries, and veins ( Figure 6.39C and E ). The surrounding capillary bed may be dilated from slow flow and portions of the capillary bed may show nonperfusion ( Figure 6.42D ). This is particularly prominent in those patients with large aneurysmal vascular anomalies in the peripheral fundus. There may be some delay in passage of dye through the telangiectatic capillary bed, particularly if there is extensive saccular aneurysmal formation. The permeability of the telangiectatic vessels is quite variable. Dye leakage is largely confined to the dilated vessels. When intraretinal serous exudation is extensive, fluorescein stains the extravascular fluid pooled in the outer layers to produce a characteristic angiographic pattern of CME ( Figure 6.44F ). The dye diffuses into the subretinal exudate. It may not, however, stain subretinal exudate pooled beneath the retina in an area remote from the telangiectatic vessels. The yellowish exudate beneath or within the retina will not show fluorescence. Retinal function remains intact in an area of telangiectasis if the permeability of the retinal vessels is relatively normal.
The natural course of retinal telangiectasis is variable. Patients who seek treatment early in life because of exudation are more likely to have more widespread retinal involvement and develop progressive detachment and degeneration. In some cases this may be followed by rubeosis, retinal and vitreous hemorrhage, secondary glaucoma, and loss of the eye. Acute orbital cellulitis secondary to transscleral movement of toxic products may occasionally occur ( Figure 6.41J–L ). This presentation closely mimics retinoblastoma. In patients with milder degrees of the disease, there may be fluctuations in the degree of vascular leakage. Spontaneous resolution of exudation may occur ( Figures 6.39H and 6.43E–G ). Patients with telangiectasis confined to several clock areas, usually inferiorly, may gradually develop over a period of many years an elevated, organized, exudative mass that may be mistaken for a melanoma or an exophytic capillary hemangioma. In some cases it may not be possible to differentiate this stage of the disease from exudative intraretinal and subretinal masses caused by primary retinal capillary hemangiomas or secondary fibrovascular proliferation caused by branch vein occlusion, focal inflammation, trauma, or chronic retinal detachment (see Figure 7.28 ). Vitreous hemorrhage secondary to localized areas of retinal or optic disc neovascularization may occasionally occur.
Primary retinal telangiectasis is rarely associated with clinical evidence of vascular anomalies elsewhere in the body. Although congenital telangiectasis of the cerebral blood vessels is occasionally found at autopsy, it rarely is associated with clinical symptoms and has not been associated with retinal involvement. Gass has seen one boy with a prominent facial angioma associated with typical retinal telangiectasis.
In treating children with Coats’ syndrome, photocoagulation and cryotherapy should be used whenever possible to destroy telangiectatic vessels so as to preserve visual function and prevent rubeotic glaucoma ( Figure 6.39D–F and J–L ). Drainage of the subretinal exudate may be required in some cases to treat highly elevated abnormal blood vessels. A more conservative approach is possible in older patients who seek treatment later in life because of peripheral localized detachment or mild loss of central vision caused by telangiectasis confined to the paracentral retina. Some patients with chronic cystoid edema caused by juxtafoveal telangiectasis may retain nearly normal visual acuity for many years ( Figure 6.43A–D ). Those showing progressive accumulation of yellowish exudate in the central macular area should, however, be considered for laser treatment if the telangiectasis is localized outside the papillomacular bundle region ( Figure 6.44A–H ). Recently intravitreal anti-VEGF agents have been used in conjunction with laser photocoagulation with the intention of trying to decrease the accumulation of lipid under the macula. Intravitreal triamcinolone in addition to laser photocoagulation has also been tried with variable success. Surgery to remove the submacular lipid has been tried anecdotally. Macular distortion secondary to epiretinal membrane formation and contraction may accompany retinal telangiectasis or may follow photocoagulation treatment. Gass has seen one adult patient who developed total retinal detachment and massive periretinal proliferation following cryotherapy to peripheral retinal telangiectasis in an eye with 20/20 vision discovered late in life.
The histopathology of advanced retinal telangiectasis in eyes enucleated with the incorrect clinical diagnosis of retinoblastoma reveals irregular dilation of the retinal capillaries, arteries, and veins and is often associated with a massive outpouring of periodic acid–Schiff-positive exudate into the outer retinal layers ( Figure 6.41D–I ). This outpouring is associated with varying degrees of degeneration and disruption of the normal retinal architecture. Retinal detachment may or may not be present. Cholesterol clefts are seen within the subretinal exudates and lipid-laden macrophages are usually found remote from the site of the retinal telangiectasis, both beneath and in the outer layers of the overlying retina ( Figure 6.41I ). Marked retinal vascular endothelial proliferation and hemorrhagic infarction of the retina may occur in some children with severe retinal telangiectasis ( Figure 6.41A–F ).
Shields et al., in an attempt to streamline management and understand the prognosis, have classified Coats’ disease as
stage 1: telangiectasia only
stage 2: telangiectasia and exudation
stage 2A: extrafoveal exudation
stage 2B: foveal exudation
stage 3: exudative retinal detachment
stage 3A: subtotal
stage 3B: total
stage 4: total detachment with secondary glaucoma
stage 5: advanced end-stage disease.
This staging has prognostic significance, with patients presenting in stage 1 with almost no visual loss, and stage 2B with some amount of visual loss that can be treated with laser photocoagulation. Stage 3 had worse visual prognosis, although some could be treated, while eyes with stage 4 and 5 disease had to be enucleated.
In a recent finding, both a mother who had Coats’ disease and her son with Norrie’s disease had a missense mutation for the NDP gene on chromosome Xp11.2. The same investigators also analyzed retinas of nine enucleated eyes from males with Coats’ disease and found a somatic mutation of the retinal tissue in one of the nine cases. They speculated that Coats’ disease might be the result of a somatic mutation in the NDP gene, which results in deficiency of the protein norrin. Coats’ disease may occur as a postfertilization change in the X chromosome in a recessive fashion, similar to Aicardi syndrome. However, given that Aicardi’s is an X-linked dominant condition, the mutation is lethal for males. No study so far has been able to demonstrate a defect in the X chromosome in Coats’ or Aicardi syndrome.
A clinical picture of retinal telangiectasis and Coats’ syndrome may develop in one or both eyes of patients with progressive facial hemiatrophy ( Figures 6.40I–L and 15.12 ), in multiple family members with facioscapulohumeral muscular dystrophy (FSHD) and deafness ( Figure 6.40A–F ), Alport’s syndrome, the epidermal nevus syndrome, tuberous sclerosis ( Figure 6.40G and H ), isolated hemihyperplasia, and in patients with retinitis pigmentosa ( Figure 6.42F–H ). In one report of retinal telangiectasis in a patient with hypogammaglobulinemia, the retinal lesion was a cavernous retinal hemangioma rather than telangiectasis.
The differential diagnosis in young patients with exudative retinal detachment caused by congenital retinal telangiectasis includes retinoblastoma (see Figure 13.01A–F ), retrolental fibroplasia, FEVR (see Figure 6.68 ), angiomatosis retinae, Toxocara canis , incontinentia pigmenti, retinitis pigmentosa (see Figure 5.40 ), proliferative retinopathy caused by inflammatory diseases such as pars planitis or by chronic rhegmatogenous retinal detachment (see Figure 7.28 ), and endophthalmitis ( Figure 6.41J–L ). Globular, yellowish exudative detachments of the retina secondary to telangiectasis in infants and children may simulate closely those with exophytic retinoblastomas. Telangiectatic vessels may occur on the surface of the mass lesions in both cases. In retinoblastoma these dilated vessels are continuous with large vascular trunks that extend into the depth of the tumor, whereas the dilated vessels in retinal telangiectasis do not extend into the subretinal exudative mass. Fluorescein angiography may be helpful in establishing the diagnosis ( Figure 13.01A and F ). Ultrasonographic demonstration of calcium in the eye with retinoblastoma is also important in this regard. Patients with localized congenital telangiectasis associated with retinal arterial and venous aneurysms may be misdiagnosed as cavernous hemangioma of the retina (see Figure 13.16A–C ), acquired arterial macroaneurysms ( Figure 6.29 ), branch vein occlusion (see Figure 6.81C–H ), and bilateral multiple retinal arterial aneurysms associated with neuroretinitis (see Figures 6.52 and 6.53 ). (See a later subsection for the differential diagnosis of type I juxtafoveolar telangiectasis.)
Facioscapulohumeral Muscular Dystrophy and Coats’ Syndrome
FSHD is an autosomal-dominant disorder with a variable age of onset from childhood to old age, and severity from mild weakness to severe disability. A family history may be difficult to elicit because expression of the gene is variable and penetrance is incomplete. The characteristic clinical features include wasting of the shoulder girdle, upper deltoid, pectoralis, biceps, and triceps muscles, with relative preservation of the lower deltoid and prominence of the upper trapezius muscles. Muscle weakness can progress to the trunk and lower limbs over time and 20% can become confined to the wheelchair. Loss of tone of the abdominal musles leads to a protruding belly, and of the facial muscles to a drool and protruding tongue. Leg muscle involvement can lead to tiptoe walking and foot drop, resulting in an unstable gait. Loss of vision caused by retinal telangiectasis and deafness (high-frequency hearing loss) occur in some of these patients and rarely may be the initial manifestation of FSHD ( Figure 6.40A–F ). Early onset of symptoms and deafness herald more severe cases. Myoclonus and temporal-lobe absence attacks can occur. Unlike congenital retinal telangiectasis, both eyes are affected and both sexes are affected equally. The onset of visual loss is variable and may occur in early childhood. Asymptomatic family members with minimal evidence of FSHD may show evidence of retinal telangiectasis without evidence of exudation. The patients and family members should be screened for evidence of retinal telangiectasis since early treatment with photocoagulation may prevent visual loss. A young girl’s presentation with neovascular glaucoma at age 2 led to the detection of bilateral Coats’ disease; further onset of seizures led to the diagnosis of FSHD. Coats’ syndrome has also been reported in a scapulohumeral muscular dystrophy that is probably is a variant of FSHD.
Congenital and Acquired Idiopathic Macular Retinal Telangiectasia
Adult patients may develop loss of central vision caused by exudation, diffusion abnormalities, or from ischemia and nonperfusion of ectatic and incompetent retinal capillaries that are confined to the foveal and perifoveal region, which are either congenital or of unknown cause. These patients fall into several subgroups. Since the extent of the telangiectasia may vary and extend beyond the fovea, “macular telangiectasia” appears to be an appropriate name.
Group 1A: Unilateral Congenital Macular Telangiectasia
Patients with unilateral congenital foveal and parafoveolar telangiectasis probably suffer from a localized mild form of congenital retinal telangiectasis, a nonfamilial disorder affecting predominantly one eye of males without other evidence of systemic disease (see previous discussion of congenital retinal telangiectasis and Coats’ syndrome). The localized form of congenital retinal telangiectasis is typically confined to an area between 1½ and 2 disc diameters in the temporal half of the macula, where it straddles the horizontal raphe ( Figures 6.43 and 6.44 ). Approximately one-third of patients will have some focal telangiectasis in the extramacular area, usually temporally. Yellow, lipid-rich exudation is usually present at the outer margins of the area of telangiectasis, often in a ring configuration ( Figures 6.43I, and 6.44A and E ). The mean age of onset of symptoms is approximately 35 years. Polycystic macular edema and exudation are the cause of the loss of acuity, which usually ranges from 20/25 to 20/40. Telangiectatic capillaries are easily visualized with biomicroscopy and fluorescein angiography. Blunted right-angle venules, superficial retinal crystals, intraretinal pigment plaques, and subretinal neovascularization, features of group 2 juxtafoveal capillary telangiectasis, are not found in these patients. Early-phase stereoscopic fluorescein angiography shows prompt filling of the telangiectatic vessels, affecting both the superficial and the deep capillary network, and late intraretinal staining. The natural course of this disorder is variable. Some patients may retain excellent visual acuity for many years in spite of chronic waxing and waning CME ( Figure 6.43A–I ). Those with yellow lipid exudate in or near the center of the macula are probably at greatest risk of developing progressive loss of visual acuity. Focal applications of laser photocoagulation of the telangiectatic vessels may be helpful in restoring and preserving central acuity ( Figure 6.44A–H ). Congenital telangiectasis confined to the capillary bed in the region of the macular area should be differentiated from idiopathic bilateral acquired juxtafoveal capillary telangiectasis ( Figures 6.45–6.48 ), and telangiectasis caused by branch vein obstruction (see Figure 6.79D–F ), diabetic retinopathy ( Figure 6.52A–C ), X-ray irradiation retinopathy ( Figure 6.57 ), Eales’ disease, sickle-cell maculopathy, tuberous sclerosis ( Figure 6.40G and H ), and carotid artery obstruction. Group 1A patients should be clearly differentiated from patients with dilated perifoveal capillaries and evidence of vitreous cellular infiltration, whether it is caused by acquired inflammatory disease or is part of a tapetoretinal dystrophy.
Group 1B: Unilateral, Idiopathic, Focal Macular Telangiectasis
Most patients with unilateral idiopathic focal juxtafoveolar telangiectasis are middle-aged men who have mild metamorphopsia or blurring caused by exudation from a minute area of capillary telangiectasis that is usually confined to 2 hours of the clock or less at the edge of the capillary-free zone ( Figure 6.44I–L ). It may or may not be associated with a small amount of yellow exudate. The visual acuity is usually 20/25 or better. Angiography shows the focal capillary telangiectasis and minimal staining. Photocoagulation is usually not advisable because of the proximity of the leakage to the capillary-free zone and the good visual prognosis without treatment. It is uncertain whether this is an acquired lesion or merely represents a minute focus of congenital telangiectasis.
Group 2A: Bilateral, Idiopathic, Acquired Macular (Juxtafoveolar) Telangiectasia
Most of these patients are in the fifth or sixth decade of life (mean age 55 years) when they seek treatment for mild blurring of vision in one or both eyes. Both sexes are equally affected. Patients with group 2A telangiectasis typically demonstrate bilateral, symmetrically small areas, usually 1 disc diameter or less, of occult capillary telangiectasis that involves and may be confined to the temporal half of the foveolar areas or may include part or all of the nasal parafoveolar areas ( Figures 6.45 and 6.46 ). This form of telangiectasis is associated with minimal intraretinal serous exudation and no evidence of lipid exudation. Visual acuity is typically 20/30 or better when persons initially seek treatment. Biomicroscopically, the development of this disorder can be subdivided into five stages. In stage 1, usually found in the fellow asymptomatic eye, biomicroscopy demonstrates no abnormality. The early phases of stereoangiography show minimal or no evidence of capillary dilation, and late phases show mild staining at the level of the outer parafoveolar retina temporally. In stage 2 there are slight graying and loss of transparency of the parafoveolar retina and minimal or no telangiectatic vessels ( Figure 6.45A and D ). Early-phase angiography reveals evidence of mild capillary telangiectasis affecting primarily the outer capillary network temporally ( Figure 6.45B and C ). In stage 3 there is biomicroscopic evidence of one or several slightly dilated and blunted retinal venules that extend at right angles into the depth of the parafoveolar retina. These are usually first evident temporally. Stereoscopic angiography often shows unusual capillary dilation and permeability change in the outer retina beneath one or more of these venules ( Figure 6.45D–F ). A peculiar linear branching pattern of these capillaries occurs in some patients ( Figure 6.46B–D ). In stage 4, one or several stellate foci of intraretinal black hyperplastic RPE envelops the posterior extension of the right-angle venules ( Figures 6.45J–L, and 6.46A and E ). These intraretinal pigmented plaques have a characteristic appearance that should suggest the correct diagnosis, even when the telangiectasis cannot be visualized biomicroscopically. In stage 5, biomicroscopic and fluorescein angiographic evidence of type 2A subretinal neovascularization occurs in the parafoveolar area, often in the vicinity of the intraretinal pigment epithelial migration ( Figure 6.46G and I–L ). Multiple, tiny, golden, crystalline deposits develop near the inner surface of the parafoveolar retina in approximately one-half of the eyes in stages 2–5 ( Figure 6.46A, E, and G–I ). Approximately 5% of patients may develop a round, yellow, intraretinal spot 100–300 μm in diameter in the center of the foveola in one or both eyes ( Figure 6.45G ). This is usually associated with minimal loss of the foveolar depression.
OCT shows one or more cysts or lacunae in the inner or outer retina in all stages of the disease ( Figure 6.47H and I ). These cysts or lacunae may be the result of breakdown and loss of the Müller cell bodies in the Müller cell cone and the rest of the fovea.
Visual acuity is usually normal in stages 1 and 2. Most patients become symptomatic at stage 3, and some maintain good acuity after developing stage 4. Loss of central vision in these patients typically occurs slowly over many years and is associated with atrophy of the foveolar retina that develops in the absence of typical CME. This atrophy may produce a picture simulating a lamellar macular hole ( Figure 6.46E and F ). Fluorescein angiography in stages 1–4 fails to show late staining extending into the center of the fovea in all but a few eyes that develop angiographic evidence of capillary ingrowth into the FAZ ( Figure 6.45H and I ). OCT demonstrates some degree of thinning in almost all patients and is extremely useful in confirming this observation, made by Gass. Cystoid edema, yellow exudate, and loss of the foveolar depression develop only in those patients who develop subretinal neovascularization ( Figure 6.46G–L ). This complication may be associated with rapid loss of vision, subretinal hemorrhage, disciform scarring, and retinochoroidal anastomosis ( Figure 6.46G–L ).
The yellow foveal lesions in these patients may be mistaken for those seen in the adult form of vitelliform foveomacular dystrophy (see Figure 5.08 , Figure 5.09 ) or Best’s disease (see Figure 5.01 , Figure 5.02 ). Those with stellate pigment plaques or with choroidal neovascularization may be misdiagnosed as having senile macular degeneration or chorioretinal scars secondary to focal choroiditis.
Histopathologic examination in one patient with group 2A telangiectasis reported by Green and coworkers showed focal thickening of the sensory retina in the parafoveolar region, thickening of the retinal vessel walls, evidence of capillary endothelial abnormalities, but minimal or no evidence of capillary telangiectasis ( Figure 6.48 ). In a review of histopathologic sections of the eye previously reported by Green and coworkers, Gass found evidence of retinal capillary invasion of the retinal receptor layer and minimal evidence of cystic accumulation of extracellular fluid ( Figure 6.48F–H ).
How do we account for the retinal staining and the absence of evidence of migration of extracellular fluid into the central macular region to form cystoid edema in patients with group 2A juxtafoveolar telangiectasis? The following sequence of events appears to occur ( Figure 6.47J ). Early fluorescein staining of the thickened capillary walls, particularly those in the deeper plexus, is responsible for the early-phase angiographic appearance of “telangiectatic” vessels. The altered structure of the capillary wall is associated with decreased metabolic exchange and minimal increased endothelial permeability. These changes result in low-grade chronic nutritional damage to the retinal cells, particularly those at the level of the inner nuclear layer that includes the Müller cells. The late diffuse staining that stereoscopically appears to occur at the middle and outer retina is probably caused by staining of minimal amounts of extracellular matrix and intracellular diffusion of fluorescein into damaged retinal cells. Further changes in the outer capillary bed, which may include capillary proliferation and invasion of the outer retina and occasionally the foveolar retina, are accompanied by alteration of the pattern of venous outflow and formation of dilated right-angled venules ( Figure 6.47J , stage 3). Nutritional deprivation of the retinal cells in the middle retina, particularly the Müller cells, leads to degeneration and atrophy of these cells and the connecting photoreceptor cells. This loss of photoreceptor cells is responsible for the gradual loss of visual acuity and biomicroscopic picture that may simulate a lamellar macular hole. Loss of photoreceptor cells permits RPE cells to migrate into the overlying retina, particularly along the right-angle venules, to form black stellate plaques ( Figure 6.47J , stage 4). Stage 5 disease results when loss of retinal cells induces proliferative changes in the deep capillary network that may eventually gain entrance into the subsensory retinal space, where a type II pattern of subretinal neovascular growth and reactive proliferation of the RPE occurs ( Figure 6.47J , stage 5). Although it is probable that this neovascularization is primarily derived from the retinal vessels, evidence of chorioretinal vascular anastomosis may eventually occur. The cause of the golden refractile structures at the inner retinal surface in the juxtafoveolar area is unknown. Their appearance suggests that they are lipid. Their location in the region of the internal limiting membrane of the retina suggests that they may be a product of degenerating Müller cells whose nuclei are located in the inner nuclear layer at the site of the altered deep retinal capillary plexus, and whose foot plates form the internal limiting membrane.
The cause for group 2A telangiectasis, which is the most common form of idiopathic juxtafoveolar telangiectasis, is unknown. Chronic venous stasis caused by obstruction of the retinal veins as they cross the retinal arteries on both sides of the horizontal raphe may be a factor. More recently, study of the FAZ using whole mounts at 26–41-week gestational age has shown that the vessels making up the temporal FAZ are the last to close in to complete the ring. The temporal juxtafoveolar vessels are the earliest vessels to be affected in type 2 juxtafoveolar telangiectasis. Whether there is a relationship between these two features is interesting and needs further exploration. Although approximately 15% of these patients may have evidence of systemic diseases including systemic hypertension, borderline diabetes, coronary artery disease, and renal failure associated with Alport’s disease, long-term follow-up studies have failed to link group 2A telangiectasis to systemic disease in the majority of patients. Familial cases of group 2A telangiectasis occur occasionally.
Patients with group 2A telangiectasis should be differentiated from cases of bilateral retinal telangiectasis with other causes, including bilateral group 1A congenital juxtafoveal telangiectasis ( Figure 6.43J–L ), juxtafoveal telangiectasis associated with Eales’ disease (see Figure 6.62A–H ), diabetes mellitus, and irradiation retinopathy.
There is limited information available concerning the results of photocoagulation treatment of group 2A telangiectasis. It is probable that photocoagulation is ineffective in restoring visual function in these patients before the development of subretinal neovascularization because loss of function is associated with retinal atrophy rather than intraretinal exudation, as in the case of group 1 telangiectasis. It is also unlikely that prophylactic photocoagulation of the paracentral retinal capillaries will either slow or prevent the loss of visual acuity. In most instances the close proximity of subretinal neovascular networks to the center of the fovea precludes photocoagulation as a means of restoring or preventing loss of central vision.
Group 2B: Juvenile Occult Familial Idiopathic Juxtafoveolar Retinal Telangiectasis
Juxtafoveolar retinal telangiectasis similar to group 2A, but without evidence of right-angle venules, superficial retinal refractile deposits, or stellate pigmented plaques, has been reported in two siblings, 9 and 12 years of age.
Group 3A: Occlusive Idiopathic Juxtafoveolar Retinal Telangiectasis
Group 3A patients experience variable degrees of loss of central vision in both eyes associated with juxtafoveolar retinal telangiectasis and progressive loss of the juxtapapillary capillary network in later life associated with a variety of systemic diseases, including polycythemia, hypoglycemia, ulcerative colitis, multiple myeloma, and chronic lymphatic leukemia ( Figure 6.49A–F ). The macular changes in this group are similar to those that occasionally occur in patients with sickle-cell retinopathy, diabetic retinopathy ( Figure 6.52 ), and X-ray radiation retinopathy ( Figure 6.57B and D ). The loss of central vision may be abrupt and be associated with ischemic whitening of the retina centrally, occlusion of the perifoveolar retinal capillaries, and minimal evidence of telangiectasis, which develops only later ( Figure 6.51A ). In others the loss of parafoveolar retinal capillaries may occur slowly and be associated with telangiectasis of the adjacent capillaries, probably as the result of development of collateral pathways of flow.
Group 3B: Occlusive Idiopathic Juxtafoveolar Retinal Telangiectasis Associated with Central Nervous System Vasculopathy
Group 3B patients have a hereditary oculocerebral syndrome characterized by the onset in middle or later life of progressive loss of central vision in both eyes caused by progressive obliteration and telangiectasis of the perifoveolar capillary network, which in some patients is associated with optic atrophy, abnormal deep tendon reflexes, and other evidence of central nervous system involvement ( Figure 6.49 ). Loss of the juxtafoveolar capillaries, marked aneurysmal dilation of the terminal capillary network, and relatively little fluorescein leakage from the affected capillary bed are features that differentiate these patients from those in groups 1 and 2. In one family the retinal telangiectasis was associated with frontoparietal-lobe pseudotumors, comprised of small blood vessel damage and fibrinoid necrosis of white matter in the absence of evidence of vasculitis. Van Effenterre et al. described three sisters with similar retinal findings involving retinal telangiectasis and capillary occlusion in the peripheral retina and posterior pole, associated with poikiloderma, graying of the hair, and idiopathic nonarteriosclerotic cerebral calcifications. Pathology studies revealed small-vessel hyalinosis caused by basement membrane thickening involving the digestive tract, kidney, and calcified areas in the brain. In another family with evidence of autosomal-dominant inheritance of both central and peripheral retinal obliterative vasculopathy, there was associated Raynaud’s phenomena and mental changes, mainly forgetfulness, aggression, and depression. Ehlers and Jensen reported similar macular lesions in three family members of two successive generations. These patients did not have optic atrophy or neurologic disease.
Cerebroretinal vasculopathy is a rare adult-onset (fourth decade onwards) autosomal-dominant disorder involving the microvessels of the brain and retina due to frameshift mutations in the gene TREX1 . Patients present with vision loss, seizures, hemiparesis, apraxia, dysarthria, or memory loss. Progression to blindness, a neurovegetative state, and death ensues within 5–10 years. It was first described by Grand et al. in 10 family members and suspected in eight others, spanning over four generations. Retinal capillary and small-vessel obliteration and telangiectasia involving the macula alone, or including the periphery, are seen. Retinal or optic disc neovascularization occurs occasionally.
Pseudotumor of the brain due to fibrinoid necrosis from ischemia can mimic a tumor in approximately half of patients, while the other half may have multiple small white-matter lesions, which may be misdiagnosed as demyelinating disease. Migraine and Raynaud’s phenomenon may be associated in some. Other organs sometimes involved include the liver with elevated enzymes, kidney, and osteonecrosis of the hip. Three disorders that appear to be related to each other and share the same genetic locus at 3p21.1-p21.3 are: (1) hereditary vascular retinopathy; (2) cerebroretinal vasculopathy; and (3) hereditary endotheliopathy with retinopathy, nephropathy, and stroke.
Hereditary Hemorrhagic Telangiectasia (Rendu–Osler–Weber Disease)
Hemorrhagic hereditary telangiectasia is a dominantly inherited disorder characterized by telangiectasias of the capillaries and venules involving many organ systems, including the skin and mucous membranes and visceral AVMs. The affected blood vessels are friable and prone to bleeding. The most frequent signs and symptoms include epistaxis, gastrointestinal tract bleeding, and dyspnea on exertion caused by either hemorrhage or shunting of blood through abnormal vessels in the nasal mucosa, gastrointestinal tract, liver, brain, and lung. Paradoxical embolization and stroke may occur when venous thrombi from the lower extremities and pelvis pass through AVMs in the lung and lodge in the brain.
Multiple spiderlike telangiectases involving the palpebral conjunctiva occur frequently and may cause bloody tearing. Involvement of the retinal blood vessels occurs infrequently. Brant and coworkers examined 20 patients with hereditary hemorrhagic telangiectasia and found retinal telangiectasis in two patients. In their review of the literature they cited reports of four patients with retinal vascular malformations, primarily AVMs, in association with hereditary hemorrhagic telangiectasia. Geisthoff and coworkers examined 75 patients, of whom none had retinal telangiectasia, but 28 had conjunctival telangiectases. Intraoperative choroidal hemorrhage has been reported in each eye of a 68-year-old Caucasian woman, one during vitrectomy and the other during phacoemulsification, and large choroidal vessels visible on fluorescein and indocyanine green angiography in a 73-year-old with serous RPE detachments.
Two types of hereditary hemorrhagic telangiectasia, HHT-1 (more frequent pulmonary and cerebral AVMs), from mutation in the endoglin gene ( ENG ) and HHT-2 (more frequent hepatic AVMs) from mutation in activin receptor-like kinase 1 gene ( ACVRL1, ALK1 , chromosome 12q13) are known.
Idiopathic Retinal Vasculitis, Aneurysms, and Neuroretinopathy: Bilateral Neuroretinopathy with Multiple Retinal Arterial Aneurysms
Multiple, peculiar, saccular, and fusiform aneurysms involving all of the major retinal arteries in both eyes may be accompanied by neuroretinopathy, vitreous and anterior-chamber inflammatory cell infiltration, and angiographic evidence of arteritis in children and young adults ( Figures 6.50 and 6.51 ). The multiple aneurysms protruding from both sides of the retinal arteries, as well as the Y-shaped aneurysms affecting the arterial bifurcations, give the impression of a series of knots in the arterial tree ( Figures 6.50 and 6.51 ). They may extend from the optic nerve head into the midperiphery of the fundus and may be associated with irregular dilation of the retinal veins, vascular sheathing, focal areas of capillary telangiectasis, retinal hemorrhages, peripheral zones of occlusion of the retinal circulation, retinal neovascularization, and vitreous hemorrhage. Swelling of the optic nerve head may be accompanied by retinal exudation, juxtapapillary retinal detachment, and a macular star ( Figures 6.50 and 6.51 ). Fluorescein angiography may demonstrate dye leakage from some of the arterial aneurysms, focal perivenous staining, optic nerve head staining, focal areas of retinal capillary staining, peripheral zones of capillary nonperfusion ( Figures 6.50 and 6.51 ), and retinal neovascularization. Development of these arterial aneurysms over a 3-year period has been observed in a young woman who presented initially with symptoms related to peripheral retinal neovascularization. It is uncertain whether the arterial aneurysms and the other retinal vascular alterations are caused by a congenital retinal arterial defect or are the product of an acquired inflammatory allergic vascular disease. If the latter is true, then these patients may have some pathogenetic relationship to those with Eales’ disease. The value of anti-inflammatory medications including steroids and immunosuppressives and photocoagulation in the management of exudative complications is uncertain but should be tried in appropriate cases. Panretinal photocoagulation (PRP) is required for those eyes with extensive retinal nonperfusion and new-vessel formation ( Figure 6.50 ).
Diabetes mellitus is a heterogeneous disorder of carbohydrate metabolism with multiple etiologic factors that ultimately lead to hyperglycemia. There are two primary types of diabetes. Type 1 insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by hyperglycemia resulting from loss of the pancreatic islet cells. Up to 90% of these patients and 3.1% of their nondiabetic relatives have demonstrable serum titers of islet cell antibodies. The age of onset is before 30 years and often the disease begins in childhood. Type 2 noninsulin-dependent diabetes (NIDDM) is characterized by late-onset hyperglycemia typically occurring in obese patients who are often asymptomatic at the time of diagnosis. It appears to result from deficiency in the regulation of insulin secretion and/or in its action at the cellular level in the liver and peripheral tissues. Secondary types of diabetes may be associated with pancreatic disease, excess counterinsulin hormonal disorders, and drug-induced and gestational diabetes. In all types, hyperglycemia, although of primary importance, is only one of many pathogenetic factors (aldose reductase-mediated cell damage; vasoproliferative factors produced by hypoxic retina; growth hormone and erythrocyte, platelet, and blood viscosity abnormalities) involved in this complex metabolic disorder affecting all of the major organ systems, including the eye. Although there has been much emphasis on the importance of the alterations of the blood vessels in regard to the morbidity associated with diabetes, primary metabolic damage to the parenchymal cells is important. For example, the development of color vision abnormalities (acquired blue-yellow defect), abnormalities in contrast sensitivity, and electroretinographic alterations in some diabetics may precede any demonstrable evidence of retinal vascular abnormalities.
India ink injection techniques, trypsin digestion preparations, and fluorescein angiography have been important in elucidating the anatomic and physiologic changes that constitute diabetic retinopathy. The initial changes involve the retinal capillary bed and include selective loss of pericytes, microaneurysm formation, thickening of the basement membrane, focal closure of the capillary bed, dilation of adjacent capillaries, shunt formation, and permeability alterations ( Figure 6.52 ). These changes may be followed by arteriolar closure, large zones of vascular nonperfusion, and proliferative neovascular changes within and on the inner retinal surface. Microaneurysms develop as outpouchings that initially involve primarily the prevenular capillaries at sites of loss of pericytes (perithelial cells). They may arise as an isolated change or may be clustered around focal zones of capillary occlusion. Their walls may be thin by weakening or thickened by proliferation of the endothelial basement membrane. Their lumen occasionally may be packed with agglutinated erythrocytes or a thrombus. Focal zones of loss of capillary endothelial cells, thickening of the capillary basement membrane, and reduction of blood flow develop and are associated with surrounding areas of compensatory capillary dilation, capillary endothelial proliferation, and permeability alterations. This change in permeability of the dilated capillaries and microaneurysms is associated with extravasation of serous and lipoproteinaceous exudate and, in some cases, intraretinal bleeding ( Figure 6.52J ). Other physiologic changes accompanying diabetic retinopathy include alterations of blood flow and blood viscosity. Autoregulation causes venous dilation when local tissue hypoxia and hypoglycemia are detected. With constant changes in the vessel caliber from fluctuating tissue glucose levels, the venous tone is eventually lost, resulting in chronic venous dilation. Hyperglycemia per se can cause dysfunction of autoregulation.
These early anatomic and physiologic changes are responsible for the ophthalmoscopic changes referred to as background and nonproliferative diabetic retinopathy. These include red dotlike microaneurysms, areas of dilated retinal capillaries, superficial flame-shaped or deeper dot and blot retinal hemorrhages, white-centered hemorrhages, yellow exudates, and focal areas of gray-whitening of the retina (cotton-wool spots) ( Figure 6.52 ). Microaneurysms are the earliest clinical sign of diabetic retinopathy ( Figure 6.52 A ). They may occur anywhere in the retina. In some cases they are widely distributed, whereas in others they may be concentrated in the central macular area.
Visual loss in patients with nonproliferative diabetic retinopathy occurs primarily as the result of macular exudation, particularly in patients with late-onset diabetes ( Figure 6.52 A-F ). This may occur either as the result of focal leakage of exudate from one or more clusters of microaneurysms and dilated capillaries, each often surrounded by a ring of yellow, deep retinal exudates, or as the result of diffuse leakage from most of the retinal vasculature in the macular area. In general, the loss of central vision parallels the degree of intraretinal exudation seen biomicroscopically and angiographically. Minimal loss of acuity may be associated with mild intraretinal exudation from capillary microaneurysms that are either confined to the posterior pole or are more widely scattered. More pronounced degrees of intraretinal exudation are often associated with greater evidence of dilation of both the small and large retinal blood vessels. Scattered yellow exudates, retinal hemorrhages, and occasional cotton-wool spots may be present. Cotton-wool spots in diabetic retinopathy are indicative of focal zones of relative retinal ischemia caused by either partial or, in some cases, complete closure of the capillary bed in the zone of retinal whitening ( Figure 6.53 ). They occur commonly during the early development of nonproliferative diabetic retinopathy, are not necessarily related to elevated blood pressure, and do not necessarily suggest a high risk of progression of the retinopathy. In general they persist for a longer period of time in diabetes than in hypertension. When they resolve, they may be associated with a local scotoma, nerve fiber bundle scotoma, or no scotoma. The presence of numerous cotton-wool spots, particularly when associated with other signs of preproliferative retinopathy, may indicate rapidly progressing retinopathy.
A frequent clinical picture seen in patients with early loss of vision is that of one or more circinate zones of yellow, lipid-rich exudation, usually centered in the paramacular area and extending into the fovea ( Figures 6.52B and C, and 6.53D ). The yellowish deposits surround clusters of microaneurysms and cloudy intraretinal and subretinal exudate. Circinate zones may be round, oval, or irregular. They are most frequently centered in the temporal portion of the macula. The amount of lipid exudation around the retinal capillary abnormalities in these patients is related to their serum lipid levels and their diastolic blood pressure. The presence of extensive deposits of intraretinal lipid exudates may be indicative of hyperlipidemia (see Figure 6.85J–L ). (See discussion of hyperlipemic retinopathy, p. 610.) Transudation of serum lipids into the vitreous in such patients may occasionally simulate endophthalmitis.
Some patients with diffuse retinal capillary leakage and CME angiographically may show minimal evidence of yellow exudate and loss of retinal transparency biomicroscopically. The edema may wax and wane, remain stationary for long periods, or steadily progress. Occasionally the CME may occur in the absence of prominent background retinopathy and dilation of the major retinal vessels. Other causes of central vision loss in diabetic patients include hemorrhage from the perifoveal capillary abnormalities ( Figure 6.52 ), perifoveolar capillary occlusion ( Figure 6.52 ), vitreofoveal traction ( Figure 7.09I and J ), and epiretinal membrane formation.
When the vascular occlusive phenomenon caused by diabetes begins to involve the precapillary arterioles and larger retinal arterioles, fundus changes characteristic of preproliferative retinopathy develop. These include multiple cotton-wool spots and retinal hemorrhages, dark blot hemorrhages, venous beading and loops, irregular dilated segments of the capillary bed (intraretinal microvascular abnormalities, or IRMA), and large areas of loss of retinal vascular details or “featureless” retina ( Figures 6.52G and 6.54A-B ). These latter areas show extensive vascular nonperfusion angiographically ( Figure 6.54 ). This process of vascular occlusion frequently involves the peripheral retina and in some cases may initially be largely confined to the extramacular areas. In other cases capillary nonperfusion affects the central macular area early and may cause loss of visual acuity. The IRMA occur near areas of vascular nonperfusion and in some cases represent dilated segments of the capillary bed or shunt vessels, whereas in other cases they are intraretinal newly developed blood vessels.
The risk of developing proliferative diabetic retinopathy (PDR) is approximately 50% within 15 months in eyes with preproliferative diabetic retinopathy. It is important to realize that, by the time neovascularization has commenced, many of the signs of active preproliferative retinopathy may no longer be present. Neovascularization usually begins within 45° of the optic disc and often arises on the optic disc. New vessels are subdivided on the basis of their location as follows: those arising on or within 1 disc diameter of the optic disc (NVD), and those elsewhere in the fundus (NVE). The NVD begins as fine loops or networks of vessels lying on the surface of the optic disc or bridging across the physiologic cup. They may be difficult to differentiate from dilated optic nerve vessels. Likewise, differentiating NVE from IRMA may also be difficult, particularly when the NVE do not yet show any of their characteristic features, including wheel-like network, extension across both arterial and venous branches of the underlying retinal vascular network, and accompanying fibrous proliferation. Fluorescein angiography is helpful in distinguishing new vessels, which leak diffusely, from vessels located within the optic disc and retina, which show minimal leakage. New vessels typically form networks simulating sea fans ( Figure 6.55A-C ), but, in some cases, particularly when they arise from the optic disc, they may grow across the retinal surface and present the appearance of mature retinal blood vessels ( Figure 6.55F to H ). Patients with new vessels are often asymptomatic until vitreous separation elevates the new vessels and causes intravitreal bleeding. Vitreous separation often begins along the superotemporal vessels, temporal to the macula, and above or below the optic disc. The vitreous usually does not separate from the disc in patients with NVD. Traction on the new vessels by the partly separated vitreous may cause vitreous hemorrhage. Bleeding into the vitreous may also be caused by avulsion of retinal blood vessels (usually a vein) or a retinal tear. Displacement and distortion of the macula caused by vitreoretinal traction and epiretinal membrane contraction and tractional detachment of the macula may cause loss of visual acuity, dimness of vision, metamorphopsia, and diplopia. Focal serous detachment of the macula is an infrequent complication of diabetic retinopathy unless it occurs secondary to vitreous traction with or without macular hole formation ( Figure 7.08E–H ).
A peculiar form of occult vitreomacular traction occurring in patients, particularly after unsuccessful scatter macular photocoagulation, may be responsible for severe macular edema and diffuse fluorescein staining of the macula. Visual function in these latter patients may improve dramatically following pars plana vitrectomy (see Figure 7.05G and H , Figure 7.08I–K ). Nasrallah et al. found that adult-onset diabetic eyes with macular edema were less likely to have posterior vitreous detachment than eyes without edema. They found the reverse was true in eyes of patients with type 1 diabetes.
PDR may occur in the perimacular area ( Figure 6.55 ) but it infrequently occurs near the center of the macula. What may be an aborted form of intraretinal and preretinal neovascularization may give rise to a peculiar cluster of coiled aneurysmal blood vessels in the juxtafoveolar area, particularly in insulin-dependent diabetics with evidence of macular capillary nonperfusion and following PRP ( Figure 6.53 ). These juxtafoveolar aneurysmal changes are associated with excellent visual acuity and good visual prognosis and may occur in both eyes. Similar abortive nodular neovascular outgrowths without an extravascular fibrous component may arise along the major vascular arcades in eyes with extensive areas of capillary nonperfusion ( Figure 6.53A-C ). Histopathologically, they are nodules of vessels with gross hyalinization of their walls and without a fibrous component. These lesions may represent aborted forms of neovascularization that develop in the absence of a vitreous scaffold.
There are significant differences in the natural courses of IDDM and NIDDM. In childhood-onset type 1 diabetes, retinal microaneurysms and other diabetic retinopathy seldom develop before puberty. In a population-based study of 271 insulin-dependent patients diagnosed before 30 years of age and without retinopathy at the time of initial examination, 59% of patients developed retinopathy, including 11% with proliferative retinopathy, by the time they were examined 4 years later. Overall worsening of retinopathy occurred in 41% of the population, whereas improvement occurred in only 7%. The incidence of proliferative retinopathy rose with increasing duration until 13–14 years of diabetes and thereafter remained between 14% and 17%. Klein and coworkers found that 10.2% of adult-onset diabetics have retinopathy at the time of initial diagnosis. During a 4-year period they found that 47% nonusers of insulin without retinopathy developed it, that 7% of those without proliferative retinopathy developed it, and that worsening of the retinopathy occurred in 34% of all of the patients. For nonusers of insulin the corresponding rates were 34% for any retinopathy, 2% for developing proliferative retinopathy, and 25% for worsening retinopathy. In those initially free of retinopathy approximately 50% of those using insulin and 35% of nonusers will develop retinopathy within 4 years of diagnosis. During this same period of time approximately 35% of users and 25% of nonusers will develop worsening of their retinopathy.
The most important risk factor for developing diabetic retinopathy is duration of the disease. Retinopathy in IDDM occurs infrequently before 5 years after onset of the disease. It is present in 27% of patients with disease duration of 5–10 years, in 71% with longer than 10 years, and in over 90% after 30 years. The prevalence of background retinopathy in NIDDM 11–13 years after the onset is 23%, after 16 or more years it is 60%, and after 11 or more years 3% have proliferative retinopathy. Other risk factors associated with progression of diabetic retinopathy include number of microaneurysms, albuminuria, elevation of blood pressure, posterior vitreous attachment, increased foveal thickening, blue or gray irides, smoking, increased testosterone levels in males with type 1 diabetes, previous irradiation to the eye, reduction in electroretinographic oscillatory potentials, environmental and racial factors, pregnancy, and cataract extraction. Carotid artery obstruction may have a favorable effect on diabetic retinopathy in some patients.
Fluorescein angiography has provided great understanding of the microvascular changes caused by diabetes. Clinicopathologic correlations have helped in interpreting and understanding these findings. The development of microaneurysms and alterations in the capillary permeability are the earliest changes detectable with angiography in the diabetic retina ( Figure 6.52A ). The microaneurysms are predominantly on the venular side of the capillary bed. Round and occasionally fusiform microaneurysms are scattered in the macula and perimacular region and have no particular relationship to the distribution of the major retinal vessels such as occurs in hypertensive retinopathy. Focal areas of capillary closure may develop within the capillary bed affected by marked aneurysm formation. Capillary closure occurs much more frequently and to a greater extent initially in the mid peripheral fundus and generally increases towards the periphery. Some enlargement of the FAZ occurs commonly in diabetes but is usually unassociated with visual loss until the FAZ approaches 1000 μm in diameter ( Figure 6.52G to I ). Capillary closure occurs less frequently in the macula and rarely, if ever, in the area of the juxtapapillary radial capillary network. Extensive mid peripheral and peripheral capillary closure may be relatively inapparent ophthalmoscopically, and its extent is directly correlated with the development of disc and retinal neovascularization. Dilated, tortuous, shunt capillaries may traverse large areas of capillary closure that are often more evident in the more peripheral retina. Extensive microaneurysmal changes in the capillary bed may be demonstrated angiographically in the macular region in patients who do not have significant loss of visual acuity. The permeability changes in the capillary bed and the degree of serous exudation into the extracellular space of the retina are variable and are the most important factors causing loss of macular function. In some cases, however, progressive closure of the perifoveal capillary network is the cause of loss of macular function ( Figures 6.52G and I, and 6.54A to J ). This closure occurs more commonly in patients with juvenile-onset diabetes. There is no fluorescein angiographic evidence of choroidal vascular disease to account for the loss of central vision in diabetes. There is some indocyanine green angiographic, histopathologic, and scanning electron microscopic evidence that the choroidal vessels may be affected in diabetes. Areas of neovascular proliferation on the surface of the retina are always accompanied by angiographic evidence of dye leakage from these vessels ( Figure 6.55 ).
The pathogenesis of diabetic retinopathy is complicated, controversial, and beyond the scope of this book. There is overwhelming evidence that hyperglycemia is important in the pathogenesis of retinopathy, but genetic and other factors are important. Release of angiogenic factors (VEGF) in the hypoperfused hypoxic retina is important in the development of proliferative retinopathy.
Photocoagulation treatment has been advocated for treatment of exudative and PDR for many years. In recent years randomized controlled clinical trials have established useful guidelines for use of photocoagulation and vitrectomy for the treatment of diabetic retinopathy. Before publication of the results of the Early Treatment Diabetic Retinopathy Study (ETDRS), several randomized clinical trials reported photocoagulation to be of value in the treatment of diabetic macular edema. Although employing somewhat different protocols and case selection, all of these studies have concluded that laser treatment is effective in reducing the rate of visual loss in eyes with macular edema but results in significant visual improvement in only a limited number of cases. The ETDRS concluded that eyes with mild to moderate nonproliferative diabetic retinopathy and clinically significant macular edema, when treated with focal argon blue-green or argon green laser to microaneurysms and a grid treatment to zones of diffuse leakage and nonperfusion, show the maximum benefit of treatment ( Figures 6.52D-F, and 6.53A-F ). Clinically significant macular edema was defined as: (1) retinal thickening involving, or within 500 μm from, the center of the macula; (2) hard exudate(s) (with thickening of the adjacent retina) at or within 500 μm from the center of the macula; and (3) a zone of retinal thickening 1 disc area or larger in size, any part of which is within 1 disc diameter from the center of the macula.
Because of the risk involved in treating lesions closer than 500 μm to the center of the macula, it may be prudent to follow eyes with clinically significant macular edema showing such lesions when the visual acuity is normal and the center of the macula is uninvolved. There is little risk in following such eyes to determine whether the edema is worsening. Olk and coworkers have used a modified grid pattern technique for treating diffuse diabetic macular edema, emphasizing treatment of diffuse leakage rather than focal leakage. They have demonstrated that visual acuity and foveal threshold in these patients are preserved at the expense of generalized loss of threshold sensitivity across the central 10° of visual fields.
In eyes with mild to moderate macular edema, PRP should not be used till the macular edema is treated. PRP treatment increases the risk of loss of visual acuity, particularly in patients with macular edema. Reduction in the area of retina needing to be perfused following PRP redirects more blood flow to the posterior pole, thus increasing the intravascular hydrostatic force within these vessels, causing increased leakage. Treatment of the macular edema with focal and grid treatment given before scatter treatment reduces this risk. If high-risk characteristics for PDR are also present, dividing the scatter treatment into multiple sessions beginning with the nasal quadrants, using a more peripheral pattern of scatter treatment, using smaller spot size applications, and using less intense treatment are techniques that may reduce the risk of aggravating the macular edema.
PRP treatment should be carried out promptly in most eyes with PDR that have well-established NVD and/or vitreous or preretinal hemorrhage. When high-risk characteristics are present, scatter photocoagulation should be carried out even in the presence of fibrous proliferations and/or localized traction retinal detachment. Likewise, scatter treatment is indicated in eyes with extensive neovascularization of the anterior-chamber angle, or in eyes with preproliferative retinopathy and evidence of rapidly progressive closure of the retinal capillary, whether or not high-risk characteristics are present ( Figure 6.54A-J ). These latter patients should be warned of the high risk of further loss of central vision caused by occlusion of the remaining vessels supplying the macula.
The prognosis for recovery of central vision is poor in patients with angiographic evidence of loss of the perifoveal capillary network; severe CME, particularly when associated with significant background retinopathy; organized yellow exudate in the macula; and severe renal disease and hypertension. Retreatment of eyes that fail to show an initial response to scatter treatment is indicated and is successful in approximately 50% of cases. Those who fail after retreatment have an unfavorable prognosis.
The wavelength of laser light used for the treatment of the various stages of diabetic retinopathy appears to be relatively unimportant. Although all of the clinical trials have used fluorescein angiography as part of the investigation of patients with diabetic exudative maculopathy, the decision as to whether to treat, and where to treat, depends primarily on biomicroscopic observations. For that reason some have suggested that pretreatment angiography is unnecessary.
The favorable effect of photocoagulation treatment on diabetic retinopathy is multifactorial. Hypotheses to explain how photocoagulation causes resolution of the neovascular and exudative complications of diabetic retinopathy include reduction of VEGF levels, improvement of the blood–outer retinal barrier by photocoagulation debridement of sick or fatigued RPE cells; release by photocoagulation-damaged RPE cells of a factor that reduces retinal capillary endothelial proliferation and causes restoration of the integrity of the blood–inner retinal barrier ; and increased oxygen tension at the inner retinal surface caused by partial photocoagulation destruction of the retinal receptor cells and RPE cells. The increased oxygen tension occurs in spite of the partial loss of the choriocapillaris that accompanies PRP. Long-term follow-up studies after panphotocoagulation have demonstrated persistence of the treatment effect for as long as 15 years.
Complications of laser photocoagulation treatment of diabetic retinopathy include development of subretinal neovascularization, subfoveal fibrosis, serous macular detachment, ciliochoroidal detachment, and enlargement of photocoagulation scars.
Transscleral cryotherapy is a useful adjunct to photocoagulation treatment when recurrent vitreous hemorrhage occurs without visible new vessels posteriorly. It is likely small new vessels are present very anteriorly; these can be easily destroyed by two or more rows of transconjunctival peripheral cryopexy. This is also especially useful in those eyes that show recurrent vitreous hemorrhages after pars plana vitrectomy where no new vessels can be found. Applying two to three spots to the sclerostomy sites helps in those eyes where a vessel may be bridging the sclerostomy site on the inside.
Pars plana vitrectomy has become the standard treatment for serious visual loss caused by dense, nonclearing vitreous hemorrhage; traction retinal detachment; and macular heterotopia. Early vitrectomy is beneficial in patients with type 1 diabetes and recent severe diabetic vitreous hemorrhage reducing visual acuity to 5/200 or less for at least 1 month. In older patients with type 2 diabetes and recent severe diabetic retinal hemorrhage, it is reasonable to allow time for spontaneous clearing of the vitreous hemorrhage for 4–6 weeks before considering vitrectomy. Partial posterior vitreous separation that may follow a vitreous hemorrhage in some cases may help in en bloc dissection during vitrectomy. Early vitrectomy should be considered as an adjunct to photocoagulation in eyes with useful vision and advanced, active PDR with extensive new vessels that fail to show substantial regression after photocoagulation, or when additional photocoagulation is precluded by vitreous hemorrhage and when iris vessels begin to appear. Although vitrectomy is of value in restoring central vision in patients who have developed macular detachment secondary to vitreous traction detachment, it may not be indicated when the traction detachment does not extend into the macula. Because of the high association of cataracts in diabetes and their frequent development soon after vitrectomy, combined vitrectomy and intraocular lens insertions are frequently done in these patients. The 5-year survival rate of patients undergoing vitrectomy for complications of diabetic retinopathy is approximately 75%.